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Sample records for genomic instability induced

  1. Radiation induced genomic instability

    International Nuclear Information System (INIS)

    Morgan, W.

    2003-01-01

    This presentation will focus on delayed genetic effects occurring in the progeny of cells after exposure to ionizing radiation. We have developed a model system for investigating those genetic effects occurring multiple generations after radiation exposure. The presentation will describe some of the delayed effects observed after radiation exposures including delayed chromosomal rearrangements, and recombination events as determined by a plasmid based assay system. We will present new data on how changes in gene expression as measured by differential display and DNA microarray analysis provides a mechanism by which cells display a memory of irradiation, and introduce candidate genes that may play a role in initiating and perpetuation the unstable phenotype. These results will be discussed in terms of the recently described non-targeted Death Inducing Effect (DIE) where by secreted factors from clones of unstable cells can elicit effects in non irradiated cells and may serve to perpetuate the unstable phenotype in cells that themselves were not irradiated

  2. Radiation-induced instability of human genome

    International Nuclear Information System (INIS)

    Ryabchenko, N.N.; Demina, Eh.A.

    2014-01-01

    A brief review is dedicated to the phenomenon of radiation-induced genomic instability where the increased level of genomic changes in the offspring of irradiated cells is characteristic. Particular attention is paid to the problems of genomic instability induced by the low-dose radiation, role of the bystander effect in formation of radiation-induced instability, and its relationship with individual radiosensitivity. We believe that in accordance with the paradigm of modern radiobiology the increased human individual radiosensitivity can be formed due to the genome instability onset and is a significant risk factor for radiation-induced cancer

  3. Mechanisms of cadmium induced genomic instability

    Energy Technology Data Exchange (ETDEWEB)

    Filipic, Metka, E-mail: metka.filipic@nib.si [National Institute of Biology, Department for Genetic Toxicology and Cancer Biology, Ljubljana (Slovenia)

    2012-05-01

    Cadmium is an ubiquitous environmental contaminant that represents hazard to humans and wildlife. It is found in the air, soil and water and, due to its extremely long half-life, accumulates in plants and animals. The main source of cadmium exposure for non-smoking human population is food. Cadmium is primarily toxic to the kidney, but has been also classified as carcinogenic to humans by several regulatory agencies. Current evidence suggests that exposure to cadmium induces genomic instability through complex and multifactorial mechanisms. Cadmium dose not induce direct DNA damage, however it induces increase in reactive oxygen species (ROS) formation, which in turn induce DNA damage and can also interfere with cell signalling. More important seems to be cadmium interaction with DNA repair mechanisms, cell cycle checkpoints and apoptosis as well as with epigenetic mechanisms of gene expression control. Cadmium mediated inhibition of DNA repair mechanisms and apoptosis leads to accumulation of cells with unrepaired DNA damage, which in turn increases the mutation rate and thus genomic instability. This increases the probability of developing not only cancer but also other diseases associated with genomic instability. In the in vitro experiments cadmium induced effects leading to genomic instability have been observed at low concentrations that were comparable to those observed in target organs and tissues of humans that were non-occupationally exposed to cadmium. Therefore, further studies aiming to clarify the relevance of these observations for human health risks due to cadmium exposure are needed.

  4. Mechanisms of cadmium induced genomic instability

    International Nuclear Information System (INIS)

    Filipič, Metka

    2012-01-01

    Cadmium is an ubiquitous environmental contaminant that represents hazard to humans and wildlife. It is found in the air, soil and water and, due to its extremely long half-life, accumulates in plants and animals. The main source of cadmium exposure for non-smoking human population is food. Cadmium is primarily toxic to the kidney, but has been also classified as carcinogenic to humans by several regulatory agencies. Current evidence suggests that exposure to cadmium induces genomic instability through complex and multifactorial mechanisms. Cadmium dose not induce direct DNA damage, however it induces increase in reactive oxygen species (ROS) formation, which in turn induce DNA damage and can also interfere with cell signalling. More important seems to be cadmium interaction with DNA repair mechanisms, cell cycle checkpoints and apoptosis as well as with epigenetic mechanisms of gene expression control. Cadmium mediated inhibition of DNA repair mechanisms and apoptosis leads to accumulation of cells with unrepaired DNA damage, which in turn increases the mutation rate and thus genomic instability. This increases the probability of developing not only cancer but also other diseases associated with genomic instability. In the in vitro experiments cadmium induced effects leading to genomic instability have been observed at low concentrations that were comparable to those observed in target organs and tissues of humans that were non-occupationally exposed to cadmium. Therefore, further studies aiming to clarify the relevance of these observations for human health risks due to cadmium exposure are needed.

  5. Study of genomic instability induced by low dose ionizing radiation

    International Nuclear Information System (INIS)

    Seoane, A.; Crudeli, C.; Dulout, F.

    2006-01-01

    The crews of commercial flights and services staff of radiology and radiotherapy from hospitals are exposed to low doses of ionizing radiation. Genomic instability includes those adverse effects observed in cells, several generations after the exposure occurred. The purpose of this study was to analyze the occurrence of genomic instability by very low doses of ionizing radiation [es

  6. Genomic instability following irradiation

    International Nuclear Information System (INIS)

    Hacker-Klom, U.B.; Goehde, W.

    2001-01-01

    Ionising irradiation may induce genomic instability. The broad spectrum of stress reactions in eukaryontic cells to irradiation complicates the discovery of cellular targets and pathways inducing genomic instability. Irradiation may initiate genomic instability by deletion of genes controlling stability, by induction of genes stimulating instability and/or by activating endogeneous cellular viruses. Alternatively or additionally it is discussed that the initiation of genomic instability may be a consequence of radiation or other agents independently of DNA damage implying non nuclear targets, e.g. signal cascades. As a further mechanism possibly involved our own results may suggest radiation-induced changes in chromatin structure. Once initiated the process of genomic instability probably is perpetuated by endogeneous processes necessary for proliferation. Genomic instability may be a cause or a consequence of the neoplastic phenotype. As a conclusion from the data available up to now a new interpretation of low level radiation effects for radiation protection and in radiotherapy appears useful. The detection of the molecular mechanisms of genomic instability will be important in this context and may contribute to a better understanding of phenomenons occurring at low doses <10 cSv which are not well understood up to now. (orig.)

  7. Dioxin induces genomic instability in mouse embryonic fibroblasts.

    Directory of Open Access Journals (Sweden)

    Merja Korkalainen

    Full Text Available Ionizing radiation and certain other exposures have been shown to induce genomic instability (GI, i.e., delayed genetic damage observed many cell generations later in the progeny of the exposed cells. The aim of this study was to investigate induction of GI by a nongenotoxic carcinogen, 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD. Mouse embryonic fibroblasts (C3H10T1/2 were exposed to 1, 10 or 100 nM TCDD for 2 days. Micronuclei (MN and expression of selected cancer-related genes were assayed both immediately and at a delayed point in time (8 days. For comparison, similar experiments were done with cadmium, a known genotoxic agent. TCDD treatment induced an elevated frequency of MN at 8 days, but not directly after the exposure. TCDD-induced alterations in gene expression were also mostly delayed, with more changes observed at 8 days than at 2 days. Exposure to cadmium produced an opposite pattern of responses, with pronounced effects immediately after exposure but no increase in MN and few gene expression changes at 8 days. Although all responses to TCDD alone were delayed, menadione-induced DNA damage (measured by the Comet assay, was found to be increased directly after a 2-day TCDD exposure, indicating that the stability of the genome was compromised already at this time point. The results suggested a flat dose-response relationship consistent with dose-response data reported for radiation-induced GI. These findings indicate that TCDD, although not directly genotoxic, induces GI, which is associated with impaired DNA damage response.

  8. Causes of genome instability

    DEFF Research Database (Denmark)

    Langie, Sabine A S; Koppen, Gudrun; Desaulniers, Daniel

    2015-01-01

    function, chromosome segregation, telomere length). The purpose of this review is to describe the crucial aspects of genome instability, to outline the ways in which environmental chemicals can affect this cancer hallmark and to identify candidate chemicals for further study. The overall aim is to make......Genome instability is a prerequisite for the development of cancer. It occurs when genome maintenance systems fail to safeguard the genome's integrity, whether as a consequence of inherited defects or induced via exposure to environmental agents (chemicals, biological agents and radiation). Thus...

  9. Ionizing radiation induced genomic instability and its relation to radiation carcinogenesis

    International Nuclear Information System (INIS)

    Wang Zhongwen

    2000-01-01

    There are widespread testimonies that the genomic instability induced by ionizing irradiation exits in mammal and its vitro cells. Genomic instability can enhance the frequency of genetic changes among the progeny of the original irradiated cells. In the radiation-leukemogenesis, there is no significant difference between controls and CBA/H mouses of PPI (preconception patent irradiation), but the offsprings of the PPI recipients show a different character (shorter latent period and higher incidence) after an extra γ-radiation. The radiation-induced genomic instability may get the genome on the verge of mutation and lead to carcinogens following mutation of some critical genes. The genomic instability, as the early event of initiation of carcinomas, may be play a specific or unique role

  10. Genomic instability and radiation

    Energy Technology Data Exchange (ETDEWEB)

    Little, John B [Harvard School of Public Health, Boston, MA 02115 (United States)

    2003-06-01

    Genomic instability is a hallmark of cancer cells, and is thought to be involved in the process of carcinogenesis. Indeed, a number of rare genetic disorders associated with a predisposition to cancer are characterised by genomic instability occurring in somatic cells. Of particular interest is the observation that transmissible instability can be induced in somatic cells from normal individuals by exposure to ionising radiation, leading to a persistent enhancement in the rate at which mutations and chromosomal aberrations arise in the progeny of the irradiated cells after many generations of replication. If such induced instability is involved in radiation carcinogenesis, it would imply that the initial carcinogenic event may not be a rare mutation occurring in a specific gene or set of genes. Rather, radiation may induce a process of instability in many cells in a population, enhancing the rate at which the multiple gene mutations necessary for the development of cancer may arise in a given cell lineage. Furthermore, radiation could act at any stage in the development of cancer by facilitating the accumulation of the remaining genetic events required to produce a fully malignant tumour. The experimental evidence for such induced instability is reviewed. (review)

  11. Genomic instability and radiation

    International Nuclear Information System (INIS)

    Little, John B

    2003-01-01

    Genomic instability is a hallmark of cancer cells, and is thought to be involved in the process of carcinogenesis. Indeed, a number of rare genetic disorders associated with a predisposition to cancer are characterised by genomic instability occurring in somatic cells. Of particular interest is the observation that transmissible instability can be induced in somatic cells from normal individuals by exposure to ionising radiation, leading to a persistent enhancement in the rate at which mutations and chromosomal aberrations arise in the progeny of the irradiated cells after many generations of replication. If such induced instability is involved in radiation carcinogenesis, it would imply that the initial carcinogenic event may not be a rare mutation occurring in a specific gene or set of genes. Rather, radiation may induce a process of instability in many cells in a population, enhancing the rate at which the multiple gene mutations necessary for the development of cancer may arise in a given cell lineage. Furthermore, radiation could act at any stage in the development of cancer by facilitating the accumulation of the remaining genetic events required to produce a fully malignant tumour. The experimental evidence for such induced instability is reviewed. (review)

  12. Pomegranate Intake Protects Against Genomic Instability Induced by Medical X-rays In Vivo in Mice.

    Science.gov (United States)

    Nallanthighal, Sameera; Shirode, Amit B; Judd, Julius A; Reliene, Ramune

    2016-01-01

    Ionizing radiation (IR) is a well-documented human carcinogen. The increased use of IR in medical procedures has doubled the annual radiation dose and may increase cancer risk. Genomic instability is an intermediate lesion in IR-induced cancer. We examined whether pomegranate extract (PE) suppresses genomic instability induced by x-rays. Mice were treated orally with PE and exposed to an x-ray dose of 2 Gy. PE intake suppressed x-ray-induced DNA double-strand breaks (DSBs) in peripheral blood and chromosomal damage in bone marrow. We hypothesized that PE-mediated protection against x-ray-induced damage may be due to the upregulation of DSB repair and antioxidant enzymes and/or increase in glutathione (GSH) levels. We found that expression of DSB repair genes was not altered (Nbs1 and Rad50) or was reduced (Mre11, DNA-PKcs, Ku80, Rad51, Rad52 and Brca2) in the liver of PE-treated mice. Likewise, mRNA levels of antioxidant enzymes were reduced (Gpx1, Cat, and Sod2) or were not altered (HO-1 and Sod1) as a function of PE treatment. In contrast, PE-treated mice with and without IR exposure displayed higher hepatic GSH concentrations than controls. Thus, ingestion of pomegranate polyphenols is associated with inhibition of x-ray-induced genomic instability and elevated GSH, which may reduce cancer risk.

  13. Transposable elements as stress adaptive capacitors induce genomic instability in fungal pathogen Magnaporthe oryzae.

    Directory of Open Access Journals (Sweden)

    Sonia Chadha

    Full Text Available A fundamental problem in fungal pathogenesis is to elucidate the evolutionary forces responsible for genomic rearrangements leading to races with fitter genotypes. Understanding the adaptive evolutionary mechanisms requires identification of genomic components and environmental factors reshaping the genome of fungal pathogens to adapt. Herein, Magnaporthe oryzae, a model fungal plant pathogen is used to demonstrate the impact of environmental cues on transposable elements (TE based genome dynamics. For heat shock and copper stress exposed samples, eight TEs belonging to class I and II family were employed to obtain DNA profiles. Stress induced mutant bands showed a positive correlation with dose/duration of stress and provided evidences of TEs role in stress adaptiveness. Further, we demonstrate that genome dynamics differ for the type/family of TEs upon stress exposition and previous reports of stress induced MAGGY transposition has underestimated the role of TEs in M. oryzae. Here, we identified Pyret, MAGGY, Pot3, MINE, Mg-SINE, Grasshopper and MGLR3 as contributors of high genomic instability in M. oryzae in respective order. Sequencing of mutated bands led to the identification of LTR-retrotransposon sequences within regulatory regions of psuedogenes. DNA transposon Pot3 was identified in the coding regions of chromatin remodelling protein containing tyrosinase copper-binding and PWWP domains. LTR-retrotransposons Pyret and MAGGY are identified as key components responsible for the high genomic instability and perhaps these TEs are utilized by M. oryzae for its acclimatization to adverse environmental conditions. Our results demonstrate how common field stresses change genome dynamics of pathogen and provide perspective to explore the role of TEs in genome adaptability, signalling network and its impact on the virulence of fungal pathogens.

  14. Genomic instability and radiation effects

    International Nuclear Information System (INIS)

    Christian Streffer

    2007-01-01

    Complete text of publication follows. Cancer, genetic mutations and developmental abnormalities are apparently associated with an increased genomic instability. Such phenomena have been frequently shown in human cancer cells in vitro and in situ. It is also well-known that individuals with a genetic predisposition for cancer proneness, such as ataxia telangiectesia, Fanconi anaemia etc. demonstrate a general high genomic instability e.g. in peripheral lymphocytes before a cancer has developed. Analogous data have been found in mice which develop a specific congenital malformation which has a genetic background. Under these aspects it is of high interest that ionising radiation can increase the genomic instability of mammalian cells after exposures in vitro an in vivo. This phenomenon is expressed 20 to 40 cell cycles after the exposure e.g. by de novo chromosomal aberrations. Such effects have been observed with high and low LET radiation, high LET radiation is more efficient. With low LET radiation a good dose response is observed in the dose range 0.2 to 2.0 Gy, Recently it has been reported that senescence and genomic instability was induced in human fibroblasts after 1 mGy carbon ions (1 in 18 cells are hit), apparently bystander effects also occurred under these conditions. The instability has been shown with DNA damage, chromosomal aberrations, gene mutation and cell death. It is also transferred to the next generation of mice with respect to gene mutations, chromosomal aberrations and congenital malformations. Several mechanisms have been discussed. The involvement of telomeres has gained interest. Genomic instability seems to be induced by a general lesion to the whole genome. The transmission of one chromosome from an irradiated cell to an non-irradiated cell leads to genomic instability in the untreated cells. Genomic instability increases mutation rates in the affected cells in general. As radiation late effects (cancer, gene mutations and congenital

  15. Genomic instability induced by 60Co γ ray radiation in normal human liver cells

    International Nuclear Information System (INIS)

    Gen Xiaohua; Guo Xianhua; Zuo Yahui; Wang Xiaoli; Wang Zhongwen

    2007-01-01

    Objective: To explore the genomic instability induced by 60 Co γ rays. Methods: The cloning efficiency and micronucleus efficiency of normal human liver cell irradiated by 60 Co γ rays were detected, and the method of single cell gel electrophoresis (SCGE) was carried out to measure DNA chains damage. The fast-growing cells were divided into different dose-groups and then irradiated by 60 Co γ rays. After 40 populations doubling, the progenies were secondly irradiated with 2 Gy 60 Co γ rays. Results: The cloning efficiency decreased with the increase of doses after the initial irradiation. After the survival cells were given second irradiation, both results of SCGE and micronucleus frequency showed that the second damage was correlated with the original irradiation doses. Conclusions: 60 Co γ rays can not only induce the immediate biological effects in liver cells, but also lead to the genomic instability in the descendants that leads to an enhanced frequency of genetic changes occurring among the progeny of the original irradiated cell. The expanding effect of second event helps to study the genomic instability. (authors)

  16. Perspectives on the role of bystander effect and genomic instability on therapy-induced secondary malignancy

    International Nuclear Information System (INIS)

    Perumal, Venkatachalam; Raavi, Venkateswarlu; Kanagaraj, Karthik; Shangamithra, V.; Paul, Solomon F.D.; Chinnadurai, M.

    2017-01-01

    Deviation from the orchestra of regulated cell division into unregulated and then result into the formation of tumor, is known as carcinogenesis. While causes and hallmarks of many cancer types are well established, newer concepts on tumor cell response to treatment, challenges established therapeutic regime and drives into alternative toward the better management. The phenomena of therapeutics induced bystander response, and genomic instability on late effects of cancer therapy is emerging as a newer challenge. Bystander response is defined as the manifestation of radiation/chemotherapy drug signatures on the unexposed cells which are in the closer vicinity of the directly exposed; on the other hand, genomic instability is defined as the expression of radiation/chemotherapy drug signatures in the progeny of exposed cells. Unequivocally, existence of those phenomena has been demonstrated with many cell types (both in vitro and in vivo) followed by radiation and widely used chemotherapeutic drugs. Nevertheless, it is also revealed that the effects are variable and depend on dose, type of radiation/chemicals agents, experimental model, type of donor and recipient cells, and biomarkers adopted; moreover, to observe those effects, reactive oxygen species has been reported as leading mediators of those responses when compared to other molecules such as interleukins, cytokines, and inflammatory markers. Available data on those phenomena and our findings suggest that a role of therapeutic drugs induced bystander effects, and genomic instability on the development of secondary malignancy cannot be ruled out completely. (author)

  17. Radiation-induced Genomic Instability and Radiation Sensitivity

    Energy Technology Data Exchange (ETDEWEB)

    Varnum, Susan M.; Sowa, Marianne B.; Kim, Grace J.; Morgan, William F.

    2013-01-19

    The obvious relationships between reactive oxygen and nitrogen species, mitochondrial dysfunction, inflammatory type responses and reactive chemokines and cytokines suggests a general stress response induced by ionizing radiation most likely leads to the non-targeted effects described after radiation exposure. We argue that true bystander effects do not occur in the radiation therapy clinic. But there is no question that effects outside the target volume do occur. These “out of field effects” are considered very low dose effects in the context of therapy. So what are the implications of non-targeted effects on radiation sensitivity? The primary goal of therapy is to eradicate the tumor. Given the genetic diversity of the human population, lifestyle and environment factors it is likely some combination of these will influence patient outcome. Non-targeted effects may contribute to a greater or lesser extent. But consider the potential situation involving a partial body exposure due to a radiation accident or radiological terrorism. Non-targeted effects suggest that the tissue at risk for demonstrating possible detrimental effects of radiation exposure might be greater than the volume actually irradiated.

  18. Radiation-induced genomic instability, and the cloning and functional analysis of its related gene

    International Nuclear Information System (INIS)

    Muto, Masahiro; Kanari, Yasuyoshi; Kubo, Eiko; Yamada, Yutaka

    2000-01-01

    Exposure to ionizing radiation produces a number of biological consequences including gene mutations, chromosome aberrations, cellular transformation and cell death. The classical view has been that mutations occur at the sites of DNA damage, that is, damage produced by radiation is converted into a mutation during subsequent DNA replication or as a consequence of enzymatic repair processes. However, many investigators have presented evidence for an alternative mechanism to explain these biological effects. This evidence suggests that radiation may induce a process of genomic instability that is transmissible over many generations of cell replication and that serves to enhance the probability of the occurrence of such genetic effects among the progeny of the irradiated cell after many generations of cell replication. If such a process exists in vivo, it could have significant implications for mechanisms of carcinogenesis. Exposure of B10 mice to fractionated X-irradiation induces a high incidence of thymic lymphomas, whereas the incidence in STS/A mice is very low. Such strain differences are presumably determined genetically, and various genetic factors have been reported to be involved in radiation-induced lymphomagenesis. The mechanism of radiation-induced lymphomagenesis appears to develop through a complex and multistep process. Using this experimental system, we characterized the prelymphoma cells induced by radiation, and identified the genetic changes preceding the development of thymic lymphomas by comparing the oncogenic alterations with the pattern of T cell receptor (TCR) γ rearrangements. In these studies, the latent expression of some chromosomal aberrations and p53 mutations in irradiated progeny has been interpreted to be a manifestation of genomic instability. In the present report we review the results of in vivo studies conducted in our laboratory that support the hypothesis of genomic instability induced by radiation, and we describe the

  19. Upregulation of FOXM1 induces genomic instability in human epidermal keratinocytes

    Directory of Open Access Journals (Sweden)

    Philpott Michael P

    2010-02-01

    Full Text Available Abstract Background The human cell cycle transcription factor FOXM1 is known to play a key role in regulating timely mitotic progression and accurate chromosomal segregation during cell division. Deregulation of FOXM1 has been linked to a majority of human cancers. We previously showed that FOXM1 was upregulated in basal cell carcinoma and recently reported that upregulation of FOXM1 precedes malignancy in a number of solid human cancer types including oral, oesophagus, lung, breast, kidney, bladder and uterus. This indicates that upregulation of FOXM1 may be an early molecular signal required for aberrant cell cycle and cancer initiation. Results The present study investigated the putative early mechanism of UVB and FOXM1 in skin cancer initiation. We have demonstrated that UVB dose-dependently increased FOXM1 protein levels through protein stabilisation and accumulation rather than de novo mRNA expression in human epidermal keratinocytes. FOXM1 upregulation in primary human keratinocytes triggered pro-apoptotic/DNA-damage checkpoint response genes such as p21, p38 MAPK, p53 and PARP, however, without causing significant cell cycle arrest or cell death. Using a high-resolution Affymetrix genome-wide single nucleotide polymorphism (SNP mapping technique, we provided the evidence that FOXM1 upregulation in epidermal keratinocytes is sufficient to induce genomic instability, in the form of loss of heterozygosity (LOH and copy number variations (CNV. FOXM1-induced genomic instability was significantly enhanced and accumulated with increasing cell passage and this instability was increased even further upon exposure to UVB resulting in whole chromosomal gain (7p21.3-7q36.3 and segmental LOH (6q25.1-6q25.3. Conclusion We hypothesise that prolonged and repeated UVB exposure selects for skin cells bearing stable FOXM1 protein causes aberrant cell cycle checkpoint thereby allowing ectopic cell cycle entry and subsequent genomic instability. The aberrant

  20. Genomic instability in rat: Breakpoints induced by ionising radiation and interstitial telomeric-like sequences

    International Nuclear Information System (INIS)

    Camats, Nuria; Ruiz-Herrera, Aurora; Parrilla, Juan Jose; Acien, Maribel; Paya, Pilar; Giulotto, Elena; Egozcue, Josep; Garcia, Francisca; Garcia, Montserrat

    2006-01-01

    The Norwegian rat (Rattus norvegicus) is the most widely studied experimental species in biomedical research although little is known about its chromosomal structure. The characterisation of possible unstable regions of the karyotype of this species would contribute to the better understanding of its genomic architecture. The cytogenetic effects of ionising radiation have been widely used for the study of genomic instability, and the importance of interstitial telomeric-like sequences (ITSs) in instability of the genome has also been reported in previous studies in vertebrates. In order to describe the unstable chromosomal regions of R. norvegicus, the distribution of breakpoints induced by X-irradiation and ITSs in its karyotype were analysed in this work. For the X-irradiation analysis, 52 foetuses (from 14 irradiated rats) were studied, 4803 metaphases were analysed, and a total of 456 breakpoints induced by X-rays were detected, located in 114 chromosomal bands, with 25 of them significantly affected by X-irradiation (hot spots). For the analysis of ITSs, three foetuses (from three rats) were studied, 305 metaphases were analysed and 121 ITSs were detected, widely distributed in the karyotype of this species. Seventy-six percent of all hot spots analysed in this study were co-localised with ITSs

  1. Genomic instability in rat: Breakpoints induced by ionising radiation and interstitial telomeric-like sequences

    Energy Technology Data Exchange (ETDEWEB)

    Camats, Nuria [Institut de Biotecnologia i Biomedicina (IBB), Universitat Autonoma de Barcelona, 08193 Barcelona (Spain); Departament de Biologia Cel.lular, Fisiologia i Immunologia Universitat Autonoma de Barcelona, 08193 Barcelona (Spain); Ruiz-Herrera, Aurora [Departament de Biologia Cel.lular, Fisiologia i Immunologia Universitat Autonoma de Barcelona, 08193 Barcelona (Spain); Parrilla, Juan Jose [Servicio de Ginecologia y Obstetricia, Hospital Universitario Virgen de la Arrixaca, Ctra, Madrid-Cartagena, s/n, El Palmar, 30120 Murcia (Spain); Acien, Maribel [Servicio de Ginecologia y Obstetricia, Hospital Universitario Virgen de la Arrixaca, Ctra, Madrid-Cartagena, s/n, El Palmar, 30120 Murcia (Spain); Paya, Pilar [Servicio de Ginecologia y Obstetricia, Hospital Universitario Virgen de la Arrixaca, Ctra, Madrid-Cartagena, s/n, El Palmar, 30120 Murcia (Spain); Giulotto, Elena [Dipartimento di Genetica e Microbiologia Adriano Buzzati Traverso, Universita degli Studi di Pavia, 27100 Pavia (Italy); Egozcue, Josep [Departament de Biologia Cel.lular, Fisiologia i Immunologia Universitat Autonoma de Barcelona, 08193 Barcelona (Spain); Garcia, Francisca [Institut de Biotecnologia i Biomedicina (IBB), Universitat Autonoma de Barcelona, 08193 Barcelona (Spain); Garcia, Montserrat [Institut de Biotecnologia i Biomedicina (IBB), Universitat Autonoma de Barcelona, 08193 Barcelona (Spain) and Departament de Biologia Cellular, Fisiologia i Immunologia Universitat Autonoma de Barcelona, 08193 Barcelona (Spain)]. E-mail: Montserrat.Garcia.Caldes@uab.es

    2006-03-20

    The Norwegian rat (Rattus norvegicus) is the most widely studied experimental species in biomedical research although little is known about its chromosomal structure. The characterisation of possible unstable regions of the karyotype of this species would contribute to the better understanding of its genomic architecture. The cytogenetic effects of ionising radiation have been widely used for the study of genomic instability, and the importance of interstitial telomeric-like sequences (ITSs) in instability of the genome has also been reported in previous studies in vertebrates. In order to describe the unstable chromosomal regions of R. norvegicus, the distribution of breakpoints induced by X-irradiation and ITSs in its karyotype were analysed in this work. For the X-irradiation analysis, 52 foetuses (from 14 irradiated rats) were studied, 4803 metaphases were analysed, and a total of 456 breakpoints induced by X-rays were detected, located in 114 chromosomal bands, with 25 of them significantly affected by X-irradiation (hot spots). For the analysis of ITSs, three foetuses (from three rats) were studied, 305 metaphases were analysed and 121 ITSs were detected, widely distributed in the karyotype of this species. Seventy-six percent of all hot spots analysed in this study were co-localised with ITSs.

  2. Bystander effects, adaptive response and genomic instability induced by prenatal irradiation

    Energy Technology Data Exchange (ETDEWEB)

    Streffer, Christian [Institute for Science and Ethics, University Duisburg-Essen, Auf dem Sutan 12, D-45239 Essen (Germany)]. E-mail: streffer.essen@t-online.de

    2004-12-02

    The developing human embryo and fetus undergo very radiosensitive stages during the prenatal development. It is likely that the induction of low dose related effects such as bystander effects, the adaptive response, and genomic instability would have profound effects on embryonic and fetal development. In this paper, I review what has been reported on the induction of these three phenomena in exposed embryos and fetuses. All three phenomena have been shown to occur in murine embryonic or fetal cells and structures, although the induction of an adaptive response (and also likely the induction of bystander effects) are limited in terms of when during development they can be induced and the dose or dose-rate used to treat animals in utero. In contrast, genomic instability can be induced throughout development, and the effects of radiation exposure on genome instability can be observed for long times after irradiation including through pre- and postnatal development and into the next generation of mice. There are clearly strain-specific differences in the induction of these phenomena and all three can lead to long-term detrimental effects. This is true for the adaptive response as well. While induction of an adaptive response can make fetuses more resistant to some gross developmental defects induced by a subsequent high dose challenge with ionizing radiation, the long-term effects of this low dose exposure are detrimental. The negative effects of all three phenomena reflect the complexity of fetal development, a process where even small changes in the timing of gene expression or suppression can have dramatic effects on the pattern of biological events and the subsequent development of the mammalian organism.

  3. Radiation-induced genomic instability is associated with DNA methylation changes in cultured human keratinocytes

    International Nuclear Information System (INIS)

    Kaup, Sahana; Grandjean, Valerie; Mukherjee, Rajarshi; Kapoor, Aparna; Keyes, Edward; Seymour, Colin B.; Mothersill, Carmel E.; Schofield, Paul N.

    2006-01-01

    The mechanism by which radiation-induced genomic instability is initiated, propagated and effected is currently under intense scrutiny. We have investigated the potential role of altered genomic methylation patterns in the cellular response to irradiation and have found evidence for widespread dysregulation of CpG methylation persisting up to 20 population doublings post-irradiation. Similar effects are seen with cells treated with medium from irradiated cells (the 'bystander effect') rather than subjected to direct irradiation. Using an arbitrarily primed methylation sensitive PCR screening method we have demonstrated that irradiation causes reproducible alterations in the methylation profile of a human keratinocyte cell line, HPV-G, and have further characterised one of these sequences as being a member of a retrotransposon element derived sequence family on chromosome 7; MLT1A. Multiple changes were also detected in the screen, which indicate that although the response of cells is predominantly hypermethylation, specific hypomethylation occurs as well. Sequence specific changes are also reported in the methylation of the pericentromeric SAT2 satellite sequence. This is the first demonstration that irradiation results in the induction of heritable methylation changes in mammalian cells, and provides a link between the various non-radiological instigators of genomic instability, the perpetuation of the unstable state and several of its manifestations

  4. Radiation-induced hyperproliferation of intestinal crypts results in elevated genome instability with inactive p53-related genomic surveillance.

    Science.gov (United States)

    Zhou, Xin; Ma, Xiaofei; Wang, Zhenhua; Sun, Chao; Wang, Yupei; He, Yang; Zhang, Hong

    2015-12-15

    Radiation-induced hyperproliferation of intestinal crypts is well documented, but its potential tumorigenic effects remain elusive. Here we aim to determine the genomic surveillance process during crypt hyperproliferation, and its consequential outcome after ionizing radiation. Crypt regeneration in the intestine was induced by a single dose of 12Gy abdominal irradiation. γ-H2AX, 53BP1 and DNA-PKcs were used as DNA repair surrogates to investigate the inherent ability of intestinal crypt cells to recognize and repair double-strand breaks. Ki67 staining and the 5-bromo-2'-deoxyuridine incorporation assay were used to study patterns of cell proliferation in regenerating crypts. Staining for ATM, p53, Chk1 and Chk2 was performed to study checkpoint activation and release. Apoptosis was evaluated through H&E staining and terminal deoxynucleotidyl transferase (dUTP) nick-end labeling. The ATM-p53 pathway was immediately activated after irradiation. A second wave of DSBs in crypt cells was observed in regenerating crypts, accompanied with significantly increased chromosomal bridges. The p53-related genomic surveillance pathway was not active during the regeneration phase despite DSBs and chromosomal bridges in the cells of regenerating crypts. Non-homologous end joining (NHEJ) DSBs repair was involved in the DSBs repair process, as indicated by p-DNA-PKcs staining. Intestinal crypt cells retained hyperproliferation with inactive p53-related genomic surveillance system. NHEJ was involved in the resultant genomic instability during hyperproliferation. Copyright © 2015 Elsevier Inc. All rights reserved.

  5. The Role of DNA Methylation Changes in Radiation-Induced Transgenerational Genomic Instability and Bystander Effects in cranial irradiated Mice

    Science.gov (United States)

    Zhang, Meng; Sun, Yeqing; Gao, Yinglong; Zhang, Baodong

    Heavy-ion radiation could lead to genome instability in the germline, and therefore to transgenerational genome and epigenome instability in offspring of exposed males. The exact mechanisms of radiation-induced genome instability in directly exposed and in bystander organ remain obscure, yet accumulating evidence points to the role of DNA methylation changes in genome instability development. The potential of localized body-part exposures to affect the germline and thus induce genome and epigenome changes in the progeny has not been studied. To investigate whether or not the paternal cranial irradiation can exert deleterious changes in the protected germline and the offsprings, we studied the alteration of DNA methylation in the shielded testes tissue. Here we report that the localized paternal cranial irradiation results in a significant altered DNA methylation in sperm cells and leads to a profound epigenetic dysregulation in the unexposed progeny conceived 3 months after paternal exposure. The possible molecular mechanisms and biological consequences of the observed changes are discussed. Keywords: Heavy-ion radiation; Transgenerational effect; Genomic Instability Bystander Effects; DNA methylation.

  6. RECQL5 Suppresses Oncogenic JAK2-Induced Replication Stress and Genomic Instability

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    Edwin Chen

    2015-12-01

    Full Text Available JAK2V617F is the most common oncogenic lesion in patients with myeloproliferative neoplasms (MPNs. Despite the ability of JAK2V617F to instigate DNA damage in vitro, MPNs are nevertheless characterized by genomic stability. In this study, we address this paradox by identifying the DNA helicase RECQL5 as a suppressor of genomic instability in MPNs. We report increased RECQL5 expression in JAK2V617F-expressing cells and demonstrate that RECQL5 is required to counteract JAK2V617F-induced replication stress. Moreover, RECQL5 depletion sensitizes JAK2V617F mutant cells to hydroxyurea (HU, a pharmacological inducer of replication stress and the most common treatment for MPNs. Using single-fiber chromosome combing, we show that RECQL5 depletion in JAK2V617F mutant cells impairs replication dynamics following HU treatment, resulting in increased double-stranded breaks and apoptosis. Cumulatively, these findings identify RECQL5 as a critical regulator of genome stability in MPNs and demonstrate that replication stress-associated cytotoxicity can be amplified specifically in JAK2V617F mutant cells through RECQL5-targeted synthetic lethality.

  7. Bystander effects in UV-induced genomic instability: Antioxidants inhibit delayed mutagenesis induced by ultraviolet A and B radiation

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    Dahle Jostein

    2005-01-01

    Full Text Available Abstract Background Genomic instability is characteristic of many types of human cancer. Recently, we reported that ultraviolet radiation induced elevated mutation rates and chromosomal instability for many cell generations after ultraviolet irradiation. The increased mutation rates of unstable cells may allow them to accumulate aberrations that subsequently lead to cancer. Ultraviolet A radiation, which primarily acts by oxidative stress, and ultraviolet B radiation, which initially acts by absorption in DNA and direct damage to DNA, both produced genomically unstable cell clones. In this study, we have determined the effect of antioxidants on induction of delayed mutations by ultraviolet radiation. Delayed mutations are indicative of genomic instability. Methods Delayed mutations in the hypoxanthine phosphoribosyl transferase (hprt gene were detected by incubating the cells in medium selectively killing hprt mutants for 8 days after irradiation, followed by a 5 day period in normal medium before determining mutation frequencies. Results The UVB-induced delayed hprt mutations were strongly inhibited by the antioxidants catalase, reduced glutathione and superoxide dismutase, while only reduced glutathione had a significant effect on UVA-induced delayed mutations. Treatment with antioxidants had only minor effects on early mutation frequenies, except that reduced glutathione decreased the UVB-induced early mutation frequency by 24 %. Incubation with reduced glutathione was shown to significantly increase the intracellular amount of reduced glutathione. Conclusion The strong effects of these antioxidants indicate that genomic instability, which is induced by the fundamentally different ultraviolet A and ultraviolet B radiation, is mediated by reactive oxygen species, including hydrogen peroxide and downstream products. However, cells take up neither catalase nor SOD, while incubation with glutathione resulted in increased intracellular levels of

  8. WARBURG EFFECT AND TRANSLOCATION-INDUCED GENOMIC INSTABILITY: TWO YEAST MODELS FOR CANCER CELLS

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    Valentina eTosato

    2013-01-01

    Full Text Available Yeast has been established as an efficient model system to study biological principles underpinning human health. In this review we focus on yeast models covering two aspects of cancer formation and progression i the activity of pyruvate kinase (PK, which recapitulates metabolic features of cancer cells, including the Warburg effect, and ii Bridge-Induced chromosome Translocation (BIT mimicking genome instability in cancer. Saccharomyces cerevisiae is an excellent model to study cancer cell metabolism, as exponentially growing yeast cells exhibit many metabolic similarities with rapidly proliferating cancer cells. The metabolic reconfiguration includes an increase in glucose uptake and fermentation, at the expense of respiration and oxidative phosphorylation (the Warburg effect, and involves a broad reconfiguration of nucleotide and amino acid metabolism. Both in yeast and humans, the regulation of this process seems to have a central player, pyruvate kinase, which is up-regulated in cancer, and to occur mostly on a post-transcriptional and posttranslational basis. Furthermore, BIT allows to generate selectable translocation-derived recombinants (translocants, between any two desired chromosomal locations, in wild-type yeast strains transformed with a linear DNA cassette carrying a selectable marker flanked by two DNA sequences homologous to different chromosomes. Using the Bridge-Induced Translocation system, targeted non-reciprocal translocations in mitosis are easily inducible. An extensive collection of different yeast translocants exhibiting genome instability and aberrant phenotypes similar to cancer cells has been produced and subjected to analysis. In this review, we hence provide an overview upon two yeast cancer models, and extrapolate general principles for mimicking human disease mechanisms in yeast.

  9. Warburg effect and translocation-induced genomic instability: two yeast models for cancer cells

    International Nuclear Information System (INIS)

    Tosato, Valentina; Grüning, Nana-Maria; Breitenbach, Michael; Arnak, Remigiusz; Ralser, Markus; Bruschi, Carlo V.

    2013-01-01

    Yeast has been established as an efficient model system to study biological principles underpinning human health. In this review we focus on yeast models covering two aspects of cancer formation and progression (i) the activity of pyruvate kinase (PK), which recapitulates metabolic features of cancer cells, including the Warburg effect, and (ii) chromosome bridge-induced translocation (BIT) mimiking genome instability in cancer. Saccharomyces cerevisiae is an excellent model to study cancer cell metabolism, as exponentially growing yeast cells exhibit many metabolic similarities with rapidly proliferating cancer cells. The metabolic reconfiguration includes an increase in glucose uptake and fermentation, at the expense of respiration and oxidative phosphorylation (the Warburg effect), and involves a broad reconfiguration of nucleotide and amino acid metabolism. Both in yeast and humans, the regulation of this process seems to have a central player, PK, which is up-regulated in cancer, and to occur mostly on a post-transcriptional and post-translational basis. Furthermore, BIT allows to generate selectable translocation-derived recombinants (“translocants”), between any two desired chromosomal locations, in wild-type yeast strains transformed with a linear DNA cassette carrying a selectable marker flanked by two DNA sequences homologous to different chromosomes. Using the BIT system, targeted non-reciprocal translocations in mitosis are easily inducible. An extensive collection of different yeast translocants exhibiting genome instability and aberrant phenotypes similar to cancer cells has been produced and subjected to analysis. In this review, we hence provide an overview upon two yeast cancer models, and extrapolate general principles for mimicking human disease mechanisms in yeast.

  10. Warburg effect and translocation-induced genomic instability: two yeast models for cancer cells

    Energy Technology Data Exchange (ETDEWEB)

    Tosato, Valentina [International Centre for Genetic Engineering and Biotechnology, Trieste (Italy); Grüning, Nana-Maria [Cambridge System Biology Center, Department of Biochemistry, University of Cambridge, Cambridge (United Kingdom); Breitenbach, Michael [Division of Genetics, Department of Cell Biology, University of Salzburg, Salzburg (Austria); Arnak, Remigiusz [International Centre for Genetic Engineering and Biotechnology, Trieste (Italy); Ralser, Markus [Cambridge System Biology Center, Department of Biochemistry, University of Cambridge, Cambridge (United Kingdom); Bruschi, Carlo V., E-mail: bruschi@icgeb.org [International Centre for Genetic Engineering and Biotechnology, Trieste (Italy)

    2013-01-18

    Yeast has been established as an efficient model system to study biological principles underpinning human health. In this review we focus on yeast models covering two aspects of cancer formation and progression (i) the activity of pyruvate kinase (PK), which recapitulates metabolic features of cancer cells, including the Warburg effect, and (ii) chromosome bridge-induced translocation (BIT) mimiking genome instability in cancer. Saccharomyces cerevisiae is an excellent model to study cancer cell metabolism, as exponentially growing yeast cells exhibit many metabolic similarities with rapidly proliferating cancer cells. The metabolic reconfiguration includes an increase in glucose uptake and fermentation, at the expense of respiration and oxidative phosphorylation (the Warburg effect), and involves a broad reconfiguration of nucleotide and amino acid metabolism. Both in yeast and humans, the regulation of this process seems to have a central player, PK, which is up-regulated in cancer, and to occur mostly on a post-transcriptional and post-translational basis. Furthermore, BIT allows to generate selectable translocation-derived recombinants (“translocants”), between any two desired chromosomal locations, in wild-type yeast strains transformed with a linear DNA cassette carrying a selectable marker flanked by two DNA sequences homologous to different chromosomes. Using the BIT system, targeted non-reciprocal translocations in mitosis are easily inducible. An extensive collection of different yeast translocants exhibiting genome instability and aberrant phenotypes similar to cancer cells has been produced and subjected to analysis. In this review, we hence provide an overview upon two yeast cancer models, and extrapolate general principles for mimicking human disease mechanisms in yeast.

  11. Radiation-induced genomic instability: Are epigenetic mechanisms the missing link?

    Energy Technology Data Exchange (ETDEWEB)

    Aypar, Umut; Morgan, William F.; Baulch, Janet E.

    2011-02-01

    Purpose: This review examines the evidence for the hypothesis that epigenetics are involved in the initiation and perpetuation of radiation-induced genomic instability (RIGI). Conclusion: In addition to the extensively studied targeted effects of radiation, it is now apparent that non-targeted delayed effects such as RIGI are also important post-irradiation outcomes. In RIGI, unirradiated progeny cells display phenotypic changes at delayed times after radiation of the parental cell. RIGI is thought to be important in the process of carcinogenesis, however, the mechanism by which this occurs remains to be elucidated. In the genomically unstable clones developed by Morgan and colleagues, radiation-induced mutations, double-strand breaks, or changes in mRNA levels alone could not account for the initiation or perpetuation of RIGI. Since changes in the DNA sequence could not fully explain the mechanism of RIGI, inherited epigenetic changes may be involved. Epigenetics are known to play an important role in many cellular processes and epigenetic aberrations can lead to carcinogenesis. Recent studies in the field of radiation biology suggest that the changes in methylation patterns may be involved in RIGI. Together these clues have led us to hypothesize that epigenetics may be the missing link in understanding the mechanism behind RIGI.

  12. Distinct Mechanisms of Nuclease-Directed DNA-Structure-Induced Genetic Instability in Cancer Genomes.

    Science.gov (United States)

    Zhao, Junhua; Wang, Guliang; Del Mundo, Imee M; McKinney, Jennifer A; Lu, Xiuli; Bacolla, Albino; Boulware, Stephen B; Zhang, Changsheng; Zhang, Haihua; Ren, Pengyu; Freudenreich, Catherine H; Vasquez, Karen M

    2018-01-30

    Sequences with the capacity to adopt alternative DNA structures have been implicated in cancer etiology; however, the mechanisms are unclear. For example, H-DNA-forming sequences within oncogenes have been shown to stimulate genetic instability in mammals. Here, we report that H-DNA-forming sequences are enriched at translocation breakpoints in human cancer genomes, further implicating them in cancer etiology. H-DNA-induced mutations were suppressed in human cells deficient in the nucleotide excision repair nucleases, ERCC1-XPF and XPG, but were stimulated in cells deficient in FEN1, a replication-related endonuclease. Further, we found that these nucleases cleaved H-DNA conformations, and the interactions of modeled H-DNA with ERCC1-XPF, XPG, and FEN1 proteins were explored at the sub-molecular level. The results suggest mechanisms of genetic instability triggered by H-DNA through distinct structure-specific, cleavage-based replication-independent and replication-dependent pathways, providing critical evidence for a role of the DNA structure itself in the etiology of cancer and other human diseases. Copyright © 2018 The Authors. Published by Elsevier Inc. All rights reserved.

  13. Radiation and chemotherapy bystander effects induce early genomic instability events: telomere shortening and bridge formation coupled with mitochondrial dysfunction.

    LENUS (Irish Health Repository)

    Gorman, Sheeona

    2012-02-01

    The bridge breakage fusion cycle is a chromosomal instability mechanism responsible for genomic changes. Radiation bystander effects induce genomic instability; however, the mechanism driving this instability is unknown. We examined if radiation and chemotherapy bystander effects induce early genomic instability events such as telomere shortening and bridge formation using a human colon cancer explant model. We assessed telomere lengths, bridge formations, mitochondrial membrane potential and levels of reactive oxygen species in bystander cells exposed to medium from irradiated and chemotherapy-treated explant tissues. Bystander cells exposed to media from 2Gy, 5Gy, FOLFOX treated tumor and matching normal tissue showed a significant reduction in telomere lengths (all p values <0.018) and an increase in bridge formations (all p values <0.017) compared to bystander cells treated with media from unirradiated tissue (0Gy) at 24h. There was no significant difference between 2Gy and 5Gy treatments, or between effects elicited by tumor versus matched normal tissue. Bystander cells exposed to media from 2Gy irradiated tumor tissue showed significant depolarisation of the mitochondrial membrane potential (p=0.012) and an increase in reactive oxygen species levels. We also used bystander cells overexpressing a mitochondrial antioxidant manganese superoxide dismutase (MnSOD) to examine if this antioxidant could rescue the mitochondrial changes and subsequently influence nuclear instability events. In MnSOD cells, ROS levels were reduced (p=0.02) and mitochondrial membrane potential increased (p=0.04). These events were coupled with a decrease in percentage of cells with anaphase bridges and a decrease in the number of cells undergoing telomere length shortening (p values 0.01 and 0.028 respectively). We demonstrate that radiation and chemotherapy bystander responses induce early genomic instability coupled with defects in mitochondrial function. Restoring mitochondrial

  14. Radiation-induced genomic instability driven by de novo chromosomal rearrangement hot spots

    International Nuclear Information System (INIS)

    Grosovsky, A.J.; Allen, R.N.; Moore, S.R.

    2003-01-01

    Genomic instability has become generally recognized as a critical contributor to tumor progression by generating the necessary number of genetic alterations required for expression of a clinically significant malignancy. Our study of chromosomal instability investigates the hypothesis that chromosomal rearrangements can generate novel breakage-prone sites, resulting in instability acting predominantly in cis. Here we present an analysis of the karyotypic distribution of instability associated chromosomal rearrangements in TK6 and derivative human lymphoblasts. Karyotypic analysis performed on a total of 455 independent clones included 183 rearrangements distributed among 100 separate unstable clones. The results demonstrate that the breakpoints of chromosomal rearrangements in unstable clones are non-randomly distributed throughout the genome. This pattern is statistically significant, and incompatible with expectations for random breakage associated with loss or alteration of a trans-acting factor. Furthermore, specific chromosomal breakage hot spots associated with instability have been identified; these occur in several independent unstable clones and are often repeatedly broken and rejoined during the outgrowth of an individual clone. In complimentary studies, genomic instability was generated without any exposure to a DNA-damaging agent, but rather by transfection with alpha heterochromatin DNA. In a prospective analysis, human-hamster hybrid AL cells containing a single human chromosome 11 were transfected with heterochromatic alpha DNA repeats and clones were analyzed by chromosome 11 painting. Transfection with alpha DNA was associated with karyotypic heterogeneity in 40% of clones examined; control transfections with plasmid alone did not lead to karyotypic heterogeneity

  15. Lack of specificity of chromosome breaks resulting from radiation-induced genomic instability in Chinese hamster cells

    International Nuclear Information System (INIS)

    Trott, K.-R.; Teibe, A.

    1998-01-01

    In V79 Chinese hamster cells, radiation-induced genomic instability results in a persistently increased frequency of micronuclei, dicentric chromosomes and apoptosis and in decreased colony-forming ability. These manifestations of radiation-induced genomic instability may be attributed to an increased rate of chromosome breakage events many generations after irradiation. This chromosomal instability does not seem to be a property which has been inflicted on individual chromosomes at the time of irradiation. Rather, it appears to be secondary to an increased level of non-specific clastogenic factors in the progeny of most if not all irradiated cells. This conclusion is drawn from the observations presented here, that all the chromosomes in surviving V79 cells are involved in the formation of dicentric chromosome aberrations 1 or 2 weeks after irradiation with about equal probability if corrections are made for chromosome length. (orig.)

  16. The role of radiation types and dose in induced genomic instability

    International Nuclear Information System (INIS)

    Kadhim Munira, A.

    2007-01-01

    Complete text of publication follows. Genomic Instability (GI) is defined as long-term alterations induced by low-dose exposure to a variety of genotoxic agents in mammalian cells that act to increase the 'apparent' spontaneous mutation frequency.GI is a hallmark of tumorigenic progression and is observed in the progeny of irradiated and bystander cells as the delayed and stochastic appearance of de novo chromosomal aberrations, gene mutations and delayed lethal mutations both in vitro and in vivo. It occurs at a frequency several orders of magnitude greater than would be expected for mutation in a single gene, implying that GI is a multigenic phenomenon. The expression of GI can be influenced by genotype, cell type and radiation quality; however the underlying mechanisms are not fully understood. While several studies have demonstrated GI induction by high and low LET radiation, our work on human and mouse primary cell systems has shown significant differences in the capacity to induce GI and the spectrum of alterations depending on LET. These differences might be attributed to differences in radiation track structure, radiation dose and radiation exposure regime (distribution of hit and un hit cells). In this presentation I shall review the role of radiation quality; describe the possible mechanisms underlining the observed differences between radiation type and present results of experiments demonstrating that the dose of low LET radiation might be the most significant factor in determining the role of radiation type in the induction of GI.

  17. Complex DNA Damage: A Route to Radiation-Induced Genomic Instability and Carcinogenesis

    Directory of Open Access Journals (Sweden)

    Ifigeneia V. Mavragani

    2017-07-01

    Full Text Available Cellular effects of ionizing radiation (IR are of great variety and level, but they are mainly damaging since radiation can perturb all important components of the cell, from the membrane to the nucleus, due to alteration of different biological molecules ranging from lipids to proteins or DNA. Regarding DNA damage, which is the main focus of this review, as well as its repair, all current knowledge indicates that IR-induced DNA damage is always more complex than the corresponding endogenous damage resulting from endogenous oxidative stress. Specifically, it is expected that IR will create clusters of damage comprised of a diversity of DNA lesions like double strand breaks (DSBs, single strand breaks (SSBs and base lesions within a short DNA region of up to 15–20 bp. Recent data from our groups and others support two main notions, that these damaged clusters are: (1 repair resistant, increasing genomic instability (GI and malignant transformation and (2 can be considered as persistent “danger” signals promoting chronic inflammation and immune response, causing detrimental effects to the organism (like radiation toxicity. Last but not least, the paradigm shift for the role of radiation-induced systemic effects is also incorporated in this picture of IR-effects and consequences of complex DNA damage induction and its erroneous repair.

  18. Genomic instability induced by 137Cs γ-ray irradiation in CHL surviving cells

    International Nuclear Information System (INIS)

    Yue Jingyin; Liu Bingchen; Wu Hongying; Zhou Jiwen; Mu Chuanjie

    1999-01-01

    Objective: To study in parallel several possible manifestations of instability of surviving CHL cells after irradiation, namely the frequencies of mutation at locus, micronuclei and apoptosis. Methods: The frequencies of mutation at HGPRT locus, micronuclei and apoptosis were assayed at various times in surviving cells irradiated with γ-rays. Results: The surviving cells showed a persistently increased frequency of mutation at the HGPRT locus after irradiation until 53 days. Mutant fraction as high as 10 -4 was scored, tens of times higher than those assayed in control cells studied in parallel. The frequency of bi nucleated cells with micronuclei determined within 24 hours after irradiation increased with dose and reached a peak value of (26.58 +- 2.48)% at 3 Gy, decreasing at higher doses to a plateau around 20%. The micronucleus frequency decreased steeply to about (14.47 +- 2.39)% within the first 3 days post-irradiation, and fluctuated at around 10% up to 56 days post-irradiation. The delayed efficiency of irradiated cells was significantly decreased. The frequency of apoptosis peaked about (24.90 +- 4.72)% at 10 Gy 48 h post-irradiation (γ-ray dose between 3-10 Gy) and then decreased to about 12% within 3 days. It was significantly higher than in control cells until 14 days. Conclusions: It shows that genomic instability induced by radiation can be transmitted to the progeny of surviving cells and may take many forms of expression such as lethal mutation, chromosome aberrations, gene mutation, etc

  19. Double-strand break repair-adox: Restoration of suppressed double-strand break repair during mitosis induces genomic instability.

    Science.gov (United States)

    Terasawa, Masahiro; Shinohara, Akira; Shinohara, Miki

    2014-12-01

    Double-strand breaks (DSBs) are one of the severest types of DNA damage. Unrepaired DSBs easily induce cell death and chromosome aberrations. To maintain genomic stability, cells have checkpoint and DSB repair systems to respond to DNA damage throughout most of the cell cycle. The failure of this process often results in apoptosis or genomic instability, such as aneuploidy, deletion, or translocation. Therefore, DSB repair is essential for maintenance of genomic stability. During mitosis, however, cells seem to suppress the DNA damage response and proceed to the next G1 phase, even if there are unrepaired DSBs. The biological significance of this suppression is not known. In this review, we summarize recent studies of mitotic DSB repair and discuss the mechanisms of suppression of DSB repair during mitosis. DSB repair, which maintains genomic integrity in other phases of the cell cycle, is rather toxic to cells during mitosis, often resulting in chromosome missegregation and aberration. Cells have multiple safeguards to prevent genomic instability during mitosis: inhibition of 53BP1 or BRCA1 localization to DSB sites, which is important to promote non-homologous end joining or homologous recombination, respectively, and also modulation of the non-homologous end joining core complex to inhibit DSB repair. We discuss how DSBs during mitosis are toxic and the multiple safeguard systems that suppress genomic instability. © 2014 The Authors. Cancer Science published by Wiley Publishing Asia Pty Ltd on behalf of Japanese Cancer Association.

  20. Epigenetic dysregulation underlies radiation-induced transgenerational genome instability in vivo

    International Nuclear Information System (INIS)

    Koturbash, Igor; Baker, Mike; Loree, Jonathan; Kutanzi, Kristy; Hudson, Darryl; Pogribny, Igor; Sedelnikova, Olga; Bonner, William; Kovalchuk, Olga

    2006-01-01

    Purpose: Although modern cancer radiation therapy has led to increased patient survival rates, the risk of radiation treatment-related complications is becoming a growing problem. Among various complications, radiation also poses a threat to the progeny of exposed parents. It causes transgenerational genome instability that is linked to transgenerational carcinogenesis. Although the occurrence of transgenerational genome instability, which manifests as elevated delayed and nontargeted mutation, has been well documented, the mechanisms by which it arises remain obscure. We hypothesized that epigenetic alterations may play a pivotal role in the molecular etiology of transgenerational genome instability. Methods and Materials: We studied the levels of cytosine DNA methylation in somatic tissues of unexposed offspring upon maternal, paternal, or combined parental exposure. Results: We observed a significant loss of global cytosine DNA methylation in the thymus tissue of the offspring upon combined parental exposure. The loss of DNA methylation was paralleled by a significant decrease in the levels of maintenance (DNMT1) and de novo methyltransferases DNMT3a and 3b and methyl-CpG-binding protein MeCP2. Along with profound changes in DNA methylation, we noted a significant accumulation of DNA strand breaks in thymus, which is a radiation carcinogenesis target organ. Conclusions: The observed changes were indicative of a profound epigenetic dysregulation in the offspring, which in turn could lead to genome destabilization and possibly could serve as precursor for transgenerational carcinogenesis. Future studies are clearly needed to address the cellular and carcinogenic repercussions of those changes

  1. Non-homologous end-joining genes are not inactivated in human radiation-induced sarcomas with genomic instability

    International Nuclear Information System (INIS)

    Lefevre, S.H.; Coquelle, A.; Gonin-Laurent, N.

    2005-01-01

    DNA double-strand break (DSB) repair pathways are implicated in the maintenance of genomic stability. However the alterations of these pathways, as may occur in human tumor cells with strong genomic instability, remain poorly characterized. We analyzed the loss of heterozygosity (LOH) and the presence of mutations for a series of genes implicated in DSB repair by non-homologous end-joining in five radiation-induced sarcomas devoid of both active Tp53 and Rb1. LOH was recurrently observed for 8 of the 9 studied genes (KU70, KU80, XRCC4, LIG4, Artemis, MRE11, RAD50, NBS1) but not for DNA-PKcs. No mutation was found in the remaining allele of the genes with LOH and the mRNA expression did not correlate with the allelic status. Our findings suggest that non-homologous end-joining repair pathway alteration is unlikely to be involved in the high genomic instability observed in these tumors. (author)

  2. Possible radioprotective effect of folic acid supplementation on low dose ionizing radiation-induced genomic instability in vitro.

    Science.gov (United States)

    Padula, Gisel; Ponzinibbio, María Virginia; Seoane, Analia I

    2016-08-01

    Ionizing radiation (IR) induces DNA damage through production of single and double-strand breaks and reactive oxygen species (ROS). Folic acid (FA) prevents radiation-induced DNA damage by modification of DNA synthesis and/or repair and as a radical scavenger. We hypothesized that in vitro supplementation with FA will decrease the sensitivity of cells to genetic damage induced by low dose of ionizing radiation. Annexin V, comet and micronucleus assays were performed in cultured CHO cells. After 7 days of pre-treatment with 0, 100, 200 or 300 nM FA, cultures were exposed to radiation (100 mSv). Two un-irradiated controls were executed (0 and 100 nM FA). Data were statistically analyzed with X2-test and linear regression analysis (P 0.05). We observed a significantly decreased frequency of apoptotic cells with the increasing FA concentration (P <0.05). The same trend was observed when analyzing DNA damage and chromosomal instability (P <0.05 for 300 nM). Only micronuclei frequencies showed significant differences for linear regression analysis (R2=94.04; P <0.01). Our results have demonstrated the radioprotective effect of folic acid supplementation on low dose ionizing radiation-induced genomic instability in vitro; folate status should be taken into account when studying the effect of low dose radiation in environmental or occupational exposure.

  3. Cadmium-induced genomic instability in Arabidopsis: Molecular toxicological biomarkers for early diagnosis of cadmium stress.

    Science.gov (United States)

    Wang, Hetong; He, Lei; Song, Jie; Cui, Weina; Zhang, Yanzhao; Jia, Chunyun; Francis, Dennis; Rogers, Hilary J; Sun, Lizong; Tai, Peidong; Hui, Xiujuan; Yang, Yuesuo; Liu, Wan

    2016-05-01

    Microsatellite instability (MSI) analysis, random-amplified polymorphic DNA (RAPD), and methylation-sensitive arbitrarily primed PCR (MSAP-PCR) are methods to evaluate the toxicity of environmental pollutants in stress-treated plants and human cancer cells. Here, we evaluate these techniques to screen for genetic and epigenetic alterations of Arabidopsis plantlets exposed to 0-5.0 mg L(-1) cadmium (Cd) for 15 d. There was a substantial increase in RAPD polymorphism of 24.5, and in genomic methylation polymorphism of 30.5-34.5 at CpG and of 14.5-20 at CHG sites under Cd stress of 5.0 mg L(-1) by RAPD and of 0.25-5.0 mg L(-1) by MSAP-PCR, respectively. However, only a tiny increase of 1.5 loci by RAPD occurred under Cd stress of 4.0 mg L(-1), and an additional high dose (8.0 mg L(-1)) resulted in one repeat by MSI analysis. MSAP-PCR detected the most significant epigenetic modifications in plantlets exposed to Cd stress, and the patterns of hypermethylation and polymorphisms were consistent with inverted U-shaped dose responses. The presence of genomic methylation polymorphism in Cd-treated seedlings, prior to the onset of RAPD polymorphism, MSI and obvious growth effects, suggests that these altered DNA methylation loci are the most sensitive biomarkers for early diagnosis and risk assessment of genotoxic effects of Cd pollution in ecotoxicology. Copyright © 2016 Elsevier Ltd. All rights reserved.

  4. Radiation-induced chromosomal instability

    International Nuclear Information System (INIS)

    Ritter, S.

    1999-01-01

    Recent studies on radiation-induced chromosomal instability in the progeny of exposed mammalian cells were briefly described as well as other related studies. For the analysis of chromosomal damage in clones, cells were seeded directly after exposure in cell well-dish to form single cell clones and post-irradiation chromosome aberrations were scored. Both exposure to isoeffective doses of X-ray or 270 MeV/u C-ions (13 keV/μm) increased the number of clones with abnormal karyotype and the increase was similar for X-ray and for C-ions. Meanwhile, in the progeny of cells for mass cultures, there was no indication of a delayed expression of chromosomal damage up to 40 population doublings after the exposure. A high number of aberrant cells were only observed directly after exposure to 10.7 MeV/u O-ions, i.e. in the first cycle cells and decreased with subsequent cell divisions. The reason for these differences in the radiation-induced chromosomal instability between clonal isolates and mass culture has not been clarified. Recent studies indicated that genomic instability occurs at a high frequency in the progeny of cells irradiated with both sparsely and densely ionizing radiation. Such genomic instability is thought likely to increase the risk of carcinogenesis, but more data are required for a well understanding of the health risks resulting from radiation-induced delayed instability. (M.N.)

  5. Radiation-induced genomic instability and bystander effects: related inflammatory-type responses to radiation-induced stress and injury? A review.

    Science.gov (United States)

    Lorimore, S A; Wright, E G

    2003-01-01

    To review studies of radiation responses in the haemopoietic system in the context of radiation-induced genomic instability, bystander effects and inflammatory-type processes. There is considerable evidence that cells that themselves are not exposed to ionizing radiation but are the progeny of cells irradiated many cell divisions previously may express a high frequency of gene mutations, chromosomal aberrations and cell death. These effects are collectively known as radiation-induced genomic instability. A second untargeted effect results in non-irradiated cells exhibiting responses typically associated with direct radiation exposure but occurs as a consequence of contact with irradiated cells or by receiving soluble signals from irradiated cells. These effects are collectively known as radiation-induced bystander effects. Reported effects include increases or decreases in damage-inducible and stress-related proteins; increases or decreases in reactive oxygen species, cell death or cell proliferation, and induction of mutations and chromosome aberrations. This array of responses is reminiscent of effects mediated by cytokines and other similar regulatory factors that may involve, but do not necessarily require, gap junction-mediated transfer, have multiple inducers and a variety of context-dependent consequences in different cell systems. That chromosomal instability in haemopoietic cells can be induced by an indirect bystander-type mechanism both in vitro and in vivo provides a potential link between these two untargeted effects and there are radiation responses in vivo consistent with the microenvironment contributing secondary cell damage as a consequence of an inflammatory-type response to radiation-induced injury. Intercellular signalling, production of cytokines and free radicals are features of inflammatory responses that have the potential for both bystander-mediated and persisting damage as well as for conferring a predisposition to malignancy. The

  6. The role of free radicals and stress signalling in persistent genomic instability induced by long wavelength UV light

    International Nuclear Information System (INIS)

    Phillipson, R.; McMillan, T.J.

    2003-01-01

    Induction of persistent genomic instability has commonly been investigated with ionising radiation. It has been characterised as a decrease in plating efficiency, and an increase in chromosomal aberrations and mutation frequency in the progeny of cells that survive the initial irradiation. We now present data demonstrating the phenomenon following exposure to long-wavelength solar UV-A (320-400nm) radiation at environmentally relevant doses. Using the spontaneously immortalised human skin keratinocyte line, HaCaT, we observed a significant decrease in plating efficiency (77 +/- 2% of control), and increase in micronuclei (2.5 fold) and mutation frequency (2 fold), 7 days after the initial radiation insult. Modification of UV-A-induced instability by incubation with exogenous catalase implicated reactive oxygen species (ROS), in-particular hydrogen peroxide, in the production and/or maintenance of the phenomenon. Assessment of anti-oxidant enzymes revealed a significant increase in glutathione-s-transferase activity (158 +/- 4% of control) at day 7 in the irradiated cell population, which was inhibited by incubation with exogenous catalase (97 +/- 3%), providing further evidence for an ROS-mediated pathway. Furthermore, inhibition of UV-A-induced micronuclei at day 7 by the flavonoid-containing-protein inhibitor diphenyleneiodonium (DPI) indicates that the NADPH oxidase family of enzymes may be involved in this phenomenon. Measurement of superoxide production by the cytochrome c reduction assay revealed that the irradiated cell population produce 50% more superoxide than the unirradiated controls, and that incubation with DPI led to a preferential reduction in superoxide production in the UV-A treated population at day 7. Finally, NADPH oxidase activity is increased significantly over controls in UV-A-treated cells. These data demonstrate that oxidative stress, analogous to that produced by ionising radiation, induces persistent genomic instability through a

  7. Merkel cell polyomavirus small T antigen induces genome instability by E3 ubiquitin ligase targeting.

    Science.gov (United States)

    Kwun, H J; Wendzicki, J A; Shuda, Y; Moore, P S; Chang, Y

    2017-12-07

    The formation of a bipolar mitotic spindle is an essential process for the equal segregation of duplicated DNA into two daughter cells during mitosis. As a result of deregulated cellular signaling pathways, cancer cells often suffer a loss of genome integrity that might etiologically contribute to carcinogenesis. Merkel cell polyomavirus (MCV) small T (sT) oncoprotein induces centrosome overduplication, aneuploidy, chromosome breakage and the formation of micronuclei by targeting cellular ligases through a sT domain that also inhibits MCV large T oncoprotein turnover. These results provide important insight as to how centrosome number and chromosomal stability can be affected by the E3 ligase targeting capacity of viral oncoproteins such as MCV sT, which may contribute to Merkel cell carcinogenesis.

  8. The problem of induced genomic instability in the child organism under conditions of long-term effect of small radiation doses

    International Nuclear Information System (INIS)

    Suskov, I.I.; Kuz'mina, N.S.

    2001-01-01

    The phenomenological aspects of the genomic instability induced in the descendants of the multi-divided cells having been exposed to the radiation are examined. It is demonstrated that the regularity of the genomic instability induction do not correspond to the classical conception of the radiation genetics (hit principle and target theory). The mechanisms and the biological significance of this new genetic phenomenon in the child organism under conditions of low-intensive effect of small-dose radiation and its connection with the state of health are discussed [ru

  9. Molecular Mechanisms of Radiation-Induced Genomic Instability in Human Cells

    Energy Technology Data Exchange (ETDEWEB)

    Howard L. Liber; Jeffrey L. Schwartz

    2005-10-31

    There are many different model systems that have been used to study chromosome instability. What is clear from all these studies is that conclusions concerning chromosome instability depend greatly on the model system and instability endpoint that is studied. The model system for our studies was the human B-lymphoblastoid cell line TK6. TK6 was isolated from a spontaneously immortalized lymphoblast culture. Thus there was no outside genetic manipulation used to immortalize them. TK6 is a relatively stable p53-normal immortal cell line (37). It shows low gene and chromosome mutation frequencies (19;28;31). Our general approach to studying instability in TK6 cells has been to isolate individual clones and analyze gene and chromosome mutation frequencies in each. This approach maximizes the possibility of detecting low frequency events that might be selected against in mass cultures.

  10. ATM Deficiency Generating Genomic Instability Sensitizes Pancreatic Ductal Adenocarcinoma Cells to Therapy-Induced DNA Damage.

    Science.gov (United States)

    Perkhofer, Lukas; Schmitt, Anna; Romero Carrasco, Maria Carolina; Ihle, Michaela; Hampp, Stephanie; Ruess, Dietrich Alexander; Hessmann, Elisabeth; Russell, Ronan; Lechel, André; Azoitei, Ninel; Lin, Qiong; Liebau, Stefan; Hohwieler, Meike; Bohnenberger, Hanibal; Lesina, Marina; Algül, Hana; Gieldon, Laura; Schröck, Evelin; Gaedcke, Jochen; Wagner, Martin; Wiesmüller, Lisa; Sipos, Bence; Seufferlein, Thomas; Reinhardt, Hans Christian; Frappart, Pierre-Olivier; Kleger, Alexander

    2017-10-15

    Pancreatic ductal adenocarcinomas (PDAC) harbor recurrent functional mutations of the master DNA damage response kinase ATM, which has been shown to accelerate tumorigenesis and epithelial-mesenchymal transition. To study how ATM deficiency affects genome integrity in this setting, we evaluated the molecular and functional effects of conditional Atm deletion in a mouse model of PDAC. ATM deficiency was associated with increased mitotic defects, recurrent genomic rearrangements, and deregulated DNA integrity checkpoints, reminiscent of human PDAC. We hypothesized that altered genome integrity might allow synthetic lethality-based options for targeted therapeutic intervention. Supporting this possibility, we found that the PARP inhibitor olaparib or ATR inhibitors reduced the viability of PDAC cells in vitro and in vivo associated with a genotype-selective increase in apoptosis. Overall, our results offered a preclinical mechanistic rationale for the use of PARP and ATR inhibitors to improve treatment of ATM-mutant PDAC. Cancer Res; 77(20); 5576-90. ©2017 AACR . ©2017 American Association for Cancer Research.

  11. Genomic instability--an evolving hallmark of cancer.

    Science.gov (United States)

    Negrini, Simona; Gorgoulis, Vassilis G; Halazonetis, Thanos D

    2010-03-01

    Genomic instability is a characteristic of most cancers. In hereditary cancers, genomic instability results from mutations in DNA repair genes and drives cancer development, as predicted by the mutator hypothesis. In sporadic (non-hereditary) cancers the molecular basis of genomic instability remains unclear, but recent high-throughput sequencing studies suggest that mutations in DNA repair genes are infrequent before therapy, arguing against the mutator hypothesis for these cancers. Instead, the mutation patterns of the tumour suppressor TP53 (which encodes p53), ataxia telangiectasia mutated (ATM) and cyclin-dependent kinase inhibitor 2A (CDKN2A; which encodes p16INK4A and p14ARF) support the oncogene-induced DNA replication stress model, which attributes genomic instability and TP53 and ATM mutations to oncogene-induced DNA damage.

  12. Enhanced micronucleus formation in the descendants of {gamma}-ray-irradiated tobacco cells: Evidence for radiation-induced genomic instability in plant cells

    Energy Technology Data Exchange (ETDEWEB)

    Yokota, Yuichiro, E-mail: yokota.yuichiro@jaea.go.jp [Life Science and Biotechnology Division, Quantum Beam Science Directorate, Japan Atomic Energy Agency, 1233 Watanuki-machi, Takasaki, Gunma 370-1292 (Japan); Funayama, Tomoo; Hase, Yoshihiro [Life Science and Biotechnology Division, Quantum Beam Science Directorate, Japan Atomic Energy Agency, 1233 Watanuki-machi, Takasaki, Gunma 370-1292 (Japan); Hamada, Nobuyuki [Radiation Safety Research Center, Nuclear Technology Research Laboratory, Central Research Institute of Electric Power Industry, 2-11-1 Iwado-kita, Komae, Tokyo 201-8511 (Japan); Kobayashi, Yasuhiko; Tanaka, Atsushi; Narumi, Issay [Life Science and Biotechnology Division, Quantum Beam Science Directorate, Japan Atomic Energy Agency, 1233 Watanuki-machi, Takasaki, Gunma 370-1292 (Japan)

    2010-09-10

    Ionizing radiation-induced genomic instability has been documented in various end points such as chromosomal aberrations and mutations, which arises in the descendants of irradiated mammalian or yeast cells many generations after the initial insult. This study aimed at addressing radiation-induced genomic instability in higher plant tobacco cells. We thus investigated micronucleus (MN) formation and cell proliferation in tobacco cells irradiated with {gamma}-rays and their descendants. In {gamma}-irradiated cells, cell cycle was arrested at G{sub 2}/M phase at around 24 h post-irradiation but released afterward. In contrast, MN frequency peaked at 48 h post-irradiation. Almost half of 40 Gy-irradiated cells had MN at 48 h post-irradiation, but proliferated as actively as sham-irradiated cells up to 120 h post-irradiation. Moreover, the descendants that have undergone at least 22 generations after irradiation still showed a two-fold MN frequency compared to sham-irradiated cells. This is the direct evidence for radiation-induced genomic instability in tobacco cells.

  13. P53 Gene Mutation as Biomarker of Radiation Induced Cell Injury and Genomic Instability

    International Nuclear Information System (INIS)

    Mukh-Syaifudin

    2006-01-01

    Gene expression profiling and its mutation has become one of the most widely used approaches to identify genes and their functions in the context of identify and categorize genes to be used as radiation effect markers including cell and tissue sensitivities. Ionizing radiation produces genetic damage and changes in gene expression that may lead to cancer due to specific protein that controlling cell proliferation altered the function, its expression or both. P53 protein encoded by p53 gene plays an important role in protecting cell by inducing growth arrest and or cell suicide (apoptosis) after deoxyribonucleic acid (DNA) damage induced by mutagen such as ionizing radiation. The mutant and thereby dysfunctional of this gene was found in more than 50% of various human cancers, but it is as yet unclear how p53 mutations lead to neoplastic development. Wild-type p53 has been postulated to play a role in DNA repair, suggesting that expression of mutant forms of p53 might alter cellular resistance to the DNA damage caused by radiation. Moreover, p53 is thought to function as a cell cycle checkpoint after irradiation, also suggesting that mutant p53 might change the cellular proliferative response to radiation. P53 mutations affect the cellular response to DNA damage, either by increasing DNA repair processes or, possibly, by increasing cellular tolerance to DNA damage. The association of p53 mutations with increased radioresistance suggests that alterations in the p53 gene might lead to oncogenic transformation. Current attractive model of carcinogenesis also showed that p53 gene is the major target of radiation. The majority of p53 mutations found so far is single base pair changes ( point mutations), which result in amino acid substitutions or truncated forms of the p53 protein, and are widely distributed throughout the evolutionary conserved regions of the gene. Examination of p53 mutations in human cancer also shows an association between particular carcinogens and

  14. The moyamoya disease susceptibility variant RNF213 R4810K (rs112735431) induces genomic instability by mitotic abnormality

    Energy Technology Data Exchange (ETDEWEB)

    Hitomi, Toshiaki [Department of Health and Environmental Sciences, Graduate School of Medicine, Kyoto University, Kyoto (Japan); Habu, Toshiyuki [Radiation Biology Center, Kyoto University, Kyoto (Japan); Kobayashi, Hatasu; Okuda, Hiroko; Harada, Kouji H. [Department of Health and Environmental Sciences, Graduate School of Medicine, Kyoto University, Kyoto (Japan); Osafune, Kenji [Center for iPS Cell Research and Application (CiRA), Kyoto University, Kyoto (Japan); Taura, Daisuke; Sone, Masakatsu [Department of Medicine and Clinical Science, Graduate School of Medicine, Kyoto University, Kyoto (Japan); Asaka, Isao; Ameku, Tomonaga; Watanabe, Akira; Kasahara, Tomoko; Sudo, Tomomi; Shiota, Fumihiko [Center for iPS Cell Research and Application (CiRA), Kyoto University, Kyoto (Japan); Hashikata, Hirokuni; Takagi, Yasushi [Department of Neurosurgery, Graduate School of Medicine, Kyoto University, Kyoto (Japan); Morito, Daisuke [Faculty of Life Sciences, Kyoto Sangyo University, Kyoto (Japan); Miyamoto, Susumu [Department of Neurosurgery, Graduate School of Medicine, Kyoto University, Kyoto (Japan); Nakao, Kazuwa [Department of Medicine and Clinical Science, Graduate School of Medicine, Kyoto University, Kyoto (Japan); Koizumi, Akio, E-mail: koizumi.akio.5v@kyoto-u.ac.jp [Department of Health and Environmental Sciences, Graduate School of Medicine, Kyoto University, Kyoto (Japan)

    2013-10-04

    Highlights: •Overexpression of RNF213 R4810K inhibited cell proliferation. •Overexpression of RNF213 R4810K had the time of mitosis 4-fold and mitotic failure. •R4810K formed a complex with MAD2 more readily than wild-type. •iPSECs from the MMD patients had elevated mitotic failure compared from the control. •RNF213 R4810K induced mitotic abnormality and increased risk of aneuploidy. -- Abstract: Moyamoya disease (MMD) is a cerebrovascular disease characterized by occlusive lesions in the Circle of Willis. The RNF213 R4810K polymorphism increases susceptibility to MMD. In the present study, we characterized phenotypes caused by overexpression of RNF213 wild type and R4810K variant in the cell cycle to investigate the mechanism of proliferation inhibition. Overexpression of RNF213 R4810K in HeLa cells inhibited cell proliferation and extended the time of mitosis 4-fold. Ablation of spindle checkpoint by depletion of mitotic arrest deficiency 2 (MAD2) did not shorten the time of mitosis. Mitotic morphology in HeLa cells revealed that MAD2 colocalized with RNF213 R4810K. Immunoprecipitation revealed an RNF213/MAD2 complex: R4810K formed a complex with MAD2 more readily than RNF213 wild-type. Desynchronized localization of MAD2 was observed more frequently during mitosis in fibroblasts from patients (n = 3, 61.0 ± 8.2%) compared with wild-type subjects (n = 6, 13.1 ± 7.7%; p < 0.01). Aneuploidy was observed more frequently in fibroblasts (p < 0.01) and induced pluripotent stem cells (iPSCs) (p < 0.03) from patients than from wild-type subjects. Vascular endothelial cells differentiated from iPSCs (iPSECs) of patients and an unaffected carrier had a longer time from prometaphase to metaphase than those from controls (p < 0.05). iPSECs from the patients and unaffected carrier had significantly increased mitotic failure rates compared with controls (p < 0.05). Thus, RNF213 R4810K induced mitotic abnormalities and increased risk of genomic instability.

  15. The moyamoya disease susceptibility variant RNF213 R4810K (rs112735431) induces genomic instability by mitotic abnormality

    International Nuclear Information System (INIS)

    Hitomi, Toshiaki; Habu, Toshiyuki; Kobayashi, Hatasu; Okuda, Hiroko; Harada, Kouji H.; Osafune, Kenji; Taura, Daisuke; Sone, Masakatsu; Asaka, Isao; Ameku, Tomonaga; Watanabe, Akira; Kasahara, Tomoko; Sudo, Tomomi; Shiota, Fumihiko; Hashikata, Hirokuni; Takagi, Yasushi; Morito, Daisuke; Miyamoto, Susumu; Nakao, Kazuwa; Koizumi, Akio

    2013-01-01

    Highlights: •Overexpression of RNF213 R4810K inhibited cell proliferation. •Overexpression of RNF213 R4810K had the time of mitosis 4-fold and mitotic failure. •R4810K formed a complex with MAD2 more readily than wild-type. •iPSECs from the MMD patients had elevated mitotic failure compared from the control. •RNF213 R4810K induced mitotic abnormality and increased risk of aneuploidy. -- Abstract: Moyamoya disease (MMD) is a cerebrovascular disease characterized by occlusive lesions in the Circle of Willis. The RNF213 R4810K polymorphism increases susceptibility to MMD. In the present study, we characterized phenotypes caused by overexpression of RNF213 wild type and R4810K variant in the cell cycle to investigate the mechanism of proliferation inhibition. Overexpression of RNF213 R4810K in HeLa cells inhibited cell proliferation and extended the time of mitosis 4-fold. Ablation of spindle checkpoint by depletion of mitotic arrest deficiency 2 (MAD2) did not shorten the time of mitosis. Mitotic morphology in HeLa cells revealed that MAD2 colocalized with RNF213 R4810K. Immunoprecipitation revealed an RNF213/MAD2 complex: R4810K formed a complex with MAD2 more readily than RNF213 wild-type. Desynchronized localization of MAD2 was observed more frequently during mitosis in fibroblasts from patients (n = 3, 61.0 ± 8.2%) compared with wild-type subjects (n = 6, 13.1 ± 7.7%; p < 0.01). Aneuploidy was observed more frequently in fibroblasts (p < 0.01) and induced pluripotent stem cells (iPSCs) (p < 0.03) from patients than from wild-type subjects. Vascular endothelial cells differentiated from iPSCs (iPSECs) of patients and an unaffected carrier had a longer time from prometaphase to metaphase than those from controls (p < 0.05). iPSECs from the patients and unaffected carrier had significantly increased mitotic failure rates compared with controls (p < 0.05). Thus, RNF213 R4810K induced mitotic abnormalities and increased risk of genomic instability

  16. DHX9 helicase is involved in preventing genomic instability induced by alternatively structured DNA in human cells.

    Science.gov (United States)

    Jain, Aklank; Bacolla, Albino; Del Mundo, Imee M; Zhao, Junhua; Wang, Guliang; Vasquez, Karen M

    2013-12-01

    Sequences that have the capacity to adopt alternative (i.e. non-B) DNA structures in the human genome have been implicated in stimulating genomic instability. Previously, we found that a naturally occurring intra-molecular triplex (H-DNA) caused genetic instability in mammals largely in the form of DNA double-strand breaks. Thus, it is of interest to determine the mechanism(s) involved in processing H-DNA. Recently, we demonstrated that human DHX9 helicase preferentially unwinds inter-molecular triplex DNA in vitro. Herein, we used a mutation-reporter system containing H-DNA to examine the relevance of DHX9 activity on naturally occurring H-DNA structures in human cells. We found that H-DNA significantly increased mutagenesis in small-interfering siRNA-treated, DHX9-depleted cells, affecting mostly deletions. Moreover, DHX9 associated with H-DNA in the context of supercoiled plasmids. To further investigate the role of DHX9 in the recognition/processing of H-DNA, we performed binding assays in vitro and chromatin immunoprecipitation assays in U2OS cells. DHX9 recognized H-DNA, as evidenced by its binding to the H-DNA structure and enrichment at the H-DNA region compared with a control region in human cells. These composite data implicate DHX9 in processing H-DNA structures in vivo and support its role in the overall maintenance of genomic stability at sites of alternatively structured DNA.

  17. Non-targeted and delayed effects of exposure to ionizing radiation: I. Radiation-induced genomic instability and bystander effects in vitro

    Science.gov (United States)

    Morgan, William F.

    2003-01-01

    A long-standing dogma in the radiation sciences is that energy from radiation must be deposited in the cell nucleus to elicit a biological effect. A number of non-targeted, delayed effects of ionizing radiation have been described that challenge this dogma and pose new challenges to evaluating potential hazards associated with radiation exposure. These effects include induced genomic instability and non-targeted bystander effects. The in vitro evidence for non-targeted effects in radiation biology will be reviewed, but the question as to how one extrapolates from these in vitro observations to the risk of radiation-induced adverse health effects such as cancer remains open.

  18. Genomic instability induced in distant progeny of bystander cells depends on the connexins expressed in the irradiated cells.

    Science.gov (United States)

    de Toledo, Sonia M; Buonanno, Manuela; Harris, Andrew L; Azzam, Edouard I

    2017-10-01

    To examine the time window during which intercellular signaling though gap junctions mediates non-targeted (bystander) effects induced by moderate doses of ionizing radiation; and to investigate the impact of gap junction communication on genomic instability in distant progeny of bystander cells. A layered cell culture system was developed to investigate the propagation of harmful effects from irradiated normal or tumor cells that express specific connexins to contiguous bystander normal human fibroblasts. Irradiated cells were exposed to moderate mean absorbed doses from 3.7 MeV α particle, 1000 MeV/u iron ions, 600 MeV/u silicon ions, or 137 Cs γ rays. Following 5 h of co-culture, pure populations of bystander cells, unexposed to secondary radiation, were isolated and DNA damage and oxidative stress was assessed in them and in their distant progeny (20-25 population doublings). Increased frequency of micronucleus formation and enhanced oxidative changes were observed in bystander cells co-cultured with confluent cells exposed to either sparsely ionizing ( 137 Cs γ rays) or densely ionizing (α particles, energetic iron or silicon ions) radiations. The irradiated cells propagated signals leading to biological changes in bystander cells within 1 h of irradiation, and the effect required cellular coupling by gap junctions. Notably, the distant progeny of isolated bystander cells also exhibited increased levels of spontaneous micronuclei. This effect was dependent on the type of junctional channels that coupled the irradiated donor cells with the bystander cells. Previous work showed that gap junctions composed of connexin26 (Cx26) or connexin43 (Cx43) mediate toxic bystander effects within 5 h of co-culture, whereas gap junctions composed of connexin32 (Cx32) mediate protective effects. In contrast, the long-term progeny of bystander cells expressing Cx26 or Cx43 did not display elevated DNA damage, whereas those coupled by Cx32 had enhanced DNA

  19. Genome instability: Linking ageing and brain degeneration.

    Science.gov (United States)

    Barzilai, Ari; Schumacher, Björn; Shiloh, Yosef

    2017-01-01

    Ageing is a multifactorial process affected by cumulative physiological changes resulting from stochastic processes combined with genetic factors, which together alter metabolic homeostasis. Genetic variation in maintenance of genome stability is emerging as an important determinant of ageing pace. Genome instability is also closely associated with a broad spectrum of conditions involving brain degeneration. Similarities and differences can be found between ageing-associated decline of brain functionality and the detrimental effect of genome instability on brain functionality and development. This review discusses these similarities and differences and highlights cell classes whose role in these processes might have been underestimated-glia and microglia. Copyright © 2016. Published by Elsevier B.V.

  20. Genome organization, instabilities, stem cells, and cancer

    Directory of Open Access Journals (Sweden)

    Senthil Kumar Pazhanisamy

    2009-01-01

    Full Text Available It is now widely recognized that advances in exploring genome organization provide remarkable insights on the induction and progression of chromosome abnormalities. Much of what we know about how mutations evolve and consequently transform into genome instabilities has been characterized in the spatial organization context of chromatin. Nevertheless, many underlying concepts of impact of the chromatin organization on perpetuation of multiple mutations and on propagation of chromosomal aberrations remain to be investigated in detail. Genesis of genome instabilities from accumulation of multiple mutations that drive tumorigenesis is increasingly becoming a focal theme in cancer studies. This review focuses on structural alterations evolve to raise a variety of genome instabilities that are manifested at the nucleotide, gene or sub-chromosomal, and whole chromosome level of genome. Here we explore an underlying connection between genome instability and cancer in the light of genome architecture. This review is limited to studies directed towards spatial organizational aspects of origin and propagation of aberrations into genetically unstable tumors.

  1. Genome instabilities arising from ribonucleotides in DNA.

    Science.gov (United States)

    Klein, Hannah L

    2017-08-01

    Genomic DNA is transiently contaminated with ribonucleotide residues during the process of DNA replication through misincorporation by the replicative DNA polymerases α, δ and ε, and by the normal replication process on the lagging strand, which uses RNA primers. These ribonucleotides are efficiently removed during replication by RNase H enzymes and the lagging strand synthesis machinery. However, when ribonucleotides remain in DNA they can distort the DNA helix, affect machineries for DNA replication, transcription and repair, and can stimulate genomic instabilities which are manifest as increased mutation, recombination and chromosome alterations. The genomic instabilities associated with embedded ribonucleotides are considered here, along with a discussion of the origin of the lesions that stimulate particular classes of instabilities. Copyright © 2017 Elsevier B.V. All rights reserved.

  2. Non-targeted and delayed effects of exposure to ionizing radiation: II. Radiation-induced genomic instability and bystander effects in vivo, clastogenic factors and transgenerational effects

    Science.gov (United States)

    Morgan, William F.

    2003-01-01

    The goal of this review is to summarize the evidence for non-targeted and delayed effects of exposure to ionizing radiation in vivo. Currently, human health risks associated with radiation exposures are based primarily on the assumption that the detrimental effects of radiation occur in irradiated cells. Over the years a number of non-targeted effects of radiation exposure in vivo have been described that challenge this concept. These include radiation-induced genomic instability, bystander effects, clastogenic factors produced in plasma from irradiated individuals that can cause chromosomal damage when cultured with nonirradiated cells, and transgenerational effects of parental irradiation that can manifest in the progeny. These effects pose new challenges to evaluating the risk(s) associated with radiation exposure and understanding radiation-induced carcinogenesis.

  3. Radiation-induced transgenerational instability.

    Science.gov (United States)

    Dubrova, Yuri E

    2003-10-13

    To date, the analysis of mutation induction has provided an irrefutable evidence for an elevated germline mutation rate in the parents directly exposed to ionizing radiation and a number of chemical mutagens. However, the results of numerous publications suggest that radiation may also have an indirect effect on genome stability, which is transmitted through the germ line of irradiated parents to their offspring. This review describes the phenomenon of transgenerational instability and focuses on the data showing increased cancer incidence and elevated mutation rates in the germ line and somatic tissues of the offspring of irradiated parents. The possible mechanisms of transgenerational instability are also discussed.

  4. Research for genetic instability of human genome

    Energy Technology Data Exchange (ETDEWEB)

    Hori, T.; Takahashi, E.; Tsuji, H.; Yamauchi, M. (National Inst. of Radiological Sciences, Chiba (Japan)); Murata, M.

    1992-01-01

    In the present review paper, the potential relevance of chromosomal fragile sites to carcinogenesis and mutagenesis is discussed based on our own and other's studies. Recent evidence indicate that fragile sites may act as predisposition factors involved in chromosomal instability of the human genome and that the sites may be preferential targets for various DNA damaging agents including ionizing radiation. It is also demonstrated that some critical genomic rearrangements at the fragile sites may contribute towards oncogenesis and that individuals carrying heritable form of fragile site may be at the risk. Although clinical significance of autosomal fragile sites has been a matter of discussion, a fragile site of the X chromosome is known to be associated with an X-linked genetic diseases, called fragile X syndrome. Molecular events leading to the fragile X syndrome have recently been elucidated. The fragile X genotype can be characterized by an increased amount of p(CCG)n repeat DNA sequence in the FMR-1 gene and the repeated sequences are shown to be unstable in both meiosis and mitosis. These repeats might exhibit higher mutation rate than is generally seen in the human genome. Further studies on the fragile sites in molecular biology and radiation biology will yield relevant data to the molecular mechanisms of genetic instability of the human genome as well as to better assessment of genetic effect of ionizing radiation. (author).

  5. Research for genetic instability of human genome

    International Nuclear Information System (INIS)

    Hori, T.; Takahashi, E.; Tsuji, H.; Yamauchi, M.; Murata, M.

    1992-01-01

    In the present review paper, the potential relevance of chromosomal fragile sites to carcinogenesis and mutagenesis is discussed based on our own and other's studies. Recent evidence indicate that fragile sites may act as predisposition factors involved in chromosomal instability of the human genome and that the sites may be preferential targets for various DNA damaging agents including ionizing radiation. It is also demonstrated that some critical genomic rearrangements at the fragile sites may contribute towards oncogenesis and that individuals carrying heritable form of fragile site may be at the risk. Although clinical significance of autosomal fragile sites has been a matter of discussion, a fragile site of the X chromosome is known to be associated with an X-linked genetic diseases, called fragile X syndrome. Molecular events leading to the fragile X syndrome have recently been elucidated. The fragile X genotype can be characterized by an increased amount of p(CCG)n repeat DNA sequence in the FMR-1 gene and the repeated sequences are shown to be unstable in both meiosis and mitosis. These repeats might exhibit higher mutation rate than is generally seen in the human genome. Further studies on the fragile sites in molecular biology and radiation biology will yield relevant data to the molecular mechanisms of genetic instability of the human genome as well as to better assessment of genetic effect of ionizing radiation. (author)

  6. Radiation-induced genomic instability and bystander effects: inter-related inflammatory-type non-targeted effects of exposure to ionizing radiation

    Energy Technology Data Exchange (ETDEWEB)

    Wright, E.G. (Molecular and Cellular Pathology Laboratories, Division of Pathology and Neuroscience, Ninewells Hospital and Medical School, Dundee, Scotland (United Kingdom))

    2008-12-15

    The dogma that genetic alterations are restricted to directly irradiated cells has been challenged by observations in which effects of ionizing radiation, characteristically associated with the consequences of energy deposition in the cell nucleus, arise in non-irradiated cells. These, so called, untargeted effects are demonstrated in cells that are the descendants of irradiated cells (radiation-induced genomic instability) or in cells that have communicated with neighbouring irradiated cells (radiation-induced bystander effects). There are also reports of long-range signals in vivo, known as clastogenic factors, with the capacity to induce damage in unirradiated cells. Clastogenic factors may be related to the inflammatory responses that have been implicated in some of the pathological consequences of radiation exposures. The phenotypic expression of untargeted effects reflects a balance between the type of signals produced and the responses of cell populations to such signals, both of which may be significantly influenced by cell type and genotype. There is accumulating evidence that untargeted effects in vitro involve inter-cellular signalling, production of cytokines and free radical generation. These are also features of inflammatory responses in vivo that are known to have the potential for both bystander-mediated and persisting damage as well as for conferring a predisposition to malignancy. At present it is far from clear how untargeted effects contribute to overall cellular radiation responses and in vivo consequences but it is possible that the various untargeted effects may reflect inter-related aspects of a non-specific inflammatory-type response to radiation-induced stress and injury and be involved in a variety of the pathological consequences of radiation exposures. (orig.)

  7. Radiation-induced genomic instability and bystander effects: inter-related inflammatory-type non-targeted effects of exposure to ionizing radiation

    International Nuclear Information System (INIS)

    Wright, E.G.

    2008-01-01

    The dogma that genetic alterations are restricted to directly irradiated cells has been challenged by observations in which effects of ionizing radiation, characteristically associated with the consequences of energy deposition in the cell nucleus, arise in non-irradiated cells. These, so called, untargeted effects are demonstrated in cells that are the descendants of irradiated cells (radiation-induced genomic instability) or in cells that have communicated with neighbouring irradiated cells (radiation-induced bystander effects). There are also reports of long-range signals in vivo, known as clastogenic factors, with the capacity to induce damage in unirradiated cells. Clastogenic factors may be related to the inflammatory responses that have been implicated in some of the pathological consequences of radiation exposures. The phenotypic expression of untargeted effects reflects a balance between the type of signals produced and the responses of cell populations to such signals, both of which may be significantly influenced by cell type and genotype. There is accumulating evidence that untargeted effects in vitro involve inter-cellular signalling, production of cytokines and free radical generation. These are also features of inflammatory responses in vivo that are known to have the potential for both bystander-mediated and persisting damage as well as for conferring a predisposition to malignancy. At present it is far from clear how untargeted effects contribute to overall cellular radiation responses and in vivo consequences but it is possible that the various untargeted effects may reflect inter-related aspects of a non-specific inflammatory-type response to radiation-induced stress and injury and be involved in a variety of the pathological consequences of radiation exposures. (orig.)

  8. Evaluation of Genomic Instability in the Abnormal Prostate

    National Research Council Canada - National Science Library

    Haaland-Pullus, Christina; Griffith, Jeffrey K

    2006-01-01

    ...: prognosis and diagnosis. Several tools are being used to investigate this effect, specifically the assessment of telomere length, allelic imbalance, and methylation status, all markers of genomic instability...

  9. Evaluation of Genomic Instability in the Abnormal Prostate

    National Research Council Canada - National Science Library

    Haaland-Pullus, Christina; Griffth, Jeffrey K

    2008-01-01

    ...: prognosis and diagnosis. Several tools are being used to investigate this effect, specifically the assessment of telomere length, allelic imbalance, and methylation status, all markers of genomic instability...

  10. Chromosomal instability induced by ionizing radiation

    International Nuclear Information System (INIS)

    Morgan, W.F.; Marder, B.A.; Day, J.P.

    1995-01-01

    There is accumulating evidence indicating genomic instability can manifest multiple generations after cellular exposure to DNA damaging agents. For instance, some cells surviving exposure to ionizing radiations show delayed reproductive cell death, delayed mutation and / or delayed chromosomal instability. Such instability, especially chromosome destabilization has been implicated in mutation, gene amplification, cellular transformation, and cell killing. To investigate chromosomal instability following DNA damage, we have used fluorescence in situ hybridization to detect chromosomal rearrangements in a human/hamster somatic hybrid cell line following exposure to ionizing radiation. Delayed chromosomal instability was detected when multiple populations of uniquely arranged metaphases were observed in clonal isolates raised from single cells. The relationship between delayed chromosomal destabilization and other endpoints of genomic instability, namely; delayed mutation and gene amplification will be discussed, as will the potential cytogenetic and molecular mechanisms contributing to delayed chromosomal instability

  11. Air pollution and genomic instability: The role of particulate matter in lung carcinogenesis

    International Nuclear Information System (INIS)

    Santibáñez-Andrade, Miguel; Quezada-Maldonado, Ericka Marel; Osornio-Vargas, Álvaro; Sánchez-Pérez, Yesennia; García-Cuellar, Claudia M.

    2017-01-01

    In this review, we summarize and discuss the evidence regarding the interaction between air pollution, especially particulate matter (PM), and genomic instability. PM has been widely studied in the context of several diseases, and its role in lung carcinogenesis gained relevance due to an increase in cancer cases for which smoking does not seem to represent the main risk factor. According to epidemiological and toxicological evidence, PM acts as a carcinogenic factor in humans, inducing high rates of genomic alterations. Here, we discuss not only how PM is capable of inducing genomic instability during the carcinogenic process but also how our genetic background influences the response to the sources of damage. - Highlights: • Air pollution represents a worldwide problem with impact on human health. • Particulate matter (PM) has a recognized carcinogenic potential in humans. • Lung cancer susceptibility depends on gene-environment interactions. • Epidemiological and experimental evidence links PM exposure to genomic instability. • PM and genomic instability are co-dependent factors during cancer continuum. - We summarize the association between particulate matter (a component of air pollution) and genomic instability as well as discuss how new strategies to study the impact of air pollution on genomic instability and lung-cancer development could improve our understanding of the lung-cancer genome.

  12. Delayed chromosomal instability induced by DNA damage

    International Nuclear Information System (INIS)

    Morgan, W.F.; Marder, B.A.; Day, J.P.

    1994-01-01

    Cellular exposure to DNA damaging agents rapidly results in a dose dependent increase in chromosomal breakage and gross structural chromosomal rearrangements. Over recent years, evidence has been accumulating indicating genomic instability can manifest multiple generations after cellular exposure to physical and chemical DNA damaging agents. Genomic instability manifests in the progeny of surviving cells, and has been implicated in mutation, gene application, cellular transformation, and cell killing. To investigate chromosome instability following DNA damage, we have used fluorescence in situ hybridization to detect chromosomal rearrangements in a human/hamster somatic hybrid cell line following exposure to ionizing radiation. Delayed chromosomal instability was detected when multiple populations of uniquely arranged metaphases were observed in clonal isolates raised from single cells surviving X-irradiation many generations after exposure. At higher radiation doses, chromosomal instability was observed in a relatively high frequency of surviving clones and, in general, those clones showed delayed chromosome instability also showed reduced survival as measured by colony forming ability

  13. Role of oxidative DNA damage in genome instability and cancer

    International Nuclear Information System (INIS)

    Bignami, M.; Kunkel, T.

    2009-01-01

    Inactivation of mismatch repair (MMR) is associated with a dramatic genomic instability that is observed experimentally as a mutator phenotype and micro satellite instability (MSI). It has been implicit that the massive genetic instability in MMR defective cells simply reflects the accumulation of spontaneous DNA polymerase errors during DNA replication. We recently identified oxidation damage, a common threat to DNA integrity to which purines are very susceptible, as an important cofactor in this genetic instability

  14. Causes of genome instability: the effect of low dose chemical exposures in modern society

    Science.gov (United States)

    Langie, Sabine A.S.; Koppen, Gudrun; Desaulniers, Daniel; Al-Mulla, Fahd; Al-Temaimi, Rabeah; Amedei, Amedeo; Azqueta, Amaya; Bisson, William H.; Brown, Dustin; Brunborg, Gunnar; Charles, Amelia K.; Chen, Tao; Colacci, Annamaria; Darroudi, Firouz; Forte, Stefano; Gonzalez, Laetitia; Hamid, Roslida A.; Knudsen, Lisbeth E.; Leyns, Luc; Lopez de Cerain Salsamendi, Adela; Memeo, Lorenzo; Mondello, Chiara; Mothersill, Carmel; Olsen, Ann-Karin; Pavanello, Sofia; Raju, Jayadev; Rojas, Emilio; Roy, Rabindra; Ryan, Elizabeth; Ostrosky-Wegman, Patricia; Salem, Hosni K.; Scovassi, Ivana; Singh, Neetu; Vaccari, Monica; Van Schooten, Frederik J.; Valverde, Mahara; Woodrick, Jordan; Zhang, Luoping; van Larebeke, Nik; Kirsch-Volders, Micheline; Collins, Andrew R.

    2015-01-01

    Genome instability is a prerequisite for the development of cancer. It occurs when genome maintenance systems fail to safeguard the genome’s integrity, whether as a consequence of inherited defects or induced via exposure to environmental agents (chemicals, biological agents and radiation). Thus, genome instability can be defined as an enhanced tendency for the genome to acquire mutations; ranging from changes to the nucleotide sequence to chromosomal gain, rearrangements or loss. This review raises the hypothesis that in addition to known human carcinogens, exposure to low dose of other chemicals present in our modern society could contribute to carcinogenesis by indirectly affecting genome stability. The selected chemicals with their mechanisms of action proposed to indirectly contribute to genome instability are: heavy metals (DNA repair, epigenetic modification, DNA damage signaling, telomere length), acrylamide (DNA repair, chromosome segregation), bisphenol A (epigenetic modification, DNA damage signaling, mitochondrial function, chromosome segregation), benomyl (chromosome segregation), quinones (epigenetic modification) and nano-sized particles (epigenetic pathways, mitochondrial function, chromosome segregation, telomere length). The purpose of this review is to describe the crucial aspects of genome instability, to outline the ways in which environmental chemicals can affect this cancer hallmark and to identify candidate chemicals for further study. The overall aim is to make scientists aware of the increasing need to unravel the underlying mechanisms via which chemicals at low doses can induce genome instability and thus promote carcinogenesis. PMID:26106144

  15. Loss of yeast peroxiredoxin Tsa1p induces genome instability through activation of the DNA damage checkpoint and elevation of dNTP levels.

    Directory of Open Access Journals (Sweden)

    Hei-Man Vincent Tang

    2009-10-01

    Full Text Available Peroxiredoxins are a family of antioxidant enzymes critically involved in cellular defense and signaling. Particularly, yeast peroxiredoxin Tsa1p is thought to play a role in the maintenance of genome integrity, but the underlying mechanism is not understood. In this study, we took a genetic approach to investigate the cause of genome instability in tsa1Delta cells. Strong genetic interactions of TSA1 with DNA damage checkpoint components DUN1, SML1, and CRT1 were found when mutant cells were analyzed for either sensitivity to DNA damage or rate of spontaneous base substitutions. An elevation in intracellular dNTP production was observed in tsa1Delta cells. This was associated with constitutive activation of the DNA damage checkpoint as indicated by phosphorylation of Rad9/Rad53p, reduced steady-state amount of Sml1p, and induction of RNR and HUG1 genes. In addition, defects in the DNA damage checkpoint did not modulate intracellular level of reactive oxygen species, but suppressed the mutator phenotype of tsa1Delta cells. On the contrary, overexpression of RNR1 exacerbated this phenotype by increasing dNTP levels. Taken together, our findings uncover a new role of TSA1 in preventing the overproduction of dNTPs, which is a root cause of genome instability.

  16. Breast tumor copy number aberration phenotypes and genomic instability

    International Nuclear Information System (INIS)

    Fridlyand, Jane; Jain, Ajay N; McLennan, Jane; Ziegler, John; Chin, Koei; Devries, Sandy; Feiler, Heidi; Gray, Joe W; Waldman, Frederic; Pinkel, Daniel; Albertson, Donna G; Snijders, Antoine M; Ylstra, Bauke; Li, Hua; Olshen, Adam; Segraves, Richard; Dairkee, Shanaz; Tokuyasu, Taku; Ljung, Britt Marie

    2006-01-01

    Genomic DNA copy number aberrations are frequent in solid tumors, although the underlying causes of chromosomal instability in tumors remain obscure. Genes likely to have genomic instability phenotypes when mutated (e.g. those involved in mitosis, replication, repair, and telomeres) are rarely mutated in chromosomally unstable sporadic tumors, even though such mutations are associated with some heritable cancer prone syndromes. We applied array comparative genomic hybridization (CGH) to the analysis of breast tumors. The variation in the levels of genomic instability amongst tumors prompted us to investigate whether alterations in processes/genes involved in maintenance and/or manipulation of the genome were associated with particular types of genomic instability. We discriminated three breast tumor subtypes based on genomic DNA copy number alterations. The subtypes varied with respect to level of genomic instability. We find that shorter telomeres and altered telomere related gene expression are associated with amplification, implicating telomere attrition as a promoter of this type of aberration in breast cancer. On the other hand, the numbers of chromosomal alterations, particularly low level changes, are associated with altered expression of genes in other functional classes (mitosis, cell cycle, DNA replication and repair). Further, although loss of function instability phenotypes have been demonstrated for many of the genes in model systems, we observed enhanced expression of most genes in tumors, indicating that over expression, rather than deficiency underlies instability. Many of the genes associated with higher frequency of copy number aberrations are direct targets of E2F, supporting the hypothesis that deregulation of the Rb pathway is a major contributor to chromosomal instability in breast tumors. These observations are consistent with failure to find mutations in sporadic tumors in genes that have roles in maintenance or manipulation of the genome

  17. Detection of genomic instability in hypospadias patients by random ...

    African Journals Online (AJOL)

    DIRECTOR

    2011-05-16

    May 16, 2011 ... organism including bacteria (Sahoo et al., 2010), fungi. (Motlagh and Anvari ... technique that detects genomic alteration correlated with human tumor is .... chromosomal instability among hypospadias patients. REFERENCES.

  18. Genomic instability: potential contributions to tumour and normal tissue response, and second tumours, after radiotherapy

    International Nuclear Information System (INIS)

    Hendry, Jolyon H.

    2001-01-01

    Purpose: Induced genomic instability generally refers to a type of damage which is transmissible down cell generations, and which results in a persistently enhanced frequency of de novo mutations, chromosomal abnormalities or lethality in a significant fraction of the descendant cell population. The potential contribution of induced genomic instability to tumour and normal tissue response, and second tumours, after radiotherapy, is explored. Results: The phenomenon of spontaneous genomic instability is well known in some rare genetic diseases (e.g. Gorlin's syndrome), and there is evidence in such cases that it can lead to a greater propensity for carcinogenesis (with shortened latency) which is enhanced after irradiation. It is unclear what role induced genomic instability plays in the response of normal individuals, but persistent chromosomal instability has been detected in vivo in lymphocytes and keratinocytes from irradiated normal individuals. Such induced genomic instability might play some role in tumour response in a subset of tumours with specific defects in damage response genes, but again its contribution to radiocurability in the majority of cancer patients is unclear. In normal tissues, genomic instability induced in wild-type cells leading to delayed cell death might contribute to more severe or prolonged early reactions as a consequence of increased cell loss, a longer time required for recovery, and greater residual injury. In tumours, induced genomic instability reflected in delayed reductions in clonogenic capacity might contribute to the radiosensitivity of primary tumours, and also to a lower incidence, longer latency and slower growth rate of recurrences and metastases. Conclusions: The evidence which is reviewed shows that there is little information at present to support these propositions, but what exists is consistent with their expectations. Also, it is not yet clear to what extent mutations associated with genomic instability

  19. p53-Dependent suppression of genome instability in germ cells

    Energy Technology Data Exchange (ETDEWEB)

    Otozai, Shinji [Department of Otorhinolaryngology and Head and Neck Surgery, Osaka University School of Medicine, Osaka 565-0871 (Japan); Ishikawa-Fujiwara, Tomoko [Department of Radiation Biology and Medical Genetics, Graduate School of Medicine, Osaka University, B4, 2-2 Yamadaoka, Suita, Osaka 565-0871 (Japan); Oda, Shoji [Department of Integrated Biosciences, Graduate School of Frontier Sciences, The University of Tokyo, Chiba 277-8562 (Japan); Kamei, Yasuhiro [Department of Radiation Biology and Medical Genetics, Graduate School of Medicine, Osaka University, B4, 2-2 Yamadaoka, Suita, Osaka 565-0871 (Japan); Ryo, Haruko [Nomura Project, National Institute of Biomedical Innovation, Osaka 565-0085 (Japan); Sato, Ayuko [Department of Pathology, Hyogo College of Medicine, Hyogo 663-8501 (Japan); Nomura, Taisei [Nomura Project, National Institute of Biomedical Innovation, Osaka 565-0085 (Japan); Mitani, Hiroshi [Department of Integrated Biosciences, Graduate School of Frontier Sciences, The University of Tokyo, Chiba 277-8562 (Japan); Tsujimura, Tohru [Department of Pathology, Hyogo College of Medicine, Hyogo 663-8501 (Japan); Inohara, Hidenori [Department of Otorhinolaryngology and Head and Neck Surgery, Osaka University School of Medicine, Osaka 565-0871 (Japan); Todo, Takeshi, E-mail: todo@radbio.med.osaka-u.ac.jp [Department of Radiation Biology and Medical Genetics, Graduate School of Medicine, Osaka University, B4, 2-2 Yamadaoka, Suita, Osaka 565-0871 (Japan)

    2014-02-15

    Highlights: • Radiation-induced microsatellite instability (MSI) was investigated in medaka fish. • msh2{sup −/−} fish had a high frequency of spontaneous MSI. • p53{sup −/−} fish had a high frequency of radiation-induced MSI. • p53 and msh2 suppress MSI by different pathways: mismatch removal and apoptosis. - Abstract: Radiation increases mutation frequencies at tandem repeat loci. Germline mutations in γ-ray-irradiated medaka fish (Oryzias latipes) were studied, focusing on the microsatellite loci. Mismatch-repair genes suppress microsatellite mutation by directly removing altered sequences at the nucleotide level, whereas the p53 gene suppresses genetic alterations by eliminating damaged cells. The contribution of these two defense mechanisms to radiation-induced microsatellite instability was addressed. The spontaneous mutation frequency was significantly higher in msh2{sup −/−} males than in wild-type fish, whereas there was no difference in the frequency of radiation-induced mutations between msh2{sup −/−} and wild-type fish. By contrast, irradiated p53{sup −/−} fish exhibited markedly increased mutation frequencies, whereas their spontaneous mutation frequency was the same as that of wild-type fish. In the spermatogonia of the testis, radiation induced a high level of apoptosis both in wild-type and msh2{sup −/−} fish, but negligible levels in p53{sup −/−} fish. The results demonstrate that the msh2 and p53 genes protect genome integrity against spontaneous and radiation-induced mutation by two different pathways: direct removal of mismatches and elimination of damaged cells.

  20. p53-Dependent suppression of genome instability in germ cells

    International Nuclear Information System (INIS)

    Otozai, Shinji; Ishikawa-Fujiwara, Tomoko; Oda, Shoji; Kamei, Yasuhiro; Ryo, Haruko; Sato, Ayuko; Nomura, Taisei; Mitani, Hiroshi; Tsujimura, Tohru; Inohara, Hidenori; Todo, Takeshi

    2014-01-01

    Highlights: • Radiation-induced microsatellite instability (MSI) was investigated in medaka fish. • msh2 −/− fish had a high frequency of spontaneous MSI. • p53 −/− fish had a high frequency of radiation-induced MSI. • p53 and msh2 suppress MSI by different pathways: mismatch removal and apoptosis. - Abstract: Radiation increases mutation frequencies at tandem repeat loci. Germline mutations in γ-ray-irradiated medaka fish (Oryzias latipes) were studied, focusing on the microsatellite loci. Mismatch-repair genes suppress microsatellite mutation by directly removing altered sequences at the nucleotide level, whereas the p53 gene suppresses genetic alterations by eliminating damaged cells. The contribution of these two defense mechanisms to radiation-induced microsatellite instability was addressed. The spontaneous mutation frequency was significantly higher in msh2 −/− males than in wild-type fish, whereas there was no difference in the frequency of radiation-induced mutations between msh2 −/− and wild-type fish. By contrast, irradiated p53 −/− fish exhibited markedly increased mutation frequencies, whereas their spontaneous mutation frequency was the same as that of wild-type fish. In the spermatogonia of the testis, radiation induced a high level of apoptosis both in wild-type and msh2 −/− fish, but negligible levels in p53 −/− fish. The results demonstrate that the msh2 and p53 genes protect genome integrity against spontaneous and radiation-induced mutation by two different pathways: direct removal of mismatches and elimination of damaged cells

  1. p53 protects against genome instability following centriole duplication failure

    Science.gov (United States)

    Lambrus, Bramwell G.; Uetake, Yumi; Clutario, Kevin M.; Daggubati, Vikas; Snyder, Michael; Sluder, Greenfield

    2015-01-01

    Centriole function has been difficult to study because of a lack of specific tools that allow persistent and reversible centriole depletion. Here we combined gene targeting with an auxin-inducible degradation system to achieve rapid, titratable, and reversible control of Polo-like kinase 4 (Plk4), a master regulator of centriole biogenesis. Depletion of Plk4 led to a failure of centriole duplication that produced an irreversible cell cycle arrest within a few divisions. This arrest was not a result of a prolonged mitosis, chromosome segregation errors, or cytokinesis failure. Depleting p53 allowed cells that fail centriole duplication to proliferate indefinitely. Washout of auxin and restoration of endogenous Plk4 levels in cells that lack centrioles led to the penetrant formation of de novo centrioles that gained the ability to organize microtubules and duplicate. In summary, we uncover a p53-dependent surveillance mechanism that protects against genome instability by preventing cell growth after centriole duplication failure. PMID:26150389

  2. Induction of genomic instability and activation of autophagy in artificial human aneuploid cells

    Energy Technology Data Exchange (ETDEWEB)

    Ariyoshi, Kentaro [Hirosaki University, Institute of Radiation Emergency Medicine, 66-1 Hon-cho, Hirosaki 036-8564 (Japan); Miura, Tomisato; Kasai, Kosuke; Fujishima, Yohei [Department of Biomedical Sciences, Hirosaki University Graduate School of Health Sciences, 66-1 Hon-cho, Hirosaki 036-8564 (Japan); Oshimura, Mitsuo [Chromosome Engineering Research Center (CERC), Tottori University, Nishicho 86, Yonago, Tottori 683-8503 (Japan); Yoshida, Mitsuaki A., E-mail: ariyoshi@hirosaki-u.ac.jp [Hirosaki University, Institute of Radiation Emergency Medicine, 66-1 Hon-cho, Hirosaki 036-8564 (Japan)

    2016-08-15

    Highlights: • Clones with artificial aneuploidy of chromosome 8 or chromosome 22 both show inhibited proliferation and genomic instability. • Increased autophagy was observed in the artificially aneuploid clones. • Inhibition of autophagy resulted in increased genomic instability and DNA damage. • Intracellular levels of reactive oxygen species were up-regulated in the artificially aneuploid clones. - Abstract: Chromosome missegregation can lead to a change in chromosome number known as aneuploidy. Although aneuploidy is a known hallmark of cancer cells, the various mechanisms by which altered gene and/or DNA copy number facilitate tumorigenesis remain unclear. To understand the effect of aneuploidy occurring in non-tumorigenic human breast epithelial cells, we generated clones harboring artificial aneuploidy using microcell-mediated chromosome transfer. Our results demonstrate that clones with artificial aneuploidy of chromosome 8 or chromosome 22 both show inhibited proliferation and genomic instability. Also, the increased autophagy was observed in the artificially aneuploidy clones, and inhibition of autophagy resulted in increased genomic instability and DNA damage. In addition, the intracellular levels of reactive oxygen species were up-regulated in the artificially aneuploid clones, and inhibition of autophagy further increased the production of reactive oxygen species. Together, these results suggest that even a single extraneous chromosome can induce genomic instability, and that autophagy triggered by aneuploidy-induced stress is a mechanism to protect cells bearing abnormal chromosome number.

  3. Induction of genomic instability and activation of autophagy in artificial human aneuploid cells

    International Nuclear Information System (INIS)

    Ariyoshi, Kentaro; Miura, Tomisato; Kasai, Kosuke; Fujishima, Yohei; Oshimura, Mitsuo; Yoshida, Mitsuaki A.

    2016-01-01

    Highlights: • Clones with artificial aneuploidy of chromosome 8 or chromosome 22 both show inhibited proliferation and genomic instability. • Increased autophagy was observed in the artificially aneuploid clones. • Inhibition of autophagy resulted in increased genomic instability and DNA damage. • Intracellular levels of reactive oxygen species were up-regulated in the artificially aneuploid clones. - Abstract: Chromosome missegregation can lead to a change in chromosome number known as aneuploidy. Although aneuploidy is a known hallmark of cancer cells, the various mechanisms by which altered gene and/or DNA copy number facilitate tumorigenesis remain unclear. To understand the effect of aneuploidy occurring in non-tumorigenic human breast epithelial cells, we generated clones harboring artificial aneuploidy using microcell-mediated chromosome transfer. Our results demonstrate that clones with artificial aneuploidy of chromosome 8 or chromosome 22 both show inhibited proliferation and genomic instability. Also, the increased autophagy was observed in the artificially aneuploidy clones, and inhibition of autophagy resulted in increased genomic instability and DNA damage. In addition, the intracellular levels of reactive oxygen species were up-regulated in the artificially aneuploid clones, and inhibition of autophagy further increased the production of reactive oxygen species. Together, these results suggest that even a single extraneous chromosome can induce genomic instability, and that autophagy triggered by aneuploidy-induced stress is a mechanism to protect cells bearing abnormal chromosome number.

  4. Genome instability in Lactobacillus rhamnosus GG

    NARCIS (Netherlands)

    Sybesma, W.; Molenaar, D.; IJcken, W. van; Venema, K.; Korta, R.

    2013-01-01

    We describe here a comparative genome analysis of three dairy product isolates of Lactobacillus rhamnosus GG (LGG) and the ATCC 53103 reference strain to the published genome sequence of L. rhamnosus GG. The analysis showed that in two of three isolates, major DNA segments were missing from the

  5. Tolerance of Whole-Genome Doubling Propagates Chromosomal Instability and Accelerates Cancer Genome Evolution

    DEFF Research Database (Denmark)

    Dewhurst, Sally M.; McGranahan, Nicholas; Burrell, Rebecca A.

    2014-01-01

    The contribution of whole-genome doubling to chromosomal instability (CIN) and tumor evolution is unclear. We use long-term culture of isogenic tetraploid cells from a stable diploid colon cancer progenitor to investigate how a genome-doubling event affects genome stability over time. Rare cells...

  6. Mechanisms of Low Dose Radio-Suppression of Genomic Instability

    Energy Technology Data Exchange (ETDEWEB)

    Engelward, Bevin P. [Massachusetts Inst. of Technology (MIT), Cambridge, MA (United States)

    2009-09-16

    The major goal of this project is to contribute toward the elucidation of the impact of long term low dose radiation on genomic stability. We have created and characterized novel technologies for delivering long term low dose radiation to animals, and we have studied genomic stability by applying cutting edge molecular analysis technologies. Remarkably, we have found that a dose rate that is 300X higher than background radiation does not lead to any detectable genomic damage, nor is there any significant change in gene expression for genes pertinent to the DNA damage response. These results point to the critical importance of dose rate, rather than just total dose, when evaluating public health risks and when creating regulatory guidelines. In addition to these studies, we have also further developed a mouse model for quantifying cells that have undergone a large scale DNA sequence rearrangement via homologous recombination, and we have applied these mice in studies of both low dose radiation and space radiation. In addition to more traditional approaches for assessing genomic stability, we have also explored radiation and possible beneficial effects (adaptive response), long term effects (persistent effects) and effects on communication among cells (bystander effects), both in vitro and in vivo. In terms of the adaptive response, we have not observed any significant induction of an adaptive response following long term low dose radiation in vivo, delivered at 300X background. In terms of persistent and bystander effects, we have revealed evidence of a bystander effect in vivo and with researchers at and demonstrated for the first time the molecular mechanism by which cells “remember” radiation exposure. Understanding the underlying molecular mechanisms by which radiation can induce genomic instability is fundamental to our ability to assess the biological impact of low dose radiation. Finally, in a parallel set of studies we have explored the effects of heavy

  7. Damage-induced tensile instability

    International Nuclear Information System (INIS)

    Hult, J.

    1975-01-01

    The paper presents a unified description of ductile and brittle rupture phenomena in structural components under tensile loading with particular emphasis on creep rupture. Two structural elements are analyzed in detail: 1) the uniform tensile bar subject to a Heaviside history of tensile force and superimposed such loadings, i.e. staircase histories, and 2) the thinwalled spherical pressure vessel subject to a Heaviside history of internal pressure. For both these structures the conditions for instantaneous as well as delayed rupture are analysed. It is shown that a state of mechanical instability will be reached at a certain load or after a certain time. The cases of purely ductile rupture and purely brittle fracture are identified as two limiting cases of this general instability phenomenon. The Kachanov-Rabotnov damage law implies that a structural component will fail in tension only when it has reached a state of complete damage, i.e. zero load carrying capacity. The extended law predicts failure at an earlier stage of the deterioration process and is therefore more compatible with experimental observation. Further experimental support is offered by predictions for staircase loading histories, both step-up and step-down type. The presented damage theory here predicts strain histories which are in closer agreement with test data than predictions based on other phenomenological theories

  8. An update on the mechanisms and pathophysiological consequences of genomic instability with a focus on ionizing radiation

    Directory of Open Access Journals (Sweden)

    Streffer C

    2015-12-01

    Full Text Available Christian Streffer Institute for Medical Radiobiology, University Clinics Essen, Essen, Germany Abstract: The genome of eukaryotic cells is generally instable. DNA damage occurs by endogenous processes and exogenous toxic agents. The efficient DNA repair pathways conserve the genetic information to a large extent throughout the life. However, exposure to genotoxic agents can increase the genomic instability. This phenomenon develops in a delayed manner after approximately 20 and more cell generations. It is comparatively thoroughly investigated after the exposure to ionizing radiation. The increase of genomic instability has been observed after exposures to ionizing radiation in vitro and in vivo as well as with many different types of radiation. The effect is induced over a wide dose range, and it has been found with cell death, chromosomal damage, cell transformations, mutations, double-strand breaks, malformations, and cancers. No specific chromosomes or genomic sites have been observed for such events. The increased genomic instability can be transmitted to the next generation. Possible mechanisms such as oxidative stress (mitochondria may be involved, reduced DNA repair, changes in telomeres, epigenetic effects are discussed. A second wave of oxidative stress has been observed after radiation exposures with considerably high doses as well as with cytotoxic agents at time periods when an increased genomic instability was seen. However, the increase of genomic instability also happens to much lower radiation doses. Hypoxia induces an increase of genomic instability. This effect is apparently connected with a reduction of DNA repair. Changes of telomeres appear as the most probable mechanisms for the increase of genomic instability. Syndromes have been described with a genetic predisposition for high radiosensitivity. These individuals show an increase of cancer, a deficient DNA repair, a disturbed regulation of the cell cycle, and an

  9. Causation of cancer by ionizing radiation and genomic instability

    International Nuclear Information System (INIS)

    Streffer, Christian

    2013-01-01

    The causation of cancer by ionizing radiation has been shown in many epidemiological (with exposed humans) as well as experimental studies with mammals especially mice but also rats, dogs and monkeys. Risk values have been determined in medium radiation dose ranges (∼100 to 2,000 mSv). However, in the low dose range (<100 mSv) the situation is unclear and unsolved up to now. A better knowledge of the mechanisms for the development of cancer in humans over decades after low to medium radiation exposures is necessary for the understanding of the open questions. An increase of chromosomal aberrations and other genetic changes have been frequently observed directly after radiation exposures in many cell systems including human cells. However, in 1989 it was found that an increase of genomic instability occurred after irradiation of mouse zygotes in the fibroblasts of the neonates developing from the irradiated zygotes. That means genomic instability developed many cell generations later in cells which never had been exposed to various qualities of ionizing radiations in vivo and any treatment and secondary cancers developed in photon irradiated M.Hodgkin patients preferentially in those patients who showed a comparatively high genomic instability in their lymphocytes. Since several decades it has been experienced that certain cancer patients show an extremely high radio-sensitivity. This clinical observation has been confirmed by experimental investigations with cells of such patients. It has been proven that this increased radio-sensitivity is due to genetic mutations. A number of syndromes could be defined on such a genetic basis like ataxia telangiectasia, bloom's syndrome, fanconi anemia, retinoblasoma and others. In all these syndromes mutations occur in genes which are to regulation of the cell cycle or DNA repair (preferentially repair of DSBs). These patients with an increased radio-sensitivity frequently develop cancer - very often lymphoma - and they also

  10. Curvature-Induced Instabilities of Shells

    Science.gov (United States)

    Pezzulla, Matteo; Stoop, Norbert; Steranka, Mark P.; Bade, Abdikhalaq J.; Holmes, Douglas P.

    2018-01-01

    Induced by proteins within the cell membrane or by differential growth, heating, or swelling, spontaneous curvatures can drastically affect the morphology of thin bodies and induce mechanical instabilities. Yet, the interaction of spontaneous curvature and geometric frustration in curved shells remains poorly understood. Via a combination of precision experiments on elastomeric spherical shells, simulations, and theory, we show how a spontaneous curvature induces a rotational symmetry-breaking buckling as well as a snapping instability reminiscent of the Venus fly trap closure mechanism. The instabilities, and their dependence on geometry, are rationalized by reducing the spontaneous curvature to an effective mechanical load. This formulation reveals a combined pressurelike term in the bulk and a torquelike term in the boundary, allowing scaling predictions for the instabilities that are in excellent agreement with experiments and simulations. Moreover, the effective pressure analogy suggests a curvature-induced subcritical buckling in closed shells. We determine the critical buckling curvature via a linear stability analysis that accounts for the combination of residual membrane and bending stresses. The prominent role of geometry in our findings suggests the applicability of the results over a wide range of scales.

  11. Myc-dependent genome instability and lifespan in Drosophila.

    Directory of Open Access Journals (Sweden)

    Christina Greer

    Full Text Available The Myc family of transcription factors are key regulators of cell growth and proliferation that are dysregulated in a large number of human cancers. When overexpressed, Myc family proteins also cause genomic instability, a hallmark of both transformed and aging cells. Using an in vivo lacZ mutation reporter, we show that overexpression of Myc in Drosophila increases the frequency of large genome rearrangements associated with erroneous repair of DNA double-strand breaks (DSBs. In addition, we find that overexpression of Myc shortens adult lifespan and, conversely, that Myc haploinsufficiency reduces mutation load and extends lifespan. Our data provide the first evidence that Myc may act as a pro-aging factor, possibly through its ability to greatly increase genome instability.

  12. A biological-based model that links genomic instability, bystander effects, and adaptive response

    International Nuclear Information System (INIS)

    Scott, B.R.

    2004-01-01

    This paper links genomic instability, bystander effects, and adaptive response in mammalian cell communities via a novel biological-based, dose-response model called NEOTRANS 3 . The model is an extension of the NEOTRANS 2 model that addressed stochastic effects (genomic instability, mutations, and neoplastic transformation) associated with brief exposure to low radiation doses. With both models, ionizing radiation produces DNA damage in cells that can be associated with varying degrees of genomic instability. Cells with persistent problematic instability (PPI) are mutants that arise via misrepair of DNA damage. Progeny of PPI cells also have PPI and can undergo spontaneous neoplastic transformation. Unlike NEOTRANS 2 , with NEOTRANS 3 newly induced mutant PPI cells and their neoplastically transformed progeny can be suppressed via our previously introduced protective apoptosis-mediated (PAM) process, which can be activated by low linear energy transfer (LET) radiation. However, with NEOTRANS 3 (which like NEOTRANS 2 involves cross-talk between nongenomically compromised [e.g., nontransformed, nonmutants] and genomically compromised [e.g., mutants, transformants, etc.] cells), it is assumed that PAM is only activated over a relatively narrow, dose-rate-dependent interval (D PAM ,D off ); where D PAM is a small stochastic activation threshold, and D off is the stochastic dose above which PAM does not occur. PAM cooperates with activated normal DNA repair and with activated normal apoptosis in guarding against genomic instability. Normal repair involves both error-free repair and misrepair components. Normal apoptosis and the error-free component of normal repair protect mammals by preventing the occurrence of mutant cells. PAM selectively removes mutant cells arising via the misrepair component of normal repair, selectively removes existing neoplastically transformed cells, and probably selectively removes other genomically compromised cells when it is activated

  13. Self-Induced Faraday Instability Laser

    Science.gov (United States)

    Perego, A. M.; Smirnov, S. V.; Staliunas, K.; Churkin, D. V.; Wabnitz, S.

    2018-05-01

    We predict the onset of self-induced parametric or Faraday instabilities in a laser, spontaneously caused by the presence of pump depletion, which leads to a periodic gain landscape for light propagating in the cavity. As a result of the instability, continuous wave oscillation becomes unstable even in the normal dispersion regime of the cavity, and a periodic train of pulses with ultrahigh repetition rate is generated. Application to the case of Raman fiber lasers is described, in good quantitative agreement between our conceptual analysis and numerical modeling.

  14. Introns Protect Eukaryotic Genomes from Transcription-Associated Genetic Instability.

    Science.gov (United States)

    Bonnet, Amandine; Grosso, Ana R; Elkaoutari, Abdessamad; Coleno, Emeline; Presle, Adrien; Sridhara, Sreerama C; Janbon, Guilhem; Géli, Vincent; de Almeida, Sérgio F; Palancade, Benoit

    2017-08-17

    Transcription is a source of genetic instability that can notably result from the formation of genotoxic DNA:RNA hybrids, or R-loops, between the nascent mRNA and its template. Here we report an unexpected function for introns in counteracting R-loop accumulation in eukaryotic genomes. Deletion of endogenous introns increases R-loop formation, while insertion of an intron into an intronless gene suppresses R-loop accumulation and its deleterious impact on transcription and recombination in yeast. Recruitment of the spliceosome onto the mRNA, but not splicing per se, is shown to be critical to attenuate R-loop formation and transcription-associated genetic instability. Genome-wide analyses in a number of distant species differing in their intron content, including human, further revealed that intron-containing genes and the intron-richest genomes are best protected against R-loop accumulation and subsequent genetic instability. Our results thereby provide a possible rationale for the conservation of introns throughout the eukaryotic lineage. Copyright © 2017 Elsevier Inc. All rights reserved.

  15. Chromosomal instability can be induced by the formation of breakage-prone chromosome rearrangement junctions

    International Nuclear Information System (INIS)

    Allen, R.N.; Ritter, L.; Moore, S.R.; Grosovsky, A.J.

    2003-01-01

    Full text: Studies in our lab have led to the hypothesis that chromosomal rearrangements can generate novel breakage-prone sites, resulting in chromosomal instability acting predominantly in cis. For example, specific breakage of large blocks of centromeric region heterochromatin on chromosome 16q by treatment with 2,6-diaminopurine (DAP) is associated with repeated rearrangement of chromosome 16q during outgrowth of DAP-treated clones, thereby establishing a link between the initial site of damage and the occurrence of persistent chromosomal instability. Similarly, karyotypic analysis of gamma ray induced instability demonstrated that chromosomal rearrangements in sub-clones were significantly clustered near the site of previously identified chromosomal rearrangement junctions in unstable parental clones. This study investigates the hypothesis that integration of transfected sequences into host chromosomes could create breakage-prone junction regions and persistent genomic instability without exposure to DNA-damage agents. These junctions may mimic the unstable chromosomal rearrangements induced by DAP or radiation, and thus provide a test of the broader hypothesis that instability can to some extent be attributed to the formation of novel chromosomal breakage hot spots. These experiments were performed using human-hamster hybrid AL cells containing a single human chromosome 11, which was used to monitor instability in a chromosomal painting assay. AL cells were transfected with a 2.5 Kb fragment containing multiple copies of the 180 bp human alpha heterochromatic repeat, which resulted in chromosomal instability in 41% of the transfected clones. Parallel exposure to gamma-radiation resulted in a similar level of chromosomal instability, although control transfections with plasmid alone did not lead to karyotypic instability. Chromosomal instability induced by integration of alpha heterochromatic repeats was also frequently associated with delayed reproductive

  16. Initiation of genome instability and preneoplastic processes through loss of Fhit expression.

    Directory of Open Access Journals (Sweden)

    Joshua C Saldivar

    Full Text Available Genomic instability drives tumorigenesis, but how it is initiated in sporadic neoplasias is unknown. In early preneoplasias, alterations at chromosome fragile sites arise due to DNA replication stress. A frequent, perhaps earliest, genetic alteration in preneoplasias is deletion within the fragile FRA3B/FHIT locus, leading to loss of Fhit protein expression. Because common chromosome fragile sites are exquisitely sensitive to replication stress, it has been proposed that their clonal alterations in cancer cells are due to stress sensitivity rather than to a selective advantage imparted by loss of expression of fragile gene products. Here, we show in normal, transformed, and cancer-derived cell lines that Fhit-depletion causes replication stress-induced DNA double-strand breaks. Using DNA combing, we observed a defect in replication fork progression in Fhit-deficient cells that stemmed primarily from fork stalling and collapse. The likely mechanism for the role of Fhit in replication fork progression is through regulation of Thymidine kinase 1 expression and thymidine triphosphate pool levels; notably, restoration of nucleotide balance rescued DNA replication defects and suppressed DNA breakage in Fhit-deficient cells. Depletion of Fhit did not activate the DNA damage response nor cause cell cycle arrest, allowing continued cell proliferation and ongoing chromosomal instability. This finding was in accord with in vivo studies, as Fhit knockout mouse tissue showed no evidence of cell cycle arrest or senescence yet exhibited numerous somatic DNA copy number aberrations at replication stress-sensitive loci. Furthermore, cells established from Fhit knockout tissue showed rapid immortalization and selection of DNA deletions and amplifications, including amplification of the Mdm2 gene, suggesting that Fhit loss-induced genome instability facilitates transformation. We propose that loss of Fhit expression in precancerous lesions is the first step in the

  17. Instability of plastid DNA in the nuclear genome.

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    Anna E Sheppard

    2009-01-01

    Full Text Available Functional gene transfer from the plastid (chloroplast and mitochondrial genomes to the nucleus has been an important driving force in eukaryotic evolution. Non-functional DNA transfer is far more frequent, and the frequency of such transfers from the plastid to the nucleus has been determined experimentally in tobacco using transplastomic lines containing, in their plastid genome, a kanamycin resistance gene (neo readymade for nuclear expression. Contrary to expectations, non-Mendelian segregation of the kanamycin resistance phenotype is seen in progeny of some lines in which neo has been transferred to the nuclear genome. Here, we provide a detailed analysis of the instability of kanamycin resistance in nine of these lines, and we show that it is due to deletion of neo. Four lines showed instability with variation between progeny derived from different areas of the same plant, suggesting a loss of neo during somatic cell division. One line showed a consistent reduction in the proportion of kanamycin-resistant progeny, suggesting a loss of neo during meiosis, and the remaining four lines were relatively stable. To avoid genomic enlargement, the high frequency of plastid DNA integration into the nuclear genome necessitates a counterbalancing removal process. This is the first demonstration of such loss involving a high proportion of recent nuclear integrants. We propose that insertion, deletion, and rearrangement of plastid sequences in the nuclear genome are important evolutionary processes in the generation of novel nuclear genes. This work is also relevant in the context of transgenic plant research and crop production, because similar processes to those described here may be involved in the loss of plant transgenes.

  18. Oxidative DNA damage causes mitochondrial genomic instability in Saccharomyces cerevisiae.

    Science.gov (United States)

    Doudican, Nicole A; Song, Binwei; Shadel, Gerald S; Doetsch, Paul W

    2005-06-01

    Mitochondria contain their own genome, the integrity of which is required for normal cellular energy metabolism. Reactive oxygen species (ROS) produced by normal mitochondrial respiration can damage cellular macromolecules, including mitochondrial DNA (mtDNA), and have been implicated in degenerative diseases, cancer, and aging. We developed strategies to elevate mitochondrial oxidative stress by exposure to antimycin and H(2)O(2) or utilizing mutants lacking mitochondrial superoxide dismutase (sod2Delta). Experiments were conducted with strains compromised in mitochondrial base excision repair (ntg1Delta) and oxidative damage resistance (pif1Delta) in order to delineate the relationship between these pathways. We observed enhanced ROS production, resulting in a direct increase in oxidative mtDNA damage and mutagenesis. Repair-deficient mutants exposed to oxidative stress conditions exhibited profound genomic instability. Elimination of Ntg1p and Pif1p resulted in a synergistic corruption of respiratory competency upon exposure to antimycin and H(2)O(2). Mitochondrial genomic integrity was substantially compromised in ntg1Delta pif1Delta sod2Delta strains, since these cells exhibit a total loss of mtDNA. A stable respiration-defective strain, possessing a normal complement of mtDNA damage resistance pathways, exhibited a complete loss of mtDNA upon exposure to antimycin and H(2)O(2). This loss was preventable by Sod2p overexpression. These results provide direct evidence that oxidative mtDNA damage can be a major contributor to mitochondrial genomic instability and demonstrate cooperation of Ntg1p and Pif1p to resist the introduction of lesions into the mitochondrial genome.

  19. GSK-3 inhibitors induce chromosome instability

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    Staples Oliver D

    2007-08-01

    Full Text Available Abstract Background Several mechanisms operate during mitosis to ensure accurate chromosome segregation. However, during tumour evolution these mechanisms go awry resulting in chromosome instability. While several lines of evidence suggest that mutations in adenomatous polyposis coli (APC may promote chromosome instability, at least in colon cancer, the underlying mechanisms remain unclear. Here, we turn our attention to GSK-3 – a protein kinase, which in concert with APC, targets β-catenin for proteolysis – and ask whether GSK-3 is required for accurate chromosome segregation. Results To probe the role of GSK-3 in mitosis, we inhibited GSK-3 kinase activity in cells using a panel of small molecule inhibitors, including SB-415286, AR-A014418, 1-Azakenpaullone and CHIR99021. Analysis of synchronised HeLa cells shows that GSK-3 inhibitors do not prevent G1/S progression or cell division. They do, however, significantly delay mitotic exit, largely because inhibitor-treated cells have difficulty aligning all their chromosomes. Although bipolar spindles form and the majority of chromosomes biorient, one or more chromosomes often remain mono-oriented near the spindle poles. Despite a prolonged mitotic delay, anaphase frequently initiates without the last chromosome aligning, resulting in chromosome non-disjunction. To rule out the possibility of "off-target" effects, we also used RNA interference to selectively repress GSK-3β. Cells deficient for GSK-3β exhibit a similar chromosome alignment defect, with chromosomes clustered near the spindle poles. GSK-3β repression also results in cells accumulating micronuclei, a hallmark of chromosome missegregation. Conclusion Thus, not only do our observations indicate a role for GSK-3 in accurate chromosome segregation, but they also raise the possibility that, if used as therapeutic agents, GSK-3 inhibitors may induce unwanted side effects by inducing chromosome instability.

  20. Bystander-mediated genomic instability after high LET radiation in murine primary haemopoietic stem cells

    International Nuclear Information System (INIS)

    Bowler, Deborah A.; Moore, Stephen R.; Macdonald, Denise A.; Smyth, Sharon H.; Clapham, Peter; Kadhim, Munira A.

    2006-01-01

    Communication between irradiated and unirradiated (bystander) cells can result in responses in unirradiated cells that are similar to responses in their irradiated counterparts. The purpose of the current experiment was to test the hypothesis that bystander responses will be similarly induced in primary murine stem cells under different cell culture conditions. The experimental systems used here, co-culture and media transfer, are similar in that they both restrict communication between irradiated and bystander cells to media borne factors, but are distinct in that with the media transfer technique, cells can only communicate after irradiation, and with co-culture, cells can communication before, during and after irradiation. In this set of parallel experiments, cell type, biological endpoint, and radiation quality and dose, were kept constant. In both experimental systems, clonogenic survival was significantly decreased in all groups, whether irradiated or bystander, suggesting a substantial contribution of bystander effects (BE) to cell killing. Genomic instability (GI) was induced under all radiation and bystander conditions in both experiments, including a situation where unirradiated cells were incubated with media that had been conditioned for 24 h with irradiated cells. The appearance of delayed aberrations (genomic instability) 10-13 population doublings after irradiation was similar to the level of initial chromosomal damage, suggesting that the bystander factor is able to induce chromosomal alterations soon after irradiation. Whether these early alterations are related to those observed at later timepoints remains unknown. These results suggest that genomic instability may be significantly induced in a bystander cell population whether or not cells communicate during irradiation

  1. PTEN C-Terminal Deletion Causes Genomic Instability and Tumor Development

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    Zhuo Sun

    2014-03-01

    Full Text Available Tumor suppressor PTEN controls genomic stability and inhibits tumorigenesis. The N-terminal phosphatase domain of PTEN antagonizes the PI3K/AKT pathway, but its C-terminal function is less defined. Here, we describe a knockin mouse model of a nonsense mutation that results in the deletion of the entire Pten C-terminal region, referred to as PtenΔC. Mice heterozygous for PtenΔC develop multiple spontaneous tumors, including cancers and B cell lymphoma. Heterozygous deletion of the Pten C-terminal domain also causes genomic instability and common fragile site rearrangement. We found that Pten C-terminal disruption induces p53 and its downstream targets. Simultaneous depletion of p53 promotes metastasis without influencing the initiation of tumors, suggesting that p53 mainly suppresses tumor progression. Our data highlight the essential role of the PTEN C terminus in the maintenance of genomic stability and suppression of tumorigenesis.

  2. The elevation of radiation load on ecosystems and genome instability of organisms

    International Nuclear Information System (INIS)

    Gaziyev, A. I.; Bezlepkin, V.Q.

    2002-01-01

    prophylaxis of human disorders. Thus, it was found that the action of low-dose ionizing radiation on living organisms might induce an adaptive repair response in them aimed at decreasing the genetic consequences of the exposure. However, the potentialities of defense and repair systems of an organism are limited, so an increase in genome lesions may cause inheritable mutations, cancer and other pathologies, and death. DNA lesions caused by ionizing radiation in small and sublethal doses can essentially be repaired, whereas unrepaired lesions and errors of repair, replication, and recombination systems lead to formation of mutational changes in DNA sequences. These changes may be transmitted to daughter cells and induce genome instability in the progeny. Induced genome instability in survived somatic cells is characterized by persistence of a high level of acquired variability in many generations of these cells. Genome instability manifests itself as an increased frequency of karyotypic anomalies, chromosome and gene mutations, clonal heterogeneity, and malignant transformation in the progeny of cells exposed to DNA-damaging agents. Besides, cells with genome instability show increased amplification of genes and changes in their expression, as well as disturbances in their differentiation, delays in reproductive death and other phenotypic characters of abnormal development. Whereas some progress has been made towards knowledge of genome instability in the somatic cells of mammals, the radiation-induced genome instability in germ cells transmitted to individuals of the next generation is still not clearly understood. At the same time, evidence has been obtained which suggests that the transmission of genome instability to the somatic cells of the progeny from the germ cells of gamma - radiation-exposed parents is possible. This conclusion is based on the data on mutation frequency in the progeny of parents exposed to DNA-damaging agents. For instance, a significant increase in

  3. Light-induced ion-acoustic instability of rarefied plasma

    International Nuclear Information System (INIS)

    Krasnov, I.V.; Sizykh, D.V.

    1987-01-01

    A new method of ion-acoustic instability excitation under the effect of coherent light, resonance to ion quantum transitions on collisionless plasma, is suggested. The light-induced ion-acoustic instability (LIIAI) considered is based on the induced progressive nonequilibrium resonance particles in the field of travelling electromagnetic wave. Principal possibility to use LIIAI in high-resolution spectroscopy and in applied problems of plasma physics, related to its instability, is pointed out

  4. Analysis of genomic instability in bronchial cells from uranium miners

    International Nuclear Information System (INIS)

    Neft, R.E.; Belinsky, S.A.; Gilliland, F.D.; Lechner, J.F.

    1994-01-01

    Epidemiological studies show that underground uranium miners have a radon progeny exposure-dependent increased risk for developing lung cancer. The odds ratio for lung cancer in uranium miners increase for all cumulative exposures above 99 Working Level Months. In addition, there is a strong multiplicative effect of cigarette smoking on the development of lung cancer in uranium miners. The purpose of this investigation was to determine whether or not early genetic changes, as indicated by genomic instability, can be detected in bronchial cells from uranium miners. Investigations of this nature may serve as a means of discovering sub-clinical disease and could lead to earlier detection of lung cancer and a better prognosis for the patient

  5. Genomic instability and the role of radiation quality

    International Nuclear Information System (INIS)

    Kadhim, M. A.; Hill, M. A.; Moore, S. R.

    2006-01-01

    Genomic instability (GI) is a hallmark of tumorigenic progression and is observed as delayed genetic damage in the progeny of irradiated and unirradiated bystander cells. The expression of GI can be influenced by genotype, cell type and radiation quality. While several studies have demonstrated the induction of GI by high and low-linear energy transfer (LET) radiation, our work on human and mouse primary cell systems has shown LET-dependent differences in the induction and expression of GI. These differences might be attributed to differences in radiation track structure, dose rate, contribution of bystander cells and radiation dose. This paper reviews the role of radiation quality in the induction of GI and describe the possible mechanisms underlining the observed differences between radiation types on its induction. The experimental results presented suggest that dose might be the most significant factor in determining induction of GI after low-LET radiation. (authors)

  6. Is there a common mechanism underlying genomic instability, bystander effects and other nontargeted effects of exposure to ionizing radiation?

    Science.gov (United States)

    Morgan, William F.

    2003-01-01

    A number of nontargeted and delayed effects associated with radiation exposure have now been described. These include radiation-induced genomic instability, death-inducing and bystander effects, clastogenic factors and transgenerational effects. It is unlikely that these nontargeted effects are directly induced by cellular irradiation. Instead, it is proposed that some as yet to be identified secreted factor can be produced by irradiated cells that can stimulate effects in nonirradiated cells (death-inducing and bystander effects, clastogenic factors) and perpetuate genomic instability in the clonally expanded progeny of an irradiated cell. The proposed factor must be soluble and capable of being transported between cells by cell-to-cell gap junction communication channels. Furthermore, it must have the potential to stimulate cellular cytokines and/or reactive oxygen species. While it is difficult to imagine a role for such a secreted factor in contributing to transgenerational effects, the other nontargeted effects of radiation may all share a common mechanism.

  7. Ectopic Expression of Testis Germ Cell Proteins in Cancer and Its Potential Role in Genomic Instability

    Directory of Open Access Journals (Sweden)

    Aaraby Yoheswaran Nielsen

    2016-06-01

    Full Text Available Genomic instability is a hallmark of human cancer and an enabling factor for the genetic alterations that drive cancer development. The processes involved in genomic instability resemble those of meiosis, where genetic material is interchanged between homologous chromosomes. In most types of human cancer, epigenetic changes, including hypomethylation of gene promoters, lead to the ectopic expression of a large number of proteins normally restricted to the germ cells of the testis. Due to the similarities between meiosis and genomic instability, it has been proposed that activation of meiotic programs may drive genomic instability in cancer cells. Some germ cell proteins with ectopic expression in cancer cells indeed seem to promote genomic instability, while others reduce polyploidy and maintain mitotic fidelity. Furthermore, oncogenic germ cell proteins may indirectly contribute to genomic instability through induction of replication stress, similar to classic oncogenes. Thus, current evidence suggests that testis germ cell proteins are implicated in cancer development by regulating genomic instability during tumorigenesis, and these proteins therefore represent promising targets for novel therapeutic strategies.

  8. Anticipating Terrorist Safe Havens from Instability Induced Conflict

    Science.gov (United States)

    Shearer, Robert; Marvin, Brett

    This chapter presents recent methods developed at the Center for Army Analysis to classify patterns of nation-state instability that lead to conflict. The ungoverned areas endemic to failed nation-states provide terrorist organizations with safe havens from which to plan and execute terrorist attacks. Identification of those states at risk for instability induced conflict should help to facilitate effective counter terrorism policy planning efforts. Nation-states that experience instability induced conflict are similar in that they share common instability factors that make them susceptible to experiencing conflict. We utilize standard pattern classification algorithms to identify these patterns. First, we identify features (political, military, economic and social) that capture the instability of a nation-state. Second, we forecast the future levels of these features for each nation-state. Third, we classify each future state’s conflict potential based upon the conflict level of those states in the past most similar to the future state.

  9. Genomic instability and radiation risk in molecular pathways to colon cancer.

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    Jan Christian Kaiser

    Full Text Available Colon cancer is caused by multiple genomic alterations which lead to genomic instability (GI. GI appears in molecular pathways of microsatellite instability (MSI and chromosomal instability (CIN with clinically observed case shares of about 15-20% and 80-85%. Radiation enhances the colon cancer risk by inducing GI, but little is known about different outcomes for MSI and CIN. Computer-based modelling can facilitate the understanding of the phenomena named above. Comprehensive biological models, which combine the two main molecular pathways to colon cancer, are fitted to incidence data of Japanese a-bomb survivors. The preferred model is selected according to statistical criteria and biological plausibility. Imprints of cell-based processes in the succession from adenoma to carcinoma are identified by the model from age dependences and secular trends of the incidence data. Model parameters show remarkable compliance with mutation rates and growth rates for adenoma, which has been reported over the last fifteen years. Model results suggest that CIN begins during fission of intestinal crypts. Chromosomal aberrations are generated at a markedly elevated rate which favors the accelerated growth of premalignant adenoma. Possibly driven by a trend of Westernization in the Japanese diet, incidence rates for the CIN pathway increased notably in subsequent birth cohorts, whereas rates pertaining to MSI remained constant. An imbalance between number of CIN and MSI cases began to emerge in the 1980s, whereas in previous decades the number of cases was almost equal. The CIN pathway exhibits a strong radio-sensitivity, probably more intensive in men. Among young birth cohorts of both sexes the excess absolute radiation risk related to CIN is larger by an order of magnitude compared to the MSI-related risk. Observance of pathway-specific risks improves the determination of the probability of causation for radiation-induced colon cancer in individual patients

  10. BYSTANDER EFFECTS GENOMIC INSTABILITY, ADAPTIVE RESPONSE AND CANCER RISK ASSESSMENT FOR RADIAION AND CHEMICAL EXPOSURES

    Science.gov (United States)

    BYSTANDER EFFECTS, GENOMIC INSTABILITY, ADAPTIVE RESPONSE AND CANCER RISK ASSESSMENT FOR RADIATION AND CHEMICAL EXPOSURESR. Julian PrestonEnvironmental Carcinogenesis Division, U.S. Environmental Protection Agency, Research Triangle Park, N.C. 27711, USAThere ...

  11. Profiles of Genomic Instability in High-Grade Serous Ovarian Cancer Predict Treatment Outcome

    DEFF Research Database (Denmark)

    Wang, Zhigang C.; Birkbak, Nicolai Juul; Culhane, Aedín C.

    2012-01-01

    Purpose: High-grade serous cancer (HGSC) is the most common cancer of the ovary and is characterized by chromosomal instability. Defects in homologous recombination repair (HRR) are associated with genomic instability in HGSC, and are exploited by therapy targeting DNA repair. Defective HRR cause...

  12. Genomic instability in human actinic keratosis and squamous cell carcinoma

    Science.gov (United States)

    Cabral, Luciana Sanches; Neto, Cyro Festa; Sanches, José A; Ruiz, Itamar R G

    2011-01-01

    OBJECTIVE: To compare the repetitive DNA patterns of human actinic keratoses and squamous cell carcinomas to determine the genetic alterations that are associated with malignant transformation. INTRODUCTION: Cancer cells are prone to genomic instability, which is often due to DNA polymerase slippage during the replication of repetitive DNA and to mutations in the DNA repair genes. The progression of benign actinic keratoses to malignant squamous cell carcinomas has been proposed by several authors. MATERIAL AND METHODS: Eight actinic keratoses and 24 squamous cell carcinomas (SCC), which were pair-matched to adjacent skin tissues and/or leucocytes, were studied. The presence of microsatellite instability (MSI) and the loss of heterozygosity (LOH) in chromosomes 6 and 9 were investigated using nine PCR primer pairs. Random Amplified Polymorphic DNA patterns were also evaluated using eight primers. RESULTS: MSI was detected in two (D6S251, D9S50) of the eight actinic keratosis patients. Among the 8 patients who had squamous cell carcinoma-I and provided informative results, a single patient exhibited two LOH (D6S251, D9S287) and two instances of MSI (D9S180, D9S280). Two LOH and one example of MSI (D6S251) were detected in three out of the 10 patients with squamous cell carcinoma-II. Among the four patients with squamous cell carcinoma-III, one patient displayed three MSIs (D6S251, D6S252, and D9S180) and another patient exhibited an MSI (D9S280). The altered random amplified polymorphic DNA ranged from 70% actinic keratoses, 76% squamous cell carcinoma-I, and 90% squamous cell carcinoma-II, to 100% squamous cell carcinoma-III. DISCUSSION: The increased levels of alterations in the microsatellites, particularly in D6S251, and the random amplified polymorphic DNA fingerprints were statistically significant in squamous cell carcinomas, compared with actinic keratoses. CONCLUSION: The overall alterations that were observed in the repetitive DNA of actinic keratoses and

  13. Trans-generational radiation-induced chromosomal instability in the female enhances the action of chemical mutagens

    International Nuclear Information System (INIS)

    Camats, Nuria; Garcia, Francisca; Parrilla, Juan Jose; Calaf, Joaquim; Martin, Miguel; Caldes, Montserrat Garcia

    2008-01-01

    Genomic instability can be produced by ionising radiation, so-called radiation-induced genomic instability, and chemical mutagens. Radiation-induced genomic instability occurs in both germinal and somatic cells and also in the offspring of irradiated individuals, and it is characterised by genetic changes including chromosomal rearrangements. The majority of studies of trans-generational, radiation-induced genomic instability have been described in the male germ line, whereas the authors who have chosen the female as a model are scarce. The aim of this work is to find out the radiation-induced effects in the foetal offspring of X-ray-treated female rats and, at the same time, the possible impact of this radiation-induced genomic instability on the action of a chemical mutagen. In order to achieve both goals, the quantity and quality of chromosomal damage were analysed. In order to detect trans-generational genomic instability, a total of 4806 metaphases from foetal tissues from the foetal offspring of X-irradiated female rats (5 Gy, acute dose) were analysed. The study's results showed that there is radiation-induced genomic instability: the number of aberrant metaphases and the breaks per total metaphases studied increased and were found to be statistically significant (p ≤ 0.05), with regard to the control group. In order to identify how this trans-generational, radiation-induced chromosomal instability could influence the chromosomal behaviour of the offspring of irradiated rat females in front of a chemical agent (aphidicolin), a total of 2481 metaphases were studied. The observed results showed that there is an enhancement of the action of the chemical agent: chromosomal breaks per aberrant metaphases show significant differences (p ≤ 0.05) in the X-ray- and aphidicolin-treated group as regards the aphidicolin-treated group. In conclusion, our findings indicate that there is trans-generational, radiation-induced chromosomal instability in the foetal cells

  14. Trans-generational radiation-induced chromosomal instability in the female enhances the action of chemical mutagens

    Energy Technology Data Exchange (ETDEWEB)

    Camats, Nuria [Institut de Biotecnologia i Biomedicina (IBB), Universitat Autonoma de Barcelona, 08193 Barcelona (Spain); Departament de Biologia Cel.lular, Fisiologia i Immunologia, Universitat Autonoma de Barcelona, 08193 Barcelona (Spain); Garcia, Francisca [Institut de Biotecnologia i Biomedicina (IBB), Universitat Autonoma de Barcelona, 08193 Barcelona (Spain); Parrilla, Juan Jose [Servicio de Ginecologia y Obstetricia, Hospital Universitario Virgen de la Arrixaca, 30120 El Palmar, Murcia (Spain); Calaf, Joaquim [Servei de Ginecologia i Obstetricia, Hospital Universitari de la Santa Creu i Sant Pau, 08025 Barcelona (Spain); Martin, Miguel [Departament de Pediatria, d' Obstetricia i Ginecologia i de Medicina Preventiva, Universitat Autonoma de Barcelona, 08193 Barcelona (Spain); Caldes, Montserrat Garcia [Institut de Biotecnologia i Biomedicina (IBB), Universitat Autonoma de Barcelona, 08193 Barcelona (Spain); Departament de Biologia Cel.lular, Fisiologia i Immunologia, Universitat Autonoma de Barcelona, 08193 Barcelona (Spain)], E-mail: Montserrat.Garcia.Caldes@uab.es

    2008-04-02

    Genomic instability can be produced by ionising radiation, so-called radiation-induced genomic instability, and chemical mutagens. Radiation-induced genomic instability occurs in both germinal and somatic cells and also in the offspring of irradiated individuals, and it is characterised by genetic changes including chromosomal rearrangements. The majority of studies of trans-generational, radiation-induced genomic instability have been described in the male germ line, whereas the authors who have chosen the female as a model are scarce. The aim of this work is to find out the radiation-induced effects in the foetal offspring of X-ray-treated female rats and, at the same time, the possible impact of this radiation-induced genomic instability on the action of a chemical mutagen. In order to achieve both goals, the quantity and quality of chromosomal damage were analysed. In order to detect trans-generational genomic instability, a total of 4806 metaphases from foetal tissues from the foetal offspring of X-irradiated female rats (5 Gy, acute dose) were analysed. The study's results showed that there is radiation-induced genomic instability: the number of aberrant metaphases and the breaks per total metaphases studied increased and were found to be statistically significant (p {<=} 0.05), with regard to the control group. In order to identify how this trans-generational, radiation-induced chromosomal instability could influence the chromosomal behaviour of the offspring of irradiated rat females in front of a chemical agent (aphidicolin), a total of 2481 metaphases were studied. The observed results showed that there is an enhancement of the action of the chemical agent: chromosomal breaks per aberrant metaphases show significant differences (p {<=} 0.05) in the X-ray- and aphidicolin-treated group as regards the aphidicolin-treated group. In conclusion, our findings indicate that there is trans-generational, radiation-induced chromosomal instability in the foetal

  15. Genomic instability and telomere fusion of canine osteosarcoma cells.

    Directory of Open Access Journals (Sweden)

    Junko Maeda

    Full Text Available Canine osteosarcoma (OSA is known to present with highly variable and chaotic karyotypes, including hypodiploidy, hyperdiploidy, and increased numbers of metacentric chromosomes. The spectrum of genomic instabilities in canine OSA has significantly augmented the difficulty in clearly defining the biological and clinical significance of the observed cytogenetic abnormalities. In this study, eight canine OSA cell lines were used to investigate telomere fusions by fluorescence in situ hybridization (FISH using a peptide nucleotide acid probe. We characterized each cell line by classical cytogenetic studies and cellular phenotypes including telomere associated factors and then evaluated correlations from this data. All eight canine OSA cell lines displayed increased abnormal metacentric chromosomes and exhibited numerous telomere fusions and interstitial telomeric signals. Also, as evidence of unstable telomeres, colocalization of γ-H2AX and telomere signals in interphase cells was observed. Each cell line was characterized by a combination of data representing cellular doubling time, DNA content, chromosome number, metacentric chromosome frequency, telomere signal level, cellular radiosensitivity, and DNA-PKcs protein expression level. We have also studied primary cultures from 10 spontaneous canine OSAs. Based on the observation of telomere aberrations in those primary cell cultures, we are reasonably certain that our observations in cell lines are not an artifact of prolonged culture. A correlation between telomere fusions and the other characteristics analyzed in our study could not be identified. However, it is important to note that all of the canine OSA samples exhibiting telomere fusion utilized in our study were telomerase positive. Pending further research regarding telomerase negative canine OSA cell lines, our findings may suggest telomere fusions can potentially serve as a novel marker for canine OSA.

  16. Substrate-induced instability in gas microstrip detectors

    International Nuclear Information System (INIS)

    Bateman, J.E.; Connolly, J.F.

    1992-12-01

    The results of a programme of research into substrate-induced gain instability in gas microstrip detectors are reported. Information has been collected on a wide range of substrates including many commonly available glasses and ceramics. A theoretical model of the gain instability is proposed. While we have not yet found an acceptable substrate for the construction of high flux detectors our experience points to electronically conductive glasses as the most promising source of a stable substrate. (Author)

  17. Telomere-mediated chromosomal instability triggers TLR4 induced inflammation and death in mice.

    Directory of Open Access Journals (Sweden)

    Rabindra N Bhattacharjee

    Full Text Available BACKGROUND: Telomeres are essential to maintain chromosomal stability. Cells derived from mice lacking telomerase RNA component (mTERC-/- mice display elevated telomere-mediated chromosome instability. Age-dependent telomere shortening and associated chromosome instability reduce the capacity to respond to cellular stress occurring during inflammation and cancer. Inflammation is one of the important risk factors in cancer progression. Controlled innate immune responses mediated by Toll-like receptors (TLR are required for host defense against infection. Our aim was to understand the role of chromosome/genome instability in the initiation and maintenance of inflammation. METHODOLOGY/PRINCIPAL FINDINGS: We examined the function of TLR4 in telomerase deficient mTERC-/- mice harbouring chromosome instability which did not develop any overt immunological disorder in pathogen-free condition or any form of cancers at this stage. Chromosome instability was measured in metaphase spreads prepared from wildtype (mTERC+/+, mTERC+/- and mTERC-/- mouse splenocytes. Peritoneal and/or bone marrow-derived macrophages were used to examine the responses of TLR4 by their ability to produce inflammatory mediators TNFalpha and IL6. Our results demonstrate that TLR4 is highly up-regulated in the immune cells derived from telomerase-null (mTERC-/- mice and lipopolysaccharide, a natural ligand for TLR4 stabilises NF-kappaB binding to its promoter by down-regulating ATF-3 in mTERC-/- macrophages. CONCLUSIONS/SIGNIFICANCE: Our findings implied that background chromosome instability in the cellular level stabilises the action of TLR4-induced NF-kappaB action and sensitises cells to produce excess pro-inflammatory mediators. Chromosome/genomic instability data raises optimism for controlling inflammation by non-toxic TLR antagonists among high-risk groups.

  18. Dynamic instability of genomic methylation patterns in pluripotent stem cells

    Directory of Open Access Journals (Sweden)

    Ooi Steen KT

    2010-09-01

    Full Text Available Abstract Background Genomic methylation patterns are established during gametogenesis, and perpetuated in somatic cells by faithful maintenance methylation. There have been previous indications that genomic methylation patterns may be less stable in embryonic stem (ES cells than in differentiated somatic cells, but it is not known whether different mechanisms of de novo and maintenance methylation operate in pluripotent stem cells compared with differentiating somatic cells. Results In this paper, we show that ablation of the DNA methyltransferase regulator DNMT3L (DNA methyltransferase 3-like in mouse ES cells renders them essentially incapable of de novo methylation of newly integrated retroviral DNA. We also show that ES cells lacking DNMT3L lose DNA methylation over time in culture, suggesting that DNA methylation in ES cells is the result of dynamic loss and gain of DNA methylation. We found that wild-type female ES cells lose DNA methylation at a much faster rate than do male ES cells; this defect could not be attributed to sex-specific differences in expression of DNMT3L or of any DNA methyltransferase. We also found that human ES and induced pluripotent stem cell lines showed marked but variable loss of methylation that could not be attributed to sex chromosome constitution or time in culture. Conclusions These data indicate that DNA methylation in pluripotent stem cells is much more dynamic and error-prone than is maintenance methylation in differentiated cells. DNA methylation requires DNMT3L in stem cells, but DNMT3L is not expressed in differentiating somatic cells. Error-prone maintenance methylation will introduce unpredictable phenotypic variation into clonal populations of pluripotent stem cells, and this variation is likely to be much more pronounced in cultured female cells. This epigenetic variability has obvious negative implications for the clinical applications of stem cells.

  19. Out-of-phase flashing induced instabilities in CIRCUS facility

    Energy Technology Data Exchange (ETDEWEB)

    Christian Pablo Marcel; Van der Hagen, T.H.J.J. [Interfaculty Reactor Institute, Delft University of Technology, Mekelweg 15, 2629 JB Delft (Netherlands)

    2005-07-01

    Full text of publication follows: Flashing-induced instabilities are very important during the startup phase of natural-circulation boiling water reactors. To study this type of instability an axial fully scaled facility named CIRCUS was constructed. Experiments at low power and low pressure (typical startup conditions) are carried out on this steam/water natural circulation loop with two parallel risers. A detailed measurement of the void-fraction profile is possible by using needle-probes and the use of glass tubes for the riser and core sections allow to use optical techniques for velocity measurements. The flashing and the mechanism of flashing-induced instabilities are analyzed paying special attention on the strong coupling effect between the two riser channels. It is clear from the experiments that the out-of-phase instability is much more susceptible to occur than the in-phase instability in a system with two parallel risers. The instability region is found as soon as the operational boundary between single-phase and two-phase operation is crossed. The relation between the period of the oscillations and the fluid transient time is also investigated. The stability map constructed using this experimental data is also discussed. (authors)

  20. Occupational exposure to anesthetics leads to genomic instability, cytotoxicity and proliferative changes

    International Nuclear Information System (INIS)

    Souza, Kátina M.; Braz, Leandro G.; Nogueira, Flávia R.; Souza, Marajane B.; Bincoleto, Lahis F.; Aun, Aline G.; Corrente, José E.; Carvalho, Lídia R.; Braz, José Reinaldo C.; Braz, Mariana G.

    2016-01-01

    a lower frequency of basal cells compared with the control group. In conclusion, exposure to modern waste anesthetic gases did not induce systemic DNA damage, but it did result in genomic instability, cytotoxicity and proliferative changes, which were detected in the EBC of anesthesiologists. Thus, these professionals can be considered at risk for developing genetic alterations resulting from occupational exposure to these gases, suggesting the need to minimize this exposure.

  1. Occupational exposure to anesthetics leads to genomic instability, cytotoxicity and proliferative changes

    Energy Technology Data Exchange (ETDEWEB)

    Souza, Kátina M.; Braz, Leandro G.; Nogueira, Flávia R.; Souza, Marajane B.; Bincoleto, Lahis F.; Aun, Aline G. [Faculdade de Medicina de Botucatu, UNESP − Univ Estadual Paulista, Departamento de Anestesiologia, Botucatu (Brazil); Corrente, José E.; Carvalho, Lídia R. [Instituto de Biociências de Botucatu, UNESP − Univ Estadual Paulista, Departamento de Bioestatística, Botucatu (Brazil); Braz, José Reinaldo C. [Faculdade de Medicina de Botucatu, UNESP − Univ Estadual Paulista, Departamento de Anestesiologia, Botucatu (Brazil); Braz, Mariana G., E-mail: mgbraz@hotmail.com [Faculdade de Medicina de Botucatu, UNESP − Univ Estadual Paulista, Departamento de Anestesiologia, Botucatu (Brazil)

    2016-09-15

    pyknosis, and a lower frequency of basal cells compared with the control group. In conclusion, exposure to modern waste anesthetic gases did not induce systemic DNA damage, but it did result in genomic instability, cytotoxicity and proliferative changes, which were detected in the EBC of anesthesiologists. Thus, these professionals can be considered at risk for developing genetic alterations resulting from occupational exposure to these gases, suggesting the need to minimize this exposure.

  2. Loss of RMI2 Increases Genome Instability and Causes a Bloom-Like Syndrome.

    Directory of Open Access Journals (Sweden)

    Damien F Hudson

    2016-12-01

    Full Text Available Bloom syndrome is a recessive human genetic disorder with features of genome instability, growth deficiency and predisposition to cancer. The only known causative gene is the BLM helicase that is a member of a protein complex along with topoisomerase III alpha, RMI1 and 2, which maintains replication fork stability and dissolves double Holliday junctions to prevent genome instability. Here we report the identification of a second gene, RMI2, that is deleted in affected siblings with Bloom-like features. Cells from homozygous individuals exhibit elevated rates of sister chromatid exchange, anaphase DNA bridges and micronuclei. Similar genome and chromosome instability phenotypes are observed in independently derived RMI2 knockout cells. In both patient and knockout cell lines reduced localisation of BLM to ultra fine DNA bridges and FANCD2 at foci linking bridges are observed. Overall, loss of RMI2 produces a partially active BLM complex with mild features of Bloom syndrome.

  3. Detection of genomic instability in normal human bronchial epithelial cells exposed to 238Pu

    International Nuclear Information System (INIS)

    Kennedy, C.H.; Fukushima, N.H.; Neft, R.E.; Lechner, J.F.

    1994-01-01

    Alpha particle-emitting radon daughters constitute a risk for development of lung cancer in humans. The development of this disease involves multiple genetic alterations. These changes and the time course they follow are not yet defined despite numerous in vitro endeavors to transform human lung cells with various physical or chemical agents. However, genomic instability, characterized both by structural and numerical chromosomal aberrations and by elevated rates of point mutations, is a common feature of tumor cells. Further, both types of genomic instability have been reported in the noncancerous progeny of normal murine hemopoietic cells exposed in vitro to α-particles. The purpose of this investigation was to determine if genomic instability is also a prominent feature of normal human bronchial epithelial cells exposed to α-particle irradiation from the decay of inhaled radon daughters

  4. Epstein–Barr virus particles induce centrosome amplification and chromosomal instability

    Science.gov (United States)

    Shumilov, Anatoliy; Tsai, Ming-Han; Schlosser, Yvonne T.; Kratz, Anne-Sophie; Bernhardt, Katharina; Fink, Susanne; Mizani, Tuba; Lin, Xiaochen; Jauch, Anna; Mautner, Josef; Kopp-Schneider, Annette; Feederle, Regina; Hoffmann, Ingrid; Delecluse, Henri-Jacques

    2017-01-01

    Infections with Epstein–Barr virus (EBV) are associated with cancer development, and EBV lytic replication (the process that generates virus progeny) is a strong risk factor for some cancer types. Here we report that EBV infection of B-lymphocytes (in vitro and in a mouse model) leads to an increased rate of centrosome amplification, associated with chromosomal instability. This effect can be reproduced with virus-like particles devoid of EBV DNA, but not with defective virus-like particles that cannot infect host cells. Viral protein BNRF1 induces centrosome amplification, and BNRF1-deficient viruses largely lose this property. These findings identify a new mechanism by which EBV particles can induce chromosomal instability without establishing a chronic infection, thereby conferring a risk for development of tumours that do not necessarily carry the viral genome. PMID:28186092

  5. Molecular Mechanisms Underlying Genomic Instability in Brca-Deficient Cells

    Science.gov (United States)

    2014-11-01

    increased by hydroxyurea, ATR inhibition, deregulated c-Myc expression and by PARPi treatment of BRCA1 deficient cells. This work was recently published...Genome Stability." 6: May 27, 2013-Collaborative Research Center 655 from Cells to Tissues seminar series at the Max-Planck-Institute in Dresden, Germany ...Eisenach, Germany -“Genome Stability during DNA Replication” 8: May 3, 2013- Chemical and Systems Biology Department Seminar Series at Stanford

  6. New type of genome instability in Drosophila melanogaster

    International Nuclear Information System (INIS)

    Georgiev, P.G.; Simonova, O.B.; Gerasimova, T.I.

    1988-01-01

    During crossing of two stable laboratory lines, y 2 sc 1w aG and Df(1)Pgd-kz/FM4, y 31d sc 8 dm B, consistent instability originated reproducibly in progeny containing a y 2 sc 1 w aG chromosome and autosomes of both lines. It is expressed in active mutagenesis observed over the course of several tens of generations. Destabilization occurs independently of direction of crossing. Mutagenesis occurs both in somatic and in sex cells of males and females. It displays high locus specificity. A transpositional nature was shown for at least some of the mutations. Results of the experiments concerning hybridization in situ with different mobile elements indicates an absence or low frequency of tranpositional bursts in the system. Possible mechanisms of induction of genetic instability in the system described are discussed

  7. Tertiary Epimutations – A Novel Aspect of Epigenetic Transgenerational Inheritance Promoting Genome Instability

    Science.gov (United States)

    McCarrey, John R.; Lehle, Jake D.; Raju, Seetha S.; Wang, Yufeng; Nilsson, Eric E.; Skinner, Michael K.

    2016-01-01

    Exposure to environmental factors can induce the epigenetic transgenerational inheritance of disease. Alterations to the epigenome termed “epimutations” include “primary epimutations” which are epigenetic alterations in the absence of genetic change and “secondary epimutations” which form following an initial genetic change. To determine if secondary epimutations contribute to transgenerational transmission of disease following in utero exposure to the endocrine disruptor vinclozolin, we exposed pregnant female rats carrying the lacI mutation-reporter transgene to vinclozolin and assessed the frequency of mutations in kidney tissue and sperm recovered from F1 and F3 generation progeny. Our results confirm that vinclozolin induces primary epimutations rather than secondary epimutations, but also suggest that some primary epimutations can predispose a subsequent accelerated accumulation of genetic mutations in F3 generation descendants that have the potential to contribute to transgenerational phenotypes. We therefore propose the existence of “tertiary epimutations” which are initial primary epimutations that promote genome instability leading to an accelerated accumulation of genetic mutations. PMID:27992467

  8. Study on the relationship between DNA-PKcs and genomic instability and hyper-radiosensitivity

    International Nuclear Information System (INIS)

    Yang Kang; Zhu Jiayun; Ding Nan; Li Junhong; Hu Wentao; Su Fengtao; He Jinpeng; Li Sha

    2010-01-01

    To investigate the relationship between DNA-PKcs and genome instability and hyper-radiosensitivity, human glioma cell lines M059K and M059J, as a model expressing wild-type DNA-PKcs and a model defective in DNA-PKcs activity, were exposed to low doses of X-rays. Cells survival fractions were assessed by colony-forming assay and Cytochalasin-B micronucleus assay was employed to detect the genomic instability happening in each single irradiated colony. It has been found that as the post-incubation time increased, M059K cells expressing wild-type DNA-PKcs exhibited low-dose hyper-radiosensitivity and showed a similar genomic instability after 0.2 Gy and 0.6 Gy irradiations, but the M059J cells lacking in DNA-PKcs didn't present low-dose hyper-radiosensitivity and showed a higher genomic instability of 0.6 Gy than that of 0.2 Gy. The results indicate that DNA-PKcs may act as one of the key factors that lead to low-dose hyper-radiosensitivity. (authors)

  9. Electric field induced instabilities in free emulsion films

    Energy Technology Data Exchange (ETDEWEB)

    Tchoukov, P.; Dabros, T. [Natural Resources Canada, Devon, AB (Canada); Mostowfi, F. [Schlumberger DBR Technology Center, Edmonton, AB (Canada); Panchev, N. [Champion Technologies Inc., Houston, TX (United States); Czarnecki, J. [Alberta Univ., Edmonton, AB (Canada). Dept. of Chemical and Materials Engineering

    2009-07-01

    This presentation reported on a study that investigated the mechanism of electric field-induced breakdown of free emulsion films. Instability patterns were observed on the plane of a water-oil-water film following electric polarization. The length-scales of the instabilities were measured by analyzing images immediately after applying the electric field. Linear stability analysis was used to calculate the theoretical dominant wavelengths. The calculated values were found to be in good agreement with measured values. The films were formed in a thin film apparatus modified so that the oil film separated 2 aqueous phase compartments, each in contact with a platinum electrode. This enabled the measurement of disjoining pressure while applying the electric field to the film. It was concluded that breakdown of thin films induced by electric field has many applications, including electrostatic de-emulsification/desalination of crude oil and emulsion stability measurements. It was concluded that electroporation and dielectric breakdown may be responsible for electric field-induced breakdown. This study also presented evidence of an increase in electric field-induced instabilities in emulsion films resulting in rupture. tabs., figs.

  10. Characterization of genomic instability in Saccharomyces cerevisiae and engaging teaching strategies described in two curricula

    Science.gov (United States)

    Keller, Alexandra P.

    Cancer arises through an accumulation of mutations in the genome. In cancer cells, mutations are frequently caused by DNA rearrangements, which include chromosomal breakages, deletions, insertions, and translocations. Such events contribute to genomic instability, a known hallmark of cancer. To study cycles of chromosomal instability, we are using baker's yeast as a model organism. In yeast, a ChrVII system was previously developed (Admire et al., 2006), in which a disomic yeast strain was used to identify regions of instability on ChrVII. Using this system, a fragile site on the left arm of ChrVII (Admire et al., 2006) was identified and characterized. This study led to insight into mechanisms involved in chromosomal rearrangements and mutations that arise from them as well as to an understanding of mechanisms involved in genomic instability. To further our understanding of genomic instability, I devised a strategy to study instability on a different chromosome (ChrV) (Figure 3), so that we could determine whether lessons learned from the ChrVII system are applicable to other chromosomes, and/or whether other mechanisms of instability could be identified. A suitable strain was generated and analyzed, and our findings suggest that frequencies of instability on the right arm of ChrV are similar to those found in ChrVII. The results from the work in ChrV described in this paper support the idea that the instability found on ChrVII is not an isolated occurrence. My research was supported by an NSF GK-12 grant. The aim of this grant is to improve science education in middle schools, and as part of my participation in this program, I studied and practiced effective science communication methodologies. In attempts to explain my research to middle school students, I collaborated with others to develop methods for explaining genetics and the most important techniques I used in my research. While developing these methods, I learned more about what motivates people to learn

  11. Helicobacter pylori infection induces genetic instability of nuclear and mitochondrial DNA in gastric cells

    DEFF Research Database (Denmark)

    Machado, Ana Manuel Dantas; Figueiredo, Ceu; Touati, Eliette

    2009-01-01

    of genetic instabilities in the nuclear and mitochondrial DNA (mtDNA) were examined. EXPERIMENTAL DESIGN: We observed the effects of H. pylori infection on a gastric cell line (AGS), on C57BL/6 mice, and on individuals with chronic gastritis. In AGS cells, the effect of H. pylori infection on base excision...... cells and chronic gastritis tissue were determined by PCR, single-stranded conformation polymorphism, and sequencing. H. pylori vacA and cagA genotyping was determined by multiplex PCR and reverse hybridization. RESULTS: Following H. pylori infection, the activity and expression of base excision repair...... and MMR are down-regulated both in vitro and in vivo. Moreover, H. pylori induces genomic instability in nuclear CA repeats in mice and in mtDNA of AGS cells and chronic gastritis tissue, and this effect in mtDNA is associated with bacterial virulence. CONCLUSIONS: Our results suggest that H. pylori...

  12. Adaptive response and genomic instability: allosteric response of genome to negative impact

    International Nuclear Information System (INIS)

    Sasaki, Masao S.

    2010-01-01

    Currently, there is an upsurge concern on the unique response of living cells to low dose ionizing radiation for its inconformity to the existing paradigm of the biological action of radiation and its impact on the current understanding of risk evaluation of health effect of radiation in our workplace and environment. For the allosteric response to have significance, the cells must have an excellent sensing mechanism to discriminate tolerable and intolerable signals. In a series of experiments with mammalian, including human, cells, we demonstrated a novel sensing and signaling mechanism in the low-dose irradiated cells that was mediated by a PKCα-p3BMAPK-PLCδ1 feedback regulatory loop. Upon irradiation, PKCα is immediately activated, which in turn activate p38MAPK. The activation of p38MAPK is feedbacked to the activation of PKCα via PLCδ1, which catalyzes the hydrolysis of PtdInsP2 to generate PKCα-directed second messengers DAG and lnsP3. At low doses, the PKCα and p38MAPK continue to be activated for long time through this feedback loop, but when the cells encounter the high dose (>10 cGy or equivalent), the feedback loop is immediately comes to shutdown by deprivation of PKCα protein, known as down-regulation of PKC signaling. Thus, PKCα plays a key role in the long lasting nature of adaptive response to low doses and a binary switch to the genomic instability by too much signals. Tumor suppressor protein, p53, is a downstream effecter

  13. Gastric cancers of Western European and African patients show different patterns of genomic instability

    Directory of Open Access Journals (Sweden)

    Mulder Chris JJ

    2011-01-01

    Full Text Available Abstract Background Infection with H. pylori is important in the etiology of gastric cancer. Gastric cancer is infrequent in Africa, despite high frequencies of H. pylori infection, referred to as the African enigma. Variation in environmental and host factors influencing gastric cancer risk between different populations have been reported but little is known about the biological differences between gastric cancers from different geographic locations. We aim to study genomic instability patterns of gastric cancers obtained from patients from United Kingdom (UK and South Africa (SA, in an attempt to support the African enigma hypothesis at the biological level. Methods DNA was isolated from 67 gastric adenocarcinomas, 33 UK patients, 9 Caucasian SA patients and 25 native SA patients. Microsatellite instability and chromosomal instability were analyzed by PCR and microarray comparative genomic hybridization, respectively. Data was analyzed by supervised univariate and multivariate analyses as well as unsupervised hierarchical cluster analysis. Results Tumors from Caucasian and native SA patients showed significantly more microsatellite instable tumors (p Conclusions Gastric cancers from SA and UK patients show differences in genetic instability patterns, indicating possible different biological mechanisms in patients from different geographical origin. This is of future clinical relevance for stratification of gastric cancer therapy.

  14. Significance of genomic instability in breast cancer in atomic bomb survivors: analysis of microarray-comparative genomic hybridization

    Directory of Open Access Journals (Sweden)

    Oikawa Masahiro

    2011-12-01

    Full Text Available Abstract Background It has been postulated that ionizing radiation induces breast cancers among atomic bomb (A-bomb survivors. We have reported a higher incidence of HER2 and C-MYC oncogene amplification in breast cancers from A-bomb survivors. The purpose of this study was to clarify the effect of A-bomb radiation exposure on genomic instability (GIN, which is an important hallmark of carcinogenesis, in archival formalin-fixed paraffin-embedded (FFPE tissues of breast cancer by using microarray-comparative genomic hybridization (aCGH. Methods Tumor DNA was extracted from FFPE tissues of invasive ductal cancers from 15 survivors who were exposed at 1.5 km or less from the hypocenter and 13 calendar year-matched non-exposed patients followed by aCGH analysis using a high-density oligonucleotide microarray. The total length of copy number aberrations (CNA was used as an indicator of GIN, and correlation with clinicopathological factors were statistically tested. Results The mean of the derivative log ratio spread (DLRSpread, which estimates the noise by calculating the spread of log ratio differences between consecutive probes for all chromosomes, was 0.54 (range, 0.26 to 1.05. The concordance of results between aCGH and fluorescence in situ hybridization (FISH for HER2 gene amplification was 88%. The incidence of HER2 amplification and histological grade was significantly higher in the A-bomb survivors than control group (P = 0.04, respectively. The total length of CNA tended to be larger in the A-bomb survivors (P = 0.15. Correlation analysis of CNA and clinicopathological factors revealed that DLRSpread was negatively correlated with that significantly (P = 0.034, r = -0.40. Multivariate analysis with covariance revealed that the exposure to A-bomb was a significant (P = 0.005 independent factor which was associated with larger total length of CNA of breast cancers. Conclusions Thus, archival FFPE tissues from A-bomb survivors are useful for

  15. Significance of genomic instability in breast cancer in atomic bomb survivors: analysis of microarray-comparative genomic hybridization

    International Nuclear Information System (INIS)

    Oikawa, Masahiro; Yoshiura, Koh-ichiro; Kondo, Hisayoshi; Miura, Shiro; Nagayasu, Takeshi; Nakashima, Masahiro

    2011-01-01

    It has been postulated that ionizing radiation induces breast cancers among atomic bomb (A-bomb) survivors. We have reported a higher incidence of HER2 and C-MYC oncogene amplification in breast cancers from A-bomb survivors. The purpose of this study was to clarify the effect of A-bomb radiation exposure on genomic instability (GIN), which is an important hallmark of carcinogenesis, in archival formalin-fixed paraffin-embedded (FFPE) tissues of breast cancer by using microarray-comparative genomic hybridization (aCGH). Tumor DNA was extracted from FFPE tissues of invasive ductal cancers from 15 survivors who were exposed at 1.5 km or less from the hypocenter and 13 calendar year-matched non-exposed patients followed by aCGH analysis using a high-density oligonucleotide microarray. The total length of copy number aberrations (CNA) was used as an indicator of GIN, and correlation with clinicopathological factors were statistically tested. The mean of the derivative log ratio spread (DLRSpread), which estimates the noise by calculating the spread of log ratio differences between consecutive probes for all chromosomes, was 0.54 (range, 0.26 to 1.05). The concordance of results between aCGH and fluorescence in situ hybridization (FISH) for HER2 gene amplification was 88%. The incidence of HER2 amplification and histological grade was significantly higher in the A-bomb survivors than control group (P = 0.04, respectively). The total length of CNA tended to be larger in the A-bomb survivors (P = 0.15). Correlation analysis of CNA and clinicopathological factors revealed that DLRSpread was negatively correlated with that significantly (P = 0.034, r = -0.40). Multivariate analysis with covariance revealed that the exposure to A-bomb was a significant (P = 0.005) independent factor which was associated with larger total length of CNA of breast cancers. Thus, archival FFPE tissues from A-bomb survivors are useful for genome-wide aCGH analysis. Our results suggested that A

  16. Significance of genomic instability in breast cancer in atomic bomb survivors: analysis of microarray-comparative genomic hybridization.

    Science.gov (United States)

    Oikawa, Masahiro; Yoshiura, Koh-ichiro; Kondo, Hisayoshi; Miura, Shiro; Nagayasu, Takeshi; Nakashima, Masahiro

    2011-12-07

    It has been postulated that ionizing radiation induces breast cancers among atomic bomb (A-bomb) survivors. We have reported a higher incidence of HER2 and C-MYC oncogene amplification in breast cancers from A-bomb survivors. The purpose of this study was to clarify the effect of A-bomb radiation exposure on genomic instability (GIN), which is an important hallmark of carcinogenesis, in archival formalin-fixed paraffin-embedded (FFPE) tissues of breast cancer by using microarray-comparative genomic hybridization (aCGH). Tumor DNA was extracted from FFPE tissues of invasive ductal cancers from 15 survivors who were exposed at 1.5 km or less from the hypocenter and 13 calendar year-matched non-exposed patients followed by aCGH analysis using a high-density oligonucleotide microarray. The total length of copy number aberrations (CNA) was used as an indicator of GIN, and correlation with clinicopathological factors were statistically tested. The mean of the derivative log ratio spread (DLRSpread), which estimates the noise by calculating the spread of log ratio differences between consecutive probes for all chromosomes, was 0.54 (range, 0.26 to 1.05). The concordance of results between aCGH and fluorescence in situ hybridization (FISH) for HER2 gene amplification was 88%. The incidence of HER2 amplification and histological grade was significantly higher in the A-bomb survivors than control group (P = 0.04, respectively). The total length of CNA tended to be larger in the A-bomb survivors (P = 0.15). Correlation analysis of CNA and clinicopathological factors revealed that DLRSpread was negatively correlated with that significantly (P = 0.034, r = -0.40). Multivariate analysis with covariance revealed that the exposure to A-bomb was a significant (P = 0.005) independent factor which was associated with larger total length of CNA of breast cancers. Thus, archival FFPE tissues from A-bomb survivors are useful for genome-wide aCGH analysis. Our results suggested that A

  17. Genomic and epigenetic instability in chordoma: current insights

    Directory of Open Access Journals (Sweden)

    Feng Y

    2014-05-01

    Full Text Available Yong Feng,1,2 Jacson K Shen,1,3 Francis J Hornicek,1,3 Zhenfeng Duan1,3 1Department of Orthopedic Surgery, Massachusetts General Hospital, Boston, MA, USA; 2Department of Orthopedic Surgery, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, People’s Republic of China; 3Sarcoma Biology Laboratory, Center for Sarcoma and Connective Tissue Oncology, Massachusetts General Hospital, Boston, MA, USA Abstract: Chordoma is a malignant bone tumor, which currently can only be defined by histologic and immunohistochemical criteria. There are no prognostic biomarkers to predict the clinical outcome or response to treatment yet. Currently, chordoma pathogenesis is very poorly understood; however, recent large-scale genetic and epigenetic studies have identified some of the underlying mechanisms and pathways that may contribute to the disease. In this review, we summarize the most recent findings in the field of chordoma genomics and epigenomics, from comparative genomic hybridization to evaluate chromosomal alteration, large-scale deoxyribonucleic acid (DNA sequencing to determine the gene mutation, microarray to access messenger ribonucleic acid (RNA and microRNA gene expression, and DNA-methylation profiling. These studies may also hold valuable clinical potential in the management of chordoma. Keywords: chordoma, chromosomal alterations, sequencing, miRNA, DNA methylation

  18. Higher-Density Culture in Human Embryonic Stem Cells Results in DNA Damage and Genome Instability

    Directory of Open Access Journals (Sweden)

    Kurt Jacobs

    2016-03-01

    Full Text Available Human embryonic stem cells (hESC show great promise for clinical and research applications, but their well-known proneness to genomic instability hampers the development to their full potential. Here, we demonstrate that medium acidification linked to culture density is the main cause of DNA damage and genomic alterations in hESC grown on feeder layers, and this even in the short time span of a single passage. In line with this, we show that increasing the frequency of the medium refreshments minimizes the levels of DNA damage and genetic instability. Also, we show that cells cultured on laminin-521 do not present this increase in DNA damage when grown at high density, although the (long-term impact on their genomic stability remains to be elucidated. Our results explain the high levels of genome instability observed over the years by many laboratories worldwide, and show that the development of optimal culture conditions is key to solving this problem.

  19. Overexpressed of RAD51 suppresses recombination defects: a possible mechanism to reverse genomic instability

    Energy Technology Data Exchange (ETDEWEB)

    Schild, David; Wiese, Claudia

    2009-10-15

    RAD51, a key protein in the homologous recombinational DNA repair (HRR) pathway, is the major strand-transferase required for mitotic recombination. An important early step in HRR is the formation of single-stranded DNA (ss-DNA) coated by RPA (a ss-DNA binding protein). Displacement of RPA by RAD51 is highly regulated and facilitated by a number of different proteins known as the 'recombination mediators'. To assist these recombination mediators, a second group of proteins also is required and we are defining these proteins here as 'recombination co-mediators'. Defects in either recombination mediators or comediators, including BRCA1 and BRCA2, lead to impaired HRR that can genetically be complemented for (i.e. suppressed) by overexpression of RAD51. Defects in HRR have long been known to contribute to genomic instability leading to tumor development. Since genomic instability also slows cell growth, precancerous cells presumably require genomic restabilization to gain a growth advantage. RAD51 is overexpressed in many tumors, and therefore, we hypothesize that the complementing ability of elevated levels of RAD51 in tumors with initial HRR defects limits genomic instability during carcinogenic progression. Of particular interest, this model may also help explain the high frequency of TP53 mutations in human cancers, since wild-type p53 represses RAD51.

  20. Pressure-anisotropy-induced nonlinearities in the kinetic magnetorotational instability

    Science.gov (United States)

    Squire, J.; Quataert, E.; Kunz, M. W.

    2017-12-01

    In collisionless and weakly collisional plasmas, such as hot accretion flows onto compact objects, the magnetorotational instability (MRI) can differ significantly from the standard (collisional) MRI. In particular, pressure anisotropy with respect to the local magnetic-field direction can both change the linear MRI dispersion relation and cause nonlinear modifications to the mode structure and growth rate, even when the field and flow perturbations are very small. This work studies these pressure-anisotropy-induced nonlinearities in the weakly nonlinear, high-ion-beta regime, before the MRI saturates into strong turbulence. Our goal is to better understand how the saturation of the MRI in a low-collisionality plasma might differ from that in the collisional regime. We focus on two key effects: (i) the direct impact of self-induced pressure-anisotropy nonlinearities on the evolution of an MRI mode, and (ii) the influence of pressure anisotropy on the `parasitic instabilities' that are suspected to cause the mode to break up into turbulence. Our main conclusions are: (i) The mirror instability regulates the pressure anisotropy in such a way that the linear MRI in a collisionless plasma is an approximate nonlinear solution once the mode amplitude becomes larger than the background field (just as in magnetohyrodynamics). This implies that differences between the collisionless and collisional MRI become unimportant at large amplitudes. (ii) The break up of large-amplitude MRI modes into turbulence via parasitic instabilities is similar in collisionless and collisional plasmas. Together, these conclusions suggest that the route to magnetorotational turbulence in a collisionless plasma may well be similar to that in a collisional plasma, as suggested by recent kinetic simulations. As a supplement to these findings, we offer guidance for the design of future kinetic simulations of magnetorotational turbulence.

  1. Links between persistent DNA damage, genome instability, and aging

    Energy Technology Data Exchange (ETDEWEB)

    Dynan, William S. [Emory Univ., Atlanta, GA (United States). Dept. of Radiation Oncology

    2016-11-14

    The goal of this study was to examine long-term effects of low-dose radiation exposure. One of the hypotheses was that radiation exposure would accelerate the normal aging process. The study was jointly funded by NASA and examined both low-LET radiation (γ-rays) and high-LET radiation (1000 MeV/nucleon 56Fe ions) at doses of 0.1 Gy and up. The work used the Japanese medaka fish (Oryzias latipes), as a vertebrate model organism that can be maintained in large numbers at low cost for lifetime studies. Like other small laboratory fish, Japanese medaka share many anatomical and histological characteristics with other vertebrates, and a variety of genetic and genomic resources are available. Some work also used the zebrafish (Danio rerio), another widely used laboratory model organism.

  2. Transgenerational induction of leukaemia following parental irradiation. Genomic instability and the bystander in vivo

    Energy Technology Data Exchange (ETDEWEB)

    Lord, B.I. [Paterson Institute for Cancer Research, Christie Hospital NHS Trust, Manchester (United Kingdom)

    2003-07-01

    caused by radiation results in changes to haemopoiesis that demand stem cell proliferation, thus leading to elevated genomic instability which may be exploited by secondary leukaemia inducing agents - and evidence will be presented to demonstrate this potential. Additionally, changes in the regulatory haemopoietic microenvironment can be seen as the in vivo form of the potentiating 'bystander'. (author)

  3. Graphical analysis of electron inertia induced acoustic instability

    International Nuclear Information System (INIS)

    Karmakar, P.K.; Deka, U.; Dwivedi, C.B.

    2005-01-01

    Recently, the practical significance of the asymptotic limit of m e /m i →0 for electron density distribution has been judged in a two-component plasma system with drifting ions. It is reported that in the presence of drifting ions with drift speed exceeding the ion acoustic wave speed, the electron inertial delay effect facilitates the resonance coupling of the usual fluid ion acoustic mode with the ion-beam mode. In this contribution the same instability is analyzed by graphical and numerical methods. This is to note that the obtained dispersion relation differs from those of the other known normal modes of low frequency ion plasma oscillations and waves. This is due to consideration of electron inertial delay in derivation of the dispersion relation of the ion acoustic wave fluctuations. Numerical calculations of the dispersion relation and wave energy are carried out to depict the graphical appearance of poles and positive-negative energy modes. It is found that the electron inertia induced ion acoustic wave instability arises out of linear resonance coupling between the negative and positive energy modes. Characterization of the resonance nature of the instability in Mach number space for different wave numbers of the ion acoustic mode is presented

  4. Current-induced atomic dynamics, instabilities, and Raman signals

    DEFF Research Database (Denmark)

    Lu, Jing Tao; Brandbyge, Mads; Hedegard, Per

    2012-01-01

    We derive and employ a semiclassical Langevin equation obtained from path integrals to describe the ionic dynamics of a molecular junction in the presence of electrical current. The electronic environment serves as an effective nonequilibrium bath. The bath results in random forces describing Joule...... heating, current-induced forces including the nonconservative wind force, dissipative frictional forces, and an effective Lorentz-type force due to the Berry phase of the nonequilibrium electrons. Using a generic two-level molecular model, we highlight the importance of both current-induced forces...... and Joule heating for the stability of the system. We compare the impact of the different forces, and the wide-band approximation for the electronic structure on our result. We examine the current-induced instabilities (excitation of runaway "waterwheel" modes) and investigate the signature...

  5. Chaos of radiative heat-loss-induced flame front instability.

    Science.gov (United States)

    Kinugawa, Hikaru; Ueda, Kazuhiro; Gotoda, Hiroshi

    2016-03-01

    We are intensively studying the chaos via the period-doubling bifurcation cascade in radiative heat-loss-induced flame front instability by analytical methods based on dynamical systems theory and complex networks. Significant changes in flame front dynamics in the chaotic region, which cannot be seen in the bifurcation diagrams, were successfully extracted from recurrence quantification analysis and nonlinear forecasting and from the network entropy. The temporal dynamics of the fuel concentration in the well-developed chaotic region is much more complicated than that of the flame front temperature. It exhibits self-affinity as a result of the scale-free structure in the constructed visibility graph.

  6. Reciprocal Regulation between DNA-PKcs and Snail1 Conferring Genomic Instability

    International Nuclear Information System (INIS)

    Seo, Haeng Ran; Lee, Hae June; Jin, Yeung Bae; Bae, Sang Woo; Lee, Yun Sil; Kim, Nam Hee; Kim, Hyun Sil; Nam, Hyung Wook; Yook, Jong In

    2010-01-01

    Although the roles of DNA-dependent protein kinase catalytic subunit (DNA-PKcs) involving non-homologous end joining (NHEJ) of DNA repair are well recognized, the biological mechanisms and regulators by which DNA-PKcs regulate genomic instability are not clearly defined. We show herein that DNA-PKcs activity resulting from DNA damage caused by ionizing radiation (IR) phosphorylates Snail1 at serine 100, which results in increased Snail1 expression and its function by inhibition of GSK-3-mediated phosphorylation. Furthermore, Snail1 phosphorylated at serine 100 can reciprocally inhibit kinase activity of DNA-PKcs, resulting in an inhibition to recruit DNA-PKcs or Ku70/80 to a DNA double-strand break site, and ultimately inhibition of DNA repair activity. The impairment of repair activity by a direct interaction between Snail1 and DNA-PKcs increases the resistance to DNA damaging agents, such as IR, and genomic instability. Our findings provide a novel cellular mechanism for induction of genomic instability by reciprocal regulation of DNA-PKcs and Snail1

  7. MicroRNA-34a promotes genomic instability by a broad suppression of genome maintenance mechanisms downstream of the oncogene KSHV-vGPCR.

    Science.gov (United States)

    Krause, Claudia J; Popp, Oliver; Thirunarayanan, Nanthakumar; Dittmar, Gunnar; Lipp, Martin; Müller, Gerd

    2016-03-01

    The Kaposi's sarcoma-associated herpesvirus (KSHV)-encoded chemokine receptor vGPCR acts as an oncogene in Kaposi's sarcomagenesis. Until now, the molecular mechanisms by which the vGPCR contributes to tumor development remain incompletely understood. Here, we show that the KSHV-vGPCR contributes to tumor progression through microRNA (miR)-34a-mediated induction of genomic instability. Large-scale analyses on the DNA, gene and protein level of cell lines derived from a mouse model of vGPCR-driven tumorigenesis revealed that a vGPCR-induced upregulation of miR-34a resulted in a broad suppression of genome maintenance genes. A knockdown of either the vGPCR or miR-34a largely restored the expression of these genes and confirmed miR-34a as a downstream effector of the KSHV-vGPCR that compromises genome maintenance mechanisms. This novel, protumorigenic role of miR-34a questions the use of miR-34a mimetics in cancer therapy as they could impair genome stability.

  8. Amplification of HER2 is a marker for global genomic instability

    Directory of Open Access Journals (Sweden)

    Love Brad

    2008-10-01

    Full Text Available Abstract Background Genomic alterations of the proto-oncogene c-erbB-2 (HER-2/neu are associated with aggressive behavior and poor prognosis in patients with breast cancer. The variable clinical outcomes seen in patients with similar HER2 status, given similar treatments, suggests that the effects of amplification of HER2 can be influenced by other genetic changes. To assess the broader genomic implications of structural changes at the HER2 locus, we investigated relationships between genomic instability and HER2 status in patients with invasive breast cancer. Methods HER2 status was determined using the PathVysion® assay. DNA was extracted after laser microdissection from the 181 paraffin-embedded HER2 amplified (n = 39 or HER2 negative (n = 142 tumor specimens with sufficient tumor available to perform molecular analysis. Allelic imbalance (AI was assessed using a panel of microsatellite markers representing 26 chromosomal regions commonly altered in breast cancer. Student t-tests and partial correlations were used to investigate relationships between genomic instability and HER2 status. Results The frequency of AI was significantly higher (P P Conclusion The poor prognosis associated with HER2 amplification may be attributed to global genomic instability as cells with high frequencies of chromosomal alterations have been associated with increased cellular proliferation and aggressive behavior. In addition, high levels of DNA damage may render tumor cells refractory to treatment. In addition, specific alterations at chromosomes 11q13, 16q22-q24, and 18q21, all of which have been associated with aggressive tumor behavior, may serve as genetic modifiers to HER2 amplification. These data not only improve our understanding of HER in breast pathogenesis but may allow more accurate risk profiles and better treatment options to be developed.

  9. Role of Ku80-dependent end-joining in delayed genomic instability in mammalian cells surviving ionizing radiation

    International Nuclear Information System (INIS)

    Suzuki, Keiji; Kodama, Seiji; Watanabe, Masami

    2010-01-01

    Ionizing radiation induces delayed destabilization of the genome in the progenies of surviving cells. This phenomenon, which is called radiation-induced genomic instability, is manifested by delayed induction of radiation effects, such as cell death, chromosome aberration, and mutation in the progeny of cells surviving radiation exposure. Previously, there was a report showing that delayed cell death was absent in Ku80-deficient Chinese hamster ovary (CHO) cells, however, the mechanism of their defect has not been determined. We found that delayed induction of DNA double strand breaks and chromosomal breaks were intact in Ku80-deficient cells surviving X-irradiation, whereas there was no sign for the production of chromosome bridges between divided daughter cells. Moreover, delayed induction of dicentric chromosomes was significantly compromised in those cells compared to the wild-type CHO cells. Reintroduction of the human Ku86 gene complimented the defective DNA repair and recovered delayed induction of dicentric chromosomes and delayed cell death, indicating that defective Ku80-dependent dicentric induction was the cause of the absence of delayed cell death. Since DNA-PKcs-defective cells showed delayed phenotypes, Ku80-dependent illegitimate rejoining is involved in delayed impairment of the integrity of the genome in radiation-survived cells.

  10. Role of Ku80-dependent end-joining in delayed genomic instability in mammalian cells surviving ionizing radiation

    Energy Technology Data Exchange (ETDEWEB)

    Suzuki, Keiji, E-mail: kzsuzuki@nagasaki-u.ac.jp [Course of Life Sciences and Radiation Research, Graduate School of Biomedical Sciences, Nagasaki University, 1-12-4 Sakamoto, Nagasaki 852-8523 (Japan); Kodama, Seiji [Research Institute for Advanced Science and Technology, Osaka Prefecture University, 1-2 Gakuen-machi, Sakai 599-8570 (Japan); Watanabe, Masami [Kyoto University Research Reactor Institute, Kumatori-cho Sennan-gun, Osaka 590-0494 (Japan)

    2010-01-05

    Ionizing radiation induces delayed destabilization of the genome in the progenies of surviving cells. This phenomenon, which is called radiation-induced genomic instability, is manifested by delayed induction of radiation effects, such as cell death, chromosome aberration, and mutation in the progeny of cells surviving radiation exposure. Previously, there was a report showing that delayed cell death was absent in Ku80-deficient Chinese hamster ovary (CHO) cells, however, the mechanism of their defect has not been determined. We found that delayed induction of DNA double strand breaks and chromosomal breaks were intact in Ku80-deficient cells surviving X-irradiation, whereas there was no sign for the production of chromosome bridges between divided daughter cells. Moreover, delayed induction of dicentric chromosomes was significantly compromised in those cells compared to the wild-type CHO cells. Reintroduction of the human Ku86 gene complimented the defective DNA repair and recovered delayed induction of dicentric chromosomes and delayed cell death, indicating that defective Ku80-dependent dicentric induction was the cause of the absence of delayed cell death. Since DNA-PKcs-defective cells showed delayed phenotypes, Ku80-dependent illegitimate rejoining is involved in delayed impairment of the integrity of the genome in radiation-survived cells.

  11. Survivin and chromosome instability induced by X-irradiation

    International Nuclear Information System (INIS)

    Shen Bo; Ju Guizhi; Liu Yang

    2006-01-01

    Objective: To explore the biological effect of survivin on chromosome instability induced by X-ray irradiation. Methods: Immunocytochemistry was used to detect the expression of sutvivin in HeLa cells. Carrier pSUPER-SVV was transfected into HeLa cells to interfere the expression of survivin. Flow cytometry assay was applied to detect the occurrence of polyploid at 0 h, 4 h, 12 h, and 48 h after the HeLa cells transfected with pSUPER-SVV and irradiated with 4 Gy X-rays irradiation, and compared with the group irradiated with 4 Gy X-rays but no transfection. Results: The expression of survivin was down-regulated by transfecting with small hair RNA, its depression rate was estimated to be about 32.16% at 48 h after transfection. The occurrence of polyploid giant cells was higher in the 4 Gy X-ray irradiated group at 48 h after the irradiation than the control groups (P<0.001). Being expression of survivin interfered, the occurrence at 12 h or 48 h after irradiation, however, was about two times higher than that in the control group. Conclusion: X-ray irradiation can induce chromosome instability in HeLa cells and the effect could be enhanced by interfering the expression of surviving. It was suggested that survivin plays an important role in maintaining the stability of chromosome. (authors)

  12. Nitric oxide coordinates development of genomic instability in realization of combined effect with ionizing radiation.

    Science.gov (United States)

    Mikhailenko, V M; Diomina, E A; Muzalov, I I; Gerashchenko, B I

    2013-03-01

    The aim of this study was to investigate the ability of environmental nitrogen oxides or natural nitric oxide (NO) donors to modify free radicals ba-lance and development of genomic instability alone or in combination with ionizing radiation. Genotoxicity and cytogenetic abnormalities were assessed in vitro in peripheral blood lymphocytes (PBL) isolated from healthy humans or in vivo in rats PBL. Human PBL were treated with physiologically relevant NO donor - S-Nitrosoglutathione and X-ray irradiation. The inhalation treatment of animals with NO was carried out in chamber with purified gaseous NO mixed inside with air. Levels of S-Nitrosohemoglobin and methemoglobin in the blood were assessed with electron paramagnetic resonance. The total level of reactive oxygen and nitrogen species in PBL was determined fluorometrically, and serum levels of reactive oxygen species was determined by spectrophotometric assay. DNA damages were assessed by alkaline single-cell gel electrophoresis. The frequency of chromosomal aberrations in human PBL measured with the conventional cytogenetic assay in metaphase cells on short-term (52 h) and long-term (72 h) cultures. Environmental nitrogen oxides or release of NO from stable complexes with biomolecules (such as S-Nitrosothiols) intensified generation of free radicals, DNA damage and development of genomic instability alone or in combination with ionizing radiation. Treatment of PBL by S-Nitrosoglutathione caused prevalent induction of chromatid type but irradiation - chromosome aberrations. The dose dependence of chromatid-type aberrations observed in human PBL after combined influence of S-Nitrosoglutathione and ionizing radiation indicates a crucial role of NO in the formation of chromosomal instability. NO can deregulate free radicals balance resulted in genotoxic effect, posttranslational modification of repair enzymes and thus coordinated development of genomic instability and increase of cancer risk.

  13. Human RTEL1 deficiency causes Hoyeraal-Hreidarsson syndrome with short telomeres and genome instability.

    Science.gov (United States)

    Le Guen, Tangui; Jullien, Laurent; Touzot, Fabien; Schertzer, Michael; Gaillard, Laetitia; Perderiset, Mylène; Carpentier, Wassila; Nitschke, Patrick; Picard, Capucine; Couillault, Gérard; Soulier, Jean; Fischer, Alain; Callebaut, Isabelle; Jabado, Nada; Londono-Vallejo, Arturo; de Villartay, Jean-Pierre; Revy, Patrick

    2013-08-15

    Hoyeraal-Hreidarsson syndrome (HHS), a severe variant of dyskeratosis congenita (DC), is characterized by early onset bone marrow failure, immunodeficiency and developmental defects. Several factors involved in telomere length maintenance and/or protection are defective in HHS/DC, underlining the relationship between telomere dysfunction and these diseases. By combining whole-genome linkage analysis and exome sequencing, we identified compound heterozygous RTEL1 (regulator of telomere elongation helicase 1) mutations in three patients with HHS from two unrelated families. RTEL1 is a DNA helicase that participates in DNA replication, DNA repair and telomere integrity. We show that, in addition to short telomeres, RTEL1-deficient cells from patients exhibit hallmarks of genome instability, including spontaneous DNA damage, anaphase bridges and telomeric aberrations. Collectively, these results identify RTEL1 as a novel HHS-causing gene and highlight its role as a genomic caretaker in humans.

  14. Aberrant methylation and associated transcriptional mobilization of Alu elements contributes to genomic instability in hypoxia.

    Science.gov (United States)

    Pal, Arnab; Srivastava, Tapasya; Sharma, Manish K; Mehndiratta, Mohit; Das, Prerna; Sinha, Subrata; Chattopadhyay, Parthaprasad

    2010-11-01

    Hypoxia is an integral part of tumorigenesis and contributes extensively to the neoplastic phenotype including drug resistance and genomic instability. It has also been reported that hypoxia results in global demethylation. Because a majority of the cytosine-phosphate-guanine (CpG) islands are found within the repeat elements of DNA, and are usually methylated under normoxic conditions, we suggested that retrotransposable Alu or short interspersed nuclear elements (SINEs) which show altered methylation and associated changes of gene expression during hypoxia, could be associated with genomic instability. U87MG glioblastoma cells were cultured in 0.1% O₂ for 6 weeks and compared with cells cultured in 21% O₂ for the same duration. Real-time PCR analysis showed a significant increase in SINE and reverse transcriptase coding long interspersed nuclear element (LINE) transcripts during hypoxia. Sequencing of bisulphite treated DNA as well as the Combined Bisulfite Restriction Analysis (COBRA) assay showed that the SINE loci studied underwent significant hypomethylation though there was patchy hypermethylation at a few sites. The inter-alu PCR profile of DNA from cells cultured under 6-week hypoxia, its 4-week revert back to normoxia and 6-week normoxia showed several changes in the band pattern indicating increased alu mediated genomic alteration. Our results show that aberrant methylation leading to increased transcription of SINE and reverse transcriptase associated LINE elements could lead to increased genomic instability in hypoxia. This might be a cause of genetic heterogeneity in tumours especially in variegated hypoxic environment and lead to a development of foci of more aggressive tumour cells. © 2009 The Authors Journal compilation © 2010 Foundation for Cellular and Molecular Medicine/Blackwell Publishing Ltd.

  15. Early telomere shortening and genomic instability in tubo-ovarian preneoplastic lesions.

    Science.gov (United States)

    Chene, Gautier; Tchirkov, Andrei; Pierre-Eymard, Eleonore; Dauplat, Jacques; Raoelfils, Ines; Cayre, Anne; Watkin, Emmanuel; Vago, Philippe; Penault-Llorca, Frederique

    2013-06-01

    Genetic instability plays an important role in ovarian carcinogenesis. We investigated the level of telomere shortening and genomic instability in early and preinvasive stages of ovarian cancer, serous tubal intraepithelial carcinoma (STIC), and tubo-ovarian dysplasia (TOD). Fifty-one TOD from prophylactic salpingo-oophorectomies with BRCA1 or 2 mutation, 12 STICs, 53 tubo-ovarian high-grade serous carcinoma, and 36 noncancerous controls were laser capture microdissected from formalin-fixed, paraffin-embedded sections, analyzed by comparative genomic hybridization (array CGH) and for telomere length (using quantitative real-time PCR based on the Cawthon's method). TOD and STICs were defined by morphologic scores and immunohistochemical expressions of p53, Ki67, and γH2AX. TOD showed marked telomere shortening compared with noncancerous controls (P STICs had even shorter telomeres than TOD (P = 0.0008). Ovarian carcinoma had shorter telomeres than controls but longer than STICs and dysplasia. In TOD, telomeres were significantly shorter in those with BRCA1 mutation than in those with BRCA2 mutation (P = 0.005). In addition, γH2AX expression in TOD and STIC groups with short telomeres was significantly increased (P STICs. The total number of genetic alterations was the highest in ovarian cancers. These findings suggest that genetic instability occurs in early stages of ovarian tumorigenesis. STICs and noninvasive dysplasia are likely an important step in early serous ovarian neoplasia. ©2013 AACR

  16. Strain-induced shear instability in Liverpool Bay

    Science.gov (United States)

    Wihsgott, Juliane; Palmer, Matthew R.

    2013-04-01

    Liverpool Bay is a shallow subsection of the eastern Irish Sea with large tides (10 m), which drive strong tidal currents (1 ms-1). The Bay is heavily influenced by large freshwater inputs from several Welsh and English rivers that maintain a strong and persistent horizontal density gradient. This gradient interacts with the sheared tidal currents to strain freshwater over denser pelagic water on a semi-diurnal frequency. This Strain-Induced-Periodic-Stratification (SIPS) has important implications on vertical and horizontal mixing. The subtle interaction between stratification and turbulence in this complex environment is shown to be of critical importance to freshwater transport, and subsequently the fate of associated biogeochemical and pollutant pathways. Recent work identified an asymmetry of current ellipses due to SIPS that increases shear instability in the halocline with the potential to enhance diapycnal mixing. Here, we use data from a short, high intensity process study which reveals this mid-water mechanism maintains prolonged periods of sub-critical gradient Richardson number (Ri ≤ ¼) that suggests shear instability is likely. A time series of measurements from a microstructure profiler identifies the associated increase in turbulence is short lived and 'patchy' but sufficient to promote diapycnal mixing. The significance of this mixing process is further investigated by comparing our findings with long-term observations from the Liverpool Bay Coastal Observatory. We identify that the conditions for shear instability during SIPS are regularly met and suggest that this process contributes to the current underestimates of near coastal mixing observed in regional models. To assist our understanding of the observed processes and to test the current capability of turbulence 'closure schemes' we employ a one-dimensional numerical model to investigate the physical mechanisms driving diapycnal mixing in Liverpool Bay.

  17. Corona-induced electrohydrodynamic instabilities in low conducting liquids

    Energy Technology Data Exchange (ETDEWEB)

    Vega, F.; Perez, A.T. [Depto. Electronica y Electromagnetismo, Facultad de Fisica, Universidad de Sevilla, Avda. Reina Mercedes, s/n. 41012, Sevilla (Spain)

    2003-06-01

    The rose-window electrohydrodynamic (EHD) instability has been observed when a perpendicular field with an additional unipolar ion injection is applied onto a low conducting liquid surface. This instability has a characteristic pattern with cells five to 10 times greater than those observed in volume instabilities caused by unipolar injection. We have used corona discharge from a metallic point to perform some measurements of the rose-window instability in low conducting liquids. The results are compared to the linear theoretical criterion for an ohmic liquid. They confirmed that the minimum voltage for this instability is much lower than that for the interfacial instability in high conducting liquids. This was predicted theoretically in the dependence of the critical voltage as a function of the non-dimensional conductivity. It is shown that in a non-ohmic liquid the rose window appears as a secondary instability after the volume instability. (orig.)

  18. Hydrodynamic instability induced liquid--solid contacts in film boiling

    International Nuclear Information System (INIS)

    Yao, S.; Henry, R.E.

    1976-01-01

    The film boiling liquid-solid contacts of saturated ethanol and water to horizontal flat gold plated copper are examined by using electric conductance probe. It is observed that the liquid-solid contacts occur over a wide temperature range, and generally, induced by hydrodynamic instabilities. The area of contact decreases exponentially with interface temperature and is liquid depth dependent. The averaged duration of contacts is strongly influenced by the dominant nucleation process, and thus, depends on the interface temperature and the wettability of the solid during the contact. The frequency of major contacts is about 1.5 times the bubble detaching frequency. It is found that the liquid-solid contacts may account for a large percentage of the film boiling heat transfer near the low temperature end of film boiling and decreases as the interface temperature increases

  19. Stress-induced roughening instabilities along surfaces of piezoelectric materials

    International Nuclear Information System (INIS)

    Chien, N.Y.; Gao, H.

    1993-01-01

    The possibility of using electric field to stabilize surfaces of piezoelectric solids against stress-induced morphological roughening is explored in this paper. Two types of idealized boundary conditions are considered: (1) a traction free and electrically insulating surface and (2) a traction free and electrically conducting surface. A perturbation solution for the energy variation associated with surface roughening suggests that the electric field can be used to suppress the roughening instability to various degrees. A completely stable state is possible in the insulating case, and kinetically more stable states can be attained in the conducting case. The stabilization has importance in reducing concentration of stress and electric fields due to microscopic surface roughness which might trigger failure processes involving dislocation, cracks and dielectric breakdown

  20. From NGS assembly challenges to instability of fungal mitochondrial genomes: A case study in genome complexity.

    Science.gov (United States)

    Misas, Elizabeth; Muñoz, José Fernando; Gallo, Juan Esteban; McEwen, Juan Guillermo; Clay, Oliver Keatinge

    2016-04-01

    The presence of repetitive or non-unique DNA persisting over sizable regions of a eukaryotic genome can hinder the genome's successful de novo assembly from short reads: ambiguities in assigning genome locations to the non-unique subsequences can result in premature termination of contigs and thus overfragmented assemblies. Fungal mitochondrial (mtDNA) genomes are compact (typically less than 100 kb), yet often contain short non-unique sequences that can be shown to impede their successful de novo assembly in silico. Such repeats can also confuse processes in the cell in vivo. A well-studied example is ectopic (out-of-register, illegitimate) recombination associated with repeat pairs, which can lead to deletion of functionally important genes that are located between the repeats. Repeats that remain conserved over micro- or macroevolutionary timescales despite such risks may indicate functionally or structurally (e.g., for replication) important regions. This principle could form the basis of a mining strategy for accelerating discovery of function in genome sequences. We present here our screening of a sample of 11 fully sequenced fungal mitochondrial genomes by observing where exact k-mer repeats occurred several times; initial analyses motivated us to focus on 17-mers occurring more than three times. Based on the diverse repeats we observe, we propose that such screening may serve as an efficient expedient for gaining a rapid but representative first insight into the repeat landscapes of sparsely characterized mitochondrial chromosomes. Our matching of the flagged repeats to previously reported regions of interest supports the idea that systems of persisting, non-trivial repeats in genomes can often highlight features meriting further attention. Copyright © 2016 Elsevier Ltd. All rights reserved.

  1. Hexavalent chromium induces chromosome instability in human urothelial cells

    Energy Technology Data Exchange (ETDEWEB)

    Wise, Sandra S. [Wise Laboratory of Environmental and Genetic Toxicology, Maine Center for Toxicology and Environmental Health, Department of Applied Medical Science, University of Southern Maine, Science Building, 96 Falmouth Street, Portland, ME 04103 (United States); Holmes, Amie L. [Wise Laboratory of Environmental and Genetic Toxicology, Maine Center for Toxicology and Environmental Health, Department of Applied Medical Science, University of Southern Maine, Science Building, 96 Falmouth Street, Portland, ME 04103 (United States); Department of Radiation Oncology, Dana Farber Cancer Institute, 450 Brookline Ave., Boston, MA 02215 (United States); Liou, Louis [Department of Pathology, Boston University School of Medicine, 670 Albany St., Boston, MA 02118 (United States); Adam, Rosalyn M. [Department of Surgery, Harvard Medical School, Boston, MA 02115 (United States); Wise, John Pierce Sr., E-mail: john.wise@louisville.edu [Wise Laboratory of Environmental and Genetic Toxicology, Maine Center for Toxicology and Environmental Health, Department of Applied Medical Science, University of Southern Maine, Science Building, 96 Falmouth Street, Portland, ME 04103 (United States)

    2016-04-01

    Numerous metals are well-known human bladder carcinogens. Despite the significant occupational and public health concern of metals and bladder cancer, the carcinogenic mechanisms remain largely unknown. Chromium, in particular, is a metal of concern as incidences of bladder cancer have been found elevated in chromate workers, and there is an increasing concern for patients with metal hip implants. However, the impact of hexavalent chromium (Cr(VI)) on bladder cells has not been studied. We compared chromate toxicity in two bladder cell lines; primary human urothelial cells and hTERT-immortalized human urothelial cells. Cr(VI) induced a concentration- and time-dependent increase in chromosome damage in both cell lines, with the hTERT-immortalized cells exhibiting more chromosome damage than the primary cells. Chronic exposure to Cr(VI) also induced a concentration-dependent increase in aneuploid metaphases in both cell lines which was not observed after a 24 h exposure. Aneuploidy induction was higher in the hTERT-immortalized cells. When we correct for uptake, Cr(VI) induces a similar amount of chromosome damage and aneuploidy suggesting that the differences in Cr(VI) sensitivity between the two cells lines were due to differences in uptake. The increase in chromosome instability after chronic chromate treatment suggests this may be a mechanism for chromate-induced bladder cancer, specifically, and may be a mechanism for metal-induced bladder cancer, in general. - Highlights: • Hexavalent chromium is genotoxic to human urothelial cells. • Hexavalent chromium induces aneuploidy in human urothelial cells. • hTERT-immortalized human urothelial cells model the effects seen in primary urothelial cells. • Hexavalent chromium has a strong likelihood of being carcinogenic for bladder tissue.

  2. Transgenerational genomic instability in children of irradiated parents as a result of the Chernobyl Nuclear Accident

    International Nuclear Information System (INIS)

    Aghajanyan, Anna; Suskov, Igor

    2009-01-01

    The study of families irradiated as a result of the accident at the Chernobyl Nuclear Power Plant revealed significantly increased aberrant genomes frequencies (AGFs) not only in irradiated parents (n = 106, p 137 Cs) of peripheral blood samples from the children and their parents at doses of 0.1, 0.2 and 0.3 Gy. The spectrum and frequency of chromosome aberrations were studied in the 1st and 2nd cell generations. The average AGF was significantly increased at all doses (except 0.1 Gy) in children of irradiated parents, as compared to children born from non-irradiated parents. Amplification of cells with single-break chromosome aberrations in mitosis 2, as compared to mitosis 1, suggests the replication mechanism of realization of potential damage in DNA and the occurrence of genomic instability in succeeding cell generations.

  3. Amplification of HER2 is a marker for global genomic instability

    International Nuclear Information System (INIS)

    Ellsworth, Rachel E; Ellsworth, Darrell L; Patney, Heather L; Deyarmin, Brenda; Love, Brad; Hooke, Jeffrey A; Shriver, Craig D

    2008-01-01

    Genomic alterations of the proto-oncogene c-erbB-2 (HER-2/neu) are associated with aggressive behavior and poor prognosis in patients with breast cancer. The variable clinical outcomes seen in patients with similar HER2 status, given similar treatments, suggests that the effects of amplification of HER2 can be influenced by other genetic changes. To assess the broader genomic implications of structural changes at the HER2 locus, we investigated relationships between genomic instability and HER2 status in patients with invasive breast cancer. HER2 status was determined using the PathVysion ® assay. DNA was extracted after laser microdissection from the 181 paraffin-embedded HER2 amplified (n = 39) or HER2 negative (n = 142) tumor specimens with sufficient tumor available to perform molecular analysis. Allelic imbalance (AI) was assessed using a panel of microsatellite markers representing 26 chromosomal regions commonly altered in breast cancer. Student t-tests and partial correlations were used to investigate relationships between genomic instability and HER2 status. The frequency of AI was significantly higher (P < 0.005) in HER2 amplified (27%) compared to HER2 negative tumors (19%). Samples with HER2 amplification showed significantly higher levels of AI (P < 0.05) at chromosomes 11q23, 16q22-q24 and 18q21. Partial correlations including ER status and tumor grade supported associations between HER2 status and alterations at 11q13.1, 16q22-q24 and 18q21. The poor prognosis associated with HER2 amplification may be attributed to global genomic instability as cells with high frequencies of chromosomal alterations have been associated with increased cellular proliferation and aggressive behavior. In addition, high levels of DNA damage may render tumor cells refractory to treatment. In addition, specific alterations at chromosomes 11q13, 16q22-q24, and 18q21, all of which have been associated with aggressive tumor behavior, may serve as genetic modifiers to HER2

  4. Transgenerational developmental effects and genomic instability after X-irradiation of preimplantation embryos: Studies on two mouse strains

    International Nuclear Information System (INIS)

    Jacquet, P.; Buset, J.; Neefs, M.; Vankerkom, J.; Benotmane, M.A.; Derradji, H.; Hildebrandt, G.; Baatout, S.

    2010-01-01

    Recent results have shown that irradiation of a single cell, the zygote or 1-cell embryo of various mouse strains, could lead to congenital anomalies in the fetuses. In the Heiligenberger strain, a link between the radiation-induced congenital anomalies and the development of a genomic instability was also suggested. Moreover, further studies showed that in that strain, both congenital anomalies and genomic instability could be transmitted to the next generation. The aim of the experiments described in this paper was to investigate whether such non-targeted transgenerational effects could also be observed in two other radiosensitive mouse strains (CF1 and ICR), using lower radiation doses. Irradiation of the CF1 and ICR female zygotes with 0.2 or 0.4 Gy did not result in a decrease of their fertility after birth, when they had reached sexual maturity. Moreover, females of both strains that had been X-irradiated with 0.2 Gy exhibited higher rates of pregnancy, less resorptions and more living fetuses. Additionally, the mean weight of living fetuses in these groups had significantly increased. Exencephaly and dwarfism were observed in CF1 fetuses issued from control and X-irradiated females. In the control group of that strain, polydactyly and limb deformity were also found. The yields of abnormal fetuses did not differ significantly between the control and X-irradiated groups. Polydactyly, exencephaly and dwarfism were observed in fetuses issued from ICR control females. In addition to these anomalies, gastroschisis, curly tail and open eye were observed at low frequencies in ICR fetuses issued from X-irradiated females. Again, the frequencies of abnormal fetuses found in the different groups did not differ significantly. In both CF1 and ICR mouse strains, irradiation of female zygotes did not result in the development of a genomic instability in the next generation embryos. Overall, our results suggest that, at the moderate doses used, developmental defects

  5. Transgenerational developmental effects and genomic instability after X-irradiation of preimplantation embryos: Studies on two mouse strains

    Energy Technology Data Exchange (ETDEWEB)

    Jacquet, P., E-mail: pjacquet@sckcen.be [Molecular and Cellular Biology, Institute for Environment, Health and Safety, SCK.CEN, Boeretang 200, B-2400 Mol (Belgium); Buset, J.; Neefs, M. [Molecular and Cellular Biology, Institute for Environment, Health and Safety, SCK.CEN, Boeretang 200, B-2400 Mol (Belgium); Vankerkom, J. [Division of Environmental Research, VITO, Boeretang 200, B-2400 Mol (Belgium); Benotmane, M.A.; Derradji, H. [Molecular and Cellular Biology, Institute for Environment, Health and Safety, SCK.CEN, Boeretang 200, B-2400 Mol (Belgium); Hildebrandt, G. [Department of Radiotherapy and Radiation Oncology, University of Leipzig, Stephanstrasse 9a, D-04103 Leipzig (Germany); Department of Radiotherapy, University of Rostock, Suedring 75, D-18059 Rostock (Germany); Baatout, S. [Molecular and Cellular Biology, Institute for Environment, Health and Safety, SCK.CEN, Boeretang 200, B-2400 Mol (Belgium)

    2010-05-01

    Recent results have shown that irradiation of a single cell, the zygote or 1-cell embryo of various mouse strains, could lead to congenital anomalies in the fetuses. In the Heiligenberger strain, a link between the radiation-induced congenital anomalies and the development of a genomic instability was also suggested. Moreover, further studies showed that in that strain, both congenital anomalies and genomic instability could be transmitted to the next generation. The aim of the experiments described in this paper was to investigate whether such non-targeted transgenerational effects could also be observed in two other radiosensitive mouse strains (CF1 and ICR), using lower radiation doses. Irradiation of the CF1 and ICR female zygotes with 0.2 or 0.4 Gy did not result in a decrease of their fertility after birth, when they had reached sexual maturity. Moreover, females of both strains that had been X-irradiated with 0.2 Gy exhibited higher rates of pregnancy, less resorptions and more living fetuses. Additionally, the mean weight of living fetuses in these groups had significantly increased. Exencephaly and dwarfism were observed in CF1 fetuses issued from control and X-irradiated females. In the control group of that strain, polydactyly and limb deformity were also found. The yields of abnormal fetuses did not differ significantly between the control and X-irradiated groups. Polydactyly, exencephaly and dwarfism were observed in fetuses issued from ICR control females. In addition to these anomalies, gastroschisis, curly tail and open eye were observed at low frequencies in ICR fetuses issued from X-irradiated females. Again, the frequencies of abnormal fetuses found in the different groups did not differ significantly. In both CF1 and ICR mouse strains, irradiation of female zygotes did not result in the development of a genomic instability in the next generation embryos. Overall, our results suggest that, at the moderate doses used, developmental defects

  6. Genomic instability of osteosarcoma cell lines in culture: impact on the prediction of metastasis relevant genes.

    Science.gov (United States)

    Muff, Roman; Rath, Prisni; Ram Kumar, Ram Mohan; Husmann, Knut; Born, Walter; Baudis, Michael; Fuchs, Bruno

    2015-01-01

    Osteosarcoma is a rare but highly malignant cancer of the bone. As a consequence, the number of established cell lines used for experimental in vitro and in vivo osteosarcoma research is limited and the value of these cell lines relies on their stability during culture. Here we investigated the stability in gene expression by microarray analysis and array genomic hybridization of three low metastatic cell lines and derivatives thereof with increased metastatic potential using cells of different passages. The osteosarcoma cell lines showed altered gene expression during in vitro culture, and it was more pronounced in two metastatic cell lines compared to the respective parental cells. Chromosomal instability contributed in part to the altered gene expression in SAOS and LM5 cells with low and high metastatic potential. To identify metastasis-relevant genes in a background of passage-dependent altered gene expression, genes involved in "Pathways in cancer" that were consistently regulated under all passage comparisons were evaluated. Genes belonging to "Hedgehog signaling pathway" and "Wnt signaling pathway" were significantly up-regulated, and IHH, WNT10B and TCF7 were found up-regulated in all three metastatic compared to the parental cell lines. Considerable instability during culture in terms of gene expression and chromosomal aberrations was observed in osteosarcoma cell lines. The use of cells from different passages and a search for genes consistently regulated in early and late passages allows the analysis of metastasis-relevant genes despite the observed instability in gene expression in osteosarcoma cell lines during culture.

  7. Associations between circulating carotenoids, genomic instability and the risk of high-grade prostate cancer.

    Science.gov (United States)

    Nordström, Tobias; Van Blarigan, Erin L; Ngo, Vy; Roy, Ritu; Weinberg, Vivian; Song, Xiaoling; Simko, Jeffry; Carroll, Peter R; Chan, June M; Paris, Pamela L

    2016-03-01

    Carotenoids are a class of nutrients with antioxidant properties that have been purported to protect against cancer. However, the reported associations between carotenoids and prostate cancer have been heterogeneous and lacking data on interactions with nucleotide sequence variations and genomic biomarkers. To examine the associations between carotenoid levels and the risk of high-grade prostate cancer, also considering antioxidant-related genes and tumor instability. We measured plasma levels of carotenoids and genotyped 20 single nucleotide polymorphisms (SNP) in SOD1, SOD2, SOD3, XRCC1, and OGG1 among 559 men with non-metastatic prostate cancer undergoing radical prostatectomy. We performed copy number analysis in a subset of these men (n = 67) to study tumor instability assessed as Fraction of the Genome Altered (FGA). We examined associations between carotenoids, genotypes, tumor instability and risk of high-grade prostate cancer (Gleason grade ≥ 4 + 3) using logistic and linear regression. Circulating carotenoid levels were inversely associated with the risk of high-grade prostate cancer; odds ratios (OR) and 95% confidence intervals (CI) comparing highest versus lowest quartiles were: 0.34 (95% CI: 0.18-0.66) for α-carotene, 0.31 (95% CI: 0.15-0.63) for β-carotene, 0.55 (0.28-1.08) for lycopene and 0.37 (0.18-0.75) for total carotenoids. SNPs rs25489 in XRCC1, rs699473 in SOD3 and rs1052133 in OGG1 modified these associations for α-carotene, β-carotene and lycopene, respectively (P ≤ 0.05). The proportion of men with a high degree of FGA increased with Gleason Score (P carotenoids at diagnosis, particularly among men carrying specific somatic variations, were inversely associated with risk of high-grade prostate cancer. In exploratory analyses, higher lycopene level was associated with less genomic instability among men with low-grade disease which is novel and supports the hypothesis that lycopene may inhibit progression of

  8. TopBP1/Dpb11 binds DNA anaphase bridges to prevent genome instability.

    Science.gov (United States)

    Germann, Susanne M; Schramke, Vera; Pedersen, Rune Troelsgaard; Gallina, Irene; Eckert-Boulet, Nadine; Oestergaard, Vibe H; Lisby, Michael

    2014-01-06

    DNA anaphase bridges are a potential source of genome instability that may lead to chromosome breakage or nondisjunction during mitosis. Two classes of anaphase bridges can be distinguished: DAPI-positive chromatin bridges and DAPI-negative ultrafine DNA bridges (UFBs). Here, we establish budding yeast Saccharomyces cerevisiae and the avian DT40 cell line as model systems for studying DNA anaphase bridges and show that TopBP1/Dpb11 plays an evolutionarily conserved role in their metabolism. Together with the single-stranded DNA binding protein RPA, TopBP1/Dpb11 binds to UFBs, and depletion of TopBP1/Dpb11 led to an accumulation of chromatin bridges. Importantly, the NoCut checkpoint that delays progression from anaphase to abscission in yeast was activated by both UFBs and chromatin bridges independently of Dpb11, and disruption of the NoCut checkpoint in Dpb11-depleted cells led to genome instability. In conclusion, we propose that TopBP1/Dpb11 prevents accumulation of anaphase bridges via stimulation of the Mec1/ATR kinase and suppression of homologous recombination.

  9. Combining magnetic sorting of mother cells and fluctuation tests to analyze genome instability during mitotic cell aging in Saccharomyces cerevisiae.

    Science.gov (United States)

    Patterson, Melissa N; Maxwell, Patrick H

    2014-10-16

    Saccharomyces cerevisiae has been an excellent model system for examining mechanisms and consequences of genome instability. Information gained from this yeast model is relevant to many organisms, including humans, since DNA repair and DNA damage response factors are well conserved across diverse species. However, S. cerevisiae has not yet been used to fully address whether the rate of accumulating mutations changes with increasing replicative (mitotic) age due to technical constraints. For instance, measurements of yeast replicative lifespan through micromanipulation involve very small populations of cells, which prohibit detection of rare mutations. Genetic methods to enrich for mother cells in populations by inducing death of daughter cells have been developed, but population sizes are still limited by the frequency with which random mutations that compromise the selection systems occur. The current protocol takes advantage of magnetic sorting of surface-labeled yeast mother cells to obtain large enough populations of aging mother cells to quantify rare mutations through phenotypic selections. Mutation rates, measured through fluctuation tests, and mutation frequencies are first established for young cells and used to predict the frequency of mutations in mother cells of various replicative ages. Mutation frequencies are then determined for sorted mother cells, and the age of the mother cells is determined using flow cytometry by staining with a fluorescent reagent that detects bud scars formed on their cell surfaces during cell division. Comparison of predicted mutation frequencies based on the number of cell divisions to the frequencies experimentally observed for mother cells of a given replicative age can then identify whether there are age-related changes in the rate of accumulating mutations. Variations of this basic protocol provide the means to investigate the influence of alterations in specific gene functions or specific environmental conditions on

  10. Genomic instability after targeted irradiation of human lymphocytes: Evidence for inter-individual differences under bystander conditions

    International Nuclear Information System (INIS)

    Kadhim, Munira A.; Lee, Ryonfa; Moore, Stephen R.; Macdonald, Denise A.; Chapman, Kim L.; Patel, Gaurang; Prise, Kevin M.

    2010-01-01

    Environmental 222 radon exposure is a human health concern, and many studies demonstrate that very low doses of high LET α-particle irradiation initiate deleterious genetic consequences in both irradiated and non-irradiated bystander cells. One consequence, radiation-induced genomic instability (RIGI), is a hallmark of tumorigenesis and is often assessed by measuring delayed chromosomal aberrations. We utilised a technique that facilitates transient immobilization of primary lymphocytes for targeted microbeam irradiation and have reported that environmentally relevant doses, e.g. a single 3 He 2+ particle traversal to a single cell, are sufficient to induce RIGI. Herein we sought to determine differences in radiation response in lymphocytes isolated from five healthy male donors. Primary lymphocytes were irradiated with a single particle per cell nucleus. We found evidence for inter-individual variation in radiation response (RIGI, measured as delayed chromosome aberrations). Although this was not highly significant, it was possibly masked by high levels of intra-individual variation. While there are many studies showing a link between genetic predisposition and RIGI, there are few studies linking genetic background with bystander effects in normal human lymphocytes. In an attempt to investigate inter-individual variation in the induction of bystander effects, primary lymphocytes were irradiated with a single particle under conditions where fractions of the population were traversed. We showed a marked genotype-dependent bystander response in one donor after exposure to 15% of the population. The findings may also be regarded as a radiation-induced genotype-dependent bystander effect triggering an instability phenotype.

  11. Genomic instability after targeted irradiation of human lymphocytes: Evidence for inter-individual differences under bystander conditions

    Energy Technology Data Exchange (ETDEWEB)

    Kadhim, Munira A., E-mail: mkadhim@brookes.ac.uk [School of Life Sciences, Oxford Brookes University, Oxford OX3 0BP (United Kingdom); Lee, Ryonfa [Biophysics, GSI Helmholtzzentrum fuer Schwerionenforschung GmbH, Planckstrasse 1, D-64291 Darmstadt (Germany); Moore, Stephen R.; Macdonald, Denise A. [Radiation and Genome Stability Unit, Medical Research Council, Harwell, Oxfordshire OX11 0RD (United Kingdom); Chapman, Kim L. [School of Life Sciences, Oxford Brookes University, Oxford OX3 0BP (United Kingdom); Patel, Gaurang; Prise, Kevin M. [Centre for Cancer Research and Cell Biology, Queen' s University Belfast, Belfast BT9 7BL (United Kingdom)

    2010-06-01

    Environmental {sup 222}radon exposure is a human health concern, and many studies demonstrate that very low doses of high LET {alpha}-particle irradiation initiate deleterious genetic consequences in both irradiated and non-irradiated bystander cells. One consequence, radiation-induced genomic instability (RIGI), is a hallmark of tumorigenesis and is often assessed by measuring delayed chromosomal aberrations. We utilised a technique that facilitates transient immobilization of primary lymphocytes for targeted microbeam irradiation and have reported that environmentally relevant doses, e.g. a single {sup 3}He{sup 2+} particle traversal to a single cell, are sufficient to induce RIGI. Herein we sought to determine differences in radiation response in lymphocytes isolated from five healthy male donors. Primary lymphocytes were irradiated with a single particle per cell nucleus. We found evidence for inter-individual variation in radiation response (RIGI, measured as delayed chromosome aberrations). Although this was not highly significant, it was possibly masked by high levels of intra-individual variation. While there are many studies showing a link between genetic predisposition and RIGI, there are few studies linking genetic background with bystander effects in normal human lymphocytes. In an attempt to investigate inter-individual variation in the induction of bystander effects, primary lymphocytes were irradiated with a single particle under conditions where fractions of the population were traversed. We showed a marked genotype-dependent bystander response in one donor after exposure to 15% of the population. The findings may also be regarded as a radiation-induced genotype-dependent bystander effect triggering an instability phenotype.

  12. Genomic instability in quartz dust exposed rat lungs: Is inflammation responsible?

    Energy Technology Data Exchange (ETDEWEB)

    Albrecht, C; Schins, R P F [Institut fuer Umweltmedizinische Forschung (IUF) at the Heinrich Heine University Duesseldorf (Germany); Demircigil, G Cakmak; Coskun, Erdem [Gazi University, Faculty of Pharmacy, Department of Toxicology, Ankara (Turkey); Schooten, F J van [Nutrition and Toxicology Research Institute Maastricht (NUTRIM), Department of Health Risk Analysis and Toxicology, University of Maastricht (Netherlands); Borm, P J A [Centre of Expertise in Life Sciences (Cel), Hogeschool Zuyd, Heerlen (Netherlands); Knaapen, A M, E-mail: catrin.albrecht@uni-duesseldorf.d

    2009-02-01

    the aluminium coated quartz intermediate effects were found. These findings were in line with the kinetics of inflammation and epithelial proliferation in the rat lungs for the different treatments. Notably, a highly significant correlation was observed between neutrophil numbers and micronucleus frequencies, indicative for a role of inflammation in eliciting genomic instability in target cells of quartz-induced carcinogenesis. Our ongoing investigations focus on the evaluation of the causality between both in relation to quartz exposure.

  13. Yeast Sub1 and human PC4 are G-quadruplex binding proteins that suppress genome instability at co-transcriptionally formed G4 DNA.

    Science.gov (United States)

    Lopez, Christopher R; Singh, Shivani; Hambarde, Shashank; Griffin, Wezley C; Gao, Jun; Chib, Shubeena; Yu, Yang; Ira, Grzegorz; Raney, Kevin D; Kim, Nayun

    2017-06-02

    G-quadruplex or G4 DNA is a non-B secondary DNA structure consisting of a stacked array of guanine-quartets that can disrupt critical cellular functions such as replication and transcription. When sequences that can adopt Non-B structures including G4 DNA are located within actively transcribed genes, the reshaping of DNA topology necessary for transcription process stimulates secondary structure-formation thereby amplifying the potential for genome instability. Using a reporter assay designed to study G4-induced recombination in the context of an actively transcribed locus in Saccharomyces cerevisiae, we tested whether co-transcriptional activator Sub1, recently identified as a G4-binding factor, contributes to genome maintenance at G4-forming sequences. Our data indicate that, upon Sub1-disruption, genome instability linked to co-transcriptionally formed G4 DNA in Top1-deficient cells is significantly augmented and that its highly conserved DNA binding domain or the human homolog PC4 is sufficient to suppress G4-associated genome instability. We also show that Sub1 interacts specifically with co-transcriptionally formed G4 DNA in vivo and that yeast cells become highly sensitivity to G4-stabilizing chemical ligands by the loss of Sub1. Finally, we demonstrate the physical and genetic interaction of Sub1 with the G4-resolving helicase Pif1, suggesting a possible mechanism by which Sub1 suppresses instability at G4 DNA. © The Author(s) 2017. Published by Oxford University Press on behalf of Nucleic Acids Research.

  14. Flow-Induced Instabilities in Pump-Turbines in China

    Directory of Open Access Journals (Sweden)

    Zhigang Zuo

    2017-08-01

    Full Text Available The stability of pump-turbines is of great importance to the operation of pumped storage power (PSP stations. Both hydraulic instabilities and operational instabilities have been reported in PSP stations in China. In order to provide a reference to the engineers and scientists working on pump-turbines, this paper summarizes the hydraulic instabilities and performance characteristics that promote the operational instabilities encountered in pump-turbine operations in China. Definitions, analytical methods, numerical and experimental studies, and main results are clarified. Precautions and countermeasures are also provided based on a literature review. The gaps between present studies and the need for engineering practice are pointed out.

  15. Simultaneous Aurora-A/STK15 overexpression and centrosome amplification induce chromosomal instability in tumour cells with a MIN phenotype

    International Nuclear Information System (INIS)

    Lentini, Laura; Amato, Angela; Schillaci, Tiziana; Di Leonardo, Aldo

    2007-01-01

    Genetic instability is a hallmark of tumours and preneoplastic lesions. The predominant form of genome instability in human cancer is chromosome instability (CIN). CIN is characterized by chromosomal aberrations, gains or losses of whole chromosomes (aneuploidy), and it is often associated with centrosome amplification. Centrosomes control cell division by forming a bipolar mitotic spindle and play an essential role in the maintenance of chromosomal stability. However, whether centrosome amplification could directly cause aneuploidy is not fully established. Also, alterations in genes required for mitotic progression could be involved in CIN. A major candidate is represented by Aurora-A/STK15 that associates with centrosomes and is overexpressed in several types of human tumour. Centrosome amplification were induced by hydroxyurea treatment and visualized by immunofluorescence microscopy. Aurora-A/STK15 ectopic expression was achieved by retroviral infection and puromycin selection in HCT116 tumour cells. Effects of Aurora-A/STK15 depletion on centrosome status and ploidy were determined by Aurora-A/STK15 transcriptional silencing by RNA interference. Changes in the expression levels of some mitotic genes were determined by Real time RT-PCR. We investigated whether amplification of centrosomes and overexpression of Aurora-A/STK15 induce CIN using as a model system a colon carcinoma cell line (HCT116). We found that in HCT116 cells, chromosomally stable and near diploid cells harbouring a MIN phenotype, centrosome amplification induced by hydroxyurea treatment is neither maintained nor induces aneuploidy. On the contrary, ectopic overexpression of Aurora-A/STK15 induced supernumerary centrosomes and aneuploidy. Aurora-A/STK15 transcriptional silencing by RNA interference in cells ectopically overexpressing this kinase promptly decreased cell numbers with supernumerary centrosomes and aneuploidy. Our results show that centrosome amplification alone is not sufficient

  16. Fabrication of Micromixers Utilizing Shedding Effect Induced by Electrokinetic Instability

    International Nuclear Information System (INIS)

    Fu, L-M; Tai, C-H; Tsai, C-H; Lin, C-H; Lee, C-Y

    2006-01-01

    This paper proposes a T-shaped micromixer featuring 45 deg. parallelogram barriers within the mixing channel. The proposed device obtains a rapid mixing of two sample fluids by means of the electrokinetic instability induced by shedding effect which is produced as an appropriate intensity of DC electric field of is applied. The proposed device uses a single high-voltage power source to simultaneously drive and mix the sample fluids. The effectiveness of the mixer is characterized experimentally as a function of the applied electrical field intensity and the extent to which the parallelogram barriers obstruct the mixing channel. The experimental results indicate that the mixing performance reaches 91.2% at a cross-section located 2.3 mm downstream of the T-junction when the barriers obstruct four-fifths of the channel width and an electrical field of 300V/cm is applied. The micromixing method presented in this study provides a simple low-cost solution to mixing problems in lab-on-a-chip systems

  17. High Genomic Instability Predicts Survival in Metastatic High-Risk Neuroblastoma

    Directory of Open Access Journals (Sweden)

    Sara Stigliani

    2012-09-01

    Full Text Available We aimed to identify novel molecular prognostic markers to better predict relapse risk estimate for children with high-risk (HR metastatic neuroblastoma (NB. We performed genome- and/or transcriptome-wide analyses of 129 stage 4 HR NBs. Children older than 1 year of age were categorized as “short survivors” (dead of disease within 5 years from diagnosis and “long survivors” (alive with an overall survival time ≥ 5 years. We reported that patients with less than three segmental copy number aberrations in their tumor represent a molecularly defined subgroup with a high survival probability within the current HR group of patients. The complex genomic pattern is a prognostic marker independent of NB-associated chromosomal aberrations, i.e., MYCN amplification, 1p and 11q losses, and 17q gain. Integrative analysis of genomic and expression signatures demonstrated that fatal outcome is mainly associated with loss of cell cycle control and deregulation of Rho guanosine triphosphates (GTPases functioning in neuritogenesis. Tumors with MYCN amplification show a lower chromosome instability compared to MYCN single-copy NBs (P = .0008, dominated by 17q gain and 1p loss. Moreover, our results suggest that the MYCN amplification mainly drives disruption of neuronal differentiation and reduction of cell adhesion process involved in tumor invasion and metastasis. Further validation studies are warranted to establish this as a risk stratification for patients.

  18. Temperature-gradient instability induced by conducting end walls

    International Nuclear Information System (INIS)

    Berk, H.L.; Ryutov, D.D.; Tsidulko, Yu.A.

    1990-04-01

    A new rapidly growing electron temperature gradient instability is found for a plasma in contact with a conducting wall. The linear instability analysis is presented and speculations are given for its nonlinear consequences. This instability illustrates that conducting walls can produce effects that are detrimental to plasma confinement. This mode should be of importance in open-ended systems including astrophysical plasmas, mirror machines and at the edge of tokamaks where field lines are open and are connected to limiters or divertors. 16 refs., 2 figs

  19. Genomic instability of osteosarcoma cell lines in culture: impact on the prediction of metastasis relevant genes.

    Directory of Open Access Journals (Sweden)

    Roman Muff

    Full Text Available Osteosarcoma is a rare but highly malignant cancer of the bone. As a consequence, the number of established cell lines used for experimental in vitro and in vivo osteosarcoma research is limited and the value of these cell lines relies on their stability during culture. Here we investigated the stability in gene expression by microarray analysis and array genomic hybridization of three low metastatic cell lines and derivatives thereof with increased metastatic potential using cells of different passages.The osteosarcoma cell lines showed altered gene expression during in vitro culture, and it was more pronounced in two metastatic cell lines compared to the respective parental cells. Chromosomal instability contributed in part to the altered gene expression in SAOS and LM5 cells with low and high metastatic potential. To identify metastasis-relevant genes in a background of passage-dependent altered gene expression, genes involved in "Pathways in cancer" that were consistently regulated under all passage comparisons were evaluated. Genes belonging to "Hedgehog signaling pathway" and "Wnt signaling pathway" were significantly up-regulated, and IHH, WNT10B and TCF7 were found up-regulated in all three metastatic compared to the parental cell lines.Considerable instability during culture in terms of gene expression and chromosomal aberrations was observed in osteosarcoma cell lines. The use of cells from different passages and a search for genes consistently regulated in early and late passages allows the analysis of metastasis-relevant genes despite the observed instability in gene expression in osteosarcoma cell lines during culture.

  20. Centrosome Dysfunction Contributes To Chromosome Instability, Chromoanagenesis And Genome Reprograming In Cancer.

    Directory of Open Access Journals (Sweden)

    German A Pihan

    2013-11-01

    Full Text Available The unique ability of centrosomes to nucleate and organize microtubules makes them unrivaled conductors of important interphase processes, such as intracellular payload traffic, cell polarity, cell locomotion, and organization of the immunologic synapse. But it is in mitosis that centrosomes loom large, for they orchestrate, with clockmaker’s precision, the assembly and functioning of the mitotic spindle, ensuring the equal partitioning of the replicated genome into daughter cells. Centrosome dysfunction is inextricably linked to aneuploidy and chromosome instability, both hallmarks of cancer cells. Several aspects of centrosome function in normal and cancer cells have been molecularly characterized during the last two decades, greatly enhancing our mechanistic understanding of this tiny organelle. Whether centrosome defects alone can cause cancer, remains unanswered. Until recently, the aggregate of the evidence had suggested that centrosome dysfunction, by deregulating the fidelity of chromosome segregation, promotes and accelerates the characteristic Darwinian evolution of the cancer genome enabled by increased mutational load and/or decreased DNA repair. Very recent experimental work has shown that missegreated chromosomes resulting from centrosome dysfunction may experience extensive DNA damage, suggesting additional dimensions to the role of centrosomes in cancer. Centrosome dysfunction is particularly prevalent in tumors in which the genome has undergone extensive structural rearrangements and chromosome domain reshuffling. Ongoing gene reshuffling reprograms the genome for continuous growth, survival, and evasion of the immune system. Manipulation of molecular networks controlling centrosome function may soon become a viable target for specific therapeutic intervention in cancer, particularly since normal cells, which lack centrosome alterations, may be spared the toxicity of such therapies.

  1. Developmental defects and genomic instability after x-irradiation of wild-type and genetically modified mouse pre-implantation and early post-implantation embryos

    International Nuclear Information System (INIS)

    Jacquet, P

    2012-01-01

    Results obtained from the end of the 1950s suggested that ionizing radiation could induce foetal malformations in some mouse strains when administered during early pre-implantation stages. Starting in 1989, data obtained in Germany also showed that radiation exposure during that period could lead to a genomic instability in the surviving foetuses. Furthermore, the same group reported that both malformations and genomic instability could be transmitted to the next generation foetuses after exposure of zygotes to relatively high doses of radiation. As such results were of concern for radiation protection, we investigated this in more detail during recent years, using mice with varying genetic backgrounds including mice heterozygous for mutations involved in important cellular processes like DNA repair, cell cycle regulation or apoptosis. The main parameters which were investigated included morphological development, genomic instability and gene expression in the irradiated embryos or their own progeny. The aim of this review is to critically reassess the results obtained in that field in the different laboratories and to try to draw general conclusions on the risks of developmental defects and genomic instability from an exposure of early embryos to moderate doses of ionizing radiation. Altogether and in the range of doses normally used in diagnostic radiology, the risk of induction of embryonic death and of congenital malformation following the irradiation of a newly fertilised egg is certainly very low when compared to the ‘spontaneous’ risks for such effects. Similarly, the risk of radiation induction of a genomic instability under such circumstances seems to be very small. However, this is not a reason to not apply some precaution principles when possible. One way of doing this is to restrict the use of higher dose examinations on all potentially pregnant women to the first ten days of their menstrual cycle when conception is very unlikely to have occurred

  2. The influence of elevated endogenous free radical production on apoptosis and genomic instability in transgenic growth hormone mice

    International Nuclear Information System (INIS)

    Lemon, J.A.; Rollo, D.; Boreham, D.R.

    2003-01-01

    Full text: Previous studies have shown transgenic growth hormone mice (TGM) have significantly elevated levels of endogenous reactive oxygen species (ROS) and lipid peroxidation, shortened lifespan (approximately 50% of normal siblings), greatly enhanced learning in youth, and accelerated aging with a rapid age-related loss of cognitive abilities. A complex oral antioxidant supplement was found to completely abolish the cognitive decline and significantly extend longevity in TGM. We have determined in a recently completed experiment studying radiation-induced apoptosis that the antioxidant supplement significantly reduces the elevated level of apoptosis seen in untreated old TGM compared to age-matched controls. It was also determined that older normal mice treated with the supplement also show a reduction in apoptosis. We are conducting experiments using spectral karyotyping to examine genomic instability in TGM and their normal siblings, that indicate, given their elevated ROS, TGM show an increase in chromosome aberrations compared to normal controls. Based on our previous experiments we speculate that TGM treated with the antioxidant supplement are expected to show a reduction in ROS induced chromosome aberrations

  3. A novel ATM-dependent checkpoint defect distinct from loss of function mutation promotes genomic instability in melanoma.

    Science.gov (United States)

    Spoerri, Loredana; Brooks, Kelly; Chia, KeeMing; Grossman, Gavriel; Ellis, Jonathan J; Dahmer-Heath, Mareike; Škalamera, Dubravka; Pavey, Sandra; Burmeister, Bryan; Gabrielli, Brian

    2016-05-01

    Melanomas have high levels of genomic instability that can contribute to poor disease prognosis. Here, we report a novel defect of the ATM-dependent cell cycle checkpoint in melanoma cell lines that promotes genomic instability. In defective cells, ATM signalling to CHK2 is intact, but the cells are unable to maintain the cell cycle arrest due to elevated PLK1 driving recovery from the arrest. Reducing PLK1 activity recovered the ATM-dependent checkpoint arrest, and over-expressing PLK1 was sufficient to overcome the checkpoint arrest and increase genomic instability. Loss of the ATM-dependent checkpoint did not affect sensitivity to ionizing radiation demonstrating that this defect is distinct from ATM loss of function mutations. The checkpoint defective melanoma cell lines over-express PLK1, and a significant proportion of melanomas have high levels of PLK1 over-expression suggesting this defect is a common feature of melanomas. The inability of ATM to impose a cell cycle arrest in response to DNA damage increases genomic instability. This work also suggests that the ATM-dependent checkpoint arrest is likely to be defective in a higher proportion of cancers than previously expected. © 2016 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.

  4. Genomic Instability: The Driving Force behind Refractory/Relapsing Hodgkin’s Lymphoma

    International Nuclear Information System (INIS)

    Knecht, Hans; Righolt, Christiaan; Mai, Sabine

    2013-01-01

    In classical Hodgkin’s lymphoma (HL) the malignant mononuclear Hodgkin (H) and multinuclear, diagnostic Reed-Sternberg (RS) cells are rare and generally make up <3% of the total cellular mass of the affected lymph nodes. During recent years, the introduction of laser micro-dissection techniques at the single cell level has substantially improved our understanding of the molecular pathogenesis of HL. Gene expression profiling, comparative genomic hybridization analysis, micro-RNA expression profiling and viral oncogene sequencing have deepened our knowledge of numerous facets of H- and RS-cell gene expression deregulation. The question remains whether disturbed signaling pathways and deregulated transcription factors are at the origin of refractory/relapsing Hodgkin’s lymphoma or whether these hallmarks are at least partially related to another major factor. We recently showed that the 3D nuclear organization of telomeres and chromosomes marked the transition from H- to RS-cells in HL cell lines. This transition is associated with progression of telomere dysfunction, shelterin disruption and progression of complex chromosomal rearrangements. We reported analogous findings in refractory/relapsing HL and identified the shelterin proteins TRF1, TRF2 and POT1 as targets of the LMP1 oncogene in post-germinal center B-cells. Here we summarize our findings, including data not previously published, and propose a model in which progressive disruption of nuclear integrity, a form of genomic instability, is the key-player in refractory/relapsing HL. Therapeutic approaches should take these findings into account

  5. Condensin II mutation causes T-cell lymphoma through tissue-specific genome instability

    Science.gov (United States)

    Woodward, Jessica; Taylor, Gillian C.; Soares, Dinesh C.; Boyle, Shelagh; Sie, Daoud; Read, David; Chathoth, Keerthi; Vukovic, Milica; Tarrats, Nuria; Jamieson, David; Campbell, Kirsteen J.; Blyth, Karen; Acosta, Juan Carlos; Ylstra, Bauke; Arends, Mark J.; Kranc, Kamil R.; Jackson, Andrew P.; Bickmore, Wendy A.

    2016-01-01

    Chromosomal instability is a hallmark of cancer, but mitotic regulators are rarely mutated in tumors. Mutations in the condensin complexes, which restructure chromosomes to facilitate segregation during mitosis, are significantly enriched in cancer genomes, but experimental evidence implicating condensin dysfunction in tumorigenesis is lacking. We report that mice inheriting missense mutations in a condensin II subunit (Caph2nes) develop T-cell lymphoma. Before tumors develop, we found that the same Caph2 mutation impairs ploidy maintenance to a different extent in different hematopoietic cell types, with ploidy most severely perturbed at the CD4+CD8+ T-cell stage from which tumors initiate. Premalignant CD4+CD8+ T cells show persistent catenations during chromosome segregation, triggering DNA damage in diploid daughter cells and elevated ploidy. Genome sequencing revealed that Caph2 single-mutant tumors are near diploid but carry deletions spanning tumor suppressor genes, whereas P53 inactivation allowed Caph2 mutant cells with whole-chromosome gains and structural rearrangements to form highly aggressive disease. Together, our data challenge the view that mitotic chromosome formation is an invariant process during development and provide evidence that defective mitotic chromosome structure can promote tumorigenesis. PMID:27737961

  6. Instability induced by cross-diffusion in reaction-diffusion systems

    DEFF Research Database (Denmark)

    Tian, Canrong; Lin, Zhigui; Pedersen, Michael

    2010-01-01

    In this paper the instability of the uniform equilibrium of a general strongly coupled reaction–diffusion is discussed. In unbounded domain and bounded domain the sufficient conditions for the instability are obtained respectively. The conclusion is applied to the ecosystem, it is shown that cros...... can induce the instability of an equilibrium which is stable for the kinetic system and for the self-diffusion–reaction system.......In this paper the instability of the uniform equilibrium of a general strongly coupled reaction–diffusion is discussed. In unbounded domain and bounded domain the sufficient conditions for the instability are obtained respectively. The conclusion is applied to the ecosystem, it is shown that cross-diffusion...

  7. A mutation in the centriole-associated protein centrin causes genomic instability via increased chromosome loss in Chlamydomonas reinhardtii

    Directory of Open Access Journals (Sweden)

    Marshall Wallace F

    2005-05-01

    Full Text Available Abstract Background The role of centrioles in mitotic spindle function remains unclear. One approach to investigate mitotic centriole function is to ask whether mutation of centriole-associated proteins can cause genomic instability. Results We addressed the role of the centriole-associated EF-hand protein centrin in genomic stability using a Chlamydomonas reinhardtii centrin mutant that forms acentriolar bipolar spindles and lacks the centrin-based rhizoplast structures that join centrioles to the nucleus. Using a genetic assay for loss of heterozygosity, we found that this centrin mutant showed increased genomic instability compared to wild-type cells, and we determined that the increase in genomic instability was due to a 100-fold increase in chromosome loss rates compared to wild type. Live cell imaging reveals an increased rate in cell death during G1 in haploid cells that is consistent with an elevated rate of chromosome loss, and analysis of cell death versus centriole copy number argues against a role for multipolar spindles in this process. Conclusion The increased chromosome loss rates observed in a centrin mutant that forms acentriolar spindles suggests a role for centrin protein, and possibly centrioles, in mitotic fidelity.

  8. A novel strategy to identify the critical conditions for growth-induced instabilities.

    Science.gov (United States)

    Javili, A; Steinmann, P; Kuhl, E

    2014-01-01

    Geometric instabilities in living structures can be critical for healthy biological function, and abnormal buckling, folding, or wrinkling patterns are often important indicators of disease. Mathematical models typically attribute these instabilities to differential growth, and characterize them using the concept of fictitious configurations. This kinematic approach toward growth-induced instabilities is based on the multiplicative decomposition of the total deformation gradient into a reversible elastic part and an irreversible growth part. While this generic concept is generally accepted and well established today, the critical conditions for the formation of growth-induced instabilities remain elusive and poorly understood. Here we propose a novel strategy for the stability analysis of growing structures motivated by the idea of replacing growth by prestress. Conceptually speaking, we kinematically map the stress-free grown configuration onto a prestressed initial configuration. This allows us to adopt a classical infinitesimal stability analysis to identify critical material parameter ranges beyond which growth-induced instabilities may occur. We illustrate the proposed concept by a series of numerical examples using the finite element method. Understanding the critical conditions for growth-induced instabilities may have immediate applications in plastic and reconstructive surgery, asthma, obstructive sleep apnoea, and brain development. © 2013 Elsevier Ltd. All rights reserved.

  9. [Instability and sensitivity of the genome of healthy children in Magnitogorsk].

    Science.gov (United States)

    Ingel', F I; Krivtsova, E K; Iurtseva, N A; Antipanova, N A; Legostaeva, T B

    2013-01-01

    Problem of the influence of factors of the industrial city on the hereditary apparatus of its residents has not been fully resolved, because of traditionally in such studies only the pollution of environment components is taken into account. However the existence of a set of contributing socialfactors that modify the genotoxic effects ofpollution, requires the creation of a new methodology for genetic and toxicological studies. For this purpose, in Magnitogorsk, where one of Russia's largest steel plants is located, we conducted a comprehensive survey, whose tasks included the analysis of the influence of the complex of exogenous and endogenous factors on the genome of children. In this publication there are presented the results of the fifth fragment of this work - the analysis of instability and individual sensitivity of the genome of 166 children of 5-7 years, residing in two districts of Magnitogorsk: around the steel plant and on the opposite bank of Ural river, where there are no large-scale industrial enterprises. The study was conducted in the micronucleus test on peripheral blood lymphocytes cultured with cytochalasin B. For assessment of individual sensitivity of genome blood cultures were exposed to standard N-methyl-N-nitro-N-nitrosoguanidine (MNNG) mutagen. Cytogenetic analysis was performed in binucleated cells accordingly to international protocol, as well as with the use of an extended protocol including 32 indices. Average group frequency of binuclear cells with micronuclei (0.5-0.7%) were found not differ from the levels defined in children residing in Europe, and not differ between areas of the town. However the extended protocol of cytogenetic analysis discovered that the real frequency of dividing cells with lesions in blood cultures of children was 1,49-1,66%. Higher spontaneous proliferative activity of the cells and the frequency of dividing cells with injuries were found in blood cultures of children residing in settlements around the

  10. The effect of spin induced magnetization on Jeans instability of viscous and resistive quantum plasma

    International Nuclear Information System (INIS)

    Sharma, Prerana; Chhajlani, R. K.

    2014-01-01

    The effect of spin induced magnetization and electrical resistivity incorporating the viscosity of the medium is examined on the Jeans instability of quantum magnetoplasma. Formulation of the system is done by using the quantum magnetohydrodynamic model. The analysis of the problem is carried out by normal mode analysis theory. The general dispersion relation is derived from set of perturbed equations to analyse the growth rate and condition of self-gravitational Jeans instability. To discuss the influence of resistivity, magnetization, and viscosity parameters on Jeans instability, the general dispersion relation is reduced for both transverse and longitudinal mode of propagations. In the case of transverse propagation, the gravitating mode is found to be affected by the viscosity, magnetization, resistivity, and magnetic field strength whereas Jeans criterion of instability is modified by the magnetization and quantum parameter. In the longitudinal mode of propagation, the gravitating mode is found to be modified due to the viscosity and quantum correction in which the Jeans condition of instability is influenced only by quantum parameter. The other non-gravitating Alfven mode in this direction is affected by finite electrical resistivity, spin induced magnetization, and viscosity. The numerical study for the growth rate of Jeans instability is carried out for both in the transverse and longitudinal direction of propagation to the magnetic field. The effect of various parameters on the growth rate of Jeans instability in quantum plasma is analysed

  11. On the ghost-induced instability on de Sitter background

    Science.gov (United States)

    Peter, Patrick; Salles, Filipe de O.; Shapiro, Ilya L.

    2018-03-01

    It is known that the perturbative instability of tensor excitations in higher derivative gravity may not take place if the initial frequency of the gravitational waves is below the Planck threshold. One can assume that this is a natural requirement if the cosmological background is sufficiently mild, since in this case the situation is qualitatively close to the free gravitational wave in flat space. Here, we explore the opposite situation and consider the effect of a very far from Minkowski radiation-dominated or de Sitter cosmological background with a large Hubble rate, e.g., typical of an inflationary period. It turns out that, then, for initial Planckian or even trans-Planckian frequencies, the instability is rapidly suppressed by the very fast expansion of the Universe.

  12. Folic acid deficiency increases chromosomal instability, chromosome 21 aneuploidy and sensitivity to radiation-induced micronuclei

    International Nuclear Information System (INIS)

    Beetstra, Sasja; Thomas, Philip; Salisbury, Carolyn; Turner, Julie; Fenech, Michael

    2005-01-01

    Folic acid deficiency can lead to uracil incorporation into DNA, hypomethylation of DNA, inefficient DNA repair and increase chromosome malsegregation and breakage. Because ionising radiation increases demand for efficient DNA repair and also causes chromosome breaks we hypothesised that folic acid deficiency may increase sensitivity to radiation-induced chromosome breakage. We tested this hypothesis by using the cytokinesis-block micronucleus assay in 10 day WIL2-NS cell cultures at four different folic acid concentrations (0.2, 2, 20, and 200 nM) that span the 'normal' physiological range in humans. The study showed a significant dose-dependent increase in frequency of binucleated cells with micronuclei and/or nucleoplasmic bridges with decreasing folic acid concentration (P < 0.0001, P = 0.028, respectively). These biomarkers of chromosomal instability were also increased in cells irradiated (1.5 Gy γ-rays) on day 9 relative to un-irradiated controls (P < 0.05). Folic acid deficiency and γ-irradiation were shown to have a significant interactive effect on frequency of cells containing micronuclei (two-way ANOVA, interaction P 0.0039) such that the frequency of radiation-induced micronucleated cells (i.e. after subtracting base-line frequency of un-irradiated controls) increased with decreasing folic acid concentration (P-trend < 0.0001). Aneuploidy of chromosome 21, apoptosis and necrosis were increased by folic acid deficiency but not by ionising radiation. The results of this study show that folate status has an important impact on chromosomal stability and is an important modifying factor of cellular sensitivity to radiation-induced genome damage

  13. CENPA overexpression promotes genome instability in pRb-depleted human cells

    Directory of Open Access Journals (Sweden)

    Lentini Laura

    2009-12-01

    Full Text Available Abstract Background Aneuploidy is a hallmark of most human cancers that arises as a consequence of chromosomal instability and it is frequently associated with centrosome amplification. Functional inactivation of the Retinoblastoma protein (pRb has been indicated as a cause promoting chromosomal instability as well centrosome amplification. However, the underlying molecular mechanism still remains to be clarified. Results Here we show that pRb depletion both in wild type and p53 knockout HCT116 cells was associated with the presence of multipolar spindles, anaphase bridges, lagging chromosomes and micronuclei harbouring whole chromosomes. In addition aneuploidy caused by pRb acute loss was not affected by p53 loss. Quantitative real-time RT-PCR showed that pRB depletion altered expression of genes involved in centrosome duplication, kinetochore assembly and in the Spindle Assembly Checkpoint (SAC. However, despite MAD2 up-regulation pRb-depleted cells seemed to have a functional SAC since they arrested in mitosis after treatments with mitotic poisons. Moreover pRb-depleted HCT116 cells showed BRCA1 overexpression that seemed responsible for MAD2 up-regulation. Post-transcriptional silencing of CENPA by RNA interference, resulting in CENP-A protein levels similar to those present in control cells greatly reduced aneuploid cell numbers in pRb-depleted cells. Conclusion Altogether our findings indicate a novel aspect of pRb acute loss that promotes aneuploidy mainly by inducing CENPA overexpression that in turn might induce micronuclei by affecting the correct attachment of spindle microtubules to kinetochores.

  14. Chromosomal Replication Complexity: A Novel DNA Metrics and Genome Instability Factor.

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    Andrei Kuzminov

    2016-10-01

    Full Text Available As the ratio of the copy number of the most replicated to the unreplicated regions in the same chromosome, the definition of chromosomal replication complexity (CRC appears to leave little room for variation, being either two during S-phase or one otherwise. However, bacteria dividing faster than they replicate their chromosome spike CRC to four and even eight. A recent experimental inquiry about the limits of CRC in Escherichia coli revealed two major reasons to avoid elevating it further: (i increased chromosomal fragmentation and (ii complications with subsequent double-strand break repair. Remarkably, examples of stable elevated CRC in eukaryotic chromosomes are well known under various terms like "differential replication," "underreplication," "DNA puffs," "onion-skin replication," or "re-replication" and highlight the phenomenon of static replication fork (sRF. To accurately describe the resulting "amplification by overinitiation," I propose a new term: "replification" (subchromosomal overreplication. In both prokaryotes and eukaryotes, replification, via sRF processing, causes double-strand DNA breaks and, with their repair elevating chromosomal rearrangements, represents a novel genome instability factor. I suggest how static replication bubbles could be stabilized and speculate that some tandem duplications represent such persistent static bubbles. Moreover, I propose how static replication bubbles could be transformed into tandem duplications, double minutes, or inverted triplications. Possible experimental tests of these models are discussed.

  15. Estimation of low-dose radiation-responsive proteins in the absence of genomic instability in normal human fibroblast cells.

    Science.gov (United States)

    Yim, Ji-Hye; Yun, Jung Mi; Kim, Ji Young; Nam, Seon Young; Kim, Cha Soon

    2017-11-01

    Low-dose radiation has various biological effects such as adaptive responses, low-dose hypersensitivity, as well as beneficial effects. However, little is known about the particular proteins involved in these effects. Here, we sought to identify low-dose radiation-responsive phosphoproteins in normal fibroblast cells. We assessed genomic instability and proliferation of fibroblast cells after γ-irradiation by γ-H2AX foci and micronucleus formation analyses and BrdU incorporation assay, respectively. We screened fibroblast cells 8 h after low-dose (0.05 Gy) γ-irradiation using Phospho Explorer Antibody Microarray and validated two differentially expressed phosphoproteins using Western blotting. Cell proliferation proceeded normally in the absence of genomic instability after low-dose γ-irradiation. Phospho antibody microarray analysis and Western blotting revealed increased expression of two phosphoproteins, phospho-NFκB (Ser536) and phospho-P70S6K (Ser418), 8 h after low-dose radiation. Our findings suggest that low-dose radiation of normal fibroblast cells activates the expression of phospho-NFκB (Ser536) and phospho-P70S6K (Ser418) in the absence of genomic instability. Therefore, these proteins may be involved in DNA damage repair processes.

  16. Hund's Induced Fermi-Liquid Instabilities and Enhanced Quasiparticle Interactions.

    Science.gov (United States)

    De' Medici, Luca

    2017-04-21

    Hund's coupling is shown to generally favor, in a doped half-filled Mott insulator, an increase in the compressibility culminating in a Fermi-liquid instability towards phase separation. The largest effect is found near the frontier between an ordinary and an orbitally decoupled ("Hund's") metal. The increased compressibility implies an enhancement of quasiparticle scattering, thus favoring other possible symmetry breakings. This physics is shown to happen in simulations of the 122 Fe-based superconductors, possibly implying the relevance of this mechanism in the enhancement of the critical temperature for superconductivity.

  17. Simultaneous Aurora-A/STK15 overexpression and centrosome amplification induce chromosomal instability in tumour cells with a MIN phenotype

    Directory of Open Access Journals (Sweden)

    Schillaci Tiziana

    2007-11-01

    Full Text Available Abstract Background Genetic instability is a hallmark of tumours and preneoplastic lesions. The predominant form of genome instability in human cancer is chromosome instability (CIN. CIN is characterized by chromosomal aberrations, gains or losses of whole chromosomes (aneuploidy, and it is often associated with centrosome amplification. Centrosomes control cell division by forming a bipolar mitotic spindle and play an essential role in the maintenance of chromosomal stability. However, whether centrosome amplification could directly cause aneuploidy is not fully established. Also, alterations in genes required for mitotic progression could be involved in CIN. A major candidate is represented by Aurora-A/STK15 that associates with centrosomes and is overexpressed in several types of human tumour. Methods Centrosome amplification were induced by hydroxyurea treatment and visualized by immunofluorescence microscopy. Aurora-A/STK15 ectopic expression was achieved by retroviral infection and puromycin selection in HCT116 tumour cells. Effects of Aurora-A/STK15 depletion on centrosome status and ploidy were determined by Aurora-A/STK15 transcriptional silencing by RNA interference. Changes in the expression levels of some mitotic genes were determined by Real time RT-PCR. Results We investigated whether amplification of centrosomes and overexpression of Aurora-A/STK15 induce CIN using as a model system a colon carcinoma cell line (HCT116. We found that in HCT116 cells, chromosomally stable and near diploid cells harbouring a MIN phenotype, centrosome amplification induced by hydroxyurea treatment is neither maintained nor induces aneuploidy. On the contrary, ectopic overexpression of Aurora-A/STK15 induced supernumerary centrosomes and aneuploidy. Aurora-A/STK15 transcriptional silencing by RNA interference in cells ectopically overexpressing this kinase promptly decreased cell numbers with supernumerary centrosomes and aneuploidy. Conclusion Our

  18. Alpha-induced instabilities in tandem thermal barriers

    Energy Technology Data Exchange (ETDEWEB)

    Kammash, T.; Galbraith, D.L.

    1987-01-01

    A major premise in the operation of Tandem Mirror reactors is that the fusion reactions take place in the central cell only. The alpha particles generated by the Deuterium-Tritium (DT) fusions, along with other ions, will however pass from the central cell to the thermal barriers and return to the central cell as a result of reflection by the potential hills that exist by the plugs' side of these barriers. This streaming motion gives rise to electrostatic and electomagnetic instabilities which could detract from the barrier's function as a thermal insulator. The number density and streaming velocity of these passing particles are dictated by the electrostatic potential variation and the magnetic field structure in these regions. It is shown that, in the absence of alphas, barriers with deep potential depression are less susceptible to electrostatic instabilities while particularly vulnerable to unstable electromagnetic modes. In the presence of alphas, especially the fast alphas whose mean energy is significantly larger than the barrier potentials they see, (which is twice as high as that seen by the ions) both types of modes become unstable.

  19. The Adaptive Response in p53 Cancer Prone Mice: Loss of heterozygosity and Genomic Instability

    International Nuclear Information System (INIS)

    Lavoie Jose; Dolling Jo-Anna; Mitchel Ron E J; Boreham Douglas R

    2004-01-01

    mice, only numerical aberrations were observed in 5 to 20% of the cells. There seem to be an age related increase in numerical aberrations as mice grow old. The results indicate that the presence of a defective copy of the Trp53 gene does not seem to affect spontaneous chromosomal instability or in response to chronic low dose exposure to g-radiation. In previous studies it was speculated that low dose and low dose rate in vivo exposure to g-radiation induces an adaptive response, which reduces the risk of cancer death generated by subsequent DNA damage from either spontaneous or radiation induced events due to enhanced recombinational repair. Induced recombination could result from reversion to homozygosity at Trp53 gene locus (Trp53 +/- to +/+) or loss of heterozygosity in unexposed mice (Trp53 +/- to -/-). This hypothesis was investigated using the quantitative real-time Polymerase Chain Reaction (QRT-PCR) quantification method and the novel Rolling Circle Amplification technique (RCA). For these purposes, spleenocytes and bone marrow cells from all the mice were isolated for cell fixation and DNA extraction. The defective Trp53 allele is generated by integration of a portion of the cloning vector pKONEO DNA into the coding sequence. Therefore, the genotypic changes are monitored based on the detection of the NEO allele and the normal Trp53 allele in the cells. To evaluate loss of heterozygosity at the Trp53 gene locus in a cell, detection of the NEO allele and the normal Trp53 allele using the dual color RCA was utilized. In our hands, this protocol did not give the required sensitivity. The gene signal enumeration was inconsistent and not reproducible. The protocol was modified and could not be optimized. Therefore, the QRT-PCR method was selected to evaluate the loss of heterozygosity with greater sensitivity and efficiency. A set of 4 primers was designed to target the NEO allele and the normal Trp53 allele in a PCR experiment using the LightCycler instrument

  20. Mechanical instability and titanium particles induce similar transcriptomic changes in a rat model for periprosthetic osteolysis and aseptic loosening

    Directory of Open Access Journals (Sweden)

    Mehdi Amirhosseini

    2017-12-01

    Full Text Available Wear debris particles released from prosthetic bearing surfaces and mechanical instability of implants are two main causes of periprosthetic osteolysis. While particle-induced loosening has been studied extensively, mechanisms through which mechanical factors lead to implant loosening have been less investigated. This study compares the transcriptional profiles associated with osteolysis in a rat model for aseptic loosening, induced by either mechanical instability or titanium particles. Rats were exposed to mechanical instability or titanium particles. After 15 min, 3, 48 or 120 h from start of the stimulation, gene expression changes in periprosthetic bone tissue was determined by microarray analysis. Microarray data were analyzed by PANTHER Gene List Analysis tool and Ingenuity Pathway Analysis (IPA. Both types of osteolytic stimulation led to gene regulation in comparison to unstimulated controls after 3, 48 or 120 h. However, when mechanical instability was compared to titanium particles, no gene showed a statistically significant difference (fold change ≥ ±1.5 and adjusted p-value ≤ 0.05 at any time point. There was a remarkable similarity in numbers and functional classification of regulated genes. Pathway analysis showed several inflammatory pathways activated by both stimuli, including Acute Phase Response signaling, IL-6 signaling and Oncostatin M signaling. Quantitative PCR confirmed the changes in expression of key genes involved in osteolysis observed by global transcriptomics. Inflammatory mediators including interleukin (IL-6, IL-1β, chemokine (C-C motif ligand (CCL2, prostaglandin-endoperoxide synthase (Ptgs2 and leukemia inhibitory factor (LIF showed strong upregulation, as assessed by both microarray and qPCR. By investigating genome-wide expression changes we show that, despite the different nature of mechanical implant instability and titanium particles, osteolysis seems to be induced through similar biological

  1. DNA Oncogenic Virus-Induced Oxidative Stress, Genomic Damage, and Aberrant Epigenetic Alterations

    Directory of Open Access Journals (Sweden)

    Mankgopo Magdeline Kgatle

    2017-01-01

    Full Text Available Approximately 20% of human cancers is attributable to DNA oncogenic viruses such as human papillomavirus (HPV, hepatitis B virus (HBV, and Epstein-Barr virus (EBV. Unrepaired DNA damage is the most common and overlapping feature of these DNA oncogenic viruses and a source of genomic instability and tumour development. Sustained DNA damage results from unceasing production of reactive oxygen species and activation of inflammasome cascades that trigger genomic changes and increased propensity of epigenetic alterations. Accumulation of epigenetic alterations may interfere with genome-wide cellular signalling machineries and promote malignant transformation leading to cancer development. Untangling and understanding the underlying mechanisms that promote these detrimental effects remain the major objectives for ongoing research and hope for effective virus-induced cancer therapy. Here, we review current literature with an emphasis on how DNA damage influences HPV, HVB, and EBV replication and epigenetic alterations that are associated with carcinogenesis.

  2. Clonal chromosomal and genomic instability during human multipotent mesenchymal stromal cells long-term culture.

    Directory of Open Access Journals (Sweden)

    Victoria Nikitina

    Full Text Available Spontaneous mutagenesis often leads to appearance of genetic changes in cells. Although human multipotent mesenchymal stromal cells (hMSC are considered as genetically stable, there is a risk of genomic and structural chromosome instability and, therefore, side effects of cell therapy associated with long-term effects. In this study, the karyotype, genetic variability and clone formation analyses have been carried out in the long-term culture MSC from human gingival mucosa.The immunophenotype of MSC has been examined using flow cytofluorometry and short tandem repeat (STR analysis has been carried out for authentication. The karyotype has been examined using GTG staining and mFISH, while the assessment of the aneuploidy 8 frequency has been performed using centromere specific chromosome FISH probes in interphase cells.The immunophenotype and STR loci combination did not change during the process of cultivation. From passage 23 the proliferative activity of cultured MSCs was significantly reduced. From passage 12 of cultivation, clones of cells with stable chromosome aberrations have been identified and the biggest of these (12% are tetrasomy of chromosome 8. The random genetic and structural chromosomal aberrations and the spontaneous level of chromosomal aberrations in the hMSC long-term cultures were also described.The spectrum of spontaneous chromosomal aberrations in MSC long-term cultivation has been described. Clonal chromosomal aberrations have been identified. A clone of cells with tetrasomy 8 has been detected in passage 12 and has reached the maximum size by passage 18 before and decreased along with the reduction of proliferative activity of cell line by passage 26. At later passages, the MSC line exhibited a set of cells with structural variants of the karyotype with a preponderance of normal diploid cells. The results of our study strongly suggest a need for rigorous genetic analyses of the clone formation in cultured MSCs before

  3. Preferential retrotransposition in aging yeast mother cells is correlated with increased genome instability.

    Science.gov (United States)

    Patterson, Melissa N; Scannapieco, Alison E; Au, Pak Ho; Dorsey, Savanna; Royer, Catherine A; Maxwell, Patrick H

    2015-10-01

    Retrotransposon expression or mobility is increased with age in multiple species and could promote genome instability or altered gene expression during aging. However, it is unclear whether activation of retrotransposons during aging is an indirect result of global changes in chromatin and gene regulation or a result of retrotransposon-specific mechanisms. Retromobility of a marked chromosomal Ty1 retrotransposon in Saccharomyces cerevisiae was elevated in mother cells relative to their daughter cells, as determined by magnetic cell sorting of mothers and daughters. Retromobility frequencies in aging mother cells were significantly higher than those predicted by cell age and the rate of mobility in young populations, beginning when mother cells were only several generations old. New Ty1 insertions in aging mothers were more strongly correlated with gross chromosome rearrangements than in young cells and were more often at non-preferred target sites. Mother cells were more likely to have high concentrations and bright foci of Ty1 Gag-GFP than their daughter cells. Levels of extrachromosomal Ty1 cDNA were also significantly higher in aged mother cell populations than their daughter cell populations. These observations are consistent with a retrotransposon-specific mechanism that causes retrotransposition to occur preferentially in yeast mother cells as they begin to age, as opposed to activation by phenotypic changes associated with very old age. These findings will likely be relevant for understanding retrotransposons and aging in many organisms, based on similarities in regulation and consequences of retrotransposition in diverse species. Copyright © 2015 Elsevier B.V. All rights reserved.

  4. Turbulent mixing induced by Richtmyer-Meshkov instability

    Science.gov (United States)

    Krivets, V. V.; Ferguson, K. J.; Jacobs, J. W.

    2017-01-01

    Richtmyer-Meshkov instability is studied in shock tube experiments with an Atwood number of 0.7. The interface is formed in a vertical shock tube using opposed gas flows, and three-dimensional random initial interface perturbations are generated by the vertical oscillation of gas column producing Faraday waves. Planar Laser Mie scattering is used for flow visualization and for measurements of the mixing process. Experimental image sequences are recorded at 6 kHz frequency and processed to obtain the time dependent variation of the integral mixing layer width. Measurements of the mixing layer width are compared with Mikaelian's [1] model in order to extract the growth exponent θ where a fairly wide range of values is found varying from θ ≈ 0.2 to 0.6.

  5. Field-induced magnetic instability within a superconducting condensate

    DEFF Research Database (Denmark)

    Mazzone, Daniel Gabriel; Raymond, Stephane; Gavilano, Jorge Luis

    2017-01-01

    The application of magnetic fields, chemical substitution, or hydrostatic pressure to strongly correlated electron materials can stabilize electronic phases with different organizational principles. We present evidence for a fieldinduced quantum phase transition, in superconducting Nd0.05Ce0.95Co...... that the magnetic instability is not magnetically driven, and we propose that it is driven by a modification of superconducting condensate at H*.......In5, that separates two antiferromagnetic phases with identical magnetic symmetry. At zero field, we find a spin-density wave that is suppressed at the critical field mu H-0* = 8 T. For H > H*, a spin-density phase emerges and shares many properties with the Q phase in CeCoIn5. These results suggest...

  6. The instability of the spiral wave induced by the deformation of elastic excitable media

    International Nuclear Information System (INIS)

    Ma Jun; Jia Ya; Wang Chunni; Li Shirong

    2008-01-01

    There are some similarities between the spiral wave in excitable media and in cardiac tissue. Much evidence shows that the appearance and instability of the spiral wave in cardiac tissue can be linked to one kind of heart disease. There are many models that can be used to investigate the formation and instability of the spiral wave. Cardiac tissue is excitable and elastic, and it is interesting to simulate the transition and instability of the spiral wave induced by media deformation. For simplicity, a class of the modified Fitzhugh-Nagumo (MFHN) model, which can generate a stable rotating spiral wave, meandering spiral wave and turbulence within appropriate parameter regions, will be used to simulate the instability of the spiral wave induced by the periodical deformation of media. In the two-dimensional case, the total acreage of elastic media is supposed to be invariable in the presence of deformation, and the problem is described with L x x L y = N x ΔxN x Δy = L' x L' y = N x Δx'N x Δy'. In our studies, elastic media are decentralized into N x N sites and the space of the adjacent sites is changed to simulate the deformation of elastic media. Based on the nonlinear dynamics theory, the deformation effect on media is simplified and simulated by perturbing the diffusion coefficients D x and D y with different periodical signals, but the perturbed diffusion coefficients are compensatory. The snapshots of our numerical results find that the spiral wave can coexist with the spiral turbulence, instability of the spiral wave and weak deformation of the spiral wave in different conditions. The ratio parameter ε and the frequency of deformation forcing play a deterministic role in inducing instability of the spiral wave. Extensive studies confirm that the instability of the spiral wave can be induced and developed only if an appropriate frequency for deformation is used. We analyze the power spectrum for the time series of the mean activator of four sampled sites

  7. The instability of the spiral wave induced by the deformation of elastic excitable media

    Science.gov (United States)

    Ma, Jun; Jia, Ya; Wang, Chun-Ni; Li, Shi-Rong

    2008-09-01

    There are some similarities between the spiral wave in excitable media and in cardiac tissue. Much evidence shows that the appearance and instability of the spiral wave in cardiac tissue can be linked to one kind of heart disease. There are many models that can be used to investigate the formation and instability of the spiral wave. Cardiac tissue is excitable and elastic, and it is interesting to simulate the transition and instability of the spiral wave induced by media deformation. For simplicity, a class of the modified Fitzhugh-Nagumo (MFHN) model, which can generate a stable rotating spiral wave, meandering spiral wave and turbulence within appropriate parameter regions, will be used to simulate the instability of the spiral wave induced by the periodical deformation of media. In the two-dimensional case, the total acreage of elastic media is supposed to be invariable in the presence of deformation, and the problem is described with Lx × Ly = N × ΔxN × Δy = L'xL'y = N × Δx'N × Δy'. In our studies, elastic media are decentralized into N × N sites and the space of the adjacent sites is changed to simulate the deformation of elastic media. Based on the nonlinear dynamics theory, the deformation effect on media is simplified and simulated by perturbing the diffusion coefficients Dx and Dy with different periodical signals, but the perturbed diffusion coefficients are compensatory. The snapshots of our numerical results find that the spiral wave can coexist with the spiral turbulence, instability of the spiral wave and weak deformation of the spiral wave in different conditions. The ratio parameter ɛ and the frequency of deformation forcing play a deterministic role in inducing instability of the spiral wave. Extensive studies confirm that the instability of the spiral wave can be induced and developed only if an appropriate frequency for deformation is used. We analyze the power spectrum for the time series of the mean activator of four sampled sites

  8. Rayleigh-Taylor and Richtmyer-Meshkov instability induced flow, turbulence, and mixing. I

    Science.gov (United States)

    Zhou, Ye

    2017-12-01

    Rayleigh-Taylor (RT) and Richtmyer-Meshkov (RM) instabilities play an important role in a wide range of engineering, geophysical, and astrophysical flows. They represent a triggering event that, in many cases, leads to large-scale turbulent mixing. Much effort has been expended over the past 140 years, beginning with the seminal work of Lord Rayleigh, to predict the evolution of the instabilities and of the instability-induced mixing layers. The objective of Part I of this review is to provide the basic properties of the flow, turbulence, and mixing induced by RT, RM, and Kelvin-Helmholtz (KH) instabilities. Historical efforts to study these instabilities are briefly reviewed, and the significance of these instabilities is discussed for a variety of flows, particularly for astrophysical flows and for the case of inertial confinement fusion. Early experimental efforts are described, and analytical attempts to model the linear, and nonlinear regimes of these mixing layers are examined. These analytical efforts include models for both single-mode and multi-mode initial conditions, as well as multi-scale models to describe the evolution. Comparisons of these models and theories to experimental and simulation studies are then presented. Next, attention is paid to the issue of the influence of stabilizing mechanisms (e.g., viscosity, surface tension, and diffuse interface) on the evolution of these instabilities, as well as the limitations and successes of numerical methods. Efforts to study these instabilities and mixing layers using group-theoretic ideas, as well as more formal notions of turbulence cascade processes during the later stages of the induced mixing layers, are inspected. A key element of the review is the discussion of the late-time self-similar scaling for the RT and RM growth factors, α and θ. These parameters are influenced by the initial conditions and much of the observed variation can be explained by this. In some cases, these instabilities

  9. Self-induced temporal instability from a neutrino antenna

    Energy Technology Data Exchange (ETDEWEB)

    Capozzi, Francesco [Dipartimento di Fisica e Astronomia “Galileo Galilei”,Via Marzolo 8, 35131 Padova (Italy); INFN - Sezione di Padova,Via Marzolo 8, 35131 Padova (Italy); Dasgupta, Basudeb [Tata Institute of Fundamental Research,Homi Bhabha Road, Mumbai, 400005 (India); Mirizzi, Alessandro [Dipartimento Interateneo di Fisica “Michelangelo Merlin”,Via Amendola 173, 70126 Bari (Italy); INFN - Sezione di Bari,Via Amendola 173, 70126 Bari (Italy)

    2016-04-21

    It has been recently shown that the flavor composition of a self-interacting neutrino gas can spontaneously acquire a time-dependent pulsating component during its flavor evolution. In this work, we perform a more detailed study of this effect in a model where neutrinos are assumed to be emitted in a two-dimensional plane from an infinite line that acts as a neutrino antenna. We consider several examples with varying matter and neutrino densities and find that temporal instabilities with various frequencies are excited in a cascade. We compare the numerical calculations of the flavor evolution with the predictions of linearized stability analysis of the equations of motion. The results obtained with these two approaches are in good agreement in the linear regime, while a dramatic speed-up of the flavor conversions occurs in the non-linear regime due to the interactions among the different pulsating modes. We show that large flavor conversions can take place if some of the temporal modes are unstable for long enough, and that this can happen even if the matter and neutrino densities are changing, as long as they vary slowly.

  10. Agent Model Development for Assessing Climate-Induced Geopolitical Instability.

    Energy Technology Data Exchange (ETDEWEB)

    Boslough, Mark B.; Backus, George A.

    2005-12-01

    We present the initial stages of development of new agent-based computational methods to generate and test hypotheses about linkages between environmental change and international instability. This report summarizes the first year's effort of an originally proposed three-year Laboratory Directed Research and Development (LDRD) project. The preliminary work focused on a set of simple agent-based models and benefited from lessons learned in previous related projects and case studies of human response to climate change and environmental scarcity. Our approach was to define a qualitative model using extremely simple cellular agent models akin to Lovelock's Daisyworld and Schelling's segregation model. Such models do not require significant computing resources, and users can modify behavior rules to gain insights. One of the difficulties in agent-based modeling is finding the right balance between model simplicity and real-world representation. Our approach was to keep agent behaviors as simple as possible during the development stage (described herein) and to ground them with a realistic geospatial Earth system model in subsequent years. This work is directed toward incorporating projected climate data--including various C02 scenarios from the Intergovernmental Panel on Climate Change (IPCC) Third Assessment Report--and ultimately toward coupling a useful agent-based model to a general circulation model.3

  11. [Study of genome instability using DNA fingerprinting of the offspring of male mice subjected to chronic low dose gamma irradiation].

    Science.gov (United States)

    Bezlepkin, V G; Vasil'eva, G V; Lomaeva, M G; Sirota, N P; Gaziev, A I

    2000-01-01

    By a polymerase chain reaction with an arbitrary primer (AP-PCR), the possibility of transmission of genome instability to somatic cells of the offspring (F1 generation) from male parents of mice exposed to chronic low-level gamma-radiation was studied. Male BALB/c mice 15 days after exposure to 10-50 cGy were mated with unirradiated females. Biopsies were taken from tale tips of two month-old offspring mice and DNA was isolated. The primer in the AP-PCR was a 20-mer oligonucleotide flanking the microsatellite locus Atp1b2 on chromosome 11 of the mouse. A comparative analysis of individual fingerprints of AP-PCR products on DNA-templates from the offspring of irradiated and unirradiated male mice revealed an increased variability of microsatellite-associated sequences in the genome of the offspring of the males exposed to 25 and 50 cGy. The DNA-fingerprints of the offspring of male mice exposed to chronic irradiation with the doses 10 and 25 cGy 15 days before fertilization (at the post-meiotic stage of spermatogenesis) showed an increased frequency of "non-parent bands". The results of the study point to the possibility of transmission to the offspring somatic cells of changes increasing genome instability from male parents exposed to chronic low-level radiation prior to fertilization.

  12. Experimental and numerical investigations on flashing-induced instabilities in a single channel

    Energy Technology Data Exchange (ETDEWEB)

    Marcel, Christian P.; Rohde, M.; Van Der Hagen, T.H.J.J. [Department of Physics of Nuclear Reactors, Delft University of Technology (TUDelft), Delft, 2629 JB (Netherlands)

    2009-11-15

    During the start-up phase, natural circulation BWRs (NC-BWRs) need to be operated at low pressure conditions. Such conditions favor flashing-induced instabilities due to the large hydrostatic pressure drop induced by the tall chimney. Moreover, in novel NC-BWR designs the steam separation is performed in the steam separators which create large pressure drops at the chimney outlet, which effect on stability has not been investigated yet. In this work, flashing-induced oscillations occurring in a tall, bottom heated channel are numerically investigated by using a simple linear model with three regions and an accurate implementation for estimating the water properties. The model is used to investigate flashing-induced instabilities in a channel for different values of the core inlet friction value. The results are compared with experiments obtained by using the CIRCUS facility at the same conditions, showing a good agreement. In addition, the experiments on flashing-induced instabilities are presented in a novel manner allowing visualizing new details of the phenomenon numerical stability investigations on the effect of the friction distribution are also done. It is found that by increasing the total restriction in the channel the system is destabilized. In addition, the chimney outlet restriction has a stronger destabilizing effect than the core inlet restriction. A stable two-phase region is observed prior to the instabilities in the experiments and the numerical simulations which may help to pressurize the vessel of NC-BWRs and thus reducing the effects of flashing instabilities during start-up. (author)

  13. Radiation induced chromosomal instability in lymphocytes of cancer patients

    International Nuclear Information System (INIS)

    Sudo, H.; Sagara, M.; Ban, S.; Noda, S.; Iwakawa, M.; Harada, Y.; Imai, T.; Cologne, J.B.

    2003-01-01

    Full text: Cytokinesis-blocked micronucleus (CBMN) assay has been extensively used to evaluate the radiation sensitivity of human individuals. Using the CBMN assay, Scott et al (1998, 1999) demonstrated that a fraction of radiosensitive individuals in breast cancer case population was larger than in normal individual population. However, Vral et al were very skeptical about the Scott et al's findings (2002). Under the approval from the ethical committee of NIRS, peripheral blood was obtained from 46 normal healthy females, 131 breast cancer patients, 32 cervical cancer patients and 7 female head and neck cancer patients. Radiosensitivity of T-lymphocytes was assessed by using a CBMN assay. The frequencies of MN per binucleated cell in healthy donors were 0.031(±0.010) and 0.151(±0.066) for cells treated before and after X-ray-irradiation (2Gy), respectively. Spontaneous MN frequencies in cancer patients were significantly higher than healthy donors (p < 0.001). Radiation sensitivities of breast- and head and neck-cancer patients were significantly higher than normal individuals (p < 0.001). Cervical cancer patients were more resistant to irradiation than healthy donors, though the number of cases for statistical analysis was small. (p < 0.001). We are considering that the HPV infection affected the radiosensitivity of cervical cancer cases. Because it is widely believed that one key mechanism which leads to spontaneous micronucleus formation involves an imbalance of chromosomal segregation and a chromosomal instability in patients' lymphocytes might be greater than that in normal individuals' lymphocytes. Recently, Kuschel et al (2002) demonstrated that ratios in two SNPs on XRCC3 were significantly different between cancer patients and healthy females. Then, we can suppose that the radiation-related genes with low penetrance may be involved in tumorigenesis of mammary- and head and neck-cells, and also, in patients' radiation susceptibility

  14. Evidence of a genetic instability induced by the incorporation of a DNA precursor marked with tritium

    International Nuclear Information System (INIS)

    Saintigny, Y.; Laurent, D.; Lahayel, J.B.; Roche, St.; Meynard, D.; Lopez, B.S.

    2009-01-01

    The authors report a molecular geno-toxicology investigation which allowed molecular events induced par intracellular incorporation of tritium to be studied, and the genetic instability resulting from a chronic exposure even at low dose to be analysed. For this purpose, they developed cell models (hamster tumorous cells and human fibroblasts) in which they know how to incorporate given quantities of marked nucleotides in the DNA. They show that the incorporation of tritium, even with doses which are said to be non toxic, causes a prolonged exposure of the cell to a genotoxic stress, and maybe a genetic instability due to a too great number of recombination events

  15. Genomic Instability Promoted by Overexpression of Mismatch Repair Factors in Yeast: A Model for Understanding Cancer Progression.

    Science.gov (United States)

    Chakraborty, Ujani; Dinh, Timothy A; Alani, Eric

    2018-04-13

    Mismatch repair (MMR) proteins act in spellchecker roles to excise misincorporation errors that occur during DNA replication. Curiously, large-scale analyses of a variety of cancers showed that increased expression of MMR proteins often correlated with tumor aggressiveness, metastasis, and early recurrence. To better understand these observations, we used the TCGA and GENT databases to analyze MMR protein expression in cancers. We found that the MMR genes MSH2 and MSH6 are overexpressed more frequently than MSH3 , and that MSH2 and MSH6 are often co-overexpressed as a result of copy number amplifications of these genes. These observations encouraged us to test the effects of upregulating MMR protein levels in baker's yeast, where we can sensitively monitor genome instability phenotypes associated with cancer initiation and progression. Msh6 overexpression (2 to 4-fold) almost completely disrupted mechanisms that prevent recombination between divergent DNA sequences by interacting with the DNA polymerase processivity clamp PCNA and by sequestering the Sgs1 helicase. Importantly, co-overexpression of Msh2 and Msh6 (∼8-fold) conferred, in a PCNA interaction dependent manner, several genome instability phenotypes including increased mutation rate, increased sensitivity to the DNA replication inhibitor hydroxyurea and the DNA damaging agents methyl methanesulfonate and 4-nitroquinoline N-oxide, and elevated loss of heterozygosity. Msh2 and Msh6 co-overexpression also altered the cell cycle distribution of exponentially growing cells, resulting in an increased fraction of unbudded cells, consistent with a larger percentage of cells in G1. These novel observations suggested that overexpression of MSH factors affected the integrity of the DNA replication fork, causing genome instability phenotypes that could be important for promoting cancer progression. Copyright © 2018, Genetics.

  16. Dysregulation of mitotic machinery genes precedes genome instability during spontaneous pre-malignant transformation of mouse ovarian surface epithelial cells

    Directory of Open Access Journals (Sweden)

    Ulises Urzúa

    2016-10-01

    suggests altered control of nuclear RNA maturation, features recently linked to impaired DNA damage response leading to genome instability. These results, combined with cytogenetic analysis by other authors in this model, suggest that transcriptional profile at passage 14 might induce cytokinesis failure by which tetraploid cells approach a near-tetraploid stage containing primary chromosome aberrations that initiate the tumorigenic drive.

  17. A simulation study of electron-cloud instability and beam-induced multipacting in the LHC

    International Nuclear Information System (INIS)

    Zimmermann, F.

    1997-02-01

    In the LHC beam pipe, photoemission and secondary emission give rise to a quasi-stationary electron cloud, which is established after a few bunch passages. The response of this electron cloud to a transversely displaced bunch resembles a short-range wakefield and can cause a fast instability. In addition, beam-induced multipacting of the electrons may lead to an enhanced gas desorption and an associated pressure increase. In this paper the authors report preliminary simulation results of the electron-cloud build-up both in a dipole magnet and in a straight section of the LHC at top energy. The effective wakefield created by the electron cloud translates into an instability rise time of about 25 ms horizontally and 130 ms vertically. This rise time is not much larger than that of the resistive-wall instability at injection energy

  18. Experimental study of the Richtmyer-Meshkov instability induced by a Mach 3 shock wave

    International Nuclear Information System (INIS)

    BP Puranik; JG Oakley; MH Anderson; R Bonaazza

    2003-01-01

    OAK-B135 An experimental investigation of a shock-induced interfacial instability (Richtmyer-Meshkov instability) is undertaken in an effort to study temporal evolution of interfacial perturbations in the late stages of development. The experiments are performed in a vertical shock tube with a square cross-section. A membraneless interface is prepared by retracting a sinusoidally shaped metal plate initially separating carbon dioxide from air, with both gases initially at atmospheric pressure. With carbon dioxide above the plate, the Rayleigh-Taylor instability commences as the plate is retracted and the amplitude of the initial sinusoidal perturbation imposed on the interface begins to grow. The interface is accelerated by a strong shock wave (M=3.08) while its shape is still sinusoidal and before the Kelvin-Helmhotz instability distorts it into the well known mushroom-like structures; its initial amplitude to wavelength ratio is large enough that the interface evolution enters its nonlinear stage very shortly after shock acceleration. The pre-shock evolution of the interface due to the Rayleigh-Taylor instability and the post-shock evolution of the interface due to the Richtmyer-Meshkov instability are visualized using planar Mie scattering. The pre-shock evolution of the interface is carried out in an independent set of experiments. The initial conditions for the Richtmyer-Meshkov experiment are determined from the pre-shock Rayleigh-Taylor growth. One image of the post-shock interface is obtained per experiment and image sequences, showing the post-shock evolution of the interface, are constructed from several experiments. The growth rate of the perturbation amplitude is measured and compared with two recent analytical models of the Richtmyer-Meshkov instability

  19. Lead Exposure Induces Telomere Instability in Human Cells.

    Directory of Open Access Journals (Sweden)

    Géraldine Pottier

    Full Text Available Lead (Pb is an important environmental contaminant due to its widespread use over many centuries. While it affects primarily every organ system of the body, the most pernicious effects of Pb are on the central nervous system leading to cognitive and behavioral modification. Despite decades of research, the mechanisms responsible for Pb toxicity remain poorly understood. Recent work has suggested that Pb exposure may have consequences on chromosomal integrity as it was shown that Pb exposure leads to the generation of γH2Ax foci, a well-established biomarker for DNA double stranded break (DSB formation. As the chromosomal localization of γH2Ax foci plays an important role in determining the molecular mechanism responsible for their formation, we examined the localization of Pb-induced foci with respect to telomeres. Indeed, short or dysfunctional telomeres (uncapped or damaged telomeres may be recognized as DSB by the DNA repair machinery, leading to "telomere-Induced Foci" (TIFs. In the current study, we show that while Pb exposure did not increase intra-chromosomal foci, it significantly induced TIFs, leading in some cases, to chromosomal abnormalities including telomere loss. The evidence suggests that these chromosomal abnormalities are likely due to perturbation of telomere replication, in particular on the lagging DNA strand. We propose a mechanism by which Pb exposure leads to the loss of telomere maintenance. As numerous studies have demonstrated a role for telomere maintenance in brain development and tissue homeostasis, our results suggest a possible mechanism for lead-induced neurotoxicity.

  20. Cavitation instabilities and rotordynamic effects in turbopumps and hydroturbines turbopump and inducer cavitation, experiments and design

    CERN Document Server

    Salvetti, Maria

    2017-01-01

    The book provides a detailed approach to the physics, fluid dynamics, modeling, experimentation and numerical simulation of cavitation phenomena, with special emphasis on cavitation-induced instabilities and their implications on the design and operation of high performance turbopumps and hydraulic turbines. The first part covers the fundamentals (nucleation, dynamics, thermodynamic effects, erosion) and forms of cavitation (attached cavitation, cloud cavitation, supercavitation, vortex cavitation) relevant to hydraulic turbomachinery, illustrates modern experimental techniques for the characterization, visualization and analysis of cavitating flows, and introduces the main aspects of the hydrodynamic design and performance of axial inducers, centrifugal turbopumps and hydo-turbines. The second part focuses on the theoretical modeling, experimental analysis, and practical control of cavitation-induced fluid-dynamic and rotordynamic instabilities of hydraulic turbomachinery, with special emphasis on cavitating...

  1. Delay-induced wave instabilities in single-species reaction-diffusion systems

    Science.gov (United States)

    Otto, Andereas; Wang, Jian; Radons, Günter

    2017-11-01

    The Turing (wave) instability is only possible in reaction-diffusion systems with more than one (two) components. Motivated by the fact that a time delay increases the dimension of a system, we investigate the presence of diffusion-driven instabilities in single-species reaction-diffusion systems with delay. The stability of arbitrary one-component systems with a single discrete delay, with distributed delay, or with a variable delay is systematically analyzed. We show that a wave instability can appear from an equilibrium of single-species reaction-diffusion systems with fluctuating or distributed delay, which is not possible in similar systems with constant discrete delay or without delay. More precisely, we show by basic analytic arguments and by numerical simulations that fast asymmetric delay fluctuations or asymmetrically distributed delays can lead to wave instabilities in these systems. Examples, for the resulting traveling waves are shown for a Fisher-KPP equation with distributed delay in the reaction term. In addition, we have studied diffusion-induced instabilities from homogeneous periodic orbits in the same systems with variable delay, where the homogeneous periodic orbits are attracting resonant periodic solutions of the system without diffusion, i.e., periodic orbits of the Hutchinson equation with time-varying delay. If diffusion is introduced, standing waves can emerge whose temporal period is equal to the period of the variable delay.

  2. Electromagnetic interference-induced instability in CPP-GMR read heads

    International Nuclear Information System (INIS)

    Khunkitti, P.; Siritaratiwat, A.; Kaewrawang, A.; Mewes, T.; Mewes, C.K.A.; Kruesubthaworn, A.

    2016-01-01

    Electromagnetic interference (EMI) has been a significant issue for the current perpendicular-to-the-plane giant magnetoresistance (CPP-GMR) read heads because it can cause magnetic failure. Furthermore, the magnetic noise induced by the spin transfer torque (STT) effect has played an important role in the CPP read heads because it can affect the stability of the heads. Accordingly, this work proposed an investigation of the magnetic instabilities induced by EMI through the STT effect in a CPP-GMR read head via micromagnetic simulations. The magnetization fluctuation caused by EMI was examined, and then, magnetic noise was evaluated by using power spectral density analysis. It was found that the magnetization orientation can be fluctuated by EMI in close proximity to the head. The results also showed a multimode spectral density. The main contributions of the spectral density were found to originate at the edges of the stripe height sides due to the characteristics of the demagnetization field inside the free layer. Hence, the magnetic instabilities produced by EMI become a significant factor that essentially impacts the reliability of the CPP-GMR read heads. - Highlights: • The instability induced by electromagnetic interference in read head is examined. • The magnetization orientation can be fluctuated by electromagnetic interference. • The electromagnetic interference can induce additional noise spectra to the system. • The noise is mainly located at stripe height of the read head. • The noise induced by electromagnetic interference is a crucial factor for the head.

  3. Electromagnetic interference-induced instability in CPP-GMR read heads

    Energy Technology Data Exchange (ETDEWEB)

    Khunkitti, P.; Siritaratiwat, A.; Kaewrawang, A. [KKU-Seagate Cooperation Research Laboratory, Department of Electrical Engineering, Faculty of Engineering, Khon Kaen University, Khon Kaen 40002 (Thailand); Mewes, T.; Mewes, C.K.A. [Department of Physics and Astronomy, MINT Center, University of Alabama, Tuscaloosa, AL 35487 (United States); Kruesubthaworn, A., E-mail: anankr@kku.ac.th [KKU-Seagate Cooperation Research Laboratory, Department of Electrical Engineering, Faculty of Engineering, Khon Kaen University, Khon Kaen 40002 (Thailand)

    2016-08-15

    Electromagnetic interference (EMI) has been a significant issue for the current perpendicular-to-the-plane giant magnetoresistance (CPP-GMR) read heads because it can cause magnetic failure. Furthermore, the magnetic noise induced by the spin transfer torque (STT) effect has played an important role in the CPP read heads because it can affect the stability of the heads. Accordingly, this work proposed an investigation of the magnetic instabilities induced by EMI through the STT effect in a CPP-GMR read head via micromagnetic simulations. The magnetization fluctuation caused by EMI was examined, and then, magnetic noise was evaluated by using power spectral density analysis. It was found that the magnetization orientation can be fluctuated by EMI in close proximity to the head. The results also showed a multimode spectral density. The main contributions of the spectral density were found to originate at the edges of the stripe height sides due to the characteristics of the demagnetization field inside the free layer. Hence, the magnetic instabilities produced by EMI become a significant factor that essentially impacts the reliability of the CPP-GMR read heads. - Highlights: • The instability induced by electromagnetic interference in read head is examined. • The magnetization orientation can be fluctuated by electromagnetic interference. • The electromagnetic interference can induce additional noise spectra to the system. • The noise is mainly located at stripe height of the read head. • The noise induced by electromagnetic interference is a crucial factor for the head.

  4. Mitigation of radiation-pressure-induced angular instability of a Fabry–Perot cavity consisting of suspended mirrors

    Energy Technology Data Exchange (ETDEWEB)

    Nagano, Koji, E-mail: knagano@icrr.u-tokyo.ac.jp [KAGRA Observatory, Institute for Cosmic Ray Research, The University of Tokyo, 5-1-5 Kashiwa-no-Ha, Kashiwa, Chiba 277-8582 (Japan); Enomoto, Yutaro; Nakano, Masayuki [KAGRA Observatory, Institute for Cosmic Ray Research, The University of Tokyo, 5-1-5 Kashiwa-no-Ha, Kashiwa, Chiba 277-8582 (Japan); Furusawa, Akira [Department of Applied Physics, School of Engineering, The University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo 113-8656 (Japan); Kawamura, Seiji [KAGRA Observatory, Institute for Cosmic Ray Research, The University of Tokyo, 5-1-5 Kashiwa-no-Ha, Kashiwa, Chiba 277-8582 (Japan)

    2016-12-01

    To observe radiation pressure noise in optical cavities consisting of suspended mirrors, high laser power is necessary. However, because the radiation pressure on the mirrors could cause an angular anti-spring effect, the high laser power could induce angular instability to the cavity. An angular control system using radiation pressure as an actuator, which was previously invented to reduce the anti-spring effect for the low power case, was applied to the higher power case where the angular instability would occur. As a result the angular instability was mitigated. It was also demonstrated that the cavity was unstable without this control system. - Highlights: • High laser power could cause angular instability to a suspended Fabry–Perot cavity. • To mitigate the instability, the control system using radiation pressure is applied. • Mitigating the radiation-pressure-induced angular instability is demonstrated. • It is also confirmed that the cavity would be unstable without the control system.

  5. Effects of As2O3 on DNA methylation, genomic instability, and LTR retrotransposon polymorphism in Zea mays.

    Science.gov (United States)

    Erturk, Filiz Aygun; Aydin, Murat; Sigmaz, Burcu; Taspinar, M Sinan; Arslan, Esra; Agar, Guleray; Yagci, Semra

    2015-12-01

    Arsenic is a well-known toxic substance on the living organisms. However, limited efforts have been made to study its DNA methylation, genomic instability, and long terminal repeat (LTR) retrotransposon polymorphism causing properties in different crops. In the present study, effects of As2O3 (arsenic trioxide) on LTR retrotransposon polymorphism and DNA methylation as well as DNA damage in Zea mays seedlings were investigated. The results showed that all of arsenic doses caused a decreasing genomic template stability (GTS) and an increasing Random Amplified Polymorphic DNAs (RAPDs) profile changes (DNA damage). In addition, increasing DNA methylation and LTR retrotransposon polymorphism characterized a model to explain the epigenetically changes in the gene expression were also found. The results of this experiment have clearly shown that arsenic has epigenetic effect as well as its genotoxic effect. Especially, the increasing of polymorphism of some LTR retrotransposon under arsenic stress may be a part of the defense system against the stress.

  6. Dormant origins as a built-in safeguard in eukaryotic DNA replication against genome instability and disease development.

    Science.gov (United States)

    Shima, Naoko; Pederson, Kayla D

    2017-08-01

    DNA replication is a prerequisite for cell proliferation, yet it can be increasingly challenging for a eukaryotic cell to faithfully duplicate its genome as its size and complexity expands. Dormant origins now emerge as a key component for cells to successfully accomplish such a demanding but essential task. In this perspective, we will first provide an overview of the fundamental processes eukaryotic cells have developed to regulate origin licensing and firing. With a special focus on mammalian systems, we will then highlight the role of dormant origins in preventing replication-associated genome instability and their functional interplay with proteins involved in the DNA damage repair response for tumor suppression. Lastly, deficiencies in the origin licensing machinery will be discussed in relation to their influence on stem cell maintenance and human diseases. Copyright © 2017 Elsevier B.V. All rights reserved.

  7. Light induced modulation instability of surfaces under intense illumination

    KAUST Repository

    Burlakov, V. M.

    2013-12-17

    We show that a flat surface of a polymer in rubber state illuminated with intense electromagnetic radiation is unstable with respect to periodic modulation. Initial periodic perturbation is amplified due to periodic thermal expansion of the material heated by radiation. Periodic heating is due to focusing-defocusing effects caused by the initial surface modulation. The surface modulation has a period longer than the excitation wavelength and does not require coherent light source. Therefore, it is not related to the well-known laser induced periodic structures on polymer surfaces but may contribute to their formation and to other phenomena of light-matter interaction.

  8. Genomic instability in mutation induction on normal human fibroblasts irradiated with chronic low-dose radiations in heavy-ion radiation field

    International Nuclear Information System (INIS)

    Suzuki, M.; Tsuruoka, C.; Uchihori, Y.; Yasuda, H.; Fujitaka, K.

    2003-01-01

    Full text: At a time when manned space exploration is more a reality with the planned the International Space Station (ISS) underway, the potential exposure of crews in a spacecraft to chronic low-dose radiations in the field of low-flux galactic cosmic rays (GCR) and the subsequent biological effects have become one of the major concerns of space science. We have studied both in vitro life span and genomic instability in cellular effects in normal human skin fibroblasts irradiated with chronic low-dose radiations in heavy-ion radiation field. Cells were cultured in a CO2 incubator, which was set in the irradiation room for the biological study of heavy ions in the Heavy Ion Medical Accelerator in Chiba (HIMAC) at National Institute of Radiological Sciences (NIRS), and irradiated with scattered radiations produced from heavy ions. Absorbed dose measured using a thermoluminescence dosimeter (TLD) and a Si-semiconductor detector was to be around 1.4 mGy per day when operating the HIMAC machine for biological experiments. The total population doubling number (tPDN) of low-dose irradiated cells was significantly smaller (79-93%) than that of unirradiated cells. The results indicate that the life span of the cell population shortens by irradiating with low-dose scattered radiations in the heavy-ion irradiation field. Genomic instability in cellular responses was examined to measure either cell killing or mutation induction in low-dose accumulated cells after exposing to X-ray challenging doses. The results showed that there was no enhanced effect on cell killing between low-dose accumulated and unirradiated cells after exposing to defined challenging doses of 200kV X rays. On the contrary, the mutation frequency on hprt locus of low-dose accumulated cells was much higher than that of unirradiated cells. The results suggested that genomic instability was induced in mutagenesis by the chronic low-dose irradiations in heavy-ion radiation field

  9. ATM-deficiency increases genomic instability and metastatic potential in a mouse model of pancreatic cancer.

    Science.gov (United States)

    Drosos, Yiannis; Escobar, David; Chiang, Ming-Yi; Roys, Kathryn; Valentine, Virginia; Valentine, Marc B; Rehg, Jerold E; Sahai, Vaibhav; Begley, Lesa A; Ye, Jianming; Paul, Leena; McKinnon, Peter J; Sosa-Pineda, Beatriz

    2017-09-11

    Germline mutations in ATM (encoding the DNA-damage signaling kinase, ataxia-telangiectasia-mutated) increase Familial Pancreatic Cancer (FPC) susceptibility, and ATM somatic mutations have been identified in resected human pancreatic tumors. Here we investigated how Atm contributes to pancreatic cancer by deleting this gene in a murine model of the disease expressing oncogenic Kras (Kras G12D ). We show that partial or total ATM deficiency cooperates with Kras G12D to promote highly metastatic pancreatic cancer. We also reveal that ATM is activated in pancreatic precancerous lesions in the context of DNA damage and cell proliferation, and demonstrate that ATM deficiency leads to persistent DNA damage in both precancerous lesions and primary tumors. Using low passage cultures from primary tumors and liver metastases we show that ATM loss accelerates Kras-induced carcinogenesis without conferring a specific phenotype to pancreatic tumors or changing the status of the tumor suppressors p53, p16 Ink4a and p19 Arf . However, ATM deficiency markedly increases the proportion of chromosomal alterations in pancreatic primary tumors and liver metastases. More importantly, ATM deficiency also renders murine pancreatic tumors highly sensitive to radiation. These and other findings in our study conclusively establish that ATM activity poses a major barrier to oncogenic transformation in the pancreas via maintaining genomic stability.

  10. Nuclear DNA-Content in Mesenchymal Lesions in Dogs: Its Value as Marker of Malignancy and Extent of Genomic Instability

    Science.gov (United States)

    Boerkamp, Kim M.; Rutteman, Gerard R.; Kik, Marja J. L.; Kirpensteijn, Jolle; Schulze, Christoph; Grinwis, Guy C. M.

    2012-01-01

    DNA-aneuploidy may reflect the malignant nature of mesenchymal proliferations and herald gross genomic instability as a mechanistic factor in tumor genesis. DNA-ploidy and -index were determined by flow cytometry in canine inflammatory or neoplastic mesenchymal tissues and related to clinico-pathological features, biological behavior and p53 gene mutational status. Half of all sarcomas were aneuploid. Benign mesenchymal neoplasms were rarely aneuploid and inflammatory lesions not at all. The aneuploidy rate was comparable to that reported for human sarcomas with significant variation amongst subtypes. DNA-ploidy status in canines lacked a relation with histological grade of malignancy, in contrast to human sarcomas. While aneuploidy was related to the development of metastases in soft tissue sarcomas it was not in osteosarcomas. No relation amongst sarcomas was found between ploidy status and presence of P53 gene mutations. Heterogeneity of the DNA index between primary and metastatic sarcoma sites was present in half of the cases examined. Hypoploidy is more common in canine sarcomas and hyperploid cases have less deviation of the DNA index than human sarcomas. The variation in the presence and extent of aneuploidy amongst sarcoma subtypes indicates variation in genomic instability. This study strengthens the concept of interspecies variation in the evolution of gross chromosomal aberrations during cancer development. PMID:24213507

  11. Nuclear DNA-Content in Mesenchymal Lesions in Dogs: Its Value as Marker of Malignancy and Extent of Genomic Instability

    Energy Technology Data Exchange (ETDEWEB)

    Boerkamp, Kim M., E-mail: K.M.Boerkamp@uu.nl; Rutteman, Gerard R. [Department of Clinical Science of Companion Animals, Faculty of Veterinary Medicine, UU, Yalelaan 104, 3584 CM, Utrecht (Netherlands); Kik, Marja J. L. [Department of Pathobiology, Faculty of Veterinary Medicine, UU, Yalelaan 1, 3508 TD, Utrecht (Netherlands); Kirpensteijn, Jolle [Department of Clinical Science of Companion Animals, Faculty of Veterinary Medicine, UU, Yalelaan 104, 3584 CM, Utrecht (Netherlands); Schulze, Christoph; Grinwis, Guy C. M. [Department of Pathobiology, Faculty of Veterinary Medicine, UU, Yalelaan 1, 3508 TD, Utrecht (Netherlands)

    2012-12-03

    DNA-aneuploidy may reflect the malignant nature of mesenchymal proliferations and herald gross genomic instability as a mechanistic factor in tumor genesis. DNA-ploidy and -index were determined by flow cytometry in canine inflammatory or neoplastic mesenchymal tissues and related to clinico-pathological features, biological behavior and p53 gene mutational status. Half of all sarcomas were aneuploid. Benign mesenchymal neoplasms were rarely aneuploid and inflammatory lesions not at all. The aneuploidy rate was comparable to that reported for human sarcomas with significant variation amongst subtypes. DNA-ploidy status in canines lacked a relation with histological grade of malignancy, in contrast to human sarcomas. While aneuploidy was related to the development of metastases in soft tissue sarcomas it was not in osteosarcomas. No relation amongst sarcomas was found between ploidy status and presence of P53 gene mutations. Heterogeneity of the DNA index between primary and metastatic sarcoma sites was present in half of the cases examined. Hypoploidy is more common in canine sarcomas and hyperploid cases have less deviation of the DNA index than human sarcomas. The variation in the presence and extent of aneuploidy amongst sarcoma subtypes indicates variation in genomic instability. This study strengthens the concept of interspecies variation in the evolution of gross chromosomal aberrations during cancer development.

  12. Nuclear DNA-Content in Mesenchymal Lesions in Dogs: Its Value as Marker of Malignancy and Extent of Genomic Instability

    Directory of Open Access Journals (Sweden)

    Christoph Schulze

    2012-12-01

    Full Text Available DNA-aneuploidy may reflect the malignant nature of mesenchymal proliferations and herald gross genomic instability as a mechanistic factor in tumor genesis. DNA-ploidy and -index were determined by flow cytometry in canine inflammatory or neoplastic mesenchymal tissues and related to clinico-pathological features, biological behavior and p53 gene mutational status. Half of all sarcomas were aneuploid. Benign mesenchymal neoplasms were rarely aneuploid and inflammatory lesions not at all. The aneuploidy rate was comparable to that reported for human sarcomas with significant variation amongst subtypes. DNA-ploidy status in canines lacked a relation with histological grade of malignancy, in contrast to human sarcomas. While aneuploidy was related to the development of metastases in soft tissue sarcomas it was not in osteosarcomas. No relation amongst sarcomas was found between ploidy status and presence of P53 gene mutations. Heterogeneity of the DNA index between primary and metastatic sarcoma sites was present in half of the cases examined. Hypoploidy is more common in canine sarcomas and hyperploid cases have less deviation of the DNA index than human sarcomas. The variation in the presence and extent of aneuploidy amongst sarcoma subtypes indicates variation in genomic instability. This study strengthens the concept of interspecies variation in the evolution of gross chromosomal aberrations during cancer development.

  13. Nuclear DNA-Content in Mesenchymal Lesions in Dogs: Its Value as Marker of Malignancy and Extent of Genomic Instability

    International Nuclear Information System (INIS)

    Boerkamp, Kim M.; Rutteman, Gerard R.; Kik, Marja J. L.; Kirpensteijn, Jolle; Schulze, Christoph; Grinwis, Guy C. M.

    2012-01-01

    DNA-aneuploidy may reflect the malignant nature of mesenchymal proliferations and herald gross genomic instability as a mechanistic factor in tumor genesis. DNA-ploidy and -index were determined by flow cytometry in canine inflammatory or neoplastic mesenchymal tissues and related to clinico-pathological features, biological behavior and p53 gene mutational status. Half of all sarcomas were aneuploid. Benign mesenchymal neoplasms were rarely aneuploid and inflammatory lesions not at all. The aneuploidy rate was comparable to that reported for human sarcomas with significant variation amongst subtypes. DNA-ploidy status in canines lacked a relation with histological grade of malignancy, in contrast to human sarcomas. While aneuploidy was related to the development of metastases in soft tissue sarcomas it was not in osteosarcomas. No relation amongst sarcomas was found between ploidy status and presence of P53 gene mutations. Heterogeneity of the DNA index between primary and metastatic sarcoma sites was present in half of the cases examined. Hypoploidy is more common in canine sarcomas and hyperploid cases have less deviation of the DNA index than human sarcomas. The variation in the presence and extent of aneuploidy amongst sarcoma subtypes indicates variation in genomic instability. This study strengthens the concept of interspecies variation in the evolution of gross chromosomal aberrations during cancer development

  14. Inhibiting extracellular matrix metalloproteinase inducer maybe beneficial for diminishing the atherosclerotic plaque instability

    Directory of Open Access Journals (Sweden)

    Xie S

    2009-01-01

    Full Text Available Atherosclerotic plaque rupture and local thrombosis activation in the artery cause acute serious incidents such as acute coronary syndrome and stroke. The exact mechanism of plaque rupture remains unclear but excessive degradation of the extracellular matrix scaffold by matrix-degrading metalloproteinases (MMPs has been implicated as one of the major molecular mechanisms in this process. Convincing evidence is available to prove that extracellular matrix metalloproteinase inducer (EMMPRIN induces MMP expression and is involved in the inflammatory responses in the artery wall. The inflammation and MMPs have been shown to play a critical role for atherosclerotic lesion development and progression. More recent data showed that increased EMMPRIN expression was associated with vulnerable atherosclerotic lesions. Therefore, we speculate that EMMPRIN may be pivotal for atherosclerotic plaque instability, and hence inhibition of EMMPRIN expression could be a promising approach for the prevention or treatment of atheroma instability.

  15. Comprehensive characterization of genomic instability in pluripotent stem cells and their derived neuroprogenitor cell lines

    Directory of Open Access Journals (Sweden)

    Nestor Luis Lopez Corrales

    2012-12-01

    Full Text Available The genomic integrity of two human pluripotent stem cells and their derived neuroprogenitor cell lines was studied, applying a combination of high-resolution genetic methodologies. The usefulness of combining array-comparative genomic hybridization (aCGH and multiplex fluorescence in situ hybridization (M-FISH techniques should be delineated to exclude/detect a maximum of possible genomic structural aberrations. Interestingly, in parts different genomic imbalances at chromosomal and subchromosomal levels were detected in pluripotent stem cells and their derivatives. Some of the copy number variations were inherited from the original cell line, whereas other modifications were presumably acquired during the differentiation and manipulation procedures. These results underline the necessity to study both pluripotent stem cells and their differentiated progeny by as many approaches as possible in order to assess their genomic stability before using them in clinical therapies.

  16. Nonlinear instabilities induced by the F coil power amplifier at FTU: Modeling and control

    International Nuclear Information System (INIS)

    Zaccarian, L.; Boncagni, L.; Cascone, D.; Centioli, C.; Cerino, S.; Gravanti, F.; Iannone, F.; Mecocci, F.; Pangione, L.; Podda, S.; Vitale, V.; Vitelli, R.

    2009-01-01

    In this paper we focus on the instabilities caused by the nonlinear behavior of the F coil current amplifier at FTU. This behavior induces closed-loop instability of the horizontal position stabilizing loop whenever the requested current is below the circulating current level. In the paper we first illustrate a modeling phase where nonlinear dynamics are derived and identified to reproduce the open-loop responses measured by the F coil current amplifier. The derived model is shown to successfully reproduce the experimental behavior by direct comparison with experimental data. Based on this dynamic model, we then reproduce the closed-loop scenario of the experiment and show that the proposed nonlinear model successfully reproduces the nonlinear instabilities experienced in the experimental sessions. Given the simulation setup, we next propose a nonlinear control solution to this instability problem. The proposed solution is shown to recover stability in closed-loop simulations. Experimental tests are scheduled for the next experimental campaign after the FTU restart.

  17. Saturation of radiation-induced parametric instabilities by excitation of Langmuir turbulence

    Energy Technology Data Exchange (ETDEWEB)

    Dubois, D.F.; Rose, H.A. [Los Alamos National Lab., NM (United States); Russell, D. [Lodestar Research Inc., Boulder, CO (United States)

    1995-12-01

    Progress made in the last few years in the calculation of the saturation spectra of parametric instabilities which involve Langmuir daughter waves will be reviewed. These instabilities include the ion acoustic decay instability, the two plasmon decay instability (TPDI), and stimulated Raman scattering (SRS). In particular I will emphasize spectral signatures which can be directly compared with experiment. The calculations are based on reduced models of driven Laugmuir turbulence. Thomson scattering from hf-induced Langmuir turbulence in the unpreconditioned ionosphere has resulted in detailed agreement between theory and experiment at early times. Strong turbulence signatures dominate in this regime where the weak turbulence approximation fails completely. Recent experimental studies of the TPDI have measured the Fourier spectra of Langmuir waves as well as the angular and frequency, spectra of light emitted near 3/2 of the pump frequency again permitting some detailed comparisons with theory. The experiments on SRS are less detailed but by Thomson scattering the secondary decay of the daughter Langmuir wave has been observed. Scaling laws derived from a local model of SRS saturation are compared with full simulations and recent Nova experiments.

  18. Electron-cloud instabilities and beam-induced multipacting in the LHC and in the VLHC

    International Nuclear Information System (INIS)

    Zimmermann, F.

    1997-10-01

    In the beam pipe of the Large Hadron Collider (LHC), photoemission and secondary emission give rise to a quasi-stationary electron cloud, which is established after a few buncn passages. The response of this electron cloud to a transversely displaced bunch resembles a short-range wakefield and can cause a fast instability. In additoin, beam-induced multipacting of the electrons may lead to an enhanced gas desorption and an associated pressure increase. In this paper the authors report preliminary simulation results of the electron-cloud build-up both in a dipole magnet and in a straight section of the LHC at top energy. The effective wakefield created by the electron cloud translates into an instability rise time of about 40 ms horizontally and 500 ms vertically. This rise time is not much larger than that of the resistive-wall instability at injection energy. Similar simulation studies show that the instability rise time for the proposed Very Large Hadron Collider (VLHC) is about 3--4 s in both trasnverse planes. The smaller growth rate in the VLHC, as compared with the LHC, is primarily due to the much lower bunch population

  19. Saturation of radiation-induced parametric instabilities by excitation of Langmuir turbulence

    International Nuclear Information System (INIS)

    DuBois, D.F.

    1996-01-01

    Progress made in the last few years in the calculation of the saturation spectra of parametric instabilities which involve Langmuir daughter waves will be reviewed. These instabilities include the ion acoustic decay instability, the two plasmon decay instability (TPDI), and stimulated Raman scattering (SRS). In particular we will emphasize spectral signatures which can be directly compared with experiment. The calculations are based on reduced models of driven Langmuir turbulence. Thomson scattering from hf-induced Langmuir turbulence in the unpreconditioned ionosphere has resulted in detailed agreement between theory and experiment at early times. Strong turbulence signatures dominate in this regime where the weak turbulence approximation fails completely. Recent experimental studies of the TPDI have measured the Fourier spectra of Langmuir waves as well as the angular and frequency spectra of light emitted near 3/2 of the pump frequency again permitting some detailed comparisons with theory. Thomson scattering measurements of the Langmuir wave spectra from SRS are consistent with the saturation by secondary and tertiary decay of the primary SRS Langmuir waves. Scaling laws derived from a local model of SRS saturation are compared with full simulations and recent Nova experiments. (orig.)

  20. An Experimental Study of Roughness-Induced Instabilities in a Supersonic Boundary Layer

    Science.gov (United States)

    Kegerise, Michael A.; King, Rudolph A.; Choudhari, Meelan; Li, Fei; Norris, Andrew

    2014-01-01

    Progress on an experimental study of laminar-to-turbulent transition induced by an isolated roughness element in a supersonic laminar boundary layer is reported in this paper. Here, the primary focus is on the effects of roughness planform shape on the instability and transition characteristics. Four different roughness planform shapes were considered (a diamond, a circle, a right triangle, and a 45 degree fence) and the height and width of each one was held fixed so that a consistent frontal area was presented to the oncoming boundary layer. The nominal roughness Reynolds number was 462 and the ratio of the roughness height to the boundary layer thickness was 0.48. Detailed flow- field surveys in the wake of each geometry were performed via hot-wire anemometry. High- and low-speed streaks were observed in the wake of each roughness geometry, and the modified mean flow associated with these streak structures was found to support a single dominant convective instability mode. For the symmetric planform shapes - the diamond and circular planforms - the instability characteristics (mode shapes, growth rates, and frequencies) were found to be similar. For the asymmetric planform shapes - the right-triangle and 45 degree fence planforms - the mode shapes were asymmetrically distributed about the roughness-wake centerline. The instability growth rates for the asymmetric planforms were lower than those for the symmetric planforms and therefore, transition onset was delayed relative to the symmetric planforms.

  1. Moisture-induced solid state instabilities in α-chymotrypsin and their reduction through chemical glycosylation

    Directory of Open Access Journals (Sweden)

    Solá Ricardo J

    2010-08-01

    Full Text Available Abstract Background Protein instability remains the main factor limiting the development of protein therapeutics. The fragile nature (structurally and chemically of proteins makes them susceptible to detrimental events during processing, storage, and delivery. To overcome this, proteins are often formulated in the solid-state which combines superior stability properties with reduced operational costs. Nevertheless, solid protein pharmaceuticals can also suffer from instability problems due to moisture sorption. Chemical protein glycosylation has evolved into an important tool to overcome several instability issues associated with proteins. Herein, we employed chemical glycosylation to stabilize a solid-state protein formulation against moisture-induced deterioration in the lyophilized state. Results First, we investigated the consequences of moisture sorption on the stability and structural conformation of the model enzyme α-chymotrypsin (α-CT under controlled humidity conditions. Results showed that α-CT aggregates and inactivates as a function of increased relative humidity (RH. Furthermore, α-CT loses its native secondary and tertiary structure rapidly at increasing RH. In addition, H/D exchange studies revealed that α-CT structural dynamics increased at increasing RH. The magnitude of the structural changes in tendency parallels the solid-state instability data (i.e., formation of buffer-insoluble aggregates, inactivation, and loss of native conformation upon reconstitution. To determine if these moisture-induced instability issues could be ameliorated by chemical glycosylation we proceeded to modify our model protein with chemically activated glycans of differing lengths (lactose and dextran (10 kDa. The various glycoconjugates showed a marked decrease in aggregation and an increase in residual activity after incubation. These stabilization effects were found to be independent of the glycan size. Conclusion Water sorption leads to

  2. R-loops cause genomic instability in T helper lymphocytes from patients with Wiskott-Aldrich syndrome.

    Science.gov (United States)

    Sarkar, Koustav; Han, Seong-Su; Wen, Kuo-Kuang; Ochs, Hans D; Dupré, Loïc; Seidman, Michael M; Vyas, Yatin M

    2017-12-15

    Wiskott-Aldrich syndrome (WAS), X-linked thrombocytopenia (XLT), and X-linked neutropenia, which are caused by WAS mutations affecting Wiskott-Aldrich syndrome protein (WASp) expression or activity, manifest in immunodeficiency, autoimmunity, genomic instability, and lymphoid and other cancers. WASp supports filamentous actin formation in the cytoplasm and gene transcription in the nucleus. Although the genetic basis for XLT/WAS has been clarified, the relationships between mutant forms of WASp and the diverse features of these disorders remain ill-defined. We sought to define how dysfunctional gene transcription is causally linked to the degree of T H cell deficiency and genomic instability in the XLT/WAS clinical spectrum. In human T H 1- or T H 2-skewing cell culture systems, cotranscriptional R-loops (RNA/DNA duplex and displaced single-stranded DNA) and DNA double-strand breaks (DSBs) were monitored in multiple samples from patients with XLT and WAS and in normal T cells depleted of WASp. WASp deficiency provokes increased R-loops and R-loop-mediated DSBs in T H 1 cells relative to T H 2 cells. Mechanistically, chromatin occupancy of serine 2-unphosphorylated RNA polymerase II is increased, and that of topoisomerase 1, an R-loop preventing factor, is decreased at R-loop-enriched regions of IFNG and TBX21 (T H 1 genes) in T H 1 cells. These aberrations accompany increased unspliced (intron-retained) and decreased spliced mRNA of IFNG and TBX21 but not IL13 (T H 2 gene). Significantly, increased cellular load of R-loops and DSBs, which are normalized on RNaseH1-mediated suppression of ectopic R-loops, inversely correlates with disease severity scores. Transcriptional R-loop imbalance is a novel molecular defect causative in T H 1 immunodeficiency and genomic instability in patients with WAS. The study proposes that cellular R-loop load could be used as a potential biomarker for monitoring symptom severity and prognostic outcome in the XLT-WAS clinical spectrum

  3. Living with genome instability: the adaptation of phytoplasmas todiverse environments of their insect and plant hosts

    Energy Technology Data Exchange (ETDEWEB)

    Bai, Xiaodong; Zhang, Jianhua; Ewing, Adam; Miller, Sally A.; Radek, Agnes; Shevchenko, Dimitriy; Tsukerman, Kiryl; Walunas, Theresa; Lapidus, Alla; Campbell, John W.; Hogenhout Saskia A.

    2006-02-17

    Phytoplasmas (Candidatus Phytoplasma, Class Mollicutes) cause disease in hundreds of economically important plants, and are obligately transmitted by sap-feeding insects of the order Hemiptera, mainly leafhoppers and psyllids. The 706,569-bp chromosome and four plasmids of aster yellows phytoplasma strain witches broom (AY-WB) were sequenced and compared to the onion yellows phytoplasma strain M (OY-M) genome. The phytoplasmas have small repeat-rich genomes. The repeated DNAs are organized into large clusters, potential mobile units (PMUs), which contain tra5 insertion sequences (ISs), and specialized sigma factors and membrane proteins. So far, PMUs are unique to phytoplasmas. Compared to mycoplasmas, phytoplasmas lack several recombination and DNA modification functions, and therefore phytoplasmas probably use different mechanisms of recombination, likely involving PMUs, for the creation of variability, allowing phytoplasmas to adjust to the diverse environments of plants and insects. The irregular GC skews and presence of ISs and large repeated sequences in the AY-WB and OY-M genomes are indicative of high genomic plasticity. Nevertheless, segments of {approx}250 kb, located between genes lplA and glnQ are syntenic between the two phytoplasmas, contain the majority of the metabolic genes and no ISs. AY-WB is further along in the reductive evolution process than OY-M. The AY-WB genome is {approx}154 kb smaller than the OY-M genome, primarily as a result of fewer multicopy sequences, including PMUs. Further, AY-WB lacks genes that are truncated and are part of incomplete pathways in OY-M. This is the first comparative phytoplasma genome analysis and report of the existence of PMUs in phytoplasma genomes.

  4. Detection of genomic instability in descendants of male mice exposed to chronic low-level gamma-radiation using the test 'adaptive response'

    International Nuclear Information System (INIS)

    Rozanova, O.M.; Zaichkina, S.I.; Akhmadieva, A.; Aptikaeva, G.F.; Klokov, D.J.

    2003-01-01

    Full text: The goal of the present study was to examine whether the genomic instability can be revealed in vivo using the test 'adaptive response' (AR). Two-month-old BALB/C male mice were subjected to chronic irradiation in the gamma-field with a dose of 0.1 Gy (0.01 Gy/day) and a dose of 0.5 Gy (0.01 and 0.05 Gy/day). Control animals were kept under similar conditions but without irradiation. Fifteen days after the irradiation, males from the irradiated and control groups were mated in separate cages with unirradiated females for 2 weeks. The males, descendants from irradiated and unirradiated parents, at an age of two months were subjected to additional irradiation with a dose of 1.5 Gy. To reveal the genetic instability using the AR test, another group of males, the descendants from irradiated and unirradiated parents, were exposed to acute irradiation by the scheme of AR: with an adapting dose (D1) of 0.1 Gy (0.125 Gy/min) followed after a day by a challenging dose (D2) of 1.5 Gy (0.47 Gy/min). After 28 h, the animals of all groups were killed. Bone marrow specimens for calculating micronuclei (MN) in polychromatophyl erythrocytes (PCE) were prepared. It was found that in descendants that resulted from unirradiated parents and the parents irradiated with a dose of 0.1 Gy, the percentages of PCE with injuries were nearly equal. Upon irradiation of parents with a dose of 0.5 Gy, the percentage of PCE with MN in descendants increased. The examination of radiosensitivity of descendants from irradiated parents showed that the percentage of PCE with MN decreased three-to-fourfold (depending on the dose of irradiation of the parents) compared to descendants from unirradiated parents. If the descendants from exposed parents were irradiated by the scheme of AR, no AR was observed. Thus, the experimental data indicated that, it is possible to detect the transition of gamma-radiation-induced genomic instability in sex cells of male parents into somatic cells of mice (F1

  5. Crossing the LINE toward genomic instability: LINE-1 retrotransposition in cancer

    Science.gov (United States)

    Kemp, Jacqueline; Longworth, Michelle

    2015-12-01

    Retrotransposons are repetitive DNA sequences that are positioned throughout the human genome. Retrotransposons are capable of copying themselves and mobilizing new copies to novel genomic locations in a process called retrotransposition. While most retrotransposon sequences in the human genome are incomplete and incapable of mobilization, the LINE-1 retrotransposon, which comprises approximately 17% of the human genome, remains active. The disruption of cellular mechanisms that suppress retrotransposon activity is linked to the generation of aneuploidy, a potential driver of tumor development. When retrotransposons insert into a novel genomic region, they have the potential to disrupt the coding sequence of endogenous genes and alter gene expression, which can lead to deleterious consequences for the organism. Additionally, increased LINE-1 copy numbers provide more chances for recombination events to occur between retrotransposons, which can lead to chromosomal breaks and rearrangements. LINE-1 activity is increased in various cancer cell lines and in patient tissues resected from primary tumors. LINE-1 activity also correlates with increased cancer metastasis. This review aims to give a brief overview of the connections between LINE-1 retrotransposition and the loss of genome stability. We will also discuss the mechanisms that repress retrotransposition in human cells and their links to cancer.

  6. Colorectal carcinomas from Middle East: Molecular and tissue microarray analysis of genomic instability pathways

    International Nuclear Information System (INIS)

    Bavi, P.P.; Abubaker, Jehad A.; Jehan, Zeenath D.; Al-Jomah, Naif A.; Siraj, Abdul K.; Al-Harbi, Sayer R.; Atizado, Valerie L.; Uddin, S.; Al-Kuraya, Khawla S.; Abduljabbar, Alaa S.; Al-Homoud, Samar J.; Ashari, Luai H.; Al-Sanea, Nasser A.; Al-Dayel, Fouad H.

    2008-01-01

    Objective was to evaluate the overall incidence of microsatellite instability (MSI), hereditary non polyposis colorectal cancer and tumor suppressor gene (TP53) mutations in Saudi colorectal carcinomas. We studied the MSI pathway in Saudi colorectal cancers (CRC) from 179 unselected patients using 2 methods: MSI by polymerase chain reaction and immunohistochemistry detection of mutL homologs 1 and mutS homologs 2 proteins. The TP53 mutations were studied by sequencing exons 5, 6, 7 and 8. Of the 150 colorectal carcinomas analyzed for MSI, 16% of the tumors showed high level instability (MSI-H), 19.3% had low level instability (MSI-L) and the remaining 64% tumors were stable. Survival of the MSI-H group was better as compared to the MSI-L or microsatellite stable group (p=0.0217). In the MSI-H group, 48% were familial MSI tumors which could be attributable to the high incidence of consanguinity in the Saudi population. The TP53 mutations were found in 24% of the cases studied. A high production of familial MSI cases and a lower incidence of TP53 mutations are some of the hallmarks of the Saudi colorectal carcinomas which need to be explored further. (author)

  7. From Genomics to Gene Therapy: Induced Pluripotent Stem Cells Meet Genome Editing.

    Science.gov (United States)

    Hotta, Akitsu; Yamanaka, Shinya

    2015-01-01

    The advent of induced pluripotent stem (iPS) cells has opened up numerous avenues of opportunity for cell therapy, including the initiation in September 2014 of the first human clinical trial to treat dry age-related macular degeneration. In parallel, advances in genome-editing technologies by site-specific nucleases have dramatically improved our ability to edit endogenous genomic sequences at targeted sites of interest. In fact, clinical trials have already begun to implement this technology to control HIV infection. Genome editing in iPS cells is a powerful tool and enables researchers to investigate the intricacies of the human genome in a dish. In the near future, the groundwork laid by such an approach may expand the possibilities of gene therapy for treating congenital disorders. In this review, we summarize the exciting progress being made in the utilization of genomic editing technologies in pluripotent stem cells and discuss remaining challenges toward gene therapy applications.

  8. Mass-induced instability of SAdS black hole in Einstein-Ricci cubic gravity

    Science.gov (United States)

    Myung, Yun Soo

    2018-05-01

    We perform the stability analysis of Schwarzschild-AdS (SAdS) black hole in the Einstein-Ricci cubic gravity. It shows that the Ricci tensor perturbations exhibit unstable modes for small black holes. We call this the mass-induced instability of SAdS black hole because the instability of small black holes arises from the massiveness in the linearized Einstein-Ricci cubic gravity, but not a feature of higher-order derivative theory giving ghost states. Also, we point out that the correlated stability conjecture holds for the SAdS black hole by computing the Wald entropy of SAdS black hole in Einstein-Ricci cubic gravity.

  9. Modulational instability for an induced field in the far-wake region of a space vehicle

    International Nuclear Information System (INIS)

    Liao Jingjing; Deng Qian; Qu Wen

    2012-01-01

    The behavior of the induced field and the generation of density cavitons in the far-wake region (|k 0 | → 0) of a space vehicle can be described by a set of nonlinear coupling equations. Modulational instability of the induced field is investigated on the basis of the nonlinear equations. The results show that the induced field is modulationally unstable and will collapse into spatial localized structures; meanwhile, density cavitons will be generated. The characteristic scale and the maximum growth rate of the induced field depend not only on the angle between the amplitude of pump waves E 0 and the perturbation wave vector k, but also on the energy density of pump waves |E 0 | 2 . (paper)

  10. The induction of genomic instability in related human lymphoblasts following exposure to Cs gamma radiation vs accelerated 56Fe Ions

    International Nuclear Information System (INIS)

    Evans, H.H.; Horng, M.-F.; Ricanati, M.; Diaz-Insua, M.

    2003-01-01

    Full text: The induction of genomic instability by exposure to Cs-137 gamma radiation and Fe-56 accelerated ions was investigated by measuring the frequency and characteristics of TK6 and WTK1 unstable clones isolated 36 generations after exposure. While the two cell lines are related, TK6 is more sensitive to radiation, has normal p53 expression, and is repair deficient. Clones surviving the radiation and respective controls were analyzed for 17 characteristics including chromosomal aberrations, growth defects, alterations in response to a second radiation and mutant frequencies at two different loci. Putative unstable clones were defined as those exhibiting a significant alteration in one or more characteristics as compared to the respective control medians. Over half of the unstable WTK1 clones and over 90% of the TK6 unstable clones surviving exposure to either radiation exhibited chromosomal instability, the major aberrations consisting of chromatid breaks and dicentric chromosomes formed by end-to-end fusions. Alterations in the other measured characteristics occurred much less often than cytogenetic alterations in the TK6 unstable clones. The phenotype of the WTK1 unstable clones was more diverse and complex than in the case of TK6 unstable clones. The phenotype of the TK6 unstable clones differed in the survivors of Cs-137 vs. Fe-56. In the clones surviving Cs-137, the aberrations consisted mainly of dicentric chromosomes, while clones surviving exposure to Fe-56 exhibited both breaks and dicentrics. The uniform prevalence of chromosomal aberrations in the unstable TK6 clones vs. the relatively diverse phenotype of the unstable WTK1 clones suggests that the deficiency in DNA double-strand break repair in TK6 cells may be accompanied by a deficiency in telomere maintenance that leads to telomere fusion, dicentric chromosomes, anaphase bridges, breakage and the occurrence of chromosomal instability in the majority of clones isolated following exposure

  11. Genomic instability in mice is greater in Fanconi anemia caused by deficiency of Fancd2 than Fancg.

    Science.gov (United States)

    Reliene, Ramune; Yamamoto, Mitsuko L; Rao, P Nagesh; Schiestl, Robert H

    2010-12-01

    Fanconi anemia (FA) results from mutations in the FANC genes and is characterized by bone marrow failure, birth defects, and a high incidence of cancer. FANCG is a part of the FA core complex that is responsible for monoubiquitination of FANCD2 and FANCI. The precise role of the FA pathway is not well understood, although it may be involved in homologous recombination (HR), nonhomologous end joining, and translesion synthesis (TLS). Fancd2(-/-) mice have a more severe phenotype than Fancg(-/-), and other FA core complex-deficient mice, although both Fancg and Fancd2 belong to the same FA pathway. We hypothesized that Fancd2 deficiency results in a more severe phenotype because Fancd2 also has a FA pathway-independent function in the maintenance of genomic integrity. To test this hypothesis, we determined the level of DNA damage and genomic instability in Fancd2(-/-), Fancg(-/-), and wild-type controls. Fancd2(-/-) mice displayed a higher magnitude of chromosomal breakage and micronucleus formation than the wild-type or Fancg(-/-) mice. Also, DNA strand breaks were increased in Fancd2(-/-) but not in Fancg(-/-) mice. In addition, Fancd2(-/-) mice displayed an elevated frequency of DNA deletions, resulting from HR at the endogenous p(un) locus. In contrast, in Fancg(-/-) mice, the frequency of DNA deletions was decreased. Thus, Fancd2 but not Fancg deficiency results in elevated chromosomal/DNA breakage and permanent genome rearrangements. This provides evidence that Fancd2 plays an additional role in the maintenance of genomic stability than Fancg, which might explain the higher predisposition to cancer seen in the Fancd2(-/-) mice.

  12. Staining Against Phospho-H2AX (gamma-H2AX) as a Marker for DNA Damage and Genomic Instability in Cancer Tissues and Cells

    NARCIS (Netherlands)

    Nagelkerke, A.P.; Span, P.N.

    2016-01-01

    Phospho-H2AX or gamma-H2AX- is a marker of DNA double-stranded breaks and can therefore be used to monitor DNA repair after, for example, irradiation. In addition, positive staining for phospho-H2AX may indicate genomic instability and telomere dysfunction in tumour cells and tissues. Here, we

  13. Combined array-comparative genomic hybridization and single-nucleotide polymorphism-loss of heterozygosity analysis reveals complex changes and multiple forms of chromosomal instability in colorectal cancers

    DEFF Research Database (Denmark)

    Gaasenbeek, Michelle; Howarth, Kimberley; Rowan, Andrew J

    2006-01-01

    Cancers with chromosomal instability (CIN) are held to be aneuploid/polyploid with multiple large-scale gains/deletions, but the processes underlying CIN are unclear and different types of CIN might exist. We investigated colorectal cancer cell lines using array-comparative genomic hybridization...

  14. Significance of genetic predisposition and genomic instability for individual sensitivity to radiation. Implications for radiation protection

    International Nuclear Information System (INIS)

    Heller, H.

    2001-01-01

    At its closed-door meeting on 20/21 January 2000 the Radiation Protection Committee dedicated much of its attention to the significance of genetic predisposition and genetic instability for individual radiation sensitivity and to the implication of this for radiation protection. The statements and contributions to the closing plenary discussion touched on many aspects of ethics, personal rights, occupational medicine and insurance issues relating to this subject, all of which extend far beyond the purely technical issues of radiation protection. The present volume contains the lecture manuscripts of the meeting as well as a summarising assessment by the Radiation Protection Committee [de

  15. Telomere-Centromere-Driven Genomic Instability Contributes to Karyotype Evolution in a Mouse Model of Melanoma

    Directory of Open Access Journals (Sweden)

    Amanda Gonçalves dos Santos Silva

    2010-01-01

    Full Text Available Aneuploidy and chromosomal instability (CIN are hallmarks of most solid tumors. These alterations may result from inaccurate chromosomal segregation during mitosis, which can occur through several mechanisms including defective telomere metabolism, centrosome amplification, dysfunctional centromeres, and/or defective spindle checkpoint control. In this work, we used an in vitro murine melanoma model that uses a cellular adhesion blockade as a transforming factor to characterize telomeric and centromeric alterations that accompany melanocyte transformation. To study the timing of the occurrence of telomere shortening in this transformation model, we analyzed the profile of telomere length by quantitative fluorescent in situ hybridization and found that telomere length significantly decreased as additional rounds of cell adhesion blockages were performed. Together with it, an increase in telomere-free ends and complex karyotypic aberrations were also found, which include Robertsonian fusions in 100% of metaphases of the metastatic melanoma cells. These findings are in agreement with the idea that telomere length abnormalities seem to be one of the earliest genetic alterations acquired in the multistep process of malignant transformation and that telomere abnormalities result in telomere aggregation, breakage-bridge-fusion cycles, and CIN. Another remarkable feature of this model is the abundance of centromeric instability manifested as centromere fragments and centromeric fusions. Taken together, our results illustrate for this melanoma model CIN with a structural signature of centromere breakage and telomeric loss.

  16. Genomic rearrangement in radiation-induced murine myeloid leukemia

    International Nuclear Information System (INIS)

    Ishihara, Hiroshi

    1994-01-01

    After whole body irradiation of 3Gy X ray to C3H/He male mice, acute myeloid leukemia is induced at an incidence of 20 to 30% within 2 years. We have studied the mechanism of occurrence of this radiation-induced murine myeloid leukemia. Detection and isolation of genomic structural aberration which may be accumulated accompanied with leukemogenesis are helpful in analyzing the complicated molecular process from radiation damage to leukemogenesis. So, our research work was done in three phases. First, structures of previously characterized oncogenes and cytokine-related genes were analyzed, and abnormal structures of fms(protooncogene encoding M-CSF receptor gene)-related and myc-related genes were found in several leukemia cells. Additionally, genomic structural aberration of IL-3 gene was observed in some leukemia cells, so that construction of genomic libraries and cloning of the abnormal IL-3 genomic DNAs were performed to characterize the structure. Secondly, because the breakage of chromosome 2 that is frequently observed in myeloid leukemia locates in proximal position of IL-1 gene cluster in some cases, the copy number of IL-1 gene was determined and the gene was cloned. Lastly, the abnormal genome of leukemia cell was cloned by in-gel competence reassociation method. We discussed these findings and evaluated the analysis of the molecular process of leukemogenesis using these cloned genomic fragments. (author)

  17. Phosphate steering by Flap Endonuclease 1 promotes 5′-flap specificity and incision to prevent genome instability

    KAUST Repository

    Tsutakawa, Susan E.

    2017-06-27

    DNA replication and repair enzyme Flap Endonuclease 1 (FEN1) is vital for genome integrity, and FEN1 mutations arise in multiple cancers. FEN1 precisely cleaves single-stranded (ss) 5\\'-flaps one nucleotide into duplex (ds) DNA. Yet, how FEN1 selects for but does not incise the ss 5\\'-flap was enigmatic. Here we combine crystallographic, biochemical and genetic analyses to show that two dsDNA binding sites set the 5\\'polarity and to reveal unexpected control of the DNA phosphodiester backbone by electrostatic interactions. Via phosphate steering\\', basic residues energetically steer an inverted ss 5\\'-flap through a gateway over FEN1\\'s active site and shift dsDNA for catalysis. Mutations of these residues cause an 18,000-fold reduction in catalytic rate in vitro and large-scale trinucleotide (GAA) repeat expansions in vivo, implying failed phosphate-steering promotes an unanticipated lagging-strand template-switch mechanism during replication. Thus, phosphate steering is an unappreciated FEN1 function that enforces 5\\'-flap specificity and catalysis, preventing genomic instability.

  18. Progress in understanding turbulent mixing induced by Rayleigh-Taylor and Richtmyer-Meshkov instabilities

    International Nuclear Information System (INIS)

    Zhou Ye; Remington, B.A.; Robey, H.F.; Cook, A.W.; Glendinning, S.G.; Dimits, A.; Buckingham, A.C.; Zimmerman, G.B.; Burke, E.W.; Peyser, T.A.; Cabot, W.; Eliason, D.

    2003-01-01

    Turbulent hydrodynamic mixing induced by the Rayleigh-Taylor (RT) and Richtmyer-Meshkov (RM) instabilities occurs in settings as varied as exploding stars (supernovae), inertial confinement fusion (ICF) capsule implosions, and macroscopic flows in fluid dynamics facilities such as shock tubes. Turbulence theory and modeling have been applied to RT and RM induced flows and developed into a quantitative description of turbulence from the onset to the asymptotic end-state. The treatment, based on a combined approach of theory, direct numerical simulation (DNS), and experimental data analysis, has broad generality. Three areas of progress will be reported. First, a robust, easy to apply criteria will be reported for the mixing transition in a time-dependent flow. This allows an assessment of whether flows, be they from supernova explosions or ICF experiments, should be mixed down to the molecular scale or not. Second, through DNS, the structure, scaling, and spectral evolution of the RT instability induced flow will be inspected. Finally, using these new physical insights, a two-scale, dynamic mix model has been developed that can be applied to simulations of ICF experiments and astrophysics situations alike

  19. Persistent genetic instability induced by synergistic interaction between x-irradiation and 6-thioguanine

    International Nuclear Information System (INIS)

    Grosovsky, A.J.; Nelson, S.L.; Smith, L.E.

    1995-01-01

    Clonal karyotypic analysis was performed using G-banding on four groups of clones derived from TK6 human lymphoblasts: 25 HPRT - total gene deletion mutants induced by exposure to 2 Gy of x-rays; 8 spontaneous HPRT - total gene deletion mutants; 25 clones irradiated with 2 Gy, not selected with 6-thioguanine. Ten to twenty metaphases were examined for each clone. Extensive karyotypic heterogeneity was observed among x-ray induced HPRT - mutants involving translocations, deletions, duplications and aneuploidy; recovery of chromosomal aberrations and karyotypic heterogeneity was greater than the additive effects of clones treated with x-irradiation or 6-thioguanine alone. This synergistic interaction between x-irradiation and 6-thioguanine was observed despite a 7 day phenotypic expression interval between exposure to the two agents. Thus, x-irradiated TK6 cells appear to be persistently hypersensitive to the induction of genetic instability. Several mutants appeared to exhibit evidence of clonal evolution since aberrant chromosomes observed in one metaphase, were found to be further modified in other metaphases. In order to determine if genetic instability, identified by clonal karyotypic heterogeneity, affected specific locus mutation rates, we utilized the heterozygous thymidine kinase (tk) locus as a genetic marker. Four x-ray induced HPRT - mutants with extensive karyotypic heterogeneity, exhibited mutation rates at tk ranging from 5 to 8 fold higher than the parental TK6 cells. Further analysis, using fractionated low dose radiation exposure, is currently in progress

  20. The general dispersion relation of induced streaming instabilities in quantum outflow systems

    Energy Technology Data Exchange (ETDEWEB)

    Mehdian, H., E-mail: mehdian@khu.ac.ir; Hajisharifi, K.; Hasanbeigi, A. [Department of Physics and Institute for Plasma Research, Kharazmi University, 49 Dr Mofatteh Avenue, Tehran 15614 (Iran, Islamic Republic of)

    2015-11-15

    In this manuscript the dispersion relations of streaming instabilities, by using the unique property (neutralized in charge and current by default) of plasma shells colliding, have been generalized and studied. This interesting property for interpenetrating beams enables one to find the general dispersion relations without any restrictions used in the previous works in this area. In our previous work [H. Mehdian et al., ApJ. 801, 89 (2015)], employing the plasma shell concept and boost frame method, the general dispersion relation for filamentation instability has been derived in the relativistic classical regime. But in this paper, using the above mentioned concepts, the general dispersion relations (for each of streaming instabilities, filamentation, two-stream and multi-stream) in the non-relativistic quantum regime have been derived by employing the quantum fluid equations together with Maxwell equations. The derived dispersion relations enable to describe any arbitrary system of interacting two and three beams, justified neutralization condition, by choosing the inertial reference frame embedded on the one of the beams. Furthermore, by the numerical and analytical study of these dispersion relations, many new features of streaming instabilities (E.g. their cut-off wave numbers and growth rates) in terms of all involved parameters have been illustrated. The obtained results in this paper can be used to describe many astrophysical systems and laboratory astrophysics setting, such as collision of non-parallel plasma shells over a background plasma or the collision of three neutralized plasma slabs, and justifying the many plasma phenomena such as particle accelerations and induced fields.

  1. Pad-mode-induced instantaneous mode instability for simple models of brake systems

    Science.gov (United States)

    Oberst, S.; Lai, J. C. S.

    2015-10-01

    Automotive disc brake squeal is fugitive, transient and remains difficult to predict. In particular, instantaneous mode squeal observed experimentally does not seem to be associated with mode coupling and its mechanism is not clear. The effects of contact pressures, friction coefficients as well as material properties (pressure and temperature dependency and anisotropy) for brake squeal propensity have not been systematically explored. By analysing a finite element model of an isotropic pad sliding on a plate similar to that of a previously reported experimental study, pad modes have been identified and found to be stable using conventional complex eigenvalue analysis. However, by subjecting the model to contact pressure harmonic excitation for a range of pressures and friction coefficients, a forced response analysis reveals that the dissipated energy for pad modes is negative and becomes more negative with increasing contact pressures and friction coefficients, indicating the potential for instabilities. The frequency of the pad mode in the sliding direction is within the range of squeal frequencies observed experimentally. Nonlinear time series analysis of the vibration velocity also confirms the evolution of instabilities induced by pad modes as the friction coefficient increases. By extending this analysis to a more realistic but simple brake model in the form of a pad-on-disc system, in-plane pad-modes, which a complex eigenvalue analysis predicts to be stable, have also been identified by negative dissipated energy for both isotropic and anisotropic pad material properties. The influence of contact pressures on potential instabilities has been found to be more dominant than changes in material properties owing to changes in pressure or temperature. Results here suggest that instantaneous mode squeal is likely caused by in-plane pad-mode instabilities.

  2. AID/APOBEC cytosine deaminase induces genome-wide kataegis

    Directory of Open Access Journals (Sweden)

    Lada Artem G

    2012-12-01

    Full Text Available Abstract Clusters of localized hypermutation in human breast cancer genomes, named “kataegis” (from the Greek for thunderstorm, are hypothesized to result from multiple cytosine deaminations catalyzed by AID/APOBEC proteins. However, a direct link between APOBECs and kataegis is still lacking. We have sequenced the genomes of yeast mutants induced in diploids by expression of the gene for PmCDA1, a hypermutagenic deaminase from sea lamprey. Analysis of the distribution of 5,138 induced mutations revealed localized clusters very similar to those found in tumors. Our data provide evidence that unleashed cytosine deaminase activity is an evolutionary conserved, prominent source of genome-wide kataegis events. Reviewers This article was reviewed by: Professor Sandor Pongor, Professor Shamil R. Sunyaev, and Dr Vladimir Kuznetsov.

  3. Genomic mutation study for long-term cells induced by carbon ions

    International Nuclear Information System (INIS)

    Wang, X.; Furusawa, Y.; Suzuki, M.; Hirayama, R.; Matsumoto, Y.; Qin, Y.

    2007-01-01

    Complete text of publication follows. Objective: Densely ionizing (high LET) radiation can increase the relative biological effectiveness of cell and tissue. Astronauts in the space exploration have the potential exposure of chronic low-dose radiations in the field of low-flux galactic cosmic rays (GCR) and the subsequent biological effects have become one of the major concerns of space science. Furthermore, Heavy ions also are used new radiation therapy owing increased lethal effectiveness of high LET radiation. During radiation therapy, normal tissues also are exposed to ionizing radiation. Radiation can induce genomic mutation and instability in descendants of irradiated cells. Induction of genomic instability can represent one of the initiating steps leading to malignant transformation. Higher frequencies of mutation can be expected to provide higher rates of carcinogenicity with human exposure. Therefore, the study of radiation induced genomic mutation and instability is relevant to the estimates of the risk of secondary malignancies associated with radiation therapy and the carcinogenic effects of space environmental radiation. The hypoxanthine-guanine phosphoribosyltransferase (hprt) locus has been the most commonly used as a target gene for mutation detection studies. In this study, we investigated the generation expression dependence of mutation induction on HPRT locus in CHO cells irradiated with carbon ions. Methods: Chinese hamster ovary (CHO) cells were irradiated with graded doses of carbon ions (290MeV/u, LET:13kev/um) accelerated with Heavy Ion Medical Accelerator in Chiba (HIMAC) at National Institute of Radiological Sciences(NIRS). The survival effect of cells plated immediately after irradiation was measured with cell colony formation assay. After irradiation, cells were continues reseeding and cultures for lone-term proliferation. Cell samples were collected at 6, 12, 18, 24, 30, 37 and 44 days post irradiation. Mutation induction of cell

  4. Telomerase as a potential anticancer target: growth inhibition and genomic instability.

    Science.gov (United States)

    Faraoni, Isabella; Graziani, Grazia

    2000-02-01

    Stabilization of telomere length in chromosomes by an RNA-dependent DNA polymerase (telomerase) appears to be responsible for the replicative immortality of cancer cells. These findings provide the rational basis for generating experimental models to develop anti-telomerase drugs. However, there is conflicting evidence in the literature about the outcome of telomerase inhibition. While tumor cytostatic and cytotoxic effects associated with telomerase inhibition have been described, absence of telomerase has been associated with genetic instability and tumor development. Therefore, a therapeutic strategy based on telomerase inhibition will likely have to cope with problems related to innate or acquired mechanisms of drug resistance and possibly to therapy-related tumors. Copyright 2000 Harcourt Publishers Ltd.

  5. Generation of an ICF syndrome model by efficient genome editing of human induced pluripotent stem cells using the CRISPR system.

    Science.gov (United States)

    Horii, Takuro; Tamura, Daiki; Morita, Sumiyo; Kimura, Mika; Hatada, Izuho

    2013-09-30

    Genome manipulation of human induced pluripotent stem (iPS) cells is essential to achieve their full potential as tools for regenerative medicine. To date, however, gene targeting in human pluripotent stem cells (hPSCs) has proven to be extremely difficult. Recently, an efficient genome manipulation technology using the RNA-guided DNase Cas9, the clustered regularly interspaced short palindromic repeats (CRISPR) system, has been developed. Here we report the efficient generation of an iPS cell model for immunodeficiency, centromeric region instability, facial anomalies syndrome (ICF) syndrome using the CRISPR system. We obtained iPS cells with mutations in both alleles of DNA methyltransferase 3B (DNMT3B) in 63% of transfected clones. Our data suggest that the CRISPR system is highly efficient and useful for genome engineering of human iPS cells.

  6. Generation of an ICF Syndrome Model by Efficient Genome Editing of Human Induced Pluripotent Stem Cells Using the CRISPR System

    Directory of Open Access Journals (Sweden)

    Izuho Hatada

    2013-09-01

    Full Text Available Genome manipulation of human induced pluripotent stem (iPS cells is essential to achieve their full potential as tools for regenerative medicine. To date, however, gene targeting in human pluripotent stem cells (hPSCs has proven to be extremely difficult. Recently, an efficient genome manipulation technology using the RNA-guided DNase Cas9, the clustered regularly interspaced short palindromic repeats (CRISPR system, has been developed. Here we report the efficient generation of an iPS cell model for immunodeficiency, centromeric region instability, facial anomalies syndrome (ICF syndrome using the CRISPR system. We obtained iPS cells with mutations in both alleles of DNA methyltransferase 3B (DNMT3B in 63% of transfected clones. Our data suggest that the CRISPR system is highly efficient and useful for genome engineering of human iPS cells.

  7. Systemic chemotherapy induces microsatellite instability in the peripheral blood mononuclear cells of breast cancer patients

    International Nuclear Information System (INIS)

    Fonseca, Fernando LA; Sant Ana, Aleksandra VL; Bendit, Israel; Arias, Vitor; Costa, Luciano J; Pinhal, Aparecida A; Giglio, Auro del

    2005-01-01

    Systemic chemotherapy is an important part of treatment for breast cancer. We conducted the present study to evaluate whether systemic chemotherapy could produce microsatellite instability (MSI) in the peripheral blood mononuclear cell fraction of breast cancer patients. We studied 119 sequential blood samples from 30 previously untreated breast cancer patients before, during and after chemotherapy. For comparison, we also evaluated 20 women who had no relevant medical history (control group). In 27 out of 30 patients we observed MSI in at least one sample, and six patients had loss of heterozygosity. We found a significant correlation between the number of MSI events per sample and chemotherapy with alkylating agents (P < 0.0001). We also observed an inverse correlation between the percentage of cells positive for hMSH2 and the number of MSI events per sample (P = 0.00019) and use of alkylating agents (P = 0.019). We conclude that systemic chemotherapy may induce MSI and loss of heterozygosity in peripheral blood mononuclear cells from breast cancer patients receiving alkylating agents, possibly mediated by a chemotherapy-induced decrease in the expression of hMSH2. These effects may be related to the generation of secondary leukaemia in some patients, and may also intensify the genetic instability of tumours and increase resistance to treatment

  8. Visible-light-induced instability in amorphous metal-oxide based TFTs for transparent electronics

    Directory of Open Access Journals (Sweden)

    Tae-Jun Ha

    2014-10-01

    Full Text Available We investigate the origin of visible-light-induced instability in amorphous metal-oxide based thin film transistors (oxide-TFTs for transparent electronics by exploring the shift in threshold voltage (Vth. A large hysteresis window in amorphous indium-gallium-zinc-oxide (a-IGZO TFTs possessing large optical band-gap (≈3 eV was observed in a visible-light illuminated condition whereas no hysteresis window was shown in a dark measuring condition. We also report the instability caused by photo irradiation and prolonged gate bias stress in oxide-TFTs. Larger Vth shift was observed after photo-induced stress combined with a negative gate bias than the sum of that after only illumination stress and only negative gate bias stress. Such results can be explained by trapped charges at the interface of semiconductor/dielectric and/or in the gate dielectric which play a role in a screen effect on the electric field applied by gate voltage, for which we propose that the localized-states-assisted transitions by visible-light absorption can be responsible.

  9. Visible-light-induced instability in amorphous metal-oxide based TFTs for transparent electronics

    Energy Technology Data Exchange (ETDEWEB)

    Ha, Tae-Jun [Department of Electronic Materials Engineering, Kwangwoon University, Seoul 139-701 (Korea, Republic of)

    2014-10-15

    We investigate the origin of visible-light-induced instability in amorphous metal-oxide based thin film transistors (oxide-TFTs) for transparent electronics by exploring the shift in threshold voltage (V{sub th}). A large hysteresis window in amorphous indium-gallium-zinc-oxide (a-IGZO) TFTs possessing large optical band-gap (≈3 eV) was observed in a visible-light illuminated condition whereas no hysteresis window was shown in a dark measuring condition. We also report the instability caused by photo irradiation and prolonged gate bias stress in oxide-TFTs. Larger V{sub th} shift was observed after photo-induced stress combined with a negative gate bias than the sum of that after only illumination stress and only negative gate bias stress. Such results can be explained by trapped charges at the interface of semiconductor/dielectric and/or in the gate dielectric which play a role in a screen effect on the electric field applied by gate voltage, for which we propose that the localized-states-assisted transitions by visible-light absorption can be responsible.

  10. Non-thermal plasma instabilities induced by deformation of the electron energy distribution function

    Science.gov (United States)

    Dyatko, N. A.; Kochetov, I. V.; Napartovich, A. P.

    2014-08-01

    Non-thermal plasma is a key component in gas lasers, microelectronics, medical applications, waste gas cleaners, ozone generators, plasma igniters, flame holders, flow control in high-speed aerodynamics and others. A specific feature of non-thermal plasma is its high sensitivity to variations in governing parameters (gas composition, pressure, pulse duration, E/N parameter). This sensitivity is due to complex deformations of the electron energy distribution function (EEDF) shape induced by variations in electric field strength, electron and ion number densities and gas excitation degree. Particular attention in this article is paid to mechanisms of instabilities based on non-linearity of plasma properties for specific conditions: gas composition, steady-state and decaying plasma produced by the electron beam, or by an electric current pulse. The following effects are analyzed: the negative differential electron conductivity; the absolute negative electron mobility; the stepwise changes of plasma properties induced by the EEDF bi-stability; thermo-current instability and the constriction of the glow discharge column in rare gases. Some of these effects were observed experimentally and some of them were theoretically predicted and still wait for experimental confirmation.

  11. Investigation of flashing-induced instabilities at Circus test facility with the code ATHLET

    Energy Technology Data Exchange (ETDEWEB)

    Schafer, F.; Manera, A. [Forschungzentrum Rossendorf e.V., Institute of Safety Research, P.O. Box 510119, D-01314 Dresden (Germany)]. E-mail: F.Schaefer@fz-rossendorf.de; A.Manera@fz-rossendorf.de

    2006-07-01

    The test facility CIRCUS (CIRculation Under Start-up) was built to study the start-up phase of a natural-circulation BWR. During the start-up,so-called flashing-induced instabilities can arise. These instabilities are induced by flashing (i.e., steam production in adiabatic conditions) of the coolant in the long riser section, which is placed above the core to enhance the flow rate. The flashing that occurs in the riser causes an imbalance between driving force and pressure losses in the natural-circulation loop, giving rise to flow oscillations. Within the European-Union 5th Framework Programme, a project, NACUSP (Natural circulation and stability performance of BWRs), has been started in December 2000, having as one of its main aims the understanding of the physics of the phenomena involved during the start-up phase of natural-circulation-cooled BWRs, providing a large experimental database and validating state-of-the-art thermo-hydraulic codes in the low-pressure, low-power operational region of these reactors. One part of this project deals with the modelling of selected CIRCUS tests using the thermo-hydraulic code ATHLET (Analysis of THermal-hydraulics of LEaks and Transients). This paper gives an overview about experiments and simulations. The code ATHLET is used to investigate the dynamic behaviour of the CIRCUS test facility and the results of the calculations are compared with the experimental data. (author)

  12. Grain Boundary Induced Bias Instability in Soluble Acene-Based Thin-Film Transistors

    Science.gov (United States)

    Nguyen, Ky V.; Payne, Marcia M.; Anthony, John E.; Lee, Jung Hun; Song, Eunjoo; Kang, Boseok; Cho, Kilwon; Lee, Wi Hyoung

    2016-01-01

    Since the grain boundaries (GBs) within the semiconductor layer of organic field-effect transistors (OFETs) have a strong influence on device performance, a substantial number of studies have been devoted to controlling the crystallization characteristics of organic semiconductors. We studied the intrinsic effects of GBs within 5,11-bis(triethylsilylethynyl) anthradithiophene (TES-ADT) thin films on the electrical properties of OFETs. The GB density was easily changed by controlling nulceation event in TES-ADT thin films. When the mixing time was increased, the number of aggregates in as-spun TES-ADT thin films were increased and subsequent exposure of the films to 1,2-dichloroethane vapor led to a significant increase in the number of nuleation sites, thereby increasing the GB density of TES-ADT spherulites. The density of GBs strongly influences the angular spread and crystallographic orientation of TES-ADT spherulites. Accordingly, the FETs with higher GB densities showed much poorer electrical characteristics than devices with lower GB density. Especially, GBs provide charge trapping sites which are responsible for bias-stress driven electrical instability. Dielectric surface treatment with a polystyrene brush layer clarified the GB-induced charge trapping by reducing charge trapping at the semiconductor-dielectric interface. Our study provides an understanding on GB induced bias instability for the development of high performance OFETs. PMID:27615358

  13. DNA repair efficiency in germ cells and early mouse embryos and consequences for radiation-induced transgenerational genomic damage

    Energy Technology Data Exchange (ETDEWEB)

    Marchetti, Francesco; Wyrobek, Andrew J.

    2009-01-18

    Exposure to ionizing radiation and other environmental agents can affect the genomic integrity of germ cells and induce adverse health effects in the progeny. Efficient DNA repair during gametogenesis and the early embryonic cycles after fertilization is critical for preventing transmission of DNA damage to the progeny and relies on maternal factors stored in the egg before fertilization. The ability of the maternal repair machinery to repair DNA damage in both parental genomes in the fertilizing egg is especially crucial for the fertilizing male genome that has not experienced a DNA repair-competent cellular environment for several weeks prior to fertilization. During the DNA repair-deficient period of spermatogenesis, DNA lesions may accumulate in sperm and be carried into the egg where, if not properly repaired, could result in the formation of heritable chromosomal aberrations or mutations and associated birth defects. Studies with female mice deficient in specific DNA repair genes have shown that: (i) cell cycle checkpoints are activated in the fertilized egg by DNA damage carried by the sperm; and (ii) the maternal genotype plays a major role in determining the efficiency of repairing genomic lesions in the fertilizing sperm and directly affect the risk for abnormal reproductive outcomes. There is also growing evidence that implicates DNA damage carried by the fertilizing gamete as a mediator of postfertilization processes that contribute to genomic instability in subsequent generations. Transgenerational genomic instability most likely involves epigenetic mechanisms or error-prone DNA repair processes in the early embryo. Maternal and embryonic DNA repair processes during the early phases of mammalian embryonic development can have far reaching consequences for the genomic integrity and health of subsequent generations.

  14. Antioxidant Supplementation Reduces Genomic Aberrations in Human Induced Pluripotent Stem Cells

    Directory of Open Access Journals (Sweden)

    Junfeng Ji

    2014-01-01

    Full Text Available Somatic cells can be reprogrammed to induced pluripotent stem cells (iPSCs using oncogenic transcription factors. However, this method leads to genetic aberrations in iPSCs via unknown mechanisms, which may limit their clinical use. Here, we demonstrate that the supplementation of growth media with antioxidants reduces the genome instability of cells transduced with the reprogramming factors. Antioxidant supplementation did not affect transgene expression level or silencing kinetics. Importantly, iPSCs made with antioxidants had significantly fewer de novo copy number variations, but not fewer coding point mutations, than iPSCs made without antioxidants. Our results suggest that the quality and safety of human iPSCs might be enhanced by using antioxidants in the growth media during the generation and maintenance of iPSCs.

  15. 56Fe particle exposure results in a long-lasting increase in a cellular index of genomic instability and transiently suppresses adult hippocampal neurogenesis in vivo

    Science.gov (United States)

    DeCarolis, Nathan A.; Rivera, Phillip D.; Ahn, Francisca; Amaral, Wellington Z.; LeBlanc, Junie A.; Malhotra, Shveta; Shih, Hung-Ying; Petrik, David; Melvin, Neal R.; Chen, Benjamin P. C.; Eisch, Amelia J.

    2014-07-01

    The high-LET HZE particles from galactic cosmic radiation pose tremendous health risks to astronauts, as they may incur sub-threshold brain injury or maladaptations that may lead to cognitive impairment. The health effects of HZE particles are difficult to predict and unfeasible to prevent. This underscores the importance of estimating radiation risks to the central nervous system as a whole as well as to specific brain regions like the hippocampus, which is central to learning and memory. Given that neurogenesis in the hippocampus has been linked to learning and memory, we investigated the response and recovery of neurogenesis and neural stem cells in the adult mouse hippocampal dentate gyrus after HZE particle exposure using two nestin transgenic reporter mouse lines to label and track radial glia stem cells (Nestin-GFP and Nestin-CreERT2/R26R:YFP mice, respectively). Mice were subjected to 56Fe particle exposure (0 or 1 Gy, at either 300 or 1000 MeV/n) and brains were harvested at early (24 h), intermediate (7 d), and/or long time points (2-3 mo) post-irradiation. 56Fe particle exposure resulted in a robust increase in 53BP1+ foci at both the intermediate and long time points post-irradiation, suggesting long-term genomic instability in the brain. However, 56Fe particle exposure only produced a transient decrease in immature neuron number at the intermediate time point, with no significant decrease at the long time point post-irradiation. 56Fe particle exposure similarly produced a transient decrease in dividing progenitors, with fewer progenitors labeled at the early time point but equal number labeled at the intermediate time point, suggesting a recovery of neurogenesis. Notably, 56Fe particle exposure did not change the total number of nestin-expressing neural stem cells. These results highlight that despite the persistence of an index of genomic instability, 56Fe particle-induced deficits in adult hippocampal neurogenesis may be transient. These data support

  16. DNA end resection by CtIP and exonuclease 1 prevents genomic instability

    DEFF Research Database (Denmark)

    Eid, Wassim; Steger, Martin; El-Shemerly, Mahmoud

    2010-01-01

    End resection of DNA-which is essential for the repair of DNA double-strand breaks (DSBs) by homologous recombination-relies first on the partnership between MRE11-RAD50-NBS1 (MRN) and CtIP, followed by a processive step involving helicases and exonucleases such as exonuclease 1 (EXO1). In this s......End resection of DNA-which is essential for the repair of DNA double-strand breaks (DSBs) by homologous recombination-relies first on the partnership between MRE11-RAD50-NBS1 (MRN) and CtIP, followed by a processive step involving helicases and exonucleases such as exonuclease 1 (EXO1...... of DNA-PK-dependent radial chromosome formation. Thus, our study identifies new functions of CtIP and EXO1 in DNA end resection and provides new information on the regulation of DSB repair pathways, which is a key factor in the maintenance of genome integrity....

  17. DNA Mismatch Repair Deficiency Promotes Genomic Instability in a Subset of Papillary Thyroid Cancers.

    Science.gov (United States)

    Javid, Mahsa; Sasanakietkul, Thanyawat; Nicolson, Norman G; Gibson, Courtney E; Callender, Glenda G; Korah, Reju; Carling, Tobias

    2018-02-01

    Efficient DNA damage repair by MutL-homolog DNA mismatch repair (MMR) enzymes, MLH1, MLH3, PMS1 and PMS2, are required to maintain thyrocyte genomic integrity. We hypothesized that persistent oxidative stress and consequent transcriptional dysregulation observed in thyroid follicles will lead to MMR deficiency and potentiate papillary thyroid tumorigenesis. MMR gene expression was analyzed by targeted microarray in 18 papillary thyroid cancer (PTC), 9 paracarcinoma normal thyroid (PCNT) and 10 normal thyroid (NT) samples. The findings were validated by qRT-PCR, and in follicular thyroid cancers (FTC) and follicular thyroid adenomas (FTA) for comparison. FOXO transcription factor expression was also analyzed. Protein expression was assessed by immunohistochemistry. Genomic integrity was evaluated by whole-exome sequencing-derived read-depth analysis and Mann-Whitney U test. Clinical correlations were assessed using Fisher's exact and t tests. Microarray and qRT-PCR revealed reduced expression of all four MMR genes in PTC compared with PCNT and of PMS2 compared with NT. FTC and FTA showed upregulation in MLH1, MLH3 and PMS2. PMS2 protein expression correlated with the mRNA expression pattern. FOXO1 showed lower expression in PMS2-deficient PTCs (log2-fold change -1.72 vs. -0.55, U = 11, p clinical characteristics. MMR deficiency, potentially promoted by FOXO1 suppression, may explain the etiology for PTC development in some patients. FTC and FTA retain MMR activity and are likely caused by a different tumorigenic pathway.

  18. Induced Pluripotent Stem Cells Meet Genome Editing.

    Science.gov (United States)

    Hockemeyer, Dirk; Jaenisch, Rudolf

    2016-05-05

    It is extremely rare for a single experiment to be so impactful and timely that it shapes and forecasts the experiments of the next decade. Here, we review how two such experiments-the generation of human induced pluripotent stem cells (iPSCs) and the development of CRISPR/Cas9 technology-have fundamentally reshaped our approach to biomedical research, stem cell biology, and human genetics. We will also highlight the previous knowledge that iPSC and CRISPR/Cas9 technologies were built on as this groundwork demonstrated the need for solutions and the benefits that these technologies provided and set the stage for their success. Copyright © 2016 Elsevier Inc. All rights reserved.

  19. Chronic p53-independent p21 expression causes genomic instability by deregulating replication licensing

    DEFF Research Database (Denmark)

    Galanos, Panagiotis; Vougas, Konstantinos; Walter, David

    2016-01-01

    The cyclin-dependent kinase inhibitor p21(WAF1/CIP1) (p21) is a cell-cycle checkpoint effector and inducer of senescence, regulated by p53. Yet, evidence suggests that p21 could also be oncogenic, through a mechanism that has so far remained obscure. We report that a subset of atypical cancerous ...

  20. dAdd1 and dXNP prevent genome instability by maintaining HP1a localization at Drosophila telomeres.

    Science.gov (United States)

    Chavez, Joselyn; Murillo-Maldonado, Juan Manuel; Bahena, Vanessa; Cruz, Ana Karina; Castañeda-Sortibrán, América; Rodriguez-Arnaiz, Rosario; Zurita, Mario; Valadez-Graham, Viviana

    2017-12-01

    Telomeres are important contributors to genome stability, as they prevent linear chromosome end degradation and contribute to the avoidance of telomeric fusions. An important component of the telomeres is the heterochromatin protein 1a (HP1a). Mutations in Su(var)205, the gene encoding HP1a in Drosophila, result in telomeric fusions, retrotransposon regulation loss and larger telomeres, leading to chromosome instability. Previously, it was found that several proteins physically interact with HP1a, including dXNP and dAdd1 (orthologues to the mammalian ATRX gene). In this study, we found that mutations in the genes encoding the dXNP and dAdd1 proteins affect chromosome stability, causing chromosomal aberrations, including telomeric defects, similar to those observed in Su(var)205 mutants. In somatic cells, we observed that dXNP and dAdd1 participate in the silencing of the telomeric HTT array of retrotransposons, preventing anomalous retrotransposon transcription and integration. Furthermore, the lack of dAdd1 results in the loss of HP1a from the telomeric regions without affecting other chromosomal HP1a binding sites; mutations in dxnp also affected HP1a localization but not at all telomeres, suggesting a specialized role for dAdd1 and dXNP proteins in locating HP1a at the tips of the chromosomes. These results place dAdd1 as an essential regulator of HP1a localization and function in the telomere heterochromatic domain.

  1. Omics Approaches for Identifying Physiological Adaptations to Genome Instability in Aging.

    Science.gov (United States)

    Edifizi, Diletta; Schumacher, Björn

    2017-11-04

    DNA damage causally contributes to aging and age-related diseases. The declining functioning of tissues and organs during aging can lead to the increased risk of succumbing to aging-associated diseases. Congenital syndromes that are caused by heritable mutations in DNA repair pathways lead to cancer susceptibility and accelerated aging, thus underlining the importance of genome maintenance for withstanding aging. High-throughput mass-spectrometry-based approaches have recently contributed to identifying signalling response networks and gaining a more comprehensive understanding of the physiological adaptations occurring upon unrepaired DNA damage. The insulin-like signalling pathway has been implicated in a DNA damage response (DDR) network that includes epidermal growth factor (EGF)-, AMP-activated protein kinases (AMPK)- and the target of rapamycin (TOR)-like signalling pathways, which are known regulators of growth, metabolism, and stress responses. The same pathways, together with the autophagy-mediated proteostatic response and the decline in energy metabolism have also been found to be similarly regulated during natural aging, suggesting striking parallels in the physiological adaptation upon persistent DNA damage due to DNA repair defects and long-term low-level DNA damage accumulation occurring during natural aging. These insights will be an important starting point to study the interplay between signalling networks involved in progeroid syndromes that are caused by DNA repair deficiencies and to gain new understanding of the consequences of DNA damage in the aging process.

  2. Omics Approaches for Identifying Physiological Adaptations to Genome Instability in Aging

    Directory of Open Access Journals (Sweden)

    Diletta Edifizi

    2017-11-01

    Full Text Available DNA damage causally contributes to aging and age-related diseases. The declining functioning of tissues and organs during aging can lead to the increased risk of succumbing to aging-associated diseases. Congenital syndromes that are caused by heritable mutations in DNA repair pathways lead to cancer susceptibility and accelerated aging, thus underlining the importance of genome maintenance for withstanding aging. High-throughput mass-spectrometry-based approaches have recently contributed to identifying signalling response networks and gaining a more comprehensive understanding of the physiological adaptations occurring upon unrepaired DNA damage. The insulin-like signalling pathway has been implicated in a DNA damage response (DDR network that includes epidermal growth factor (EGF-, AMP-activated protein kinases (AMPK- and the target of rapamycin (TOR-like signalling pathways, which are known regulators of growth, metabolism, and stress responses. The same pathways, together with the autophagy-mediated proteostatic response and the decline in energy metabolism have also been found to be similarly regulated during natural aging, suggesting striking parallels in the physiological adaptation upon persistent DNA damage due to DNA repair defects and long-term low-level DNA damage accumulation occurring during natural aging. These insights will be an important starting point to study the interplay between signalling networks involved in progeroid syndromes that are caused by DNA repair deficiencies and to gain new understanding of the consequences of DNA damage in the aging process.

  3. SERIES: Genomic instability in cancer Balancing repair and tolerance of DNA damage caused by alkylating agents

    OpenAIRE

    Fu, Dragony; Calvo, Jennifer A.; Samson, Leona D

    2012-01-01

    Alkylating agents comprise a major class of frontline chemotherapeutic drugs that inflict cytotoxic DNA damage as their main mode of action, in addition to collateral mutagenic damage. Numerous cellular pathways, including direct DNA damage reversal, base excision repair (BER), and mismatch repair (MMR) respond to alkylation damage to defend against alkylation-induced cell death or mutation. However, maintaining a proper balance of activity both within and between these pathways is crucial fo...

  4. Delayed chromosomal instability caused by large deletion

    International Nuclear Information System (INIS)

    Ojima, M.; Suzuki, K.; Kodama, S.; Watanabe, M.

    2003-01-01

    Full text: There is accumulating evidence that genomic instability, manifested by the expression of delayed phenotypes, is induced by X-irradiation but not by ultraviolet (UV) light. It is well known that ionizing radiation, such as X-rays, induces DNA double strand breaks, but UV-light mainly causes base damage like pyrimidine dimers and (6-4) photoproducts. Although the mechanism of radiation-induced genomic instability has not been thoroughly explained, it is suggested that DNA double strand breaks contribute the induction of genomic instability. We examined here whether X-ray induced gene deletion at the hprt locus induces delayed instability in chromosome X. SV40-immortalized normal human fibroblasts, GM638, were irradiated with X-rays (3, 6 Gy), and the hprt mutants were isolated in the presence of 6-thioguanine (6-TG). A 2-fold and a 60-fold increase in mutation frequency were found by 3 Gy and 6 Gy irradiation, respectively. The molecular structure of the hprt mutations was determined by multiplex polymerase chain reaction of nine exons. Approximately 60% of 3 Gy mutants lost a part or the entire hprt gene, and the other mutants showed point mutations like spontaneous mutants. All 6 Gy mutants show total gene deletion. The chromosomes of the hprt mutants were analyzed by Whole Human Chromosome X Paint FISH or Xq telomere FISH. None of the point or partial gene deletion mutants showed aberrations of X-chromosome, however total gene deletion mutants induced translocations and dicentrics involving chromosome X. These results suggest that large deletion caused by DNA double strand breaks destabilizes chromosome structure, which may be involved in an induction of radiation-induced genomic instability

  5. Instability in time-delayed switched systems induced by fast and random switching

    Science.gov (United States)

    Guo, Yao; Lin, Wei; Chen, Yuming; Wu, Jianhong

    2017-07-01

    In this paper, we consider a switched system comprising finitely or infinitely many subsystems described by linear time-delayed differential equations and a rule that orchestrates the system switching randomly among these subsystems, where the switching times are also randomly chosen. We first construct a counterintuitive example where even though all the time-delayed subsystems are exponentially stable, the behaviors of the randomly switched system change from stable dynamics to unstable dynamics with a decrease of the dwell time. Then by using the theories of stochastic processes and delay differential equations, we present a general result on when this fast and random switching induced instability should occur and we extend this to the case of nonlinear time-delayed switched systems as well.

  6. Back-Analyses of Landfill Instability Induced by High Water Level: Case Study of Shenzhen Landfill

    Directory of Open Access Journals (Sweden)

    Ren Peng

    2016-01-01

    Full Text Available In June 2008, the Shenzhen landfill slope failed. This case is used as an example to study the deformation characteristics and failure mode of a slope induced by high water levels. An integrated monitoring system, including water level gauges, electronic total stations, and inclinometers, was used to monitor the slope failure process. The field measurements suggest that the landfill landslide was caused by a deep slip along the weak interface of the composite liner system at the base of the landfill. The high water level is considered to be the main factor that caused this failure. To calculate the relative interface shear displacements in the geosynthetic multilayer liner system, a series of numerical direct shear tests were carried out. Based on the numerical results, the composite lining system simplified and the centrifuge modeling technique was used to quantitatively evaluate the effect of water levels on landfill instability.

  7. Back-Analyses of Landfill Instability Induced by High Water Level: Case Study of Shenzhen Landfill

    Science.gov (United States)

    Peng, Ren; Hou, Yujing; Zhan, Liangtong; Yao, Yangping

    2016-01-01

    In June 2008, the Shenzhen landfill slope failed. This case is used as an example to study the deformation characteristics and failure mode of a slope induced by high water levels. An integrated monitoring system, including water level gauges, electronic total stations, and inclinometers, was used to monitor the slope failure process. The field measurements suggest that the landfill landslide was caused by a deep slip along the weak interface of the composite liner system at the base of the landfill. The high water level is considered to be the main factor that caused this failure. To calculate the relative interface shear displacements in the geosynthetic multilayer liner system, a series of numerical direct shear tests were carried out. Based on the numerical results, the composite lining system simplified and the centrifuge modeling technique was used to quantitatively evaluate the effect of water levels on landfill instability. PMID:26771627

  8. K-ras2 Activation and Genome Instability Increase Proliferation and Size of FAP Adenomas

    Directory of Open Access Journals (Sweden)

    Anna Rapallo

    1999-01-01

    Full Text Available The possible role of K‐ras2 mutations and aneuploidy toward increase of proliferation and adenoma size in Familial Adenomatous Polyposis (FAP adenomas is not known. The present study addresses these issues by investigating 147 colorectal adenomas obtained from four FAP patients. The majority of adenomas had size lower than or equal to 10 mm (86%, low grade dysplasia (63%, and were preferentially located in the right colon (60%. Normal mucosa samples were obtained from 19 healthy donors. Three synchronous adenocarcinomas were also investigated. K‐ras2 mutation spectrum was analysed by PCR and Sequence Specific Oligonucleotide (SSO hybridization, while flow cytometry (FCM was used for evaluating degree of DNA ploidy and S‐phase fraction. Overall, incidences of K‐ras2 mutations, DNA aneuploidy and high S‐phase values (>7.2% were 6.6%, 5.4% and 10.5%, respectively. In particular, among the adenomas with size lower than 5 mm, K‐ras2 mutation and DNA aneuploidy frequencies were only slightly above 1%. Statistically significant correlations were found between K‐ras2 and size, DNA ploidy and size and K‐ras2 and S‐phase (p. In particular, among the wild type K‐ras2 adenomas, high S‐phase values were detected in 8% of the cases versus 57% among the K‐ras2 mutated adenomas (p=0.0005. The present series of FAP adenomas indicates that K‐ras2 activation and gross genomic changes play a role toward a proliferative gain and tumour growth in size.

  9. Genome Instability of Chironomus riparius Mg. (Diptera, Chironomidae from Polluted Water Basins in Bulgaria

    Directory of Open Access Journals (Sweden)

    Julia Ilkova

    2014-04-01

    Full Text Available Larvae of Chironomus riparius Mg. (Chironomidae, Diptera collected from two polluted water basins in Bulgaria, the Maritsa and Chaya Rivers (adjacent to Plovdiv and Asenovgrad respectively, a small pool (near Plovdiv plus controls reared in the laboratory were studied. High concentrations of the heavy metals Pb, Cu and Cd were recorded in the sediments of the polluted stations. Marked somatic structural chromosome aberrations were found in C. riparius salivary polytene chromosomes from the field stations and their frequency was significantly higher (p<0.01 compared to the control. The observed somatic chromosome changes are discussed as a response of the chironomid genome to aquatic pollution. A new cytogenetic index based on the number of aberrations found in larvae from polluted regions in comparison with the control was applied to the data to more easily evaluate the degree of heavy metal pollution in aquatic ecosystems. Our study of a polluted site near the River Chaya showed that the somatic index was very high at 3.35 for 2010 and 11.66 for 2013 compared to 0.5 in the control. The cytogenetic index was effective in showing that all studied sites were highly polluted in comparison with the control. To determine the mechanism involved in the concentration of aberration breakpoints within specific regions of the chironomid polytene chromosome the FISH method was applied. The localization of a transposable element TFB1 along the polytene chromosomes of C. riparius was analyzed and the sites of localization were compared with breakpoints of chromosome aberrations. A significant correlation (p<0.05 was found which shows that most of the aberrations do not appear randomly but are concentrated in sites rich in transposable elements.

  10. Characterization of Axial Inducer Cavitation Instabilities via High Speed Video Recordings

    Science.gov (United States)

    Arellano, Patrick; Peneda, Marinelle; Ferguson, Thomas; Zoladz, Thomas

    2011-01-01

    Sub-scale water tests were undertaken to assess the viability of utilizing high resolution, high frame-rate digital video recordings of a liquid rocket engine turbopump axial inducer to characterize cavitation instabilities. These high speed video (HSV) images of various cavitation phenomena, including higher order cavitation, rotating cavitation, alternating blade cavitation, and asymmetric cavitation, as well as non-cavitating flows for comparison, were recorded from various orientations through an acrylic tunnel using one and two cameras at digital recording rates ranging from 6,000 to 15,700 frames per second. The physical characteristics of these cavitation forms, including the mechanisms that define the cavitation frequency, were identified. Additionally, these images showed how the cavitation forms changed and transitioned from one type (tip vortex) to another (sheet cavitation) as the inducer boundary conditions (inlet pressures) were changed. Image processing techniques were developed which tracked the formation and collapse of cavitating fluid in a specified target area, both in the temporal and frequency domains, in order to characterize the cavitation instability frequency. The accuracy of the analysis techniques was found to be very dependent on target size for higher order cavitation, but much less so for the other phenomena. Tunnel-mounted piezoelectric, dynamic pressure transducers were present throughout these tests and were used as references in correlating the results obtained by image processing. Results showed good agreement between image processing and dynamic pressure spectral data. The test set-up, test program, and test results including H-Q and suction performance, dynamic environment and cavitation characterization, and image processing techniques and results will be discussed.

  11. SERIES: Genomic instability in cancer Balancing repair and tolerance of DNA damage caused by alkylating agents

    Science.gov (United States)

    Fu, Dragony; Calvo, Jennifer A.; Samson, Leona D

    2013-01-01

    Alkylating agents comprise a major class of frontline chemotherapeutic drugs that inflict cytotoxic DNA damage as their main mode of action, in addition to collateral mutagenic damage. Numerous cellular pathways, including direct DNA damage reversal, base excision repair (BER), and mismatch repair (MMR) respond to alkylation damage to defend against alkylation-induced cell death or mutation. However, maintaining a proper balance of activity both within and between these pathways is crucial for an organism's favorable response to alkylating agents. Furthermore, an individual's response to alkylating agents can vary considerably from tissue to tissue and from person to person, pointing to genetic and epigenetic mechanisms that modulate alkylating agent toxicity. PMID:22237395

  12. Onset of Absolute Instability Induced by Viscous Dissipation in the Poiseuille-Darcy-Benard Convection of a Newtonian Fluid

    International Nuclear Information System (INIS)

    Brandão, P V; Alves, L S de B; Barletta, A

    2014-01-01

    The present paper investigates the transition from convective to absolute instability induced by viscous dissipation. As far as the authors are aware, this is the first time such a study is reported in the literature. Its framework is provided by the Poiseuille-Darcy-Benard convection of a Newtonian fluid. We found the same behaviour observed in the absence of viscous dissipation whenever the Gebhart number is smaller than Ge < 0.95, which is the stabilising effect of the cross flow. When 0.95 < Ge < 4.31, weak cross flows still stabilise the onset of absolute instability but stronger cross flows destabilise it. For a stronger viscous dissipation, i.e. Ge > 4.31, the cross flow always destabilises this onset. The latter two conditions create a scenario where viscous dissipation is capable of inducing a transition to absolute instability in the absence of wall heating, i.e. with a zero Rayleigh number

  13. Universal model of bias-stress-induced instability in inkjet-printed carbon nanotube networks field-effect transistors

    Science.gov (United States)

    Jung, Haesun; Choi, Sungju; Jang, Jun Tae; Yoon, Jinsu; Lee, Juhee; Lee, Yongwoo; Rhee, Jihyun; Ahn, Geumho; Yu, Hye Ri; Kim, Dong Myong; Choi, Sung-Jin; Kim, Dae Hwan

    2018-02-01

    We propose a universal model for bias-stress (BS)-induced instability in the inkjet-printed carbon nanotube (CNT) networks used in field-effect transistors (FETs). By combining two experimental methods, i.e., a comparison between air and vacuum BS tests and interface trap extraction, BS instability is explained regardless of either the BS polarity or ambient condition, using a single platform constituted by four key factors: OH- adsorption/desorption followed by a change in carrier concentration, electron concentration in CNT channel corroborated with H2O/O2 molecules in ambient, charge trapping/detrapping, and interface trap generation. Under negative BS (NBS), the negative threshold voltage shift (ΔVT) is dominated by OH- desorption, which is followed by hole trapping in the interface and/or gate insulator. Under positive BS (PBS), the positive ΔVT is dominated by OH- adsorption, which is followed by electron trapping in the interface and/or gate insulator. This instability is compensated by interface trap extraction; PBS instability is slightly more complicated than NBS instability. Furthermore, our model is verified using device simulation, which gives insights on how much each mechanism contributes to BS instability. Our result is potentially useful for the design of highly stable CNT-based flexible circuits in the Internet of Things wearable healthcare era.

  14. FANCG knockout CHO cells display sensitivity to diverse DNA damaging agents and possible genomic instability

    International Nuclear Information System (INIS)

    Hinz, J.M.; Tebbs, R.S.; Yamada, N.A.; Salazar, E.P.; Kopf, V.L.; Thompson, L.H.

    2003-01-01

    Full text: The function of the proteins encoded by the genes responsible for the disease Fanconi anemia (FA) have not been elucidated. Several of these proteins (FancA, C, E, F, and G) form a complex in the nucleus, and cells deficient in any one of these proteins are sensitive to crosslinking agents, suggesting a possible role for these proteins in some aspect of DNA repair, chromosomal maintenance, or replication. We constructed a FancG knockout mutant (FGKO40) in CHO AA8 cells, as well as FancG-corrected FGKO40 cells (KO40BP6, which is a pool of six BAC-clone transformants). FGKO40 cells are sensitive to a wide variety of DNA damaging agents. Sensitivity to the cross-linking agents MMC (3x) and chloroethyl-nitrosourea (3x) does not exceed that of methyl methanesulfonate (MMS) (4x), methyl-nitrosourea (4x), or ethyl-nitrosourea (3x), or the purine analog 6-thioguanine (5x). Other agents show mild sensitivity in FGKO40 cells: ionizing radiation (1.2x), UV-C (1.5x), hydroxyurea (1.2x), camptothecin (1.2x), and excess thymidine (normal). The length of S phase was carefully measured by monitoring the progression of highly synchronous G1 cells obtained by centrifugal elutriation. FGKO40 cells traversed S phase normally but had a slightly longer G2 phase than parental cells. Treatment of synchronized G1 cells with MMS did not increase S phase in parental or mutant cells, but again G2 was slightly longer for FGKO40. Mutation rates were measured at the hrpt and aprt loci, where gene inactivation confers resistance to 6-thioguanine or 8-azaadenine, respectively. FGKO40 had a slightly reduced mutation rate for hprt mutants, suggesting reduced recovery of large deletions at this locus. Moreover, the rate of methotrexate resistance was elevated 2.5-fold in mutant cells compared to controls. Resistance to this drug is generally associated with amplification of the dhfr locus, suggesting FancG plays a role in this aspect of genome stability. We suggest that the defect in FGKO

  15. Oxidative Stress, Bone Marrow Failure, and Genome Instability in Hematopoietic Stem Cells

    Directory of Open Access Journals (Sweden)

    Christine Richardson

    2015-01-01

    Full Text Available Reactive oxygen species (ROS can be generated by defective endogenous reduction of oxygen by cellular enzymes or in the mitochondrial respiratory pathway, as well as by exogenous exposure to UV or environmental damaging agents. Regulation of intracellular ROS levels is critical since increases above normal concentrations lead to oxidative stress and DNA damage. A growing body of evidence indicates that the inability to regulate high levels of ROS leading to alteration of cellular homeostasis or defective repair of ROS-induced damage lies at the root of diseases characterized by both neurodegeneration and bone marrow failure as well as cancer. That these diseases may be reflective of the dynamic ability of cells to respond to ROS through developmental stages and aging lies in the similarities between phenotypes at the cellular level. This review summarizes work linking the ability to regulate intracellular ROS to the hematopoietic stem cell phenotype, aging, and disease.

  16. Arsenic-induced Aurora-A activation contributes to chromosome instability and tumorigenesis

    Science.gov (United States)

    Wu, Chin-Han; Tseng, Ya-Shih; Yang, Chao-Chun; Kao, Yu-Ting; Sheu, Hamm-Ming; Liu, Hsiao-Sheng

    2013-11-01

    Arsenic may cause serious environmental pollution and is a serious industrial problem. Depending on the dosage, arsenic may trigger the cells undergoing either proliferation or apoptosis-related cell death. Because of lack of the proper animal model to study arsenic induced tumorigenesis, the accurate risk level of arsenic exposure has not been determined. Arsenic shows genotoxic effect on human beings who uptake water contaminated by arsenic. Chromosome aberration is frequently detected in arsenic exposure-related diseases and is associated with increased oxidative stress and decreased DNA repairing activity, but the underlying mechanism remains elusive. Aurora-A is a mitotic kinase, over-expression of Aurora-A leads to centrosome amplification, chromosomal instability and cell transformation. We revealed that Aurora-A is over-expressed in the skin and bladder cancer patients from blackfoot-disease endemic areas. Our cell line studies reveal that arsenic exposure between 0.5 μM and 1 μM for 2-7 days are able to induce Aurora-A expression and activation based on promoter activity, RNA and protein analysis. Aurora-A overexpression further increases the frequency of unsymmetrical chromosome segregation through centrosome amplification followed by cell population accumulated at S phase in immortalized keratinocyte (HaCaT) and uroepithelial cells (E7). Furthermore, Aurora-A over-expression was sustained for 1-4 weeks by chronic treatment of immortalized bladder and skin cells with NaAsO2. Aurora-A promoter methylation and gene amplification was not detected in the long-term arsenic treated E7 cells. Furthermore, the expression level of E2F1 transcription factor (E2F1) is increased in the presence of arsenic, and arsenic-related Aurora-A over-expression is transcriptionally regulated by E2F1. We further demonstrated that overexpression of Aurora-A and mutant Ha-ras or Aurora-A and mutant p53 may act additively to trigger arsenic-related bladder and skin cancer

  17. Oxidized low density lipoprotein induced caspase-1 mediated pyroptotic cell death in macrophages: implication in lesion instability?

    Directory of Open Access Journals (Sweden)

    Jing Lin

    Full Text Available BACKGROUND: Macrophage death in advanced lesion has been confirmed to play an important role in plaque instability. However, the mechanism underlying lesion macrophage death still remains largely unknown. METHODS AND RESULTS: Immunohistochemistry showed that caspase-1 activated in advanced lesion and co-located with macrophages and TUNEL positive reaction. In in-vitro experiments showed that ox-LDL induced caspase-1 activation and this activation was required for ox-LDL induced macrophages lysis, IL-1β and IL-18 production as well as DNA fragmentation. Mechanism experiments showed that CD36 and NLRP3/caspase-1/pathway involved in ox-LDL induced macrophage pyroptosis. CONCLUSION: Our study here identified a novel cell death, pyroptosis in ox-LDL induced human macrophage, which may be implicated in lesion macrophages death and play an important role in lesion instability.

  18. Microsatellite instability in pediatric high grade glioma is associated with genomic profile and differential target gene inactivation.

    Directory of Open Access Journals (Sweden)

    Marta Viana-Pereira

    Full Text Available High grade gliomas (HGG are one of the leading causes of cancer-related deaths in children, and there is increasing evidence that pediatric HGG may harbor distinct molecular characteristics compared to adult tumors. We have sought to clarify the role of microsatellite instability (MSI in pediatric versus adult HGG. MSI status was determined in 144 patients (71 pediatric and 73 adults using a well established panel of five quasimonomorphic mononucleotide repeat markers. Expression of MLH1, MSH2, MSH6 and PMS2 was determined by immunohistochemistry, MLH1 was assessed for mutations by direct sequencing and promoter methylation using MS-PCR. DNA copy number profiles were derived using array CGH, and mutations in eighteen MSI target genes studied by multiplex PCR and genotyping. MSI was found in 14/71 (19.7% pediatric cases, significantly more than observed in adults (5/73, 6.8%; p = 0.02, Chi-square test. MLH1 expression was downregulated in 10/13 cases, however no mutations or promoter methylation were found. MSH6 was absent in one pediatric MSI-High tumor, consistent with an inherited mismatch repair deficiency associated with germline MSH6 mutation. MSI was classed as Type A, and associated with a remarkably stable genomic profile. Of the eighteen classic MSI target genes, we identified mutations only in MSH6 and DNAPKcs and described a polymorphism in MRE11 without apparent functional consequences in DNA double strand break detection and repair. This study thus provides evidence for a potential novel molecular pathway in a proportion of gliomas associated with the presence of MSI.

  19. Smad4 loss in mice causes spontaneous head and neck cancer with increased genomic instability and inflammation.

    Science.gov (United States)

    Bornstein, Sophia; White, Ruth; Malkoski, Stephen; Oka, Masako; Han, Gangwen; Cleaver, Timothy; Reh, Douglas; Andersen, Peter; Gross, Neil; Olson, Susan; Deng, Chuxia; Lu, Shi-Long; Wang, Xiao-Jing

    2009-11-01

    Smad4 is a central mediator of TGF-beta signaling, and its expression is downregulated or lost at the malignant stage in several cancer types. In this study, we found that Smad4 was frequently downregulated not only in human head and neck squamous cell carcinoma (HNSCC) malignant lesions, but also in grossly normal adjacent buccal mucosa. To gain insight into the importance of this observation, we generated mice in which Smad4 was deleted in head and neck epithelia (referred to herein as HN-Smad4-/- mice) and found that they developed spontaneous HNSCC. Interestingly, both normal head and neck tissue and HNSCC from HN-Smad4-/- mice exhibited increased genomic instability, which correlated with downregulated expression and function of genes encoding proteins in the Fanconi anemia/Brca (Fanc/Brca) DNA repair pathway linked to HNSCC susceptibility in humans. Consistent with this, further analysis revealed a correlation between downregulation of Smad4 protein and downregulation of the Brca1 and Rad51 proteins in human HNSCC. In addition to the above changes in tumor epithelia, both normal head and neck tissue and HNSCC from HN-Smad4-/- mice exhibited severe inflammation, which was associated with increased expression of TGF-beta1 and activated Smad3. We present what we believe to be the first single gene-knockout model for HNSCC, in which both HNSCC formation and invasion occurred as a result of Smad4 deletion. Our results reveal an intriguing connection between Smad4 and the Fanc/Brca pathway and highlight the impact of epithelial Smad4 loss on inflammation.

  20. Detection of genomic instability in α-irradiated and bystander human fibroblasts

    International Nuclear Information System (INIS)

    Ponnaiya, B.; Jenkins-Baker, G.; Bigelow, A.; Marino, S.; Geard, C.R.

    2003-01-01

    Full text: We have previously demonstrated a radiation induced bystander effect using novel co-culturing techniques where irradiated and bystander cells were cultured on two surfaces of mylar separated by media. Here we present data from experiments designed to investigate the induction of chromosomal aberrations in irradiated and bystander fibroblasts using these co-culturing techniques. Immortalized fibroblasts ((BJ1-tert) were cultured on both mylar surfaces and cells on one side were irradiated with 0.1 or 1 Gy -particles (an average of 1 and 10 particles per cell nucleus respectively), the two sides were separated 1 hour post irradiation and analyzed for chromosomal aberrations using standard Giemsa staining at either immediate or delayed time points. At 24-30 hours post irradiation, frequencies of chromosomal aberrations in irradiated populations were increased in a dose dependent manner as expected. Populations that received 0.1 and 1 Gy had 0.3 and 1.3 aberrations/cell; these aberrations were almost exclusively chromosome type aberrations. In contrast, at these times bystander populations had elevated yields of chromatid-type aberrations. When assayed at later times (15-20 population doublings post irradiation) both irradiated and bystander cells demonstrated elevated frequencies of chromatid-type aberrations. Frequencies in the irradiated populations ranged from 0.07 to 0.09 aberrations/ cell at 15 doublings, and 0.09-0.14/cell at 20 doublings, with no apparent dose response. Aberration frequencies in the bystander populations were between 0.08-0.14 per cell at the delayed time points assayed. Interestingly, the chromatid-type aberrations observed immediately post irradiation in the bystander cells, and at later times in both the irradiated and bystander populations were qualitatively similar to those previously observed at delayed times in neutron irradiated epithelial cells. Furthermore, there was a similar lack of a dose response in those studies as

  1. An analytical study on excitation of nuclear-coupled thermal-hydraulic instability due to seismically induced resonance in BWR

    Energy Technology Data Exchange (ETDEWEB)

    Hirano, Masashi [Japan Atomic Energy Research Institute, Ibaraki-ken (Japan)

    1997-07-01

    This paper describes the results of a scoping study on seismically induced resonance of nuclear-coupled thermal-hydraulic instability in BWRs, which was conducted by using TRAC-BF1 within a framework of a point kinetics model. As a result of the analysis, it is shown that a reactivity insertion could occur accompanied by in-surge of coolant into the core resulted from the excitation of the nuclear-coupled instability by the external acceleration. In order to analyze this phenomenon more in detail, it is necessary to couple a thermal-hydraulic code with a three-dimensional nuclear kinetics code.

  2. Analysis of radiation-induced genome alterations in Vigna unguiculata

    Directory of Open Access Journals (Sweden)

    van der Vyver C

    2011-09-01

    Full Text Available Christell van der Vyver1, B Juan Vorster2, Karl J Kunert3, Christopher A Cullis41Institute for Plant Biotechnology, Department of Genetics, University of Stellenbosch, Stellenbosch, South Africa; 2Department of Plant Production and Soil Science, and 3Department of Plant Science, Forestry and Agricultural Biotechnology Institute, University of Pretoria, Pretoria, South Africa; 4Case Western Reserve University, Department of Biology, Cleveland, OH, USAAbstract: Seeds from an inbred Vigna unguiculata (cowpea cultivar were gamma-irradiated with a dose of 180 Gy in order to identify and characterize possible mutations. Three techniques, ie, random amplified polymorphic DNA, microsatellites, and representational difference analysis, were used to characterize possible DNA variation among the mutants and nonirradiated control plants both immediately after irradiation and in subsequent generations. A large portion of putative radiation-induced genome changes had significant similarities to chloroplast sequences. The frequency of mutation at three of these isolated polymorphic regions with chloroplast similarity was further determined by polymerase chain reaction screening using a large number of individual parental, M1, and M2 plants. Analysis of these sequences indicated that the rate at which various regions of the genome is mutated in irradiation experiments differs significantly and also that mutations have variable “repair” rates. Furthermore, regions of the nuclear DNA derived from the chloroplast genome are highly susceptible to modification by radiation treatment. Overall, data have provided detailed information on the effects of gamma irradiation on the cowpea genome and about the ability of the plant to repair these genome changes in subsequent plant generations.Keywords: mutation breeding, gamma radiation, genetic mutations, cowpea, representational difference analysis

  3. Investigation of genomic instability by assay of DNA fingerprint from the offspring of male mice exposed to chronic low-level γ-radiation

    International Nuclear Information System (INIS)

    Bezlepkin, V.G.; Vasil'eva, G.V.; Lomaeva, M.G.; Sirota, N.P.; Gaziev, A.I.

    2000-01-01

    By polymerase chain reaction with arbitrary primer (AP-PCR), the possibility of transmission of genome instability to somatic cells of the offspring (F 1 generation) from male parents of mice exposed to chronic low-dose γ-radiation was studied. Male mice 15 days after exposure to 10-50 cGy were mated with unirradiated females. Biopsies were taken from tale tips of two month-old mice progeny for DNA separation. Primer in the AP-PCR was 20-mer oligonucleotide flanking the micro-satellite locus Atplb2 on chromosome 11 of the mouse. Comparative analysis of individual fingerprints of AP-PCR products on DNA-templates from the offspring of irradiated and unirradiated male mice revealed an increased variability of micro-satellite-associated sequences in the genome of the offspring of males exposed to 25 and 50 cGy. DNA-fingerprints of the offspring of male mice exposed to chronic irradiation doses 10 and 25 cGy. 15 days before fertilization (at the post-meiotic stage of spermatogenesis) showed an increased frequency of non-parent bands. Result of the study point to the possibility of transmission to the offspring somatic cells of changes increasing genome instability from male parents exposed to chronic low-dose radiation prior to fertilization [ru

  4. Influence of core NA on thermal-induced mode instabilities in high power fiber amplifiers

    International Nuclear Information System (INIS)

    Tao, Rumao; Ma, Pengfei; Wang, Xiaolin; Zhou, Pu; Liu, Zejin

    2015-01-01

    We report on the influence of core NA on thermal-induced mode instabilities (MI) in high power fiber amplifiers. The influence of core NA and the V-parameter on MI has been investigated numerically. It shows that core NA has a larger influence on MI for fibers with a smaller core-cladding-ratio, and the influence of core NA on the threshold is more obvious when the amplifiers are pumped at 915 nm. The dependence of the threshold on the V-parameter revealed that the threshold increases linearly as the V-parameter decreases when the V-parameter is larger than 3.5, and the threshold shows an exponential increase as the V-parameter decreases when the V-parameter is less than 3.5. We also discussed the effect of linewidth on MI, which indicates that the influence of linewidth can be neglected for a linewidth smaller than 1 nm when the fiber core NA is smaller than 0.07 and the fiber length is shorter than 20 m. Fiber amplifiers with different core NA were experimentally analyzed, which agreed with the theoretical predictions. (letter)

  5. Microbunching-instability-induced sidebands in a seeded free-electron laser

    Directory of Open Access Journals (Sweden)

    Zhen Zhang

    2016-05-01

    Full Text Available Measurements of the multishot-averaged, soft x-ray, self-seeding spectrum at the LCLS free-electron laser often have a pedestal-like distribution around the seeded wavelength, which limits the spectral purity and can negatively affect some user applications not employing a post-undulator monochromator. In this paper, we study the origins of such pedestals, focusing on longitudinal phase space modulations produced by the microbunching instability upstream of the free-electron laser (FEL undulator. We show from theory and numerical simulation that both energy and density modulations can induce sidebands in a high-gain, seeded FEL whose fractional strength typically grows as the square of the undulator length. The results place a tight constraint on the longitudinal phase space uniformity of the electron beam for a seeded FEL, possibly requiring the amplitude of long-wavelength modulations to be much smaller than the typical incoherent energy spread if the output sideband power is to remain only a couple percent or less of the amplified seed power.

  6. Motion of Passive Scalar by Elasticity-Induced Instability in Curved Microchannel

    Directory of Open Access Journals (Sweden)

    Xiao-Bin Li

    2014-08-01

    Full Text Available This paper presented a direct numerical simulation (DNS study on the elasticity-induced irregular flow, passive mixing, and scalar evolution in the curvilinear microchannel. The mixing enhancement was achieved at vanishingly low-Reynolds-number chaotic flow raised by elastic instabilities. Along with the mixing process, the passive scalar transportation carried by the flow was greatly affected by the flow structure and the underlying interaction between microstructures of viscoelastic fluid and flow structure itself. The simulations are conducted for a wide range of viscoelasticity. As the elastic effect exceeds the critical value, the flow tends to a chaotic state, while the evolution of scalar gets strong and fast, showing excellent agreement with experimental results. For the temporal changing of scalar gradients, they vary rapidly in the form of isosurfaces, with the shape of “rolls” in the bulk and evolving into “threads” near the wall. That indicates that the flow fields should be related to the deformation of viscoelastic micromolecules. The probability distribution function analysis between micromolecular deformation and flow field deformation shows that the main direction of molecular stretching is perpendicular to the main direction of flow field deformation. It implies they are weakly correlated, due to the confinement of channel wall.

  7. Study of fracture and stress-induced morphological instabilities in polymeric materials

    Science.gov (United States)

    Sabouri-Ghomi, Mohsen

    We study the phenomena of fracture in polymers at the molecular and continuum level. At a molecular level, we study the failure of polymer/polymer interfaces. Our main focus is on a specific mode of failure known as chain pull-out fracture, which is common to weak adhesive junctions, and polymer blends and mixtures. In the case of the interface between incompatible polymers, reinforcement is achieved by adding a block copolymer to the interface. We introduce a microscopic model based on Brownian dynamics to investigate the effect of the polymerization index N, of the block connector chain, on fracture toughness of such reinforced polymeric junctions. We consider the mushroom regime, where connector chains are grafted with low surface density, for the case of large pulling velocity. We find that for short chains the interface fracture toughness depends linearly on the polymerization index N of the connector chains, while for longer chains the dependence becomes N 3/2. We propose a scaling argument, based on the geometry of the initial configuration, that accounts for both short and long chains and the crossover between them. At the continuum level, we study the pattern selection mechanism of finger-like crack growth phenomena in gradient driven growth problems in general, and the structure of stress-induced morphological instabilities in crazing of polymer glasses in particular. We simulate solidification in a narrow channel through the use of a phase-field model with an adaptive grid. By tuning a dimensionless parameter, the Peclet number, we show a continuous crossover from a free dendrite at high Peclet numbers to anisotropic viscous fingering at low Peclet numbers. At low Peclet numbers we find good agreement between our results, theoretical predictions, and experiment, providing the first quantitative test of solvability theory for anisotropic viscous fingers. For high undercoolings, we find new phenomena, a solid forger which satisfies stability and

  8. Laser induced ablatively driven interfacial nonlinear fluid instabilities in multilayer targets

    International Nuclear Information System (INIS)

    Manoranjan Khan; Gupta, M.R.; Mandal, L.K.; Roy, S.; Banerjee, R.

    2010-01-01

    Complete text of publication follows. High power laser driven shock waves in condensed matter have important application for studying equation of state (EOS) and high pressure physics. This is an important phenomenon in fuel compression for Inertial Confinement Fusion (ICF) experiments where multilayer targets of differing shock impedance are interacted by laser induced shocks. The interface between the two fluid becomes unstable when driven by the impulsive force (Richtmyer-Meshkov) due to such a shock wave or a continuously acting force e.g., gravity (Rayleigh-Taylor). In the nonlinear stage, the fluid interface is found to develop structures having finger-like shapes. The structures resemble a bubble (spike) accordingly as a lighter (heavier) fluid pushes in a heavier (lighter) fluid. These effects need to be mitigated for efficient compression in ICF experiment. We have studied the effect of density variation on R-T and R-M instability on the temporal development of nonlinear two fluid interfacial structures like bubble and spike. It is shown that the velocity of bubble or spike decreases leading to stabilization if the density of the fluids leads to lowering of the Atwood number. The Atwood number A = ρ a -ρ b / ρ a +ρ b changes to A* = ρ a *ρ b */ ρ a *ρ b * where ρ* m = ρ m (1-1/γ m ), m = [a,b], assuming ρ a > ρ b . It has been seen that the stabilization or destabilization (depending on the algebraic sign of the gradient) will be proportional to the pressure p 0 at the interface. The set of equation describing the dynamics of the bubbles and spikes in presence of fluid density variation are not analytically integrable in closed form. All the results are derived by numerical methods and are represented and interpreted. Analytical calculations are performed (not presented here) to modify the dynamical boundary condition between the two fluids and we have finally arrived at the following expression for the asymptotic bubble velocity ν b 2 = 2(r

  9. Genome-wide analysis in UK Biobank identifies four loci associated with mood instability and genetic correlation with major depressive disorder, anxiety disorder and schizophrenia.

    Science.gov (United States)

    Ward, Joey; Strawbridge, Rona J; Bailey, Mark E S; Graham, Nicholas; Ferguson, Amy; Lyall, Donald M; Cullen, Breda; Pidgeon, Laura M; Cavanagh, Jonathan; Mackay, Daniel F; Pell, Jill P; O'Donovan, Michael; Escott-Price, Valentina; Smith, Daniel J

    2017-11-30

    Mood instability is a core clinical feature of affective and psychotic disorders. In keeping with the Research Domain Criteria approach, it may be a useful construct for identifying biology that cuts across psychiatric categories. We aimed to investigate the biological validity of a simple measure of mood instability and evaluate its genetic relationship with several psychiatric disorders, including major depressive disorder (MDD), bipolar disorder (BD), schizophrenia, attention deficit hyperactivity disorder (ADHD), anxiety disorder and post-traumatic stress disorder (PTSD). We conducted a genome-wide association study (GWAS) of mood instability in 53,525 cases and 60,443 controls from UK Biobank, identifying four independently associated loci (on chromosomes 8, 9, 14 and 18), and a common single-nucleotide polymorphism (SNP)-based heritability estimate of ~8%. We found a strong genetic correlation between mood instability and MDD (r g  = 0.60, SE = 0.07, p = 8.95 × 10 -17 ) and a small but significant genetic correlation with both schizophrenia (r g  = 0.11, SE = 0.04, p = 0.01) and anxiety disorders (r g  = 0.28, SE = 0.14, p = 0.04), although no genetic correlation with BD, ADHD or PTSD was observed. Several genes at the associated loci may have a role in mood instability, including the DCC netrin 1 receptor (DCC) gene, eukaryotic translation initiation factor 2B subunit beta (eIF2B2), placental growth factor (PGF) and protein tyrosine phosphatase, receptor type D (PTPRD). Strengths of this study include the very large sample size, but our measure of mood instability may be limited by the use of a single question. Overall, this work suggests a polygenic basis for mood instability. This simple measure can be obtained in very large samples; our findings suggest that doing so may offer the opportunity to illuminate the fundamental biology of mood regulation.

  10. Effect of magnetic field on ablatively driven Richtmyer-Meshkov instability induced by interfacial nonlinear structure

    International Nuclear Information System (INIS)

    Labakanta Mandal; Banerjee, R.; Roy, S.; Khan, M.; Gupta, M.R.

    2010-01-01

    Complete text of publication follows. In an Inertial Confinement Fusion (ICF) situation, laser driven ablation front of an imploding capsule is subjected to the fluid instabilities like Rayleigh-Taylor (RT), Richtmyer-Meshkov (RM) and Kelvin-Helmholtz (KH) instability. In this case dense core is compressed and accelerated by low density ablating plasma. During this process laser driven shocks interact the interface and hence it becomes unstable due to the formation of nonlinear structure like bubble and spike. The nonlinear structure is called bubble if the lighter fluid pushes inside the heavier fluid and spike, if opposite takes place. R-M instability causes non-uniform compression of ICF fuel pellets and needs to be mitigated. Scientists and researchers are much more interested on RM instability both from theoretical and experimental points of view. In this article, we have presented the analytical expression for the growth rate and velocity for the nonlinear structures due to the effect of magnetic field of fluid using potential flow model. The magnetic field is assumed to be parallel to the plane of two fluid interfaces. If the magnetic field is restricted only to either side of interface the R-M instability can be stabilized or destabilized depending on whether the magnetic pressure on the interface opposes the instability driving shock pressure or acts in the same direction. An interesting result is that if both the fluids are magnetized, interface as well as velocity of bubble and spike will show oscillating stabilization and R-M instability is mitigated. All analytical results are also supported by numerical results. Numerically it is seen that magnetic field above certain minimum value reduces the instability for compression the target in ICF.

  11. Energetic-particle-driven instabilities and induced fast-ion transport in a reversed field pinch

    International Nuclear Information System (INIS)

    Lin, L.; Brower, D. L.; Ding, W. X.; Anderson, J. K.; Capecchi, W.; Eilerman, S.; Forest, C. B.; Koliner, J. J.; Nornberg, M. D.; Reusch, J.; Sarff, J. S.; Liu, D.

    2014-01-01

    Multiple bursty energetic-particle (EP) driven modes with fishbone-like structure are observed during 1 MW tangential neutral-beam injection in a reversed field pinch (RFP) device. The distinguishing features of the RFP, including large magnetic shear (tending to add stability) and weak toroidal magnetic field (leading to stronger drive), provide a complementary environment to tokamak and stellarator configurations for exploring basic understanding of EP instabilities. Detailed measurements of the EP mode characteristics and temporal-spatial dynamics reveal their influence on fast ion transport. Density fluctuations exhibit a dynamically evolving, inboard-outboard asymmetric spatial structure that peaks in the core where fast ions reside. The measured mode frequencies are close to the computed shear Alfvén frequency, a feature consistent with continuum modes destabilized by strong drive. The frequency pattern of the dominant mode depends on the fast-ion species. Multiple frequencies occur with deuterium fast ions compared to single frequency for hydrogen fast ions. Furthermore, as the safety factor (q) decreases, the toroidal mode number of the dominant EP mode transits from n=5 to n=6 while retaining the same poloidal mode number m=1. The transition occurs when the m=1, n=5 wave-particle resonance condition cannot be satisfied as the fast-ion safety factor (q fi ) decreases. The fast-ion temporal dynamics, measured by a neutral particle analyzer, resemble a classical predator-prey relaxation oscillation. It contains a slow-growth phase arising from the beam fueling followed by a rapid drop when the EP modes peak, indicating that the fluctuation-induced transport maintains a stiff fast-ion density profile. The inferred transport rate is strongly enhanced with the onset of multiple EP modes

  12. Chromosomal Instability and Molecular Defects in Induced Pluripotent Stem Cells from Nijmegen Breakage Syndrome Patients

    Directory of Open Access Journals (Sweden)

    Tomer Halevy

    2016-08-01

    Full Text Available Nijmegen breakage syndrome (NBS results from the absence of the NBS1 protein, responsible for detection of DNA double-strand breaks (DSBs. NBS is characterized by microcephaly, growth retardation, immunodeficiency, and cancer predisposition. Here, we show successful reprogramming of NBS fibroblasts into induced pluripotent stem cells (NBS-iPSCs. Our data suggest a strong selection for karyotypically normal fibroblasts to go through the reprogramming process. NBS-iPSCs then acquire numerous chromosomal aberrations and show a delayed response to DSB induction. Furthermore, NBS-iPSCs display slower growth, mitotic inhibition, a reduced apoptotic response to stress, and abnormal cell-cycle-related gene expression. Importantly, NBS neural progenitor cells (NBS-NPCs show downregulation of neural developmental genes, which seems to be mediated by P53. Our results demonstrate the importance of NBS1 in early human development, shed light on the molecular mechanisms underlying this severe syndrome, and further expand our knowledge of the genomic stress cells experience during the reprogramming process.

  13. Ataxia-telangiectasia mutated (ATM) deficiency decreases reprogramming efficiency and leads to genomic instability in iPS cells

    Energy Technology Data Exchange (ETDEWEB)

    Kinoshita, Taisuke [Department of Cell Differentiation, The Sakaguchi Laboratory, School of Medicine, Keio University, Tokyo 160-8582 (Japan); Nagamatsu, Go, E-mail: gonag@sc.itc.keio.ac.jp [Department of Cell Differentiation, The Sakaguchi Laboratory, School of Medicine, Keio University, Tokyo 160-8582 (Japan); Precursory Research for Embryonic Science and Technology, Japan Science and Technology Agency, Kawaguchi, Saitama 332-0012 (Japan); Kosaka, Takeo [Department of Urology, School of Medicine, Keio University, Tokyo 160-8582 (Japan); Takubo, Keiyo [Department of Cell Differentiation, The Sakaguchi Laboratory, School of Medicine, Keio University, Tokyo 160-8582 (Japan); Hotta, Akitsu [Precursory Research for Embryonic Science and Technology, Japan Science and Technology Agency, Kawaguchi, Saitama 332-0012 (Japan); Department of Reprogramming Science, Center for iPS Cell Research and Application (CiRA), Kyoto University, Kyoto (Japan); Ellis, James [Ontario Human iPS Cell Facility, Molecular Genetics, University of Toronto, Developmental and Stem Cell Biology, SickKids, Toronto, Canada MG1L7 (Canada); Suda, Toshio, E-mail: sudato@sc.itc.keio.ac.jp [Department of Cell Differentiation, The Sakaguchi Laboratory, School of Medicine, Keio University, Tokyo 160-8582 (Japan)

    2011-04-08

    Highlights: {yields} iPS cells were induced with a fluorescence monitoring system. {yields} ATM-deficient tail-tip fibroblasts exhibited quite a low reprogramming efficiency. {yields} iPS cells obtained from ATM-deficient cells had pluripotent cell characteristics. {yields} ATM-deficient iPS cells had abnormal chromosomes, which were accumulated in culture. -- Abstract: During cell division, one of the major features of somatic cell reprogramming by defined factors, cells are potentially exposed to DNA damage. Inactivation of the tumor suppressor gene p53 raised reprogramming efficiency but resulted in an increased number of abnormal chromosomes in established iPS cells. Ataxia-telangiectasia mutated (ATM), which is critical in the cellular response to DNA double-strand breaks, may also play an important role during reprogramming. To clarify the function of ATM in somatic cell reprogramming, we investigated reprogramming in ATM-deficient (ATM-KO) tail-tip fibroblasts (TTFs). Although reprogramming efficiency was greatly reduced in ATM-KO TTFs, ATM-KO iPS cells were successfully generated and showed the same proliferation activity as WT iPS cells. ATM-KO iPS cells had a gene expression profile similar to ES cells and WT iPS cells, and had the capacity to differentiate into all three germ layers. On the other hand, ATM-KO iPS cells accumulated abnormal genome structures upon continuous passages. Even with the abnormal karyotype, ATM-KO iPS cells retained pluripotent cell characteristics for at least 20 passages. These data indicate that ATM does participate in the reprogramming process, although its role is not essential.

  14. Ataxia-telangiectasia mutated (ATM) deficiency decreases reprogramming efficiency and leads to genomic instability in iPS cells

    International Nuclear Information System (INIS)

    Kinoshita, Taisuke; Nagamatsu, Go; Kosaka, Takeo; Takubo, Keiyo; Hotta, Akitsu; Ellis, James; Suda, Toshio

    2011-01-01

    Highlights: → iPS cells were induced with a fluorescence monitoring system. → ATM-deficient tail-tip fibroblasts exhibited quite a low reprogramming efficiency. → iPS cells obtained from ATM-deficient cells had pluripotent cell characteristics. → ATM-deficient iPS cells had abnormal chromosomes, which were accumulated in culture. -- Abstract: During cell division, one of the major features of somatic cell reprogramming by defined factors, cells are potentially exposed to DNA damage. Inactivation of the tumor suppressor gene p53 raised reprogramming efficiency but resulted in an increased number of abnormal chromosomes in established iPS cells. Ataxia-telangiectasia mutated (ATM), which is critical in the cellular response to DNA double-strand breaks, may also play an important role during reprogramming. To clarify the function of ATM in somatic cell reprogramming, we investigated reprogramming in ATM-deficient (ATM-KO) tail-tip fibroblasts (TTFs). Although reprogramming efficiency was greatly reduced in ATM-KO TTFs, ATM-KO iPS cells were successfully generated and showed the same proliferation activity as WT iPS cells. ATM-KO iPS cells had a gene expression profile similar to ES cells and WT iPS cells, and had the capacity to differentiate into all three germ layers. On the other hand, ATM-KO iPS cells accumulated abnormal genome structures upon continuous passages. Even with the abnormal karyotype, ATM-KO iPS cells retained pluripotent cell characteristics for at least 20 passages. These data indicate that ATM does participate in the reprogramming process, although its role is not essential.

  15. Observation of instability-induced current redistribution in a spherical-torus plasma.

    Science.gov (United States)

    Menard, J E; Bell, R E; Gates, D A; Kaye, S M; LeBlanc, B P; Levinton, F M; Medley, S S; Sabbagh, S A; Stutman, D; Tritz, K; Yuh, H

    2006-09-01

    A motional Stark effect diagnostic has been utilized to reconstruct the parallel current density profile in a spherical-torus plasma for the first time. The measured current profile compares favorably with neoclassical theory when no large-scale magnetohydrodynamic instabilities are present in the plasma. However, a current profile anomaly is observed during saturated interchange-type instability activity. This apparent anomaly can be explained by redistribution of neutral beam injection current drive and represents the first observation of interchange-type instabilities causing such redistribution. The associated current profile modifications contribute to sustaining the central safety factor above unity for over five resistive diffusion times, and similar processes may contribute to improved operational scenarios proposed for ITER.

  16. Electron-temperature-gradient-induced instability in tokamak scrape-off layers

    International Nuclear Information System (INIS)

    Berk, H.L.; Ryutov, D.D.; Tsidulko, Y.A.; Xu, X.Q.

    1992-08-01

    An electron temperature instability driven by the Kunkel-Guillory sheath impedance, has been applied to the scrape-off layer of tokamaks. The formalism has been generalized to more fully account for parallel wavelength dynamics, to differentiate between electromagnetic and electrostatic perturbations and to account for particle recycling effects. It is conjectured that this conducting wall instability leads to edge fluctuations in tokamaks that produce scrape-off widths of many ion Larmor radii ≅10. The predicted instability characteristics correlate somewhat with DIII-D edge fluctuation data, and the scrape-off layer width in the DIII-D experiment agrees with theoretical estimates that can be derived from mixing lenght theory

  17. Maternal effects of the scid mutation on radiation-induced transgenerational instability in mice.

    NARCIS (Netherlands)

    Hatch, T.; Derijck, A.H.A.; Black, P.D.; Heijden, G.W. van der; Boer, P. de; Dubrova, Y.E.

    2007-01-01

    The results of a number of recent studies show that mutation rates in the offspring of irradiated parents are substantially elevated, however, the effect of parental genotype on transgenerational instability remains poorly understood. Here, we have analysed the mutation frequency at an expanded

  18. Asymptotic behavior of the mixed mass in Rayleigh–Taylor and Richtmyer–Meshkov instability induced flows

    Energy Technology Data Exchange (ETDEWEB)

    Zhou, Ye; Cabot, William H. [Lawrence Livermore National Laboratory, Livermore, California 94550 (United States); Thornber, Ben [The University of Sydney, School of Aerospace, Mechanical and Mechatronic Engineering, New South Wales 2006, Sydney (Australia)

    2016-05-15

    Rayleigh–Taylor instability (RTI) and Richtmyer–Meshkov instability (RMI) are serious practical issues in inertial confinement fusion research, and also have relevance to many cases of astrophysical fluid dynamics. So far, much of the attention has been paid to the late-time scaling of the mixed width, which is used as a surrogate to how well the fluids have been mixed. Yet, the actual amount of mixed mass could be viewed as a more direct indicator on the evolution of the mixing layers due to hydrodynamic instabilities. Despite its importance, there is no systematic study as yet on the scaling of the mixed mass for either the RTI or the RMI induced flow. In this article, the normalized mixed mass (Ψ) is introduced for measuring the efficiency of the mixed mass. Six large numerical simulation databases have been employed: the RTI cases with heavy-to-light fluid density ratios of 1.5, 3, and 9; the single shock RMI cases with density ratios of 3 and 20; and a reshock RMI case with density ratio of 3. Using simulated flow fields, the normalized mixed mass Ψ is shown to be more sensitive in discriminating the variation with Atwood number for the RTI flows. Moreover, Ψ is demonstrated to provide more consistent results for both the RTI and RMI flows when compared with the traditional mixedness parameters, Ξ and Θ.

  19. Stratified flow instability and slug formation leading to condensation-induced water hammer in a horizontal refrigerant pipe

    International Nuclear Information System (INIS)

    Samuel Martin, C.

    2005-01-01

    Full text of publication follows: An experimental apparatus was designed for the purpose of investigating the phenomenon of condensation-induced water hammer in an ammonia refrigeration system. Water hammer was initiated by introducing warm ammonia gas over static subcooled ammonia liquid placed in a horizontal 146.3 mm diameter carbon steel pipe 6.0 m in length. By means of fast response piezoelectric pressure transducers and a high speed data acquisition system rapid dynamic pressures were recorded whenever a shock event occurred. Moreover, by means of top-mounted diaphragm pressure transducers the speed of liquid slugs propagating along the pipe was determined. The occurrence of condensation induced water hammer depended upon three major variables; namely, (1) initial liquid depth, (2) liquid temperature, and (3) mass flow rate of warm gas. For given liquid depth and temperature, once the warm gas threshold conditions were exceeded shocks occurred with greater magnitude as the mass flow rate of gas input was increased. With adequate subcooling condensation-induced water hammer occurred for initial liquid depths ranging from 25% to 95% of internal pipe diameter. The threshold mass flow rate of warm gas necessary to initiate water hammer was greater as the initial liquid depth was lowered. Based upon experimental results obtained from four pressure transducers located on the top of the test pipe conditions corresponding to bridging were ascertained. For various initial liquid depths the onset of instability from stratified flow to bridging was correlated with the Taitel-Dukler instability criterion. (author)

  20. Do Deregulated Cas Proteins Induce Genomic Instability In Early Stage Ovarian Cancer?

    Science.gov (United States)

    2007-12-01

    Tensional homeostasis and the malignant phenotype. Cancer Cell 2005;8:241–54. [PubMed: 16169468] 40. Zhang Z, Hernandez- Lagunas L, Horne WC, Baron R...disassembly. Nat Cell Biol 2004;6:154–61. [PubMed: 14743221] 58. Huang J, Hamasaki H, Nakamoto T, Honda H, Hirai H, Saito M, Takato T, Sakai R...Cell Struct Funct 2001;26:619–26. [PubMed: 11942617] 87. Yi J, Kloeker S, Jensen CC, Bockholt S, Honda H, Hirai H, Beckerle MC. Members of the zyxin

  1. Genomic stability during cellular reprogramming: Mission impossible?

    Energy Technology Data Exchange (ETDEWEB)

    Joest, Mathieu von; Búa Aguín, Sabela; Li, Han, E-mail: han.li@pasteur.fr

    2016-06-15

    The generation of induced pluripotent stem cells (iPSCs) from adult somatic cells is one of the most exciting discoveries in recent biomedical research. It holds tremendous potential in drug discovery and regenerative medicine. However, a series of reports highlighting genomic instability in iPSCs raises concerns about their clinical application. Although the mechanisms cause genomic instability during cellular reprogramming are largely unknown, several potential sources have been suggested. This review summarizes current knowledge on this active research field and discusses the latest efforts to alleviate the genomic insults during cellular reprogramming to generate iPSCs with enhanced quality and safety.

  2. Suppression of Genomic Instabilities Caused by Chromosome Mis-segregation: A Perspective From Studying BubR1 and Sgo1

    Science.gov (United States)

    Dai, Wei

    2013-01-01

    Aneuploidy is a major manifestation of chromosomal instability, which is defined as a numerical abnormality of chromosomes in diploid cells. It is highly prevalent in a variety of human malignancies. Increased chromosomal instability is the major driving force for tumor development and progression. To suppress genomic stability during cell division, eukaryotic cells have evolved important molecular mechanisms, commonly referred to as checkpoints. The spindle checkpoint ensures that cells with defective mitotic spindles or a defective interaction between the spindles and kinetochores do not initiate chromosomal segregation during mitosis. Extensive studies have identified and characterized more than a dozen genes that play important roles in the regulation of the spindle checkpoint in mammalian cells. During the past decade, we have carried out extensive investigation of the role of BubR1 (Bub1-related kinase) and Sgo1 (shugoshin 1), two important gene products that safeguard accurate chromosome segregation during mitosis. This mini-review summarizes our studies, as well as those by other researchers in the field, on the functions of these two checkpoint proteins and their molecular regulation during mitosis. Further elucidation of the molecular mechanisms of the spindle checkpoint regulation has the potential to identify important mitotic targets for rational anticancer drug design. PMID:20040454

  3. Suppression of Genomic Instabilities Caused by Chromosome Mis-segregation: A Perspective From Studying BubR1 and Sgo1

    Directory of Open Access Journals (Sweden)

    Wei Dai

    2009-12-01

    Full Text Available Aneuploidy is a major manifestation of chromosomal instability, which is defined as a numerical abnormality of chromosomes in diploid cells. It is highly prevalent in a variety of human malignancies. Increased chromosomal instability is the major driving force for tumor development and progression. To suppress genomic stability during cell division, eukaryotic cells have evolved important molecular mechanisms, commonly referred to as checkpoints. The spindle checkpoint ensures that cells with defective mitotic spindles or a defective interaction between the spindles and kinetochores do not initiate chromosomal segregation during mitosis. Extensive studies have identified and characterized more than a dozen genes that play important roles in the regulation of the spindle checkpoint in mammalian cells. During the past decade, we have carried out extensive investigation of the role of BubR1 (Bub1-related kinase and Sgo1 (shugoshin 1, two important gene products that safeguard accurate chromosome segregation during mitosis. This mini-review summarizes our studies, as well as those by other researchers in the field, on the functions of these two checkpoint proteins and their molecular regulation during mitosis. Further elucidation of the molecular mechanisms of the spindle checkpoint regulation has the potential to identify important mitotic targets for rational anticancer drug design.

  4. Joint Instability and Osteoarthritis

    Directory of Open Access Journals (Sweden)

    Darryl Blalock

    2015-01-01

    Full Text Available Joint instability creates a clinical and economic burden in the health care system. Injuries and disorders that directly damage the joint structure or lead to joint instability are highly associated with osteoarthritis (OA. Thus, understanding the physiology of joint stability and the mechanisms of joint instability-induced OA is of clinical significance. The first section of this review discusses the structure and function of major joint tissues, including periarticular muscles, which play a significant role in joint stability. Because the knee, ankle, and shoulder joints demonstrate a high incidence of ligament injury and joint instability, the second section summarizes the mechanisms of ligament injury-associated joint instability of these joints. The final section highlights the recent advances in the understanding of the mechanical and biological mechanisms of joint instability-induced OA. These advances may lead to new opportunities for clinical intervention in the prevention and early treatment of OA.

  5. Joint instability and osteoarthritis.

    Science.gov (United States)

    Blalock, Darryl; Miller, Andrew; Tilley, Michael; Wang, Jinxi

    2015-01-01

    Joint instability creates a clinical and economic burden in the health care system. Injuries and disorders that directly damage the joint structure or lead to joint instability are highly associated with osteoarthritis (OA). Thus, understanding the physiology of joint stability and the mechanisms of joint instability-induced OA is of clinical significance. The first section of this review discusses the structure and function of major joint tissues, including periarticular muscles, which play a significant role in joint stability. Because the knee, ankle, and shoulder joints demonstrate a high incidence of ligament injury and joint instability, the second section summarizes the mechanisms of ligament injury-associated joint instability of these joints. The final section highlights the recent advances in the understanding of the mechanical and biological mechanisms of joint instability-induced OA. These advances may lead to new opportunities for clinical intervention in the prevention and early treatment of OA.

  6. Pathogenesis of spinal cord involvement induced by lower cervical instability in rheumatoid spondylitis

    Energy Technology Data Exchange (ETDEWEB)

    Taniguchi, Hironobu; Kuwabara, Shigeru; Fukuda, Kenji; Kuroki, Tatsuji; Tajima, Naoya (Miyazaki Medical Coll., Kiyotake (Japan))

    1994-07-01

    To examine prognostic factors in rheumatoid arthritis (RA), plain radiography findings and magnetic resonance imaging (MRI) findings were compared with histopathological findings in 129 RA patients who had local or neurologic symptoms due to the cervical spine. All patients underwent plain radiography, and subdislocation more than 2 mm towards the anterior and posterior directions on plain radiographs was defined as instability. In predicting induction of instability of the inferior cervical spine and risk for spinal compression, erosion of the vertebral rim, as seen on plain X-rays, and irregular findings of the end-plate of the vertebral body and Gd-enhanced nodules around the intervertebral disk, as seen on MRI, seemed to be important. (N.K.).

  7. Applications of Analytical Self-Similar Solutions of Reynolds-Averaged Models for Instability-Induced Turbulent Mixing

    Science.gov (United States)

    Hartland, Tucker; Schilling, Oleg

    2017-11-01

    Analytical self-similar solutions to several families of single- and two-scale, eddy viscosity and Reynolds stress turbulence models are presented for Rayleigh-Taylor, Richtmyer-Meshkov, and Kelvin-Helmholtz instability-induced turbulent mixing. The use of algebraic relationships between model coefficients and physical observables (e.g., experimental growth rates) following from the self-similar solutions to calibrate a member of a given family of turbulence models is shown. It is demonstrated numerically that the algebraic relations accurately predict the value and variation of physical outputs of a Reynolds-averaged simulation in flow regimes that are consistent with the simplifying assumptions used to derive the solutions. The use of experimental and numerical simulation data on Reynolds stress anisotropy ratios to calibrate a Reynolds stress model is briefly illustrated. The implications of the analytical solutions for future Reynolds-averaged modeling of hydrodynamic instability-induced mixing are briefly discussed. This work was performed under the auspices of the U.S. Department of Energy by Lawrence Livermore National Laboratory under Contract DE-AC52-07NA27344.

  8. Induction of genetic instability by ionizing radiation

    International Nuclear Information System (INIS)

    Little, J.B.

    1999-01-01

    Evidence is presented to support the hypothesis that radiation may induce a heritable, genome-wide process of instability that leads to an enhanced frequency of genetic changes occurring among the progeny of the original irradiated cell. This instability is transmissible over many generations of cell replication. Mutational instability is induced in a relatively large fraction (approximately 10 %) of the cell population, and may be modulated by factors acting in vivo. Thus, it cannot be a targeted event involving a specific gene or set of genes. There is no dose-response relationship in the range 2-12 Gy, suggesting that the instability phenotype may be induced by quite low radiation doses. The molecular mechanisms associated with the genesis of mutations in unstable populations differ from those for direct X-ray-induced mutations. These results suggest that it may not be possible to predict the nature of the dose-response relationship for the ultimate genetic effects of radiation based on a qualitative or quantitative analysis of the original DNA lesions. (author)

  9. Chromosomal instability in the progeny of irradiated parents

    International Nuclear Information System (INIS)

    Voro btsova, I.E.; Vorobyova, M.V.; Bogomazova, A.N.

    1997-01-01

    Genomic instability have been demonstrated in irradiated cells as the increased frequency of sporadic chromosome aberrations persisted over multiple generations of cell divisions. We found that chromosomal instability characterized as well the somatic cells of irradiated parents progeny. It means that radiation induced genomic instability can be transmitted via germ line cells. As a measure of instability the sensitivity of chromosomes to radiation was estimated. In animal experiments the irradiation of mature germ cells of male rats (dose - 4.5 Gy of X-rays) increase the frequency of chromosome aberrations induced by challenging irradiation in regenerating hepatocytes, in bone marrow cells and in fetal fibroblasts in the progeny of irradiated male rats. The chromosomal sensitivity of cultivated lymphocytes to in vitro irradiation (1.5 Gy of γ(rays 137 Cs) is increased in the children born parents undergone antitumor radiotherapy or worked as 'liquidators' of Chernobyl accident consequences before conception in comparison to the children of unexposed parents. The cytogenetic radiosensitivity of lymphocytes to irradiation in vitro is also increased in children evacuated from contaminated by radionuclides areas ('positive' control group). The increased spontaneous frequency of chromatid-type acentric was found in all group of children with irradiation history. The instability of genome of irradiated parents progeny seems could be the mechanism of these health effects. (authors)

  10. The genome structure of Arachis hypogaea (Linnaeus, 1753 and an induced Arachis allotetraploid revealed by molecular cytogenetics

    Directory of Open Access Journals (Sweden)

    Eliza F. de M. B. do Nascimento

    2018-03-01

    Full Text Available Peanut, Arachis hypogaea (Linnaeus, 1753 is an allotetraploid cultivated plant with two subgenomes derived from the hybridization between two diploid wild species, A. duranensis (Krapovickas & W. C. Gregory, 1994 and A. ipaensis (Krapovickas & W. C. Gregory, 1994, followed by spontaneous chromosomal duplication. To understand genome changes following polyploidy, the chromosomes of A. hypogaea, IpaDur1, an induced allotetraploid (A. ipaensis × A. duranensis4x and the diploid progenitor species were cytogenetically compared. The karyotypes of the allotetraploids share the number and general morphology of chromosomes; DAPI+ bands pattern and number of 5S rDNA loci. However, one 5S rDNA locus presents a heteromorphic FISH signal in both allotetraploids, relative to corresponding progenitor. Whilst for A. hypogaea the number of 45S rDNA loci was equivalent to the sum of those present in the diploid species, in IpaDur1, two loci have not been detected. Overall distribution of repetitive DNA sequences was similar in both allotetraploids, although A. hypogaea had additional CMA3+ bands and few slight differences in the LTR-retrotransposons distribution compared to IpaDur1. GISH showed that the chromosomes of both allotetraploids had preferential hybridization to their corresponding diploid genomes. Nevertheless, at least one pair of IpaDur1 chromosomes had a clear mosaic hybridization pattern indicating recombination between the subgenomes, clear evidence that the genome of IpaDur1 shows some instability comparing to the genome of A. hypogaea that shows no mosaic of subgenomes, although both allotetraploids derive from the same progenitor species. For some reasons, the chromosome structure of A. hypogaea is inherently more stable, or, it has been at least, partially stabilized through genetic changes and selection.

  11. Field-induced magnetic instability and quantum criticality in the antiferromagnet CeCu2Ge2.

    Science.gov (United States)

    Liu, Yi; Xie, Donghua; Wang, Xiaoying; Zhu, Kangwei; Yang, Ruilong

    2016-01-13

    The magnetic quantum criticality in strongly correlated electron systems has been considered to be closely related with the occurrence of unconventional superconductivity. Control parameters such as magnetic field, pressure or chemical doping are frequently used to externally tune the quantum phase transition for a deeper understanding. Here we report the research of a field-induced quantum phase transition using conventional bulk physical property measurements in the archetypal antiferromagnet CeCu2Ge2, which becomes superconductive under a pressure of about 10 GPa with Tc ~ 0.64 K. We offer strong evidence that short-range dynamic correlations start appearing above a magnetic field of about 5 T. Our demonstrations of the magnetic instability and the field-induced quantum phase transition are crucial for the quantum criticality, which may open a new route in experimental investigations of the quantum phase transition in heavy-fermion systems.

  12. Phyllanthus emblica Fruit Extract Activates Spindle Assembly Checkpoint, Prevents Mitotic Aberrations and Genomic Instability in Human Colon Epithelial NCM460 Cells

    Directory of Open Access Journals (Sweden)

    Xihan Guo

    2016-09-01

    Full Text Available The fruit of Phyllanthus emblica Linn. (PE has been widely consumed as a functional food and folk medicine in Southeast Asia due to its remarkable nutritional and pharmacological effects. Previous research showed PE delays mitotic progress and increases genomic instability (GIN in human colorectal cancer cells. This study aimed to investigate the similar effects of PE by the biomarkers related to spindle assembly checkpoint (SAC, mitotic aberrations and GIN in human NCM460 normal colon epithelial cells. Cells were treated with PE and harvested differently according to the biomarkers observed. Frequencies of micronuclei (MN, nucleoplasmic bridge (NPB and nuclear bud (NB in cytokinesis-block micronucleus assay were used as indicators of GIN. Mitotic aberrations were assessed by the biomarkers of chromosome misalignment, multipolar division, chromosome lagging and chromatin bridge. SAC activity was determined by anaphase-to- metaphase ratio (AMR and the expression of core SAC gene budding uninhibited by benzimidazoles related 1 (BubR1. Compared with the control, PE-treated cells showed (1 decreased incidences of MN, NPB and NB (p < 0.01; (2 decreased frequencies of all mitotic aberration biomarkers (p < 0.01; and (3 decreased AMR (p < 0.01 and increased BubR1 expression (p < 0.001. The results revealed PE has the potential to protect human normal colon epithelial cells from mitotic and genomic damages partially by enhancing the function of SAC.

  13. Assessment of whole genome amplification-induced bias through high-throughput, massively parallel whole genome sequencing

    Directory of Open Access Journals (Sweden)

    Plant Ramona N

    2006-08-01

    Full Text Available Abstract Background Whole genome amplification is an increasingly common technique through which minute amounts of DNA can be multiplied to generate quantities suitable for genetic testing and analysis. Questions of amplification-induced error and template bias generated by these methods have previously been addressed through either small scale (SNPs or large scale (CGH array, FISH methodologies. Here we utilized whole genome sequencing to assess amplification-induced bias in both coding and non-coding regions of two bacterial genomes. Halobacterium species NRC-1 DNA and Campylobacter jejuni were amplified by several common, commercially available protocols: multiple displacement amplification, primer extension pre-amplification and degenerate oligonucleotide primed PCR. The amplification-induced bias of each method was assessed by sequencing both genomes in their entirety using the 454 Sequencing System technology and comparing the results with those obtained from unamplified controls. Results All amplification methodologies induced statistically significant bias relative to the unamplified control. For the Halobacterium species NRC-1 genome, assessed at 100 base resolution, the D-statistics from GenomiPhi-amplified material were 119 times greater than those from unamplified material, 164.0 times greater for Repli-G, 165.0 times greater for PEP-PCR and 252.0 times greater than the unamplified controls for DOP-PCR. For Campylobacter jejuni, also analyzed at 100 base resolution, the D-statistics from GenomiPhi-amplified material were 15 times greater than those from unamplified material, 19.8 times greater for Repli-G, 61.8 times greater for PEP-PCR and 220.5 times greater than the unamplified controls for DOP-PCR. Conclusion Of the amplification methodologies examined in this paper, the multiple displacement amplification products generated the least bias, and produced significantly higher yields of amplified DNA.

  14. Analysis of rainfall-induced slope instability using a field of local factor of safety

    Science.gov (United States)

    Lu, Ning; Şener-Kaya, Başak; Wayllace, Alexandra; Godt, Jonathan W.

    2012-01-01

    Slope-stability analyses are mostly conducted by identifying or assuming a potential failure surface and assessing the factor of safety (FS) of that surface. This approach of assigning a single FS to a potentially unstable slope provides little insight on where the failure initiates or the ultimate geometry and location of a landslide rupture surface. We describe a method to quantify a scalar field of FS based on the concept of the Coulomb stress and the shift in the state of stress toward failure that results from rainfall infiltration. The FS at each point within a hillslope is called the local factor of safety (LFS) and is defined as the ratio of the Coulomb stress at the current state of stress to the Coulomb stress of the potential failure state under the Mohr-Coulomb criterion. Comparative assessment with limit-equilibrium and hybrid finite element limit-equilibrium methods show that the proposed LFS is consistent with these approaches and yields additional insight into the geometry and location of the potential failure surface and how instability may initiate and evolve with changes in pore water conditions. Quantitative assessments applying the new LFS field method to slopes under infiltration conditions demonstrate that the LFS has the potential to overcome several major limitations in the classical FS methodologies such as the shape of the failure surface and the inherent underestimation of slope instability. Comparison with infinite-slope methods, including a recent extension to variably saturated conditions, shows further enhancement in assessing shallow landslide occurrence using the LFS methodology. Although we use only a linear elastic solution for the state of stress with no post-failure analysis that require more sophisticated elastoplastic or other theories, the LFS provides a new means to quantify the potential instability zones in hillslopes under variably saturated conditions using stress-field based methods.

  15. Excitation of an instability by neutral particle ionization induced fluxes in the tokamak edge plasma

    International Nuclear Information System (INIS)

    Bachmann, P.; Sunder, D.

    1991-01-01

    Strong density and potential fluctuations in the edge plasma of toroidal nuclear fusion devices can lead to anomalously fast particle and energy transport. There are some reasons to assume the level of these fluctuations to be connected with neutral particles which enter the plasma by gas puffing or recycling processes. The influence of neutral particles on the behaviour of electrostatic drift modes was investigated. Using the ballooning transformation the excitation of dissipative drift waves in tokamak was studied taking ionization and charge exchange into consideration. Ionization driven drift wave turbulence was analyzed. The higher the neutral particle density is the more important the plasma-wall interaction and the less important the action of the limiter becomes. Instabilities localized in the edge plasma and far from the limiter can be one of the reasons of such a phenomenon. In the present paper we show that such an instability may exist. Usually the neutral particle density is large in the vicinity of the limiter and decreases rapidly with the distance from it. Plasma particles generated by ionization of these neutrals outside the limiter shadow, move along the magnetic field lines into a region without neutrals and diffuse slowly across the magnetic field. We solve the stability problem for modes with a perpendicular wave length that is much larger than the ion Larmor radius with electron temperature, and much smaller than the minor plasma radius. The excitation of such modes localized far from the limiter is investigated. A one-dimensional differential equation is derived in the cold ion approximation without taking shear and toroidal effects into consideration. In the case of low flow velocities a nearly aperiodic instability is found analytically. Its growth rate is proportional to the equilibrium plasma velocity at the boundary of the neutral particle's free region and to the inverse of the extension of this zone. This mode is localized in the edge

  16. Efficient Genome Editing in Induced Pluripotent Stem Cells with Engineered Nucleases In Vitro.

    Science.gov (United States)

    Termglinchan, Vittavat; Seeger, Timon; Chen, Caressa; Wu, Joseph C; Karakikes, Ioannis

    2017-01-01

    Precision genome engineering is rapidly advancing the application of the induced pluripotent stem cells (iPSCs) technology for in vitro disease modeling of cardiovascular diseases. Targeted genome editing using engineered nucleases is a powerful tool that allows for reverse genetics, genome engineering, and targeted transgene integration experiments to be performed in a precise and predictable manner. However, nuclease-mediated homologous recombination is an inefficient process. Herein, we describe the development of an optimized method combining site-specific nucleases and the piggyBac transposon system for "seamless" genome editing in pluripotent stem cells with high efficiency and fidelity in vitro.

  17. New macroscopic theory of anamalous diffusion induced by the dissipative trapped-ion instability

    International Nuclear Information System (INIS)

    Wimmel, H.K.

    1975-03-01

    For an axisymmetric toroidal plasma of the TOKAMAK type a new set of dissipative trapped-fluid equations is established. In addition to E vector x B vector drifts and collisions of the trapped particles, these equations take full account of the effect of Esub(//) (of the trapped ion modes) on free and trapped particles, and of the effect of grad delta 0 (delta 0 = equilibrium fraction of trapped particles). From the new equations the linear-mode properties of the dissipative trapped-ion instability and the anomalous diffusion flux of the trapped particles are derived. (orig.) [de

  18. Self-induced dipole force and filamentation instability of a matter wave

    DEFF Research Database (Denmark)

    Saffman, M.

    1998-01-01

    The interaction of copropagating electromagnetic and matter waves is described with a set of coupled higher-order nonlinear Schrodinger equations. Optical self-focusing modulates an initially planar wave leading to the generation of dipole forces on the atoms. Atomic channeling due to the dipole...... forces leads, in the nonlinear regime, to filamentation of the atomic beam. Instability growth rates are calculated for atomic beams with both low and high phase space densities. In one transverse dimension an exact solution is found that describes a coupled optical and atomic soliton....

  19. Investigation on the negative bias illumination stress-induced instability of amorphous indium-tin-zinc-oxide thin film transistors

    Energy Technology Data Exchange (ETDEWEB)

    Jang, Jaeman; Kim, Dae Geun; Kim, Dong Myong; Choi, Sung-Jin; Kim, Dae Hwan, E-mail: byungdu.ahn@samsung.com, E-mail: drlife@kookmin.ac.kr [School of Electrical Engineering, Kookmin University, Seoul 136-702 (Korea, Republic of); Lim, Jun-Hyung; Lee, Je-Hun; Ahn, Byung Du, E-mail: byungdu.ahn@samsung.com, E-mail: drlife@kookmin.ac.kr [Samsung Display Co., Ltd., Yongin, Gyeonggi-Do 446-711 (Korea, Republic of); Kim, Yong-Sung [Korea Research Institute of Standards and Science, Yuseong, Daejeon 305-340 (Korea, Republic of)

    2014-10-13

    The quantitative analysis of mechanism on negative bias illumination stress (NBIS)-induced instability of amorphous indium-tin-zinc-oxide thin-film transistor (TFT) was suggested along with the effect of equivalent oxide thickness (EOT) of gate insulator. The analysis was implemented through combining the experimentally extracted density of subgap states and the device simulation. During NBIS, it was observed that the thicker EOT causes increase in both the shift of threshold voltage and the variation of subthreshold swing as well as the hump-like feature in a transfer curve. We found that the EOT-dependence of NBIS instability can be clearly explicated with the donor creation model, in which a larger amount of valence band tail states is transformed into either the ionized oxygen vacancy V{sub O}{sup 2+} or peroxide O{sub 2}{sup 2−} with the increase of EOT. It was also found that the V{sub O}{sup 2+}-related extrinsic factor accounts for 80%–92% of the total donor creation taking place in the valence band tail states while the rest is taken by the O{sub 2}{sup 2–} related intrinsic factor. The ratio of extrinsic factor compared to the total donor creation also increased with the increase of EOT, which could be explained by more prominent oxygen deficiency. The key founding of our work certainly represents that the established model should be considered very effective for analyzing the instability of the post-indium-gallium-zinc-oxide (IGZO) ZnO-based compound semiconductor TFTs with the mobility, which is much higher than those of a-IGZO TFTs.

  20. Dynamical instability induced by the zero mode under symmetry breaking external perturbation

    International Nuclear Information System (INIS)

    Takahashi, J.; Nakamura, Y.; Yamanaka, Y.

    2014-01-01

    A complex eigenvalue in the Bogoliubov–de Gennes equations for a stationary Bose-Einstein condensate in the ultracold atomic system indicates the dynamical instability of the system. We also have the modes with zero eigenvalues for the condensate, called the zero modes, which originate from the spontaneous breakdown of symmetries. Although the zero modes are suppressed in many theoretical analyses, we take account of them in this paper and argue that a zero mode can change into one with a pure imaginary eigenvalue by applying a symmetry breaking external perturbation potential. This emergence of a pure imaginary mode adds a new type of scenario of dynamical instability to that characterized by the complex eigenvalue of the usual excitation modes. For illustration, we deal with two one-dimensional homogeneous Bose–Einstein condensate systems with a single dark soliton under a respective perturbation potential, breaking the invariance under translation, to derive pure imaginary modes. - Highlights: • Zero modes are important but ignored in many theories for the cold atomic system. • We discuss the zero mode under symmetry breaking potential in this system. • We consider the zero mode of translational invariance for a single dark soliton. • We show that it turns into an anomalous or pure imaginary mode

  1. Surface-Energy-Anisotropy-Induced Orientation Effects on RayleighInstabilities in Sapphire

    Energy Technology Data Exchange (ETDEWEB)

    Santala, Melissa; Glaeser, Andreas M.

    2006-01-01

    Arrays of controlled-geometry, semi-infinite pore channels of systematically varied crystallographic orientation were introduced into undoped m-plane (10{bar 1}0) sapphire substrates using microfabrication techniques and ion-beam etching and subsequently internalized by solid-state diffusion bonding. A series of anneals at 1700 C caused the breakup of these channels into discrete pores via Rayleigh instabilities. In all cases, channels broke up with a characteristic wavelength larger than that expected for a material with isotropic surface energy, reflecting stabilization effects due to surface-energy anisotropy. The breakup wavelength and the time required for complete breakup varied significantly with channel orientation. For most orientations, the instability wavelength for channels of radius R was in the range of 13.2R-25R, and complete breakup occurred within 2-10 h. To first order, the anneal times for complete breakup scale with the square of the breakup wavelength. Channels oriented along a <11{bar 2}0> direction had a wavelength of {approx} 139R, and required 468 h for complete breakup. Cross-sectional analysis of channels oriented along a <11{bar 2}0> direction showed the channel to be completely bounded by stable c(0001), r{l_brace}{bar 1}012{r_brace}, and s{l_brace}10{bar 1}1{r_brace} facets.

  2. Parametric instability producing broad symmetrical structure in the spectrum of ionospheric heating-induced radiation

    International Nuclear Information System (INIS)

    Kuo, S.P.

    1997-01-01

    A four-wave interaction process in which an O-mode electromagnetic pump decays parametrically into a lower hybrid decay mode and two-electron Bernstein sidebands is analyzed. It is shown that the instability can be excited in a spatial region near the electron Bernstein/upper hybrid double resonance and in a narrow pump frequency range slightly below the third harmonic electron cyclotron resonance. The two electron Bernstein sidebands have about the same intensity and thus, produce Broad Symmetrical Structure (BSS) in the emission spectrum after being converted into electromagnetic radiation by scattering off background field-aligned density irregularities. The results also show that the size of the instability zone becomes very small as the pump frequency operates near a cyclotron harmonic higher than the third. Thus, the converted emission will be too weak to be detected. This explains why the BSS feature in the spectrum of stimulated electromagnetic emissions (SEEs) has only been observed in the third harmonic case. copyright 1997 American Institute of Physics

  3. In Situ Measurement of Seeking Speed and Seeking Induced Head-Disk Interface Instability in Hard Disk Drives

    Directory of Open Access Journals (Sweden)

    Yu Wang

    2015-01-01

    Full Text Available This paper investigated the instability of head-disk interface caused by the voice coil motor (VCM end crashing the crash stop during the seeking of magnetic head. To make the whole process of that clear, an in situ measurement method based on maximum likelihood estimation and extended Kalman filter for seeking speed at component level was developed first and was then calibrated by a high speed camera. Given a crash between VCM end and crash stop that may be a consequence of the continuous increasing seeking speed, the seeking speed was carefully controlled by using our developed method to find a critical value that may induce vigorous head-disk interface instability. Acoustic emission sensor and laser Doppler vibrometer were used to capture the transient dynamic behaviors of magnetic head when the crash is happening. Damage analysis and mode identification were carried out to reveal the relationship between the damage patterns on disk surface and head dynamics. The results of this study are helpful to optimize the track seeking profile during the HDD operation, as well as the design of components such as head and head arm.

  4. Vector condensate and AdS soliton instability induced by a magnetic field

    International Nuclear Information System (INIS)

    Cai, Rong-Gen; Li, Li; Li, Li-Fang; Wu, You

    2014-01-01

    We continue to study the holographic p-wave superconductor model in the Einstein-Maxwell-complex vector field theory with a non-minimal coupling between the complex vector field and the Maxwell field. In this paper we work in the AdS soliton background which describes a conformal field theory in the confined phase and focus on the probe approximation. We find that an applied magnetic field can lead to the condensate of the vector field and the AdS soliton instability. As a result, a vortex lattice structure forms in the spatial directions perpendicular to the applied magnetic field. As a comparison, we also discuss the vector condensate in the Einstein-SU(2) Yang-Mills theory and find that in the setup of the present paper, the Einstein-Maxwell-complex vector field model is a generalization of the SU(2) model in the sense that the vector field has a general mass and gyromagnetic ratio

  5. Laser-induced hydrodynamic instability and pattern formation in metallic nanofilms

    Science.gov (United States)

    Sureshkumar, R.; Trice, J.; Favazza, C.; Kalyanaraman, R.

    2007-11-01

    Cost effective methodologies for the robust generation of nanoscale patterns in thin films and at interfaces are crucial in photonic, opto-electronic and solar energy harvesting applications. When ultrathin metal films are exposed to a series of short (ns) laser pulses, spontaneous pattern formation results with spatio-temporal scales that depend on the film height and thermo-physical properties of the film/substrate bilayer. Various self-organization mechanisms have been identified, including a dewetting instability due to a competition between surface tension and dispersion forces, and intrinsic and/or extrinsic thermocapillary effects. We will discuss these mechanisms as well as the evolution of surface perturbations which have been explored using experiments, linear stability analysis and nonlinear dynamical simulations (Trice et al. Phys. Rev. B, 75, 235439 (2007); Favazza et al. Appl. Phys. Lett., 91, 043105 (2007); 88, 153118 (2006)).

  6. Thermal Instability Induced Oriented 2D Pores for Enhanced Sodium Storage.

    Science.gov (United States)

    Kong, Lingjun; Xie, Chen-Chao; Gu, Haichen; Wang, Chao-Peng; Zhou, Xianlong; Liu, Jian; Zhou, Zhen; Li, Zhao-Yang; Zhu, Jian; Bu, Xian-He

    2018-04-19

    Hierarchical porous structures are highly desired for various applications. However, it is still challenging to obtain such materials with tunable architectures. Here, this paper reports hierarchical nanomaterials with oriented 2D pores by taking advantages of thermally instable bonds in vanadium-based metal-organic frameworks (MOFs). High-temperature calcination of these MOFs accompanied by the loss of coordinated water molecules and other components enables the formation of orderly slit-like 2D pores in vanadium oxide/porous carbon nanorods (VO x /PCs). This unique combination leads to an increase of the reactive surface area. In addition, optimized VO x /PCs demonstrate high-rate capability and ultralong cycling life for sodium storage. The assembled full cells also show high capacity and cycling stability. This report provides an effective strategy for producing MOFs-derived composites with hierarchical porous architectures for energy storage. © 2018 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

  7. Suppression of photo-bias induced instability for amorphous indium tungsten oxide thin film transistors with bi-layer structure

    Energy Technology Data Exchange (ETDEWEB)

    Liu, Po-Tsun, E-mail: ptliu@mail.nctu.edu.tw; Chang, Chih-Hsiang; Chang, Chih-Jui [Department of Photonics and Institute of Electro-Optical Engineering, National Chiao Tung University, Hsinchu 30010, Taiwan (China)

    2016-06-27

    This study investigates the instability induced by bias temperature illumination stress (NBTIS) for an amorphous indium-tungsten-oxide thin film transistor (a-IWO TFT) with SiO{sub 2} backchannel passivation layer (BPL). It is found that this electrical degradation phenomenon can be attributed to the generation of defect states during the BPL process, which deteriorates the photo-bias stability of a-IWO TFTs. A method proposed by adding an oxygen-rich a-IWO thin film upon the a-IWO active channel layer could effectively suppress the plasma damage to channel layer during BPL deposition process. The bi-layer a-IWO TFT structure with an oxygen-rich back channel exhibits superior electrical reliability of device under NBTIS.

  8. Correlation of MLH1 and MGMT expression and promoter methylation with genomic instability in patients with thyroid carcinoma

    International Nuclear Information System (INIS)

    Santos, Juliana Carvalho; Bastos, André Uchimura; Cerutti, Janete Maria; Ribeiro, Marcelo Lima

    2013-01-01

    Gene silencing of the repair genes MLH1 and MGMT was shown to be a mechanism underlying the development of microsatellite instability (MSI), a phenotype frequently associated with various human malignancies. Recently, aberrant methylation of MLH1, MGMT and MSI were shown to be associated with mutations in genes such as BRAF, RAS and IDH1 in colon and brain tumours. Little is known about the methylation status of MLH1 and MGMT in thyroid tumours and its association with MSI and mutational status. In a series of 96 thyroid tumours whose mutational profiles of BRAF, IDH1 and NRAS mutations and RET/PTC were previously determined, we investigated MLH1 and MGMT expression and methylation status by qPCR and methylation-specific PCR after bisulphite treatment, respectively. MSI was determined by PCR using seven standard microsatellite markers. Samples with point mutations (BRAF, IDH1 and NRAS) show a decrease in MLH1 expression when compared to negative samples. Additionally, malignant lesions show a higher MSI pattern than benign lesions. The MSI phenotype was also associated with down-regulation of MLH1. The results of this study allow us to conclude that low expression of MLH1 is associated with BRAF V600E mutations, RET/PTC rearrangements and transitions (IDH1 and NRAS) in patients with thyroid carcinoma. In addition, a significant relationship between MSI status and histological subtypes was found

  9. Buneman instability and Pierce instability in a collisionless bounded plasma

    International Nuclear Information System (INIS)

    Iizuka, Satoru; Saeki, Koichi; Sato, Noriyoshi; Hatta, Yoshisuke

    1983-01-01

    A systematic experiment is performed on the Buneman instability and the Pierce instability in a bounded plasma consisting of beam electrons and stationary ions. Current fluctuations are confirmed to be induced by the Buneman instability. On the other hand, the Pierce instability gives rise to a current limitation. The phenomena are well explained by Mikhailovskii's theory taking account of ion motion in a bounded plasma. (author)

  10. Quantitative analysis of negative bias illumination stress-induced instability mechanisms in amorphous InGaZnO thin-film transistors

    International Nuclear Information System (INIS)

    Kim, Yong Sik; Bae, Min Kyung; Kong, Dong Sik; Jung, Hyun Kwang; Kim, Jae Hyeong; Kim, Woo Joon; Hur, In Seok; Kim, Dong Myong; Kim, Dae Hwan

    2011-01-01

    The physical origins of the negative bias illumination stress (NBIS)-induced threshold voltage shift (ΔV T ) in amorphous InGaZnO (a-IGZO) thin-film transistors (TFTs) under ambient light from a backlight unit are quantitatively and systematically investigated. Furthermore, a methodology for extracting the instability parameters is proposed and demonstrated. For the quantitative analysis, the subgap density-of-states (DOS)-based DC I-V model is intensively used. The NBIS time-evolution of the measured I DS -V GS characteristics is reproduced very well via the proposed methodology and instability parameters. Consequently, photo-excited electron detrapping, followed by ionization of oxygen vacancies (V O +2 ) and field-enhanced V O +2 diffusion, followed by hole trapping into the gate insulator, are found to be the dominant mechanisms in NBIS-induced instability of a-IGZO TFTs.

  11. Use of γ-ray-induced mutations in the genome era in rice

    International Nuclear Information System (INIS)

    Kusaba, Makoto

    2007-01-01

    Ionizing radiation has been used for inducing mutations and improving crops since the discovery by STADLER (1928) that X-rays could induce mutations in barley. At the end of 2004, the whole genome sequence of rice was determined (INTERNATIONAL RICE GENOME SEQUENCING PROJECT, 2005). What can γ-ray-induced mutations contribute now that this has been achieved? One answer could be the elucidation of the functions of the numerous genes revealed by the complete sequence of the rice genome. This includes identification of mutants through reverse genetics and the isolation of genes containing mutations through forward genetics using molecular markers and sequence information. Another answer could be mutation breeding using reverse genetics. But first we must know what kind of DNA lesions are caused by γ-rays. In this article, I describe the production of DNA lesions, and then discuss how γ-ray-induced mutations can contribute to the elucidation of gene function and to mutation breeding. (author)

  12. Delayed cell death, giant cell formation and chromosome instability induced by X-irradiation in human embryo cells

    International Nuclear Information System (INIS)

    Roy, K.; Kodama, Seiji; Suzuki, Keiji; Watanabe, Masami

    1999-01-01

    We studied X-ray-induced delayed cell death, delayed giant cell formation and delayed chromosome aberrations in normal human embryo cells to explore the relationship between initial radiation damage and delayed effect appeared at 14 to 55 population doubling numbers (PDNs) after X-irradiation. The delayed effect was induced in the progeny of X-ray survivors in a dose-dependent manner and recovered with increasing PDNs after X-irradiation. Delayed plating for 24 h post-irradiation reduced both acute and delayed lethal damage, suggesting that potentially lethal damage repair (PLDR) can be effective for relieving the delayed cell death. The chromosome analysis revealed that most of the dicentrics (more than 90%) observed in the progeny of X-ray survivors were not accompanied with fragments, in contrast with those observed in the first mitosis after X-irradiation. The present results indicate that the potentiality of genetic instability is determined during the repair process of initial radiation damage and suggest that the mechanism for formation of delayed chromosome aberrations by radiation might be different from that of direct radiation-induced chromosome aberrations. (author)

  13. Static and Dynamic Water Motion-Induced Instability in Oxide Thin-Film Transistors and Its Suppression by Using Low-k Fluoropolymer Passivation.

    Science.gov (United States)

    Choi, Seungbeom; Jo, Jeong-Wan; Kim, Jaeyoung; Song, Seungho; Kim, Jaekyun; Park, Sung Kyu; Kim, Yong-Hoon

    2017-08-09

    Here, we report static and dynamic water motion-induced instability in indium-gallium-zinc-oxide (IGZO) thin-film transistors (TFTs) and its effective suppression with the use of a simple, solution-processed low-k (ε ∼ 1.9) fluoroplastic resin (FPR) passivation layer. The liquid-contact electrification effect, in which an undesirable drain current modulation is induced by a dynamic motion of a charged liquid such as water, can cause a significant instability in IGZO TFTs. It was found that by adopting a thin (∼44 nm) FPR passivation layer for IGZO TFTs, the current modulation induced by the water-contact electrification was greatly reduced in both off- and on-states of the device. In addition, the FPR-passivated IGZO TFTs exhibited an excellent stability to static water exposure (a threshold voltage shift of +0.8 V upon 3600 s of water soaking), which is attributed to the hydrophobicity of the FPR passivation layer. Here, we discuss the origin of the current instability caused by the liquid-contact electrification as well as various static and dynamic stability tests for IGZO TFTs. On the basis of our findings, we believe that the use of a thin, solution-processed FPR passivation layer is effective in suppressing the static and dynamic water motion-induced instabilities, which may enable the realization of high-performance and environment-stable oxide TFTs for emerging wearable and skin-like electronics.

  14. Scenarios for the nonlinear evolution of alpha particle induced Alfven wave instability

    International Nuclear Information System (INIS)

    Berk, H.L.; Breizman, B.N.; Ye, Huanchun.

    1992-03-01

    Various nonlinear scenarios are given for the evolution of energetic particles that are slowing down in a background plasma and simultaneously causing instability of the background plasma waves. If the background damping is sufficiently weak, a steady-state wave is established as described by Berk and Breizman. For larger background damping rate pulsations develop. Saturation occurs when the wave amplitude rises to where the wave trapping frequency equals the growth rate. The wave then damps due to the small background dissipation present and a relatively long quiet interval exists between bursts while the free energy of the distribution is refilled by classical transport. In this scenario the anomalous energy loss of energetic particles due to diffusion is small compared to the classical collisional energy exchange with the background plasma. However, if at the trapping frequency, the wave amplitude is large enough to cause orbit stochasticity, a phase space ''explosion'' occurs where the wave amplitudes rise to higher levels which leads to rapid loss of energetic particles

  15. Validation of the RELAP5 code for the modeling of flashing-induced instabilities under natural-circulation conditions using experimental data from the CIRCUS test facility

    Energy Technology Data Exchange (ETDEWEB)

    Kozmenkov, Y. [Helmholtz-Zentrum Dresden-Rossendorf e.V. (FZD), Institute of Safety Research, P.O.B. 510119, D-01324 Dresden (Germany); Institute of Physics and Power Engineering, Obninsk (Russian Federation); Rohde, U., E-mail: U.Rohde@hzdr.de [Helmholtz-Zentrum Dresden-Rossendorf e.V. (FZD), Institute of Safety Research, P.O.B. 510119, D-01324 Dresden (Germany); Manera, A. [Paul Scherrer Institute (Switzerland)

    2012-02-15

    Highlights: Black-Right-Pointing-Pointer We report about the simulation of flashing-induced instabilities in natural circulation systems. Black-Right-Pointing-Pointer Flashing-induced instabilities are of relevance for operation of pool-type reactors of small power at low pressure. Black-Right-Pointing-Pointer The RELAP5 code is validated against measurement data from natural circulation experiments. Black-Right-Pointing-Pointer The magnitude and frequency of the oscillations were reproduced in good agreement with the measurement data. - Abstract: This paper reports on the use of the RELAP5 code for the simulation of flashing-induced instabilities in natural circulation systems. The RELAP 5 code is intended to be used for the simulation of transient processes in the Russian RUTA reactor concept operating at atmospheric pressure with forced convection of coolant. However, during transient processes, natural circulation with flashing-induced instabilities might occur. The RELAP5 code is validated against measurement data from natural circulation experiments performed within the framework of a European project (NACUSP) on the CIRCUS facility. The facility, built at the Delft University of Technology in The Netherlands, is a water/steam 1:1 height-scaled loop of a typical natural-circulation-cooled BWR. It was shown that the RELAP5 code is able to model all relevant phenomena related to flashing induced instabilities. The magnitude and frequency of the oscillations were reproduced in a good agreement with the measurement data. The close correspondence to the experiments was reached by detailed modeling of all components of the CIRCUS facility including the heat exchanger, the buffer vessel and the steam dome at the top of the facility.

  16. Instability-induced ordering, universal unfolding and the role of gravity in granular Couette flow

    Science.gov (United States)

    Alam, Meheboob; Arakeri, V. H.; Nott, P. R.; Goddard, J. D.; Herrmann, H. J.

    2005-01-01

    Linear stability theory and bifurcation analysis are used to investigate the role of gravity in shear-band formation in granular Couette flow, considering a kinetic-theory rheological model. We show that the only possible state, at low shear rates, corresponds to a "plug" near the bottom wall, in which the particles are densely packed and the shear rate is close to zero, and a uniformly sheared dilute region above it. The origin of such plugged states is shown to be tied to the spontaneous symmetry-breaking instabilities of the gravity-free uniform shear flow, leading to the formation of ordered bands of alternating dilute and dense regions in the transverse direction, via an infinite hierarchy of pitchfork bifurcations. Gravity plays the role of an "imperfection", thus destroying the "perfect" bifurcation structure of uniform shear. The present bifurcation problem admits universal unfolding of pitchfork bifurcations which subsequently leads to the formation of a sequence of a countably infinite number of "isolas", with the solution structures being a modulated version of their gravity-free counterpart. While the solution with a plug near the bottom wall looks remarkably similar to the shear-banding phenomenon in dense slow granular Couette flows, a "floating" plug near the top wall is also a solution of these equations at high shear rates. A two-dimensional linear stability analysis suggests that these floating plugged states are unstable to long-wave travelling disturbances.The unique solution having a bottom plug can also be unstable to long waves, but remains stable at sufficiently low shear rates. The implications and realizability of the present results are discussed in the light of shear-cell experiments under "microgravity" conditions.

  17. Fenton reaction induced cancer in wild type rats recapitulates genomic alterations observed in human cancer.

    Directory of Open Access Journals (Sweden)

    Shinya Akatsuka

    Full Text Available Iron overload has been associated with carcinogenesis in humans. Intraperitoneal administration of ferric nitrilotriacetate initiates a Fenton reaction in renal proximal tubules of rodents that ultimately leads to a high incidence of renal cell carcinoma (RCC after repeated treatments. We performed high-resolution microarray comparative genomic hybridization to identify characteristics in the genomic profiles of this oxidative stress-induced rat RCCs. The results revealed extensive large-scale genomic alterations with a preference for deletions. Deletions and amplifications were numerous and sometimes fragmented, demonstrating that a Fenton reaction is a cause of such genomic alterations in vivo. Frequency plotting indicated that two of the most commonly altered loci corresponded to a Cdkn2a/2b deletion and a Met amplification. Tumor sizes were proportionally associated with Met expression and/or amplification, and clustering analysis confirmed our results. Furthermore, we developed a procedure to compare whole genomic patterns of the copy number alterations among different species based on chromosomal syntenic relationship. Patterns of the rat RCCs showed the strongest similarity to the human RCCs among five types of human cancers, followed by human malignant mesothelioma, an iron overload-associated cancer. Therefore, an iron-dependent Fenton chemical reaction causes large-scale genomic alterations during carcinogenesis, which may result in distinct genomic profiles. Based on the characteristics of extensive genome alterations in human cancer, our results suggest that this chemical reaction may play a major role during human carcinogenesis.

  18. Irradiation-induced instability of MnS precipitates and its possible contribution to IASCC in light water reactors

    International Nuclear Information System (INIS)

    Garner, F.A.; Greenwood, L.R.; Chung, H.M.

    1997-01-01

    Although a number of candidate mechanisms have been proposed to participate in the IASCC phenomenon, it is not clear at this time that all of the contributing mechanisms have been identified. A new mechanism was proposed by Garner and Greenwood as a potential contribution to IASCC that involves the radiation-induced release into solution of sulphur and other deleterious elements that are normally concentrated into MnS precipitates. The instability arises from the combined action of the transmutation of manganese to iron, cascade-induced mixing and the very strong action of the inverse Kirkendall effect. The latter mechanism acts as a pump to export manganese from the precipitate surface and to replace it primarily with iron, as well as smaller amounts of chromium, nickel and other lesser elements. Evidence previously presented by Chung and coworkers appears to show that MnS precipitates in typical 300 series stainless steels become progressively depleted in manganese and enriched with iron as irradiation proceeds in boiling water reactor neutron spectra. It is shown in this paper that transmutation alone is insufficient to produce the observed behavior

  19. The pursuit of the genome instability by comet assay (single cell gel electrophoresis) in patients with cancer of the cavum in western Algerian; La recherche de l'instabilite genomique par le test des cometes (single cell gel electrophoresis) chez les malades atteints d'un cancer du cavum dans l'Ouest algerien

    Energy Technology Data Exchange (ETDEWEB)

    Boukerche, A.; Dali-Youcef, A.F. [Service de Radiotherapie, Oran (Algeria); Bouali-Youcef, Y. [Laboratoire d' Immunologie, Oran (Algeria); Mehadji, M. [Service d' ORL, Oran (Algeria); Chenal, C. [Rennes-1 Univ., UMR CNRS 6853, 35 (France)

    2007-11-15

    The analysis of results has shown a constitutional genome instability among the patients with a cavum cancer with a defect in DNA repair where some exogenous factors ( Epstein-Barr virus, EBV) seem play an important part. (N.C.)

  20. A model for moisture-induced dimensional instability in printing paper

    NARCIS (Netherlands)

    van der Sman, C.G.; Bosco, E.; Peerlings, R.H.J.

    2016-01-01

    The dimensional stability of printing paper is strongly related to changes in moisture content. This represents a major issue in the field of digital ink-jet printing, where moisture induced reversible and irreversible deformations may compromise printing quality and runnability. This paper proposes

  1. Depletion-induced instability in protein-DNA mixtures: Influence of protein charge and size

    NARCIS (Netherlands)

    Vries, de R.J.

    2006-01-01

    While there is abundant experimental and theoretical work on polymer-induced DNA condensation, it is still unclear whether globular proteins can condense linear DNA or not. We develop a simple analytical approximation for the depletion attraction between rodlike segments of semiflexible

  2. On the stability of a rod adhering to a rigid surface: Shear-induced stable adhesion and the instability of peeling

    Science.gov (United States)

    Majidi, Carmel; O'Reilly, Oliver M.; Williams, John A.

    2012-05-01

    Using variational methods, we establish conditions for the nonlinear stability of adhesive states between an elastica and a rigid halfspace. The treatment produces coupled criteria for adhesion and buckling instabilities by exploiting classical techniques from Legendre and Jacobi. Three examples that arise in a broad range of engineered systems, from microelectronics to biologically inspired fiber array adhesion, are used to illuminate the stability criteria. The first example illustrates buckling instabilities in adhered rods, while the second shows the instability of a peeling process and the third illustrates the stability of a shear-induced adhesion. The latter examples can also be used to explain how microfiber array adhesives can be activated by shearing and deactivated by peeling. The nonlinear stability criteria developed in this paper are also compared to other treatments.

  3. Radiation-induced instability of MnS precipitates and its possible consequences on IASCC of austenitic stainless steels

    International Nuclear Information System (INIS)

    Chung, H.M.; Garner, F.A.

    1996-01-01

    Irradiation assisted stress corrosion cracking (IASCC) continues to be a significant materials issue for the light water reactor industry and may also pose a problem for fusion power devices that employ water cooling. Although a number of potential mechanisms have been proposed to participate in this phenomenon, at this time it is not clear that any of these candidate mechanisms are sufficient to rationalize the observed failures. A new mechanism is proposed in this paper that involves the radiation-induced release into solution of elements not usually thought to participate in IASCC. It is shown in this paper that MnS precipitates, which contain most of the sulphur in stainless steels, are probably unstable under irradiation. First, the Mn transmutes very strongly to Fe in highly thermalized neutron spectra. Second, the combination of cascade-induced disordering and the inverse-Kirkendall effect operating at the incoherent interfaces of MnS precipitates will probably act as a pump to export Mn from the precipitate surface into the alloy matrix. Both of these processes will most likely allow some of the sulphur to re-enter the alloy matrix. Sulphur is known to exert a deleterious influence on grain boundary cracking. MnS precipitates are also thought to be a reservoir of other deleterious impurities such as fluorine which could be also released due to radiation-induced instability of the precipitates. This possibility has been confirmed by Auger electron spectroscopy of Types 304, 316, and 348 stainless steel specimens sectioned from several BWR components irradiated up to 3.5x10 21 n/cm 2 (E > 1 MeV)

  4. Radiation-induced instability of MnS precipitates and its possible consequences on IASCC of austenitic stainless steels

    Energy Technology Data Exchange (ETDEWEB)

    Chung, H.M. [Argonne National Lab., IL (United States); Garner, F.A. [Pacific Northwest National Lab., Richland, WA (United States)

    1996-10-01

    Irradiation assisted stress corrosion cracking (IASCC) continues to be a significant materials issue for the light water reactor industry and may also pose a problem for fusion power devices that employ water cooling. Although a number of potential mechanisms have been proposed to participate in this phenomenon, at this time it is not clear that any of these candidate mechanisms are sufficient to rationalize the observed failures. A new mechanism is proposed in this paper that involves the radiation-induced release into solution of elements not usually thought to participate in IASCC. It is shown in this paper that MnS precipitates, which contain most of the sulphur in stainless steels, are probably unstable under irradiation. First, the Mn transmutes very strongly to Fe in highly thermalized neutron spectra. Second, the combination of cascade-induced disordering and the inverse-Kirkendall effect operating at the incoherent interfaces of MnS precipitates will probably act as a pump to export Mn from the precipitate surface into the alloy matrix. Both of these processes will most likely allow some of the sulphur to re-enter the alloy matrix. Sulphur is known to exert a deleterious influence on grain boundary cracking. MnS precipitates are also thought to be a reservoir of other deleterious impurities such as fluorine which could be also released due to radiation-induced instability of the precipitates. This possibility has been confirmed by Auger electron spectroscopy of Types 304, 316, and 348 stainless steel specimens sectioned from several BWR components irradiated up to 3.5x10{sup 21} n/cm{sup 2} (E > 1 MeV).

  5. Genomes

    National Research Council Canada - National Science Library

    Brown, T. A. (Terence A.)

    2002-01-01

    ... of genome expression and replication processes, and transcriptomics and proteomics. This text is richly illustrated with clear, easy-to-follow, full color diagrams, which are downloadable from the book's website...

  6. Interfacial instability induced by a shock wave in a gas-liquid horizontal stratified system

    International Nuclear Information System (INIS)

    Sutradhar, S.C.; Chang, J.S.; Yoshida, H.

    1987-01-01

    The experiments are performed in a rectangular lucite duct equipped with the facility of generating shock waves. Piezo-type pressure transducers are used to monitor the strength and propagation velocity of the shock wave. As the liquid phase has high sound velocity, a prepulse wave system of flow amplitude travels in this phase at a speed faster than the principal shock wave. The magnitude of the transmitted wave in the liquid phase is estimated using a transmission coefficient for gas-liquid system. From the initial pressure ratio of the shock wave, the amplitude of the prepulse as well as the induced interfacial fluid velocity are calculated. The wave length and height of the ripples during the passage of the shock wave are estimated for a specific strength of shock wave moving through the phases. From the high speed photographs, the wave length of the ripples can be assessed. The interfacial friction factor is calculated using colebrook's equation for high speed flow. At least five distinct phenomena are observed to exist during the propagation of a shock wave. These are - (1) the energy carried by the pre-pulse is utilized in perturbing the interface; (2) shock wave induces a mass velocity at the interface; (3) the wavelength of the ripples at the interface is the product of induced interfacial mass velocity and the time period of the prepulse; (4) a portion of the liquid mass of the perturbed interface is entrained in the gas phase may be due to the hydrodynamic lift in that phase; and finally (5) waves with long wavelength are established at the interface

  7. Hopf Bifurcation and Delay-Induced Turing Instability in a Diffusive lac Operon Model

    Science.gov (United States)

    Cao, Xin; Song, Yongli; Zhang, Tonghua

    In this paper, we investigate the dynamics of a lac operon model with delayed feedback and diffusion effect. If the system is without delay or the delay is small, the positive equilibrium is stable so that there are no spatial patterns formed; while the time delay is large enough the equilibrium becomes unstable so that rich spatiotemporal dynamics may occur. We have found that time delay can not only incur temporal oscillations but also induce imbalance in space. With different initial values, the system may have different spatial patterns, for instance, spirals with one head, four heads, nine heads, and even microspirals.

  8. Genomic instability related to zinc deficiency and excess in an in vitro model: is the upper estimate of the physiological requirements recommended for children safe?

    Science.gov (United States)

    Padula, Gisel; Ponzinibbio, María Virginia; Gambaro, Rocío Celeste; Seoane, Analía Isabel

    2017-08-01

    Micronutrients are important for the prevention of degenerative diseases due to their role in maintaining genomic stability. Therefore, there is international concern about the need to redefine the optimal mineral and vitamin requirements to prevent DNA damage. We analyzed the cytostatic, cytotoxic, and genotoxic effect of in vitro zinc supplementation to determine the effects of zinc deficiency and excess and whether the upper estimate of the physiological requirement recommended for children is safe. To achieve zinc deficiency, DMEM/Ham's F12 medium (HF12) was chelated (HF12Q). Lymphocytes were isolated from healthy female donors (age range, 5-10 yr) and cultured for 7 d as follows: negative control (HF12, 60 μg/dl ZnSO 4 ); deficient (HF12Q, 12 μg/dl ZnSO 4 ); lower level (HF12Q + 80 μg/dl ZnSO 4 ); average level (HF12Q + 180 μg/dl ZnSO 4 ); upper limit (HF12Q + 280 μg/dl ZnSO 4 ); and excess (HF12Q + 380 μg/dl ZnSO 4 ). The comet (quantitative analysis) and cytokinesis-block micronucleus cytome assays were used. Differences were evaluated with Kruskal-Wallis and ANOVA (p < 0.05). Olive tail moment, tail length, micronuclei frequency, and apoptotic and necrotic percentages were significantly higher in the deficient, upper limit, and excess cultures compared with the negative control, lower, and average limit ones. In vitro zinc supplementation at the lower and average limit (80 and 180 μg/dl ZnSO 4 ) of the physiological requirement recommended for children proved to be the most beneficial in avoiding genomic instability, whereas the deficient, upper limit, and excess (12, 280, and 380 μg/dl) cultures increased DNA and chromosomal damage and apoptotic and necrotic frequencies.

  9. Clonal evolution and progression of 20-methylcholanthrene-induced squamous cell carcinoma of mouse epidermis as revealed by DNA instability and other malignancy markers

    Directory of Open Access Journals (Sweden)

    K Hirai

    2009-12-01

    Full Text Available We examined the clonal evolution of skin malignant lesions by repeated topical applications of 20- methylcholanthrene (20-MC to the skin, which induces hyperplastic epidermis, papillomatous lesion and invasive carcinoma in mice. The lesions were examined histologically and immunohistochemically with anti-single-stranded DNA after acid hydrolysis (DNA-instability test, p53, VEGF, DFF45, PCNA and AgNORs parameters analyses. Multiple clones with increased DNA instability comparable to that of invasive carcinoma were noted in early-stage (2-6 weeks hyperplastic epidermis, and their number increased in middle (7-11 weeks, and late-stages (12-25 weeks of hyperplastic epidermis, indicating that they belong to the malignancy category. All papillomatous lesions and invasive carcinomas showed a positive DNA-instability test. Positive immunostaining for various biomarkers and AgNORs parameters appeared in clones with a positive DNA-instability test in earlyor middle-stage hyperplastic epidermis, and markedly increased in late-stage hyperplastic epidermis, papillomatous lesions and invasive carcinomas. The percentage of PCNA-positive vascular endothelial cells was significantly higher in VEGFpositive lesions with a positive DNA-instability test and became higher toward the late-stage of progression. Cut-woundings were made to papillomatous and invasive carcinoma lesions, and the regeneration activity of vascular endothelial cells was determined by using flash labeling with tritiated thymidine (3H-TdR. In small papillomatous lesions, vascular endothelial cells showed regenerative response, but the response was weak in large lesions. No such response was noted in invasive carcinomas; rather, cut-wounding induced collapse of blood vessels, which in turn induced massive coagulative necrosis of cancer cells. These responses can be interpreted to reflect exhausted vascular growth activity due to excessive stimulation by VEGF-overexpression, which was persistently

  10. Genome-wide mapping for clinically relevant predictors of lamotrigine- and phenytoin-induced hypersensitivity reactions.

    LENUS (Irish Health Repository)

    McCormack, Mark

    2012-03-01

    An association between carbamazepine-induced hypersensitivity and HLA-A*3101 has been reported in populations of both European and Asian descent. We aimed to investigate HLA-A*3101 and other common variants across the genome as markers for cutaneous adverse drug reactions (cADRs) attributed to lamotrigine and phenytoin.

  11. A genome-wide association study of heparin-induced thrombocytopenia using an electronic medical record

    DEFF Research Database (Denmark)

    Karnes, Jason H; Cronin, Robert M; Rollin, Jerome

    2015-01-01

    Heparin-induced thrombocytopenia (HIT) is an unpredictable, potentially catastrophic adverse effect of heparin treatment resulting from an immune response to platelet factor 4 (PF4)/heparin complexes. No genome-wide evaluations have been performed to identify potential genetic influences on HIT. ...

  12. Mechanisms of thermally induced threshold voltage instability in GaN-based heterojunction transistors

    Energy Technology Data Exchange (ETDEWEB)

    Yang, Shu; Liu, Shenghou; Liu, Cheng; Lu, Yunyou; Chen, Kevin J., E-mail: eekjchen@ust.hk [Department of Electronic and Computer Engineering, The Hong Kong University of Science and Technology, Clear Water Bay, Kowloon (Hong Kong)

    2014-12-01

    In this work, we attempt to reveal the underlying mechanisms of divergent V{sub TH}-thermal-stabilities in III-nitride metal-insulator-semiconductor high-electron-mobility transistor (MIS-HEMT) and MOS-Channel-HEMT (MOSC-HEMT). In marked contrast to MOSC-HEMT featuring temperature-independent V{sub TH}, MIS-HEMT with the same high-quality gate-dielectric/III-nitride interface and similar interface trap distribution exhibits manifest thermally induced V{sub TH} shift. The temperature-dependent V{sub TH} of MIS-HEMT is attributed to the polarized III-nitride barrier layer, which spatially separates the critical gate-dielectric/III-nitride interface from the channel and allows “deeper” interface trap levels emerging above the Fermi level at pinch-off. This model is further experimentally validated by distinct V{sub G}-driven Fermi level movements at the critical interfaces in MIS-HEMT and MOSC-HEMT. The mechanisms of polarized III-nitride barrier layer in influencing V{sub TH}-thermal-stability provide guidelines for the optimization of insulated-gate III-nitride power switching devices.

  13. Mechanisms of thermally induced threshold voltage instability in GaN-based heterojunction transistors

    International Nuclear Information System (INIS)

    Yang, Shu; Liu, Shenghou; Liu, Cheng; Lu, Yunyou; Chen, Kevin J.

    2014-01-01

    In this work, we attempt to reveal the underlying mechanisms of divergent V TH -thermal-stabilities in III-nitride metal-insulator-semiconductor high-electron-mobility transistor (MIS-HEMT) and MOS-Channel-HEMT (MOSC-HEMT). In marked contrast to MOSC-HEMT featuring temperature-independent V TH , MIS-HEMT with the same high-quality gate-dielectric/III-nitride interface and similar interface trap distribution exhibits manifest thermally induced V TH shift. The temperature-dependent V TH of MIS-HEMT is attributed to the polarized III-nitride barrier layer, which spatially separates the critical gate-dielectric/III-nitride interface from the channel and allows “deeper” interface trap levels emerging above the Fermi level at pinch-off. This model is further experimentally validated by distinct V G -driven Fermi level movements at the critical interfaces in MIS-HEMT and MOSC-HEMT. The mechanisms of polarized III-nitride barrier layer in influencing V TH -thermal-stability provide guidelines for the optimization of insulated-gate III-nitride power switching devices

  14. Quantum-to-classical transition and gravity-induced instabilities (in progress)

    International Nuclear Information System (INIS)

    Lima, William C.C.

    2013-01-01

    Full text: It has been argued that gravitational fields produced by realistic matter distributions can induce the vacuum fluctuations of some non-minimally coupled free scalar field to go through a phase of exponential amplification. For the particular case of the formation of a neutron star, the energy density of the field in its initial vacuum state rivals the one of the star in a lapse of just a few milliseconds after the effect has been triggered. From this point on back reaction effects must be taken into account in order to predict the fate of both the star and scalar field. Classical analyses have shown that, at least for some values of the mass-radius ratio of the star and the non-minimal coupling parameter, a non-null scalar field profile could stabilize the system. The aim of our study is to shed some light on the back reaction process from the perspective of the quantum-to-classical transition that will occur once the classical background spacetime reacts to the unstable quantum field. In particular, the transition to a classical regime requires the specification of a well-defined classical initial state for the field. This can be accomplished analyzing the quantum state of the field around the time back reaction effects become important. (author)

  15. Induction of chromosomal instability in human lymphoblasts by low doses of γ-radiation

    International Nuclear Information System (INIS)

    Gibbons, C.F.; Grosovsky, A.J.

    2003-01-01

    Full text: Genomic instability is a hallmark of tumorigenic progression, and a similar phenotype is also observed in a high fraction (10 - 50%) of cells that survive exposure to ionizing radiation. In both cases unstable clones are characterized by non-clonal chromosomal rearrangements, which are indicative of a high rate of genetic change during the outgrowth of an unstable parental cell. We postulate that the remarkably high frequency of radiation-induced genomic instability is incompatible with a mutational mechanism for a specific gene, or even a large family of genes. Rather, we hypothesize that a major portion of instability is attributable to the formation of chromosomal rearrangement junction sequences that act as de novo chromosomal breakage hotspots. We further suggest that critical target sequences, which represent at least 10% of the genome and include repetitive DNA sequences such as those found in centromeric heterochromatin, can be involved in breakage and rearrangement hotspots that drive persistent genomic instability and karyotypic heterogeneity. Since chromosomal damage is induced even by low dose radiation exposure, we hypothesize that this phenotype can be efficiently induced at doses that are relevant to environmental, occupational, or medical exposure. In the present study, TK6 human B-lymphoblastoid cells were irradiated with 0, 10, 20 and 200cGy, in order to provide a set of data points for single, low dose exposures. Independent clones were analyzed karyotypically approximately 40 generations after radiation exposure. Preliminary results suggest that the fraction of clones exhibiting genomic instability after 20 cGy (0.16) is similar to and statistically indistinguishable from the fraction of unstable clones following 200 cGy (0.2) exposure. These findings support the hypothesis that instability following radiation, and perhaps also in cancer, primarily reflects non-mutational mechanisms

  16. Genetic and epigenetic alterations induced by different levels of rye genome integration in wheat recipient.

    Science.gov (United States)

    Zheng, X L; Zhou, J P; Zang, L L; Tang, A T; Liu, D Q; Deng, K J; Zhang, Y

    2016-06-17

    The narrow genetic variation present in common wheat (Triticum aestivum) varieties has greatly restricted the improvement of crop yield in modern breeding systems. Alien addition lines have proven to be an effective means to broaden the genetic diversity of common wheat. Wheat-rye addition lines, which are the direct bridge materials for wheat improvement, have been wildly used to produce new wheat cultivars carrying alien rye germplasm. In this study, we investigated the genetic and epigenetic alterations in two sets of wheat-rye disomic addition lines (1R-7R) and the corresponding triticales. We used expressed sequence tag-simple sequence repeat, amplified fragment length polymorphism, and methylation-sensitive amplification polymorphism analyses to analyze the effects of the introduction of alien chromosomes (either the entire genome or sub-genome) to wheat genetic background. We found obvious and diversiform variations in the genomic primary structure, as well as alterations in the extent and pattern of the genomic DNA methylation of the recipient. Meanwhile, these results also showed that introduction of different rye chromosomes could induce different genetic and epigenetic alterations in its recipient, and the genetic background of the parents is an important factor for genomic and epigenetic variation induced by alien chromosome addition.

  17. Relativistic gravitational instabilities

    International Nuclear Information System (INIS)

    Schutz, B.F.

    1987-01-01

    The purpose of these lectures is to review and explain what is known about the stability of relativistic stars and black holes, with particular emphases on two instabilities which are due entirely to relativistic effects. The first of these is the post-Newtonian pulsational instability discovered independently by Chandrasekhar (1964) and Fowler (1964). This effectively ruled out the then-popular supermassive star model for quasars, and it sets a limit to the central density of white dwarfs. The second instability was also discovered by Chandrasekhar (1970): the gravitational wave induced instability. This sets an upper bound on the rotation rate of neutron stars, which is near that of the millisecond pulsar PSR 1937+214, and which is beginning to constrain the equation of state of neutron matter. 111 references, 5 figures

  18. Genomic Instability and Breast Cancer

    Science.gov (United States)

    2011-06-01

    distinguish these possibilities. The possible function of human SWI5-MEI5 in meiosis also needs to be investigated. It remains to be determined whether the... human SWI5-MEI5 complex acts in meiosis and, if it does, whether it acts with DMC1, RAD51, or both. Considering that SWI5-MEI5 is the only human ...tumorigenesis. This has been clearly illustrated in familial breast cancer, since human genetic studies reveal that many genes involved in DNA damage response

  19. Genome instability in Alzheimer disease

    DEFF Research Database (Denmark)

    Hou, Yujun; Song, Hyundong; Croteau, Deborah L

    2017-01-01

    Alzheimer's disease (AD) is a progressive neurodegenerative disorder and the most common form of dementia. Autosomal dominant, familial AD (fAD) is very rare and caused by mutations in amyloid precursor protein (APP), presenilin-1 (PSEN-1), and presenilin-2 (PSEN-2) genes. The pathogenesis...

  20. Instability of chromosome number and DNA methylation variation induced by hybridization and amphidiploid formation between Raphanus sativus L. and Brassica alboglabra Bailey

    Directory of Open Access Journals (Sweden)

    Wang Yanjie

    2010-09-01

    Full Text Available Abstract Background Distant hybridization can result genome duplication and allopolyploid formation which may play a significant role in the origin and evolution of many plant species. It is unclear how the two or more divergent genomes coordinate in one nucleus with a single parental cytoplasm within allopolyploids. We used cytological and molecular methods to investigate the genetic and epigenetic instabilities associated with the process of distant hybridization and allopolyploid formation, measuring changes in chromosome number and DNA methylation across multiple generations. Results F1 plants from intergeneric hybridization between Raphanus sativus L. (2n = 18, RR and Brassica alboglabra Bailey (2n = 18, CC were obtained by hand crosses and subsequent embryo rescue. Random amplification of polymorphic DNA (RAPD markers were used to identify the F1 hybrid plants. The RAPD data indicated that the hybrids produced specific bands similar to those of parents and new bands that were not present in either parent. Chromosome number variation of somatic cells from allotetraploids in the F4 to F10 generations showed that intensive genetic changes occurred in the early generations of distant hybridization, leading to the formation of mixopolyploids with different chromosome numbers. DNA methylation variation was revealed using MSAP (methylation-sensitive amplification polymorphism, which showed that cytosine methylation patterns changed markedly in the process of hybridization and amphidiploid formation. Differences in cytosine methylation levels demonstrated an epigenetic instability of the allopolyploid of Raphanobrassica between the genetically stable and unstable generations. Conclusions Our results showed that chromosome instability occurred in the early generations of allopolyploidy and then the plants were reverted to largely euploidy in later generations. During this process, DNA methylation changed markedly. These results suggest that

  1. Radiation-induced instability of MnS precipitates and its possible consequences on irradiation-induced stress corrosion cracking of austenitic stainless steels

    International Nuclear Information System (INIS)

    Chung, H.M.; Sanecki, J.E.; Garner, F.A.

    1996-12-01

    Irradiation-assisted stress corrosion cracking (IASCC) is a significant materials issue for the light water reactor (LWR) industry and may also pose a problem for fusion power reactors that will use water as coolant. A new metallurgical process is proposed that involves the radiation-induced release into solution of minor impurity elements not usually thought to participate in IASCC. MnS-type precipitates, which contain most of the sulfur in stainless steels, are thought to be unstable under irradiation. First, Mn transmutes strongly to Fe in thermalized neutron spectra. Second, cascade-induced disordering and the inverse Kirkendall effect operating at the incoherent interfaces of MnS precipitates are thought to act as a pump to export Mn from the precipitate into the alloy matrix. Both of these processes will most likely allow sulfur, which is known to exert a deleterious influence on intergranular cracking, to re-enter the matrix. To test this hypothesis, compositions of MnS-type precipitates contained in several unirradiated and irradiated heats of Type 304, 316, and 348 stainless steels (SSs) were analyzed by Auger electron spectroscopy. Evidence is presented that shows a progressive compositional modification of MnS precipitates as exposure to neutrons increases in boiling water reactors. As the fluence increases, the Mn level in MnS decreases, whereas the Fe level increases. The S level also decreases relative to the combined level of Mn and Fe. MnS precipitates were also found to be a reservoir of other deleterious impurities such as F and O which could be also released due to radiation-induced instability of the precipitates

  2. Comparison of the coherent radiation-induced microbunching instability in a free-electron laser and a magnetic chicane

    Directory of Open Access Journals (Sweden)

    S. Reiche

    2003-04-01

    Full Text Available A self-amplified spontaneous emission free-electron laser (SASE FEL is a device which is based on the creation of a very intense, relativistic electron beam which has very little temperature in all three phase planes. The beam in this system is described as having “high brightness,” and when it is bent repetitively in a magnetic undulator, undergoes a radiation-mediated microbunching instability. This instability can amplify the original radiation amplitude at a particular, resonant wavelength by many orders of magnitude. In order to obtain high brightness beams, it is necessary to compress them to obtain higher currents than available from the electron source. Compression is accomplished by the use of magnetic chicanes, which are quite similar to, if much longer than, a single period of the undulator. It should not be surprising that such chicanes also support a radiation-mediated microbunching interaction, which has recently been investigated, and has been termed coherent synchrotron radiation (CSR instability. The purpose of this paper is to compare and contrast the characteristics of the closely related FEL and CSR microbunching instabilities. We show that a high-gain regime of the CSR instability exists which is formally similar to the FEL instability.

  3. CRISPR-Cas9-Based Genome Editing of Human Induced Pluripotent Stem Cells.

    Science.gov (United States)

    Giacalone, Joseph C; Sharma, Tasneem P; Burnight, Erin R; Fingert, John F; Mullins, Robert F; Stone, Edwin M; Tucker, Budd A

    2018-02-28

    Human induced pluripotent stem cells (hiPSCs) are the ideal cell source for autologous cell replacement. However, for patients with Mendelian diseases, genetic correction of the original disease-causing mutation is likely required prior to cellular differentiation and transplantation. The emergence of the CRISPR-Cas9 system has revolutionized the field of genome editing. By introducing inexpensive reagents that are relatively straightforward to design and validate, it is now possible to correct genetic variants or insert desired sequences at any location within the genome. CRISPR-based genome editing of patient-specific iPSCs shows great promise for future autologous cell replacement therapies. One caveat, however, is that hiPSCs are notoriously difficult to transfect, and optimized experimental design considerations are often necessary. This unit describes design strategies and methods for efficient CRISPR-based genome editing of patient- specific iPSCs. Additionally, it details a flexible approach that utilizes positive selection to generate clones with a desired genomic modification, Cre-lox recombination to remove the integrated selection cassette, and negative selection to eliminate residual hiPSCs with intact selection cassettes. © 2018 by John Wiley & Sons, Inc. Copyright © 2018 John Wiley & Sons, Inc.

  4. Multimode drug inducible CRISPR/Cas9 devices for transcriptional activation and genome editing

    Science.gov (United States)

    Lu, Jia; Zhao, Chen; Zhao, Yingze; Zhang, Jingfang; Zhang, Yue; Chen, Li; Han, Qiyuan; Ying, Yue; Peng, Shuai; Ai, Runna; Wang, Yu

    2018-01-01

    Abstract Precise investigation and manipulation of dynamic biological processes often requires molecular modulation in a controlled inducible manner. The clustered, regularly interspaced, short palindromic repeats (CRISPR)/CRISPR associated protein 9 (Cas9) has emerged as a versatile tool for targeted gene editing and transcriptional programming. Here, we designed and vigorously optimized a series of Hybrid drug Inducible CRISPR/Cas9 Technologies (HIT) for transcriptional activation by grafting a mutated human estrogen receptor (ERT2) to multiple CRISPR/Cas9 systems, which renders them 4-hydroxytamoxifen (4-OHT) inducible for the access of genome. Further, extra functionality of simultaneous genome editing was achieved with one device we named HIT2. Optimized terminal devices herein delivered advantageous performances in comparison with several existing designs. They exerted selective, titratable, rapid and reversible response to drug induction. In addition, these designs were successfully adapted to an orthogonal Cas9. HIT systems developed in this study can be applied for controlled modulation of potentially any genomic loci in multiple modes. PMID:29237052

  5. Synergistic Interactions with PI3K Inhibition that Induce Apoptosis. | Office of Cancer Genomics

    Science.gov (United States)

    Activating mutations involving the PI3K pathway occur frequently in human cancers. However, PI3K inhibitors primarily induce cell cycle arrest, leaving a significant reservoir of tumor cells that may acquire or exhibit resistance. We searched for genes that are required for the survival of PI3K mutant cancer cells in the presence of PI3K inhibition by conducting a genome scale shRNA-based apoptosis screen in a PIK3CA mutant human breast cancer cell. We identified 5 genes (PIM2, ZAK, TACC1, ZFR, ZNF565) whose suppression induced cell death upon PI3K inhibition.

  6. Carpal instability

    International Nuclear Information System (INIS)

    Schmitt, R.; Froehner, S.; Coblenz, G.; Christopoulos, G.

    2006-01-01

    This review addresses the pathoanatomical basics as well as the clinical and radiological presentation of instability patterns of the wrist. Carpal instability mostly follows an injury; however, other diseases, like CPPD arthropathy, can be associated. Instability occurs either if the carpus is unable to sustain physiologic loads (''dyskinetics'') or suffers from abnormal motion of its bones during movement (''dyskinematics''). In the classification of carpal instability, dissociative subcategories (located within proximal carpal row) are differentiated from non-dissociative subcategories (present between the carpal rows) and combined patterns. It is essential to note that the unstable wrist initially does not cause relevant signs in standard radiograms, therefore being ''occult'' for the radiologic assessment. This paper emphasizes the high utility of kinematographic studies, contrast-enhanced magnetic resonance imaging (MRI) and MR arthrography for detecting these predynamic and dynamic instability stages. Later in the natural history of carpal instability, static malalignment of the wrist and osteoarthritis will develop, both being associated with significant morbidity and disability. To prevent individual and socio-economic implications, the handsurgeon or orthopedist, as well as the radiologist, is challenged for early and precise diagnosis. (orig.)

  7. Simulated space radiation-induced mutants in the mouse kidney display widespread genomic change.

    Directory of Open Access Journals (Sweden)

    Mitchell S Turker

    Full Text Available Exposure to a small number of high-energy heavy charged particles (HZE ions, as found in the deep space environment, could significantly affect astronaut health following prolonged periods of space travel if these ions induce mutations and related cancers. In this study, we used an in vivo mutagenesis assay to define the mutagenic effects of accelerated 56Fe ions (1 GeV/amu, 151 keV/μm in the mouse kidney epithelium exposed to doses ranging from 0.25 to 2.0 Gy. These doses represent fluences ranging from 1 to 8 particle traversals per cell nucleus. The Aprt locus, located on chromosome 8, was used to select induced and spontaneous mutants. To fully define the mutagenic effects, we used multiple endpoints including mutant frequencies, mutation spectrum for chromosome 8, translocations involving chromosome 8, and mutations affecting non-selected chromosomes. The results demonstrate mutagenic effects that often affect multiple chromosomes for all Fe ion doses tested. For comparison with the most abundant sparsely ionizing particle found in space, we also examined the mutagenic effects of high-energy protons (1 GeV, 0.24 keV/μm at 0.5 and 1.0 Gy. Similar doses of protons were not as mutagenic as Fe ions for many assays, though genomic effects were detected in Aprt mutants at these doses. Considered as a whole, the data demonstrate that Fe ions are highly mutagenic at the low doses and fluences of relevance to human spaceflight, and that cells with considerable genomic mutations are readily induced by these exposures and persist in the kidney epithelium. The level of genomic change produced by low fluence exposure to heavy ions is reminiscent of the extensive rearrangements seen in tumor genomes suggesting a potential initiation step in radiation carcinogenesis.

  8. Simulated space radiation-induced mutants in the mouse kidney display widespread genomic change.

    Science.gov (United States)

    Turker, Mitchell S; Grygoryev, Dmytro; Lasarev, Michael; Ohlrich, Anna; Rwatambuga, Furaha A; Johnson, Sorrel; Dan, Cristian; Eckelmann, Bradley; Hryciw, Gwen; Mao, Jian-Hua; Snijders, Antoine M; Gauny, Stacey; Kronenberg, Amy

    2017-01-01

    Exposure to a small number of high-energy heavy charged particles (HZE ions), as found in the deep space environment, could significantly affect astronaut health following prolonged periods of space travel if these ions induce mutations and related cancers. In this study, we used an in vivo mutagenesis assay to define the mutagenic effects of accelerated 56Fe ions (1 GeV/amu, 151 keV/μm) in the mouse kidney epithelium exposed to doses ranging from 0.25 to 2.0 Gy. These doses represent fluences ranging from 1 to 8 particle traversals per cell nucleus. The Aprt locus, located on chromosome 8, was used to select induced and spontaneous mutants. To fully define the mutagenic effects, we used multiple endpoints including mutant frequencies, mutation spectrum for chromosome 8, translocations involving chromosome 8, and mutations affecting non-selected chromosomes. The results demonstrate mutagenic effects that often affect multiple chromosomes for all Fe ion doses tested. For comparison with the most abundant sparsely ionizing particle found in space, we also examined the mutagenic effects of high-energy protons (1 GeV, 0.24 keV/μm) at 0.5 and 1.0 Gy. Similar doses of protons were not as mutagenic as Fe ions for many assays, though genomic effects were detected in Aprt mutants at these doses. Considered as a whole, the data demonstrate that Fe ions are highly mutagenic at the low doses and fluences of relevance to human spaceflight, and that cells with considerable genomic mutations are readily induced by these exposures and persist in the kidney epithelium. The level of genomic change produced by low fluence exposure to heavy ions is reminiscent of the extensive rearrangements seen in tumor genomes suggesting a potential initiation step in radiation carcinogenesis.

  9. Collisionless Kelvin-Helmholtz instability and vortex-induced reconnection in the external region of the Earth magnetotail

    International Nuclear Information System (INIS)

    Pegoraro, F; Faganello, M; Califano, F

    2008-01-01

    In a magnetized plasma streaming with a non uniform velocity, the Kelvin-Helmholtz instability plays a major role in mixing different plasma regions and in stretching the magnetic field lines leading to the formation of layers with a sheared magnetic field where magnetic field line reconnection can take place. A relevant example is provided by the formation of a mixing layer between the Earth's magnetosphere and the solar wind at low latitudes during northward periods. In the considered configuration, in the presence of a magnetic field nearly perpendicular to the plane defined by the velocity field and its inhomogeneity direction, velocity shear drives a Kelvin-Helmholtz instability which advects and distorts the magnetic field configuration. If the Alfven velocity associated to the in-plane magnetic field is sufficiently weak with respect to the variation of the fluid velocity in the plasma, the Kelvin-Helmholtz instability generates fully rolled-up vortices which advect the magnetic field lines into a complex configuration, causing the formation of current layers along the inversion curves of the in-plane magnetic field component. Pairing of the vortices generated by the Kelvin-Helmholtz instability is a well know phenomenon in two-dimensional hydrodynamics. Here we investigate the development of magnetic reconnection during the vortex pairing process and show that completely different magnetic structures are produced depending on how fast the reconnection process develops on the time scale set by the pairing process.

  10. Morphological, Genome and Gene Expression Changes in Newly Induced Autopolyploid Chrysanthemum lavandulifolium (Fisch. ex Trautv. Makino

    Directory of Open Access Journals (Sweden)

    Ri Gao

    2016-10-01

    Full Text Available Autopolyploidy is widespread in higher plants and plays an important role in the process of evolution. The present study successfully induced autotetraploidys from Chrysanthemum lavandulifolium by colchicine. The plant morphology, genomic, transcriptomic, and epigenetic changes between tetraploid and diploid plants were investigated. Ligulate flower, tubular flower and leaves of tetraploid plants were greater than those of the diploid plants. Compared with diploid plants, the genome changed as a consequence of polyploidization in tetraploid plants, namely, 1.1% lost fragments and 1.6% novel fragments occurred. In addition, DNA methylation increased after genome doubling in tetraploid plants. Among 485 common transcript-derived fragments (TDFs, which existed in tetraploid and diploid progenitors, 62 fragments were detected as differentially expressed TDFs, 6.8% of TDFs exhibited up-regulated gene expression in the tetraploid plants and 6.0% exhibited down-regulation. The present study provides a reference for further studying the autopolyploidization role in the evolution of C. lavandulifolium. In conclusion, the autopolyploid C. lavandulifolium showed a global change in morphology, genome and gene expression compared with corresponding diploid.

  11. R-loops: targets for nuclease cleavage and repeat instability.

    Science.gov (United States)

    Freudenreich, Catherine H

    2018-01-11

    R-loops form when transcribed RNA remains bound to its DNA template to form a stable RNA:DNA hybrid. Stable R-loops form when the RNA is purine-rich, and are further stabilized by DNA secondary structures on the non-template strand. Interestingly, many expandable and disease-causing repeat sequences form stable R-loops, and R-loops can contribute to repeat instability. Repeat expansions are responsible for multiple neurodegenerative diseases, including Huntington's disease, myotonic dystrophy, and several types of ataxias. Recently, it was found that R-loops at an expanded CAG/CTG repeat tract cause DNA breaks as well as repeat instability (Su and Freudenreich, Proc Natl Acad Sci USA 114, E8392-E8401, 2017). Two factors were identified as causing R-loop-dependent breaks at CAG/CTG tracts: deamination of cytosines and the MutLγ (Mlh1-Mlh3) endonuclease, defining two new mechanisms for how R-loops can generate DNA breaks (Su and Freudenreich, Proc Natl Acad Sci USA 114, E8392-E8401, 2017). Following R-loop-dependent nicking, base excision repair resulted in repeat instability. These results have implications for human repeat expansion diseases and provide a paradigm for how RNA:DNA hybrids can cause genome instability at structure-forming DNA sequences. This perspective summarizes mechanisms of R-loop-induced fragility at G-rich repeats and new links between DNA breaks and repeat instability.

  12. Simulation study of electron cloud induced instabilities and emittance growth for the CERN Large Hadron Collider proton beam

    CERN Document Server

    Benedetto, Elena; Schulte, Daniel; Rumolo, Giovanni

    2005-01-01

    The electron cloud may cause transverse single-bunch instabilities of proton beams such as those in the Large Hadron Collider (LHC) and the CERN Super Proton Synchrotron (SPS). We simulate these instabilities and the consequent emittance growth with the code HEADTAIL, which models the turn-by-turn interaction between the cloud and the beam. Recently some new features were added to the code, in particular, electric conducting boundary conditions at the chamber wall, transverse feedback, and variable beta functions. The sensitivity to several numerical parameters has been studied by varying the number of interaction points between the bunch and the cloud, the phase advance between them, and the number of macroparticles used to represent the protons and the electrons. We present simulation results for both LHC at injection and SPS with LHC-type beam, for different electron-cloud density levels, chromaticities, and bunch intensities. Two regimes with qualitatively different emittance growth are observed: above th...

  13. Human Metapneumovirus Induces Formation of Inclusion Bodies for Efficient Genome Replication and Transcription.

    Science.gov (United States)

    Cifuentes-Muñoz, Nicolás; Branttie, Jean; Slaughter, Kerri Beth; Dutch, Rebecca Ellis

    2017-12-15

    induce the formation of large cytoplasmic granules, named inclusion bodies, for genome replication and transcription. Unlike other cytoplasmic structures, such as stress granules and processing bodies, inclusion bodies are exclusively present in infected cells and contain HMPV RNA and proteins to more efficiently transcribe and replicate the viral genome. Though inclusion body formation is nuanced, it corresponds to a more generalized strategy used by different viruses, including filoviruses and rhabdoviruses, for genome transcription and replication. Thus, an understanding of inclusion body formation is crucial for the discovery of innovative therapeutic targets. Copyright © 2017 American Society for Microbiology.

  14. Experimental study of linear and nonlinear regimes of density-driven instabilities induced by CO2 dissolution in water

    International Nuclear Information System (INIS)

    Outeda, R.; D'Onofrio, A.; El Hasi, C.; Zalts, A.

    2014-01-01

    Density driven instabilities produced by CO 2 (gas) dissolution in water containing a color indicator were studied in a Hele Shaw cell. The images were analyzed and instability patterns were characterized by mixing zone temporal evolution, dispersion curves, and the growth rate for different CO 2 pressures and different color indicator concentrations. The results obtained from an exhaustive analysis of experimental data show that this system has a different behaviour in the linear regime of the instabilities (when the growth rate has a linear dependence with time), from the nonlinear regime at longer times. At short times using a color indicator to see the evolution of the pattern, the images show that the effects of both the color indicator and CO 2 pressure are of the same order of magnitude: The growth rates are similar and the wave numbers are in the same range (0–30 cm −1 ) when the system is unstable. Although in the linear regime the dynamics is affected similarly by the presence of the indicator and CO 2 pressure, in the nonlinear regime, the influence of the latter is clearly more pronounced than the effects of the color indicator

  15. A plant-based chemical genomics screen for the identification of flowering inducers.

    Science.gov (United States)

    Fiers, Martijn; Hoogenboom, Jorin; Brunazzi, Alice; Wennekes, Tom; Angenent, Gerco C; Immink, Richard G H

    2017-01-01

    Floral timing is a carefully regulated process, in which the plant determines the optimal moment to switch from the vegetative to reproductive phase. While there are numerous genes known that control flowering time, little information is available on chemical compounds that are able to influence this process. We aimed to discover novel compounds that are able to induce flowering in the model plant Arabidopsis. For this purpose we developed a plant-based screening platform that can be used in a chemical genomics study. Here we describe the set-up of the screening platform and various issues and pitfalls that need to be addressed in order to perform a chemical genomics screening on Arabidopsis plantlets. We describe the choice for a molecular marker, in combination with a sensitive reporter that's active in plants and is sufficiently sensitive for detection. In this particular screen, the firefly Luciferase marker was used, fused to the regulatory sequences of the floral meristem identity gene APETALA1 (AP1) , which is an early marker for flowering. Using this screening platform almost 9000 compounds were screened, in triplicate, in 96-well plates at a concentration of 25 µM. One of the identified potential flowering inducing compounds was studied in more detail and named Flowering1 (F1). F1 turned out to be an analogue of the plant hormone Salicylic acid (SA) and appeared to be more potent than SA in the induction of flowering. The effect could be confirmed by watering Arabidopsis plants with SA or F1, in which F1 gave a significant reduction in time to flowering in comparison to SA treatment or the control. In this study a chemical genomics screening platform was developed to discover compounds that can induce flowering in Arabidopsis. This platform was used successfully, to identify a compound that can speed-up flowering in Arabidopsis.

  16. Drain Current Stress-Induced Instability in Amorphous InGaZnO Thin-Film Transistors with Different Active Layer Thicknesses

    Directory of Open Access Journals (Sweden)

    Dapeng Wang

    2018-04-01

    Full Text Available In this study, the initial electrical properties, positive gate bias stress (PBS, and drain current stress (DCS-induced instabilities of amorphous indium gallium zinc oxide (a-IGZO thin-film transistors (TFTs with various active layer thicknesses (TIGZO are investigated. As the TIGZO increased, the turn-on voltage (Von decreased, while the subthreshold swing slightly increased. Furthermore, the mobility of over 13 cm2·V−1·s−1 and the negligible hysteresis of ~0.5 V are obtained in all of the a-IGZO TFTs, regardless of the TIGZO. The PBS results exhibit that the Von shift is aggravated as the TIGZO decreases. In addition, the DCS-induced instability in the a-IGZO TFTs with various TIGZO values is revealed using current–voltage and capacitance–voltage (C–V measurements. An anomalous hump phenomenon is only observed in the off state of the gate-to-source (Cgs curve for all of the a-IGZO TFTs. This is due to the impact ionization that occurs near the drain side of the channel and the generated holes that flow towards the source side along the back-channel interface under the lateral electric field, which cause a lowered potential barrier near the source side. As the TIGZO value increased, the hump in the off state of the Cgs curve was gradually weakened.

  17. Drain Current Stress-Induced Instability in Amorphous InGaZnO Thin-Film Transistors with Different Active Layer Thicknesses.

    Science.gov (United States)

    Wang, Dapeng; Zhao, Wenjing; Li, Hua; Furuta, Mamoru

    2018-04-05

    In this study, the initial electrical properties, positive gate bias stress (PBS), and drain current stress (DCS)-induced instabilities of amorphous indium gallium zinc oxide (a-IGZO) thin-film transistors (TFTs) with various active layer thicknesses ( T IGZO ) are investigated. As the T IGZO increased, the turn-on voltage ( V on ) decreased, while the subthreshold swing slightly increased. Furthermore, the mobility of over 13 cm²·V −1 ·s −1 and the negligible hysteresis of ~0.5 V are obtained in all of the a-IGZO TFTs, regardless of the T IGZO . The PBS results exhibit that the V on shift is aggravated as the T IGZO decreases. In addition, the DCS-induced instability in the a-IGZO TFTs with various T IGZO values is revealed using current–voltage and capacitance–voltage ( C – V ) measurements. An anomalous hump phenomenon is only observed in the off state of the gate-to-source ( C gs ) curve for all of the a-IGZO TFTs. This is due to the impact ionization that occurs near the drain side of the channel and the generated holes that flow towards the source side along the back-channel interface under the lateral electric field, which cause a lowered potential barrier near the source side. As the T IGZO value increased, the hump in the off state of the C gs curve was gradually weakened.

  18. Genome Architecture and Its Roles in Human Copy Number Variation

    Directory of Open Access Journals (Sweden)

    Lu Chen

    2014-12-01

    Full Text Available Besides single-nucleotide variants in the human genome, large-scale genomic variants, such as copy number variations (CNVs, are being increasingly discovered as a genetic source of human diversity and the pathogenic factors of diseases. Recent experimental findings have shed light on the links between different genome architectures and CNV mutagenesis. In this review, we summarize various genomic features and discuss their contributions to CNV formation. Genomic repeats, including both low-copy and high-copy repeats, play important roles in CNV instability, which was initially known as DNA recombination events. Furthermore, it has been found that human genomic repeats can also induce DNA replication errors and consequently result in CNV mutations. Some recent studies showed that DNA replication timing, which reflects the high-order information of genomic organization, is involved in human CNV mutations. Our review highlights that genome architecture, from DNA sequence to high-order genomic organization, is an important molecular factor in CNV mutagenesis and human genomic instability.

  19. Instability and noise-induced thermalization of Fermi–Pasta–Ulam recurrence in the nonlinear Schrödinger equation

    International Nuclear Information System (INIS)

    Wabnitz, Stefan; Wetzel, Benjamin

    2014-01-01

    We investigate the spontaneous growth of noise that accompanies the nonlinear evolution of seeded modulation instability into Fermi–Pasta–Ulam recurrence. Results from the Floquet linear stability analysis of periodic solutions of the three-wave truncation are compared with full numerical solutions of the nonlinear Schrödinger equation. The predicted initial stage of noise growth is in a good agreement with simulations, and is expected to provide further insight into the subsequent dynamics of the field evolution after recurrence breakup

  20. Instability and noise-induced thermalization of Fermi–Pasta–Ulam recurrence in the nonlinear Schrödinger equation

    Energy Technology Data Exchange (ETDEWEB)

    Wabnitz, Stefan, E-mail: stefan.wabnitz@unibs.it [Dipartimento di Ingegneria dell' Informazione, Università degli Studi di Brescia, via Branze 38, 25123 Brescia (Italy); Wetzel, Benjamin [INRS-EMT, 1650 Blvd. Lionel-Boulet, Varennes, Québec J3X 1S2 (Canada)

    2014-07-25

    We investigate the spontaneous growth of noise that accompanies the nonlinear evolution of seeded modulation instability into Fermi–Pasta–Ulam recurrence. Results from the Floquet linear stability analysis of periodic solutions of the three-wave truncation are compared with full numerical solutions of the nonlinear Schrödinger equation. The predicted initial stage of noise growth is in a good agreement with simulations, and is expected to provide further insight into the subsequent dynamics of the field evolution after recurrence breakup.

  1. Development of radiation-induced mutation techniques and functional genomics studies

    International Nuclear Information System (INIS)

    Kim, Dong Sub; Kang, Si Yong; Kim, Jin Baek

    2012-01-01

    This project has been performed to develop plant genetic resources using radiation (gamma-rays, ion-beam, space environments), to conduct functional genomics studies with mutant resources, and to develop new radiation plant breeding techniques using various radiation sources during 3 years. In the first section, we developed flower genetic resources, functional crop resources, and bio-industrial plant resources. In the second section, we cloned several mutated genes and studied mechanisms of gene expression and genetic diversity of mutations induced by gamma-rays. In the third section, we developed new plant breeding techniques using gamma-phytotron, heavy ion-beam, and space environments. Based on these results, a total of 8 cultivars containing Chrysanthemum, Hibiscus, kenaf, rice, and soybean were applied for plant variety protection (PVP) and a total of 4 cultivars were registered for PVP. Also, license agreement for the dwarf type Hibiscus mutant 'Ggoma' was conducted with Supro co. and the manufacturing technology for natural antioxidant pear-grape vinegar was transferred into Enzenic co. Also, 8 gene sequences, such as F3'H and LDOX genes associated with flower color in Chrysanthemum and EPSPS gene from Korean lawn grass, were registered in the database of National Center for Biotechnology Information (NCBI). In the future study, we will develop new radiation mutation breeding techniques through the mutation spectrum induced by various radiation sources, the studies for mechanism of the cellular response to radiation, and the comparative·structural·functional genomics studies for useful traits

  2. Detection of induced male germline mutation: Correlations and comparisons between traditional germline mutation assays, transgenic rodent assays and expanded simple tandem repeat instability assays

    Energy Technology Data Exchange (ETDEWEB)

    Singer, Timothy M. [Mutagenesis Section, Environmental and Occupational Toxicology Division, Safe Environments Programme, 0803A, Health Canada, Ottawa, Ont., K1A 0K9 (Canada); Department of Biology, Carleton University, 1125 Colonel By Drive, Ottawa, Ont., K1S 5B6 (Canada); Lambert, Iain B. [Department of Biology, Carleton University, 1125 Colonel By Drive, Ottawa, Ont., K1S 5B6 (Canada); Williams, Andrew [Biostatistics and Epidemiology Division, Safe Environments Programme, 6604B, Health Canada, Ottawa, Ont., K1A 0K9 (Canada); Douglas, George R. [Mutagenesis Section, Environmental and Occupational Toxicology Division, Safe Environments Programme, 0803A, Health Canada, Ottawa, Ont., K1A 0K9 (Canada); Yauk, Carole L. [Mutagenesis Section, Environmental and Occupational Toxicology Division, Safe Environments Programme, 0803A, Health Canada, Ottawa, Ont., K1A 0K9 (Canada)]. E-mail: carole_yauk@hc-sc.gc.ca

    2006-06-25

    Several rodent assays are capable of monitoring germline mutation. These include traditional assays, such as the dominant lethal (DL) assay, the morphological specific locus (SL) test and the heritable translocation (HT) assay, and two assays that have been developed more recently-the expanded simple tandem repeat (ESTR) and transgenic rodent (TGR) mutation assays. In this paper, we have compiled the limited amount of experimental data that are currently available to make conclusions regarding the comparative ability of the more recently developed assays to detect germline mutations induced by chemical and radiological agents. The data suggest that ESTR and TGR assays are generally comparable with SL in detecting germline mutagenicity induced by alkylating agents and radiation, though TGR offered less sensitivity than ESTR in some cases. The DL and HT assays detect clastogenic events and are most susceptible to mutations arising in post-spermatogonial cells, and they may not provide the best comparisons with TGR and ESTR instability. The measurement of induced ESTR instability represents a relatively sensitive method of identifying agents causing germline mutation in rodents, and may also be useful for bio-monitoring exposed individuals in the human population. Any future use of the TGR and ESTR germline mutation assays in a regulatory testing context will entail more robust and extensive characterization of assay performance. This will require substantially more data, including experiments measuring multiple endpoints, a greatly expanded database of chemical agents and a focus on characterizing stage-specific activity of mutagens in these assays, preferably by sampling epididymal sperm exposed at defined pre-meiotic, meiotic and post-meiotic stages of development.

  3. Detection of induced male germline mutation: Correlations and comparisons between traditional germline mutation assays, transgenic rodent assays and expanded simple tandem repeat instability assays

    International Nuclear Information System (INIS)

    Singer, Timothy M.; Lambert, Iain B.; Williams, Andrew; Douglas, George R.; Yauk, Carole L.

    2006-01-01

    Several rodent assays are capable of monitoring germline mutation. These include traditional assays, such as the dominant lethal (DL) assay, the morphological specific locus (SL) test and the heritable translocation (HT) assay, and two assays that have been developed more recently-the expanded simple tandem repeat (ESTR) and transgenic rodent (TGR) mutation assays. In this paper, we have compiled the limited amount of experimental data that are currently available to make conclusions regarding the comparative ability of the more recently developed assays to detect germline mutations induced by chemical and radiological agents. The data suggest that ESTR and TGR assays are generally comparable with SL in detecting germline mutagenicity induced by alkylating agents and radiation, though TGR offered less sensitivity than ESTR in some cases. The DL and HT assays detect clastogenic events and are most susceptible to mutations arising in post-spermatogonial cells, and they may not provide the best comparisons with TGR and ESTR instability. The measurement of induced ESTR instability represents a relatively sensitive method of identifying agents causing germline mutation in rodents, and may also be useful for bio-monitoring exposed individuals in the human population. Any future use of the TGR and ESTR germline mutation assays in a regulatory testing context will entail more robust and extensive characterization of assay performance. This will require substantially more data, including experiments measuring multiple endpoints, a greatly expanded database of chemical agents and a focus on characterizing stage-specific activity of mutagens in these assays, preferably by sampling epididymal sperm exposed at defined pre-meiotic, meiotic and post-meiotic stages of development

  4. Chromosomal instability in mouse embryonic fibroblasts null for the transcriptional co-repressor Ski

    OpenAIRE

    Marcelain, Katherine; Armisen, Ricardo; Aguirre, Adam; Ueki, Nobuhide; Toro, Jessica; Colmenares, Clemencia; Hayman, Michael J

    2012-01-01

    Ski is a transcriptional regulator that has been considered an oncoprotein, given its ability to induce oncogenic transformation in avian model systems. However, studies in mouse and in some human tumor cells have also indicated a tumor suppressor activity for this protein. We found that Ski−/− mouse embryo fibroblasts exhibit high levels of genome instability, namely aneuploidy, consistent with a tumor suppressor function for Ski. Time-lapse microscopy revealed lagging chromosomes and chroma...

  5. Modeling of flashing-induced instabilities in the start-up phase of natural-circulation BWRs using the two-phase flow code FLOCAL

    Energy Technology Data Exchange (ETDEWEB)

    Manera, A. [Forschungszentrum Rossendorf e.V. (FZR), Institute of Safety Research, P.O.B. 510119, D-01324 Dresden (Germany) and Interfaculty Reactor Institute, Delft University of Technology, Mekelweg 15, 2629 JB Delft (Netherlands)]. E-mail: a.manera@fz-rossendorf.de; Rohde, U. [Forschungszentrum Rossendorf e.V. (FZR), Institute of Safety Research, P.O.B. 510119, D-01324 Dresden (Germany); Prasser, H.-M. [Forschungszentrum Rossendorf e.V. (FZR), Institute of Safety Research, P.O.B. 510119, D-01324 Dresden (Germany); Hagen, T.H.J.J. van der [Interfaculty Reactor Institute, Delft University of Technology, Mekelweg 15, 2629 JB Delft (Netherlands)

    2005-06-01

    This paper reports on the modeling and simulation of flashing-induced instabilities in natural-circulation systems, with special emphasis on natural-circulation boiling water reactors (BWRs). For the modeling the 4-equation two-phase model FLOCAL [Rohde, U., 1986. Ein teoretisches Modell fur Zweiphasen-stromungen in wassergekulthen Kernreaktoren und seine Anwendung zur Analyse des Naturumlaufs im Heizreaktor AST-500. Ph.D. dissertation, Akademie der Wissenschaften der DDR, Dresden], developed at the Forschungszentrum Rossendorf (FZR, Germany), has been used. The model allows for the liquid and vapor to be in thermal non-equilibrium and, via drift-flux models, to have different velocities. The phenomenology of the instability has been studied and the dominating physical effects have been determined. The results of the simulations have been compared qualitatively and quantitatively with experiments [Manera, A., van der Hagen, T.H.J.J., 2003. Stability of natural-circulation-cooled boiling water reactor during start up: experimental results. Nuc. Technol., 143] that have been carried out within the framework of a European project (NACUSP) on the CIRCUS facility. The facility, built at the Delft University of Technology in The Netherlands, is a water/steam 1:1 height-scaled loop of a typical natural-circulation-cooled BWR.

  6. Src Kinase Dependent Rapid Non-genomic Modulation of Hippocampal Spinogenesis Induced by Androgen and Estrogen

    Directory of Open Access Journals (Sweden)

    Mika Soma

    2018-05-01

    Full Text Available Dendritic spine is a small membranous protrusion from a neuron's dendrite that typically receives input from an axon terminal at the synapse. Memories are stored in synapses which consist of spines and presynapses. Rapid modulations of dendritic spines induced by hippocampal sex steroids, including dihydrotestosterone (DHT, testosterone (T, and estradiol (E2, are essential for synaptic plasticity. Molecular mechanisms underlying the rapid non-genomic modulation through synaptic receptors of androgen (AR and estrogen (ER as well as its downstream kinase signaling, however, have not been well understood. We investigated the possible involvement of Src tyrosine kinase in rapid changes of dendritic spines in response to androgen and estrogen, including DHT, T, and E2, using hippocampal slices from adult male rats. We found that the treatments with DHT (10 nM, T (10 nM, and E2 (1 nM increased the total density of spines by ~1.22 to 1.26-fold within 2 h using super resolution confocal imaging of Lucifer Yellow-injected CA1 pyramidal neurons. We examined also morphological changes of spines in order to clarify differences between three sex steroids. From spine head diameter analysis, DHT increased middle- and large-head spines, whereas T increased small- and middle-head spines, and E2 increased small-head spines. Upon application of Src tyrosine kinase inhibitor, the spine increases induced through DHT, T, and E2 treatments were completely blocked. These results imply that Src kinase is essentially involved in sex steroid-induced non-genomic modulation of the spine density and morphology. These results also suggest that rapid effects of exogenously applied androgen and estrogen can occur in steroid-depleted conditions, including “acute” hippocampal slices and the hippocampus of gonadectomized animals.

  7. Role of ZrO2 incorporation in the suppression of negative bias illumination-induced instability in Zn-Sn-O thin film transistors

    International Nuclear Information System (INIS)

    Yang, Bong Seob; Oh, Seungha; Lee, Ung Soo; Kim, Yoon Jang; Oh, Myeong Sook; Hwang, Cheol Seong; Kim, Hyeong Joon; Huh, Myung Soo; Jeong, Jae Kyeong

    2011-01-01

    Thin film transistors (TFTs) with In and Ga-free multicomponent Zn-Sn-Zr-O (ZTZO) channel layers were fabricated using the cosputtering approach. The incorporation of ZrO 2 into the Zn-Sn-O (ZTO) films increased the contact resistance, which led to the degradation of the transport properties. In contrast, the threshold voltage shift under negative bias illumination stress (NBIS) was largely improved from -12.5 V (ZTO device) to -4.2 V (ZTZO device). This improvement was attributed to the reduction in the oxygen vacancy defects in the ZTZO film, suggesting that the photoinduced transition from V O to V O 2+ was responsible for the NBIS-induced instability.

  8. Hydrogen peroxide induced loss of heterozygosity correlates with replicative lifespan and mitotic asymmetry in Saccharomyces cerevisiae

    Science.gov (United States)

    Jackson, Erin D.; Parker, Meighan C.; Gupta, Nilin; Rodrigues, Jenny

    2016-01-01

    Cellular aging in Saccharomyces cerevisiae can lead to genomic instability and impaired mitotic asymmetry. To investigate the role of oxidative stress in cellular aging, we examined the effect of exogenous hydrogen peroxide on genomic instability and mitotic asymmetry in a collection of yeast strains with diverse backgrounds. We treated yeast cells with hydrogen peroxide and monitored the changes of viability and the frequencies of loss of heterozygosity (LOH) in response to hydrogen peroxide doses. The mid-transition points of viability and LOH were quantified using sigmoid mathematical functions. We found that the increase of hydrogen peroxide dependent genomic instability often occurs before a drop in viability. We previously observed that elevation of genomic instability generally lags behind the drop in viability during chronological aging. Hence, onset of genomic instability induced by exogenous hydrogen peroxide treatment is opposite to that induced by endogenous oxidative stress during chronological aging, with regards to the midpoint of viability. This contrast argues that the effect of endogenous oxidative stress on genome integrity is well suppressed up to the dying-off phase during chronological aging. We found that the leadoff of exogenous hydrogen peroxide induced genomic instability to viability significantly correlated with replicative lifespan (RLS), indicating that yeast cells’ ability to counter oxidative stress contributes to their replicative longevity. Surprisingly, this leadoff is positively correlated with an inverse measure of endogenous mitotic asymmetry, indicating a trade-off between mitotic asymmetry and cell’s ability to fend off hydrogen peroxide induced oxidative stress. Overall, our results demonstrate strong associations of oxidative stress to genomic instability and mitotic asymmetry at the population level of budding yeast. PMID:27833823

  9. Genome-wide pharmacogenomic study of citalopram-induced side effects in STAR*D.

    Science.gov (United States)

    Adkins, D E; Clark, S L; Åberg, K; Hettema, J M; Bukszár, J; McClay, J L; Souza, R P; van den Oord, E J C G

    2012-07-03

    Affecting about 1 in 12 Americans annually, depression is a leading cause of the global disease burden. While a range of effective antidepressants are now available, failure and relapse rates remain substantial, with intolerable side effect burden the most commonly cited reason for discontinuation. Thus, understanding individual differences in susceptibility to antidepressant therapy side effects will be essential to optimize depression treatment. Here we perform genome-wide association studies (GWAS) to identify genetic variation influencing susceptibility to citalopram-induced side effects. The analysis sample consisted of 1762 depression patients, successfully genotyped for 421K single-nucleotide polymorphisms (SNPs), from the Sequenced Treatment Alternatives to Relieve Depression (STAR(*)D) study. Outcomes included five indicators of citalopram side effects: general side effect burden, overall tolerability, sexual side effects, dizziness and vision/hearing side effects. Two SNPs met our genome-wide significance criterion (qeffects of citalopram on vision/hearing side effects (P=3.27 × 10(-8), q=0.026). The second genome-wide significant finding, representing a haplotype spanning ∼30 kb and eight genotyped SNPs in a gene desert on chromosome 13, was associated with general side effect burden (P=3.22 × 10(-7), q=0.096). Suggestive findings were also found for SNPs at LAMA1, AOX2P, EGFLAM, FHIT and RTP2. Although our findings require replication and functional validation, this study demonstrates the potential of GWAS to discover genes and pathways that potentially mediate adverse effects of antidepressant medications.

  10. Genomic and proteomic analysis of soybean heritable variations induced by space flight

    Institute of Scientific and Technical Information of China (English)

    HE Jie; GAO Yong; SUN Ye-qing

    2009-01-01

    To analyze the biological effects of space environment, the diversity of genomic DNA between the space flight soybean 194(4126) with phenotype of good yield and good fruit quality induced by space flight and the soybean with ground control was studied by amplified fragment length polymorphism (AFLP) method, and the polymorphism of space flight soybean 194(4126) was 3.56%. The differences of protein expression of seeds and leaves between the two kinds of soybeans were analysed by two-dimensional electrophoresis, PDQuest software and MALDI-TOF mass spectrometry. Results show that the loss and decrease of protein expression in 194(4126) soybean are subjected to the space fight of seeds, and three special proteins including Dehydrin, MAT1 and ceQORH are identified. It is concluded that the space environment changes the phenotype and geno-type of soybeans due to the space flight of seeds.

  11. Combining Induced Pluripotent Stem Cells and Genome Editing Technologies for Clinical Applications.

    Science.gov (United States)

    Chang, Chia-Yu; Ting, Hsiao-Chien; Su, Hong-Lin; Jeng, Jing-Ren

    2018-01-01

    In this review, we introduce current developments in induced pluripotent stem cells (iPSCs), site-specific nuclease (SSN)-mediated genome editing tools, and the combined application of these two novel technologies in biomedical research and therapeutic trials. The sustainable pluripotent property of iPSCs in vitro not only provides unlimited cell sources for basic research but also benefits precision medicines for human diseases. In addition, rapidly evolving SSN tools efficiently tailor genetic manipulations for exploring gene functions and can be utilized to correct genetic defects of congenital diseases in the near future. Combining iPSC and SSN technologies will create new reliable human disease models with isogenic backgrounds in vitro and provide new solutions for cell replacement and precise therapies.

  12. Development of radiation-induced mutation techniques and functional genomics studies

    Energy Technology Data Exchange (ETDEWEB)

    Kim, Dong Sub; Kang, Si Yong; Kim, Jin Baek [KAERI, Daejeon (Korea, Republic of); and others

    2012-01-15

    This project has been performed to develop plant genetic resources using radiation (gamma-rays, ion-beam, space environments), to conduct functional genomics studies with mutant resources, and to develop new radiation plant breeding techniques using various radiation sources during 3 years. In the first section, we developed flower genetic resources, functional crop resources, and bio-industrial plant resources. In the second section, we cloned several mutated genes and studied mechanisms of gene expression and genetic diversity of mutations induced by gamma-rays. In the third section, we developed new plant breeding techniques using gamma-phytotron, heavy ion-beam, and space environments. Based on these results, a total of 8 cultivars containing Chrysanthemum, Hibiscus, kenaf, rice, and soybean were applied for plant variety protection (PVP) and a total of 4 cultivars were registered for PVP. Also, license agreement for the dwarf type Hibiscus mutant 'Ggoma' was conducted with Supro co. and the manufacturing technology for natural antioxidant pear-grape vinegar was transferred into Enzenic co. Also, 8 gene sequences, such as F3'H and LDOX genes associated with flower color in Chrysanthemum and EPSPS gene from Korean lawn grass, were registered in the database of National Center for Biotechnology Information (NCBI). In the future study, we will develop new radiation mutation breeding techniques through the mutation spectrum induced by various radiation sources, the studies for mechanism of the cellular response to radiation, and the comparative{center_dot}structural{center_dot}functional genomics studies for useful traits.

  13. A subset of herpes simplex virus replication genes induces DNA amplification within the host cell genome

    Energy Technology Data Exchange (ETDEWEB)

    Heilbronn, R.; zur Hausen, H. (Deutsches Krebsforschungszentrum, Heidelberg (West Germany))

    1989-09-01

    Herpes simplex virus (HSV) induces DNA amplification of target genes within the host cell chromosome. To characterize the HSV genes that mediate the amplification effect, combinations of cloned DNA fragments covering the entire HSV genome were transiently transfected into simian virus 40 (SV40)-transformed hamster cells. This led to amplification of the integrated SV40 DNA sequences to a degree comparable to that observed after transfection of intact virion DNA. Transfection of combinations of subclones and of human cytomegalovirus immediate-early promoter-driven expression constructs for individual open reading frames led to the identification of sic HSV genes which together were necessary and sufficient for the induction of DNA amplification: UL30 (DNA polymerase), UL29 (major DNA-binding protein), UL5, UL8, UL42, and UL52. All of these genes encode proteins necessary for HSV DNA replication. However, an additional gene coding for an HSV origin-binding protein (UL9) was required for origin-dependent HSV DNA replication but was dispensable for SV40 DNA amplification. The results show that a subset of HSV replication genes is sufficient for the induction of DNA amplification. This opens the possibility that HSV expresses functions sufficient for DNA amplification but separate from those responsible for lytic viral growth. HSV infection may thereby induce DNA amplification within the host cell genome without killing the host by lytic viral growth. This may lead to persistence of a cell with a new genetic phenotype, which would have implications for the pathogenicity of the virus in vivo.

  14. Non-genomic actions of retinoic acid induce pi3k signaling pathway and phosphorylation of nuclear proteins

    OpenAIRE

    Laserna Mendieta, Emilio J.; Masiá, Susana; Barettino, Domingo

    2007-01-01

    Retinoic acid (RA), the active form of vitamin A, induces neuroblastoma cells SH-SY5Y to differentiate. In addition to its classical transcriptional actions regulating the expression of specific genes, RA acts in an extra-genomic way, modulating the activity of relevant signalling cascades. In particular, RA treatment of SH-SY5Y neuroblastoma cells results in activation of phosphatidyl-inositol-3-kinase (PI3K) signaling pathway, and this activation is required for RA-induced differentiation (...

  15. Deoxyinosine triphosphate induces MLH1/PMS2- and p53-dependent cell growth arrest and DNA instability in mammalian cells

    Science.gov (United States)

    Yoneshima, Yasuto; Abolhassani, Nona; Iyama, Teruaki; Sakumi, Kunihiko; Shiomi, Naoko; Mori, Masahiko; Shiomi, Tadahiro; Noda, Tetsuo; Tsuchimoto, Daisuke; Nakabeppu, Yusaku

    2016-01-01

    Deoxyinosine (dI) occurs in DNA either by oxidative deamination of a previously incorporated deoxyadenosine residue or by misincorporation of deoxyinosine triphosphate (dITP) from the nucleotide pool during replication. To exclude dITP from the pool, mammals possess specific hydrolysing enzymes, such as inosine triphosphatase (ITPA). Previous studies have shown that deficiency in ITPA results in cell growth suppression and DNA instability. To explore the mechanisms of these phenotypes, we analysed ITPA-deficient human and mouse cells. We found that both growth suppression and accumulation of single-strand breaks in nuclear DNA of ITPA-deficient cells depended on MLH1/PMS2. The cell growth suppression of ITPA-deficient cells also depended on p53, but not on MPG, ENDOV or MSH2. ITPA deficiency significantly increased the levels of p53 protein and p21 mRNA/protein, a well-known target of p53, in an MLH1-dependent manner. Furthermore, MLH1 may also contribute to cell growth arrest by increasing the basal level of p53 activity. PMID:27618981

  16. Investigation of the gate-bias induced instability for InGaZnO TFTs under dark and light illumination

    International Nuclear Information System (INIS)

    Chen, T.C.; Chang, T.C.; Hsieh, T.Y.; Tsai, C.T.; Chen, S.C.; Lin, C.S.; Jian, F.Y.; Tsai, M.Y.

    2011-01-01

    Mechanism of the instability for indium–gallium–zinc oxide thin film transistors caused by gate-bias stress performed in the dark and light illumination was investigated in this paper. The parallel V t shift with no degradation of subthreshold swing (S.S) and the fine fitting to the stretched-exponential equation indicate that charge trapping model dominates the degradation behavior under positive gate-bias stress. In addition, the significant gate-bias dependence of V t shift demonstrates that electron trapping effect easily occurs under large gate-bias since the average effective energy barrier of electron injection decreases with increasing gate bias. Moreover, the noticeable decrease of threshold voltage (V t ) shift under illuminated positive gate-bias stress and the accelerated recovery rate in the light indicate that the charge detrapping mechanism occurs under light illumination. Finally, the apparent negative V t shift under illuminated negative gate-bias stress was investigated in this paper. The average effectively energy barrier of electron and hole injection were extracted to clarify that the serious V t degradation behavior comparing with positive gate-bias stress was attributed to the lower energy barrier for hole injection.

  17. Electric-field induced surface instabilities of soft dielectrics and their effects on optical transmittance and scattering

    Science.gov (United States)

    Shian, Samuel; Kjeer, Peter; Clarke, David R.

    2018-03-01

    When a voltage is applied to a percolative, mechanically compliant mat of carbon nanotubes (CNTs) on a smooth elastomer bilayer attached to an ITO coated glass substrate, the in-line optical transmittance decreases with increasing voltage. Two regimes of behavior have been identified based on optical scattering, bright field optical microscopy, and confocal optical microscopy. In the low field regime, the electric field produces a spatially inhomogeneous surface deformation of the elastomer that causes local variations in optical refraction and modulates the light transmittance. The spatial variation is associated with the distribution of the CNTs over the surface. At higher fields, above a threshold voltage, an array of pits in the surface form by a nucleation and growth mechanism and these also scatter light. The formation of pits, and creases, in the thickness of the elastomer, is due to a previously identified electro-mechanical surface instability. When the applied voltage is decreased from its maximum, the transmittance returns to its original value although there is a transmittance hysteresis and a complicated time response. When the applied voltage exceeds the threshold voltage, there can be remnant optical contrast associated with creasing of the elastomer and the recovery time appears to be dependent on local jamming of CNTs in areas where the pits formed. A potential application of this work as an electrically tunable privacy window or camouflaging devices is demonstrated.

  18. Edge instabilities of topological superconductors

    Energy Technology Data Exchange (ETDEWEB)

    Hofmann, Johannes S. [Institut fuer Theoretische Physik und Astrophysik, Universitaet Wuerzburg (Germany); Max-Planck-Institut fuer Festkoerperforschung, Stuttgart (Germany); Assaad, Fakher F. [Institut fuer Theoretische Physik und Astrophysik, Universitaet Wuerzburg (Germany); Schnyder, Andreas P. [Max-Planck-Institut fuer Festkoerperforschung, Stuttgart (Germany)

    2016-07-01

    Nodal topological superconductors display zero-energy Majorana flat bands at generic edges. The flatness of these edge bands, which is protected by time-reversal and translation symmetry, gives rise to an extensive ground state degeneracy and a diverging density of states. Therefore, even arbitrarily weak interactions lead to an instability of the flat-band edge states towards time-reversal and translation-symmetry broken phases, which lift the ground-state degeneracy. Here, we employ Monte Carlo simulations combined with mean-field considerations to examine the instabilities of the flat-band edge states of d{sub xy}-wave superconductors. We find that attractive interactions induce a complex s-wave pairing instability together with a density wave instability. Repulsive interactions, on the other hand, lead to ferromagnetism mixed with spin-triplet pairing at the edge. We discuss the implications of our findings for experiments on cuprate high-temperature superconductors.

  19. The effects of in utero irradiation on mutation induction and transgenerational instability in mice

    International Nuclear Information System (INIS)

    Barber, Ruth C.; Hardwick, Robert J.; Shanks, Morag E.; Glen, Colin D.; Mughal, Safeer K.; Voutounou, Mariel; Dubrova, Yuri E.

    2009-01-01

    Epidemiological evidence suggests that the deleterious effects of prenatal irradiation can manifest during childhood, resulting in an increased risk of leukaemia and solid cancers after birth. However, the mechanisms underlying the long-term effects of foetal irradiation remain poorly understood. This study was designed to analyse the impact of in utero irradiation on mutation rates at expanded simple tandem repeat (ESTR) DNA loci in directly exposed mice and their first-generation (F 1 ) offspring. ESTR mutation frequencies in the germline and somatic tissues of male and female mice irradiated at 12 days of gestation remained highly elevated during adulthood, which was mainly attributed to a significant increase in the frequency of singleton mutations. The prevalence of singleton mutations in directly exposed mice suggests that foetal irradiation results in genomic instability manifested both in utero and during adulthood. The frequency of ESTR mutation in the F 1 offspring of prenatally irradiated male mice was equally elevated across all tissues, which suggests that foetal exposure results in transgenerational genomic instability. In contrast, maternal in utero exposure did not affect the F 1 stability. Our data imply that the passive erasure of epigenetic marks in the maternal genome can diminish the transgenerational effects of foetal irradiation and therefore provide important clues to the still unknown mechanisms of radiation-induced genomic instability. The results of this study offer a plausible explanation for the effects of in utero irradiation on the risk of leukaemia and solid cancers after birth.

  20. Mismatch repair genes Mlh1 and Mlh3 modify CAG instability in Huntington's disease mice: genome-wide and candidate approaches.

    Science.gov (United States)

    Pinto, Ricardo Mouro; Dragileva, Ella; Kirby, Andrew; Lloret, Alejandro; Lopez, Edith; St Claire, Jason; Panigrahi, Gagan B; Hou, Caixia; Holloway, Kim; Gillis, Tammy; Guide, Jolene R; Cohen, Paula E; Li, Guo-Min; Pearson, Christopher E; Daly, Mark J; Wheeler, Vanessa C

    2013-10-01

    The Huntington's disease gene (HTT) CAG repeat mutation undergoes somatic expansion that correlates with pathogenesis. Modifiers of somatic expansion may therefore provide routes for therapies targeting the underlying mutation, an approach that is likely applicable to other trinucleotide repeat diseases. Huntington's disease Hdh(Q111) mice exhibit higher levels of somatic HTT CAG expansion on a C57BL/6 genetic background (B6.Hdh(Q111) ) than on a 129 background (129.Hdh(Q111) ). Linkage mapping in (B6x129).Hdh(Q111) F2 intercross animals identified a single quantitative trait locus underlying the strain-specific difference in expansion in the striatum, implicating mismatch repair (MMR) gene Mlh1 as the most likely candidate modifier. Crossing B6.Hdh(Q111) mice onto an Mlh1 null background demonstrated that Mlh1 is essential for somatic CAG expansions and that it is an enhancer of nuclear huntingtin accumulation in striatal neurons. Hdh(Q111) somatic expansion was also abolished in mice deficient in the Mlh3 gene, implicating MutLγ (MLH1-MLH3) complex as a key driver of somatic expansion. Strikingly, Mlh1 and Mlh3 genes encoding MMR effector proteins were as critical to somatic expansion as Msh2 and Msh3 genes encoding DNA mismatch recognition complex MutSβ (MSH2-MSH3). The Mlh1 locus is highly polymorphic between B6 and 129 strains. While we were unable to detect any difference in base-base mismatch or short slipped-repeat repair activity between B6 and 129 MLH1 variants, repair efficiency was MLH1 dose-dependent. MLH1 mRNA and protein levels were significantly decreased in 129 mice compared to B6 mice, consistent with a dose-sensitive MLH1-dependent DNA repair mechanism underlying the somatic expansion difference between these strains. Together, these data identify Mlh1 and Mlh3 as novel critical genetic modifiers of HTT CAG instability, point to Mlh1 genetic variation as the likely source of the instability difference in B6 and 129 strains and suggest that MLH1

  1. Mismatch repair genes Mlh1 and Mlh3 modify CAG instability in Huntington's disease mice: genome-wide and candidate approaches.

    Directory of Open Access Journals (Sweden)

    Ricardo Mouro Pinto

    2013-10-01

    Full Text Available The Huntington's disease gene (HTT CAG repeat mutation undergoes somatic expansion that correlates with pathogenesis. Modifiers of somatic expansion may therefore provide routes for therapies targeting the underlying mutation, an approach that is likely applicable to other trinucleotide repeat diseases. Huntington's disease Hdh(Q111 mice exhibit higher levels of somatic HTT CAG expansion on a C57BL/6 genetic background (B6.Hdh(Q111 than on a 129 background (129.Hdh(Q111 . Linkage mapping in (B6x129.Hdh(Q111 F2 intercross animals identified a single quantitative trait locus underlying the strain-specific difference in expansion in the striatum, implicating mismatch repair (MMR gene Mlh1 as the most likely candidate modifier. Crossing B6.Hdh(Q111 mice onto an Mlh1 null background demonstrated that Mlh1 is essential for somatic CAG expansions and that it is an enhancer of nuclear huntingtin accumulation in striatal neurons. Hdh(Q111 somatic expansion was also abolished in mice deficient in the Mlh3 gene, implicating MutLγ (MLH1-MLH3 complex as a key driver of somatic expansion. Strikingly, Mlh1 and Mlh3 genes encoding MMR effector proteins were as critical to somatic expansion as Msh2 and Msh3 genes encoding DNA mismatch recognition complex MutSβ (MSH2-MSH3. The Mlh1 locus is highly polymorphic between B6 and 129 strains. While we were unable to detect any difference in base-base mismatch or short slipped-repeat repair activity between B6 and 129 MLH1 variants, repair efficiency was MLH1 dose-dependent. MLH1 mRNA and protein levels were significantly decreased in 129 mice compared to B6 mice, consistent with a dose-sensitive MLH1-dependent DNA repair mechanism underlying the somatic expansion difference between these strains. Together, these data identify Mlh1 and Mlh3 as novel critical genetic modifiers of HTT CAG instability, point to Mlh1 genetic variation as the likely source of the instability difference in B6 and 129 strains and suggest

  2. Niacin deficiency delays DNA excision repair and increases spontaneous and nitrosourea-induced chromosomal instability in rat bone marrow.

    Science.gov (United States)

    Kostecki, Lisa M; Thomas, Megan; Linford, Geordie; Lizotte, Matthew; Toxopeus, Lori; Bartleman, Anne-Pascale; Kirkland, James B

    2007-12-01

    We have shown that niacin deficiency impairs poly(ADP-ribose) formation and enhances sister chromatid exchanges and micronuclei formation in rat bone marrow. We designed the current study to investigate the effects of niacin deficiency on the kinetics of DNA repair following ethylation, and the accumulation of double strand breaks, micronuclei (MN) and chromosomal aberrations (CA). Weanling male Long-Evans rats were fed niacin deficient (ND), or pair fed (PF) control diets for 3 weeks. We examined repair kinetics by comet assay in the 36h following a single dose of ethylnitrosourea (ENU) (30mg/kg bw). There was no effect of ND on mean tail moment (MTM) before ENU treatment, or on the development of strand breaks between 0 and 8h after ENU. Repair kinetics between 12 and 30h were significantly delayed by ND, with a doubling of area under the MTM curve during this period. O(6)-ethylation of guanine peaked by 1.5h, was largely repaired by 15h, and was also delayed in bone marrow cells from ND rats. ND significantly enhanced double strand break accumulation at 24h after ENU. ND alone increased chromosome and chromatid breaks (four- and two-fold). ND alone caused a large increase in MN, and this was amplified by ENU treatment. While repair kinetics suggest that ND may be acting by creating catalytically inactive PARP molecules with a dominant-negative effect on repair processes, the effect of ND alone on O(6)-ethylation, MN and CA, in the absence of altered comet results, suggests additional mechanisms are also leading to chromosomal instability. These data support the idea that the bone marrow cells of niacin deficient cancer patients may be more sensitive to the side effects of genotoxic chemotherapy, resulting in acute bone marrow suppression and chronic development of secondary leukemias.

  3. Nonlinear propagation of a spatially incoherent laser beam: self-induced smoothing and reduction of scattering instabilities

    International Nuclear Information System (INIS)

    Maximov, A.V.; Ourdev, I.G.; Rozmus, W.; Capjack, C.E.; Mounaix, Ph.; Huller, S.; Pesme, D.; Tikhonchuk, V.T.; Divol, L.

    2000-01-01

    It is shown that plasma-induced angular spreading and spectral broadening of a spatially incoherent laser beam correspond to increased spatial and temporal incoherence of the laser light. The spatial incoherence is characterized by an effective beam f-number, decreasing in space along the direction of light propagation. Plasma-induced beam smoothing can influence laser-plasma interaction physics. In particular, decreasing the correlation time of the propagating laser light may dramatically reduce the levels of backward stimulated Brillouin and Raman scattering inside the plasma. Also, the decrease of the laser beam effective f-number reduces the reflectivity of backward stimulated Brillouin scattering. (authors)

  4. Molecular subtypes in stage II-III colon cancer defined by genomic instability: early recurrence-risk associated with a high copy-number variation and loss of RUNX3 and CDKN2A.

    Directory of Open Access Journals (Sweden)

    Marianne Berg

    Full Text Available We sought to investigate various molecular subtypes defined by genomic instability that may be related to early death and recurrence in colon cancer.We sought to investigate various molecular subtypes defined by instability at microsatellites (MSI, changes in methylation patterns (CpG island methylator phenotype, CIMP or copy number variation (CNV in 8 genes. Stage II-III colon cancers (n = 64 were investigated by methylation-specific multiplex ligated probe amplification (MS-MLPA. Correlation of CNV, CIMP and MSI, with mutations in KRAS and BRAFV600E were assessed for overlap in molecular subtypes and early recurrence risk by uni- and multivariate regression.The CIMP phenotype occurred in 34% (22/64 and MSI in 27% (16/60 of the tumors, with noted CIMP/MSI overlap. Among the molecular subtypes, a high CNV phenotype had an associated odds ratio (OR for recurrence of 3.2 (95% CI 1.1-9.3; P = 0.026. Losses of CACNA1G (OR of 2.9, 95% CI 1.4-6.0; P = 0.001, IGF2 (OR of 4.3, 95% CI 1.1-15.8; P = 0.007, CDKN2A (p16 (OR of 2.0, 95% CI 1.1-3.6; P = 0.024, and RUNX3 (OR of 3.4, 95% CI 1.3-8.7; P = 0.002 were associated with early recurrence, while MSI, CIMP, KRAS or BRAF V600E mutations were not. The CNV was significantly higher in deceased patients (CNV in 6 of 8 compared to survivors (CNV in 3 of 8. Only stage and loss of RUNX3 and CDKN2A were significant in the multivariable risk-model for early recurrence.A high copy number variation phenotype is a strong predictor of early recurrence and death, and may indicate a dose-dependent relationship between genetic instability and outcome. Loss of tumor suppressors RUNX3 and CDKN2A were related to recurrence-risk and warrants further investigation.

  5. Radiation-induced colon cancer with high frequency microsatellite instability (MSI-H), report of a case

    Energy Technology Data Exchange (ETDEWEB)

    Arai, Masami; Ueno, Masashi; Koizumi, Koichi [Japanese Foundation for Cancer Research, Tokyo (Japan). Hospital] [and others

    2002-07-01

    We report a 67-year-old female with radiation-induced colon cancer which developed 23 years after radiation therapy for cancer of the endometrium. She was strongly suspected to be a case of hereditary nonpolyposis colorectal cancer (HNPCC) due to her clinical manifestations, i.e. metachronous multiple cancer developed in the endometrium and colon. MSI test and immunohistochemistry for mismatch repair (MMR) proteins revealed that MSI was highly positive and expression of hMSH2 was lost in the colon cancers. Further, on examining the genetic change, the point mutation, ACG{yields}ATG, responsible for amino acid change, was detected in codon8 (exon1) of the hMSH2 gene. The change, however, could be a polymorphism of this gene and further analyses were necessitated to confirm the genetic background for HNPCC. Interestingly, three cancers with adenoma were located in the mucosa of radiation colitis, in which several atypical glands were also found. This is the only case of radiation-induced colorectal cancer with MSI-H in our hospital. Because of our previous studies, we believe that the genetic pathway in carcinogenesis of the radiation-induced colon cancer is different from that of HNPCC, despite their having several kinds of clinical and pathological features in common. (author)

  6. Radiation-induced colon cancer with high frequency microsatellite instability (MSI-H), report of a case

    International Nuclear Information System (INIS)

    Arai, Masami; Ueno, Masashi; Koizumi, Koichi

    2002-01-01

    We report a 67-year-old female with radiation-induced colon cancer which developed 23 years after radiation therapy for cancer of the endometrium. She was strongly suspected to be a case of hereditary nonpolyposis colorectal cancer (HNPCC) due to her clinical manifestations, i.e. metachronous multiple cancer developed in the endometrium and colon. MSI test and immunohistochemistry for mismatch repair (MMR) proteins revealed that MSI was highly positive and expression of hMSH2 was lost in the colon cancers. Further, on examining the genetic change, the point mutation, ACG→ATG, responsible for amino acid change, was detected in codon8 (exon1) of the hMSH2 gene. The change, however, could be a polymorphism of this gene and further analyses were necessitated to confirm the genetic background for HNPCC. Interestingly, three cancers with adenoma were located in the mucosa of radiation colitis, in which several atypical glands were also found. This is the only case of radiation-induced colorectal cancer with MSI-H in our hospital. Because of our previous studies, we believe that the genetic pathway in carcinogenesis of the radiation-induced colon cancer is different from that of HNPCC, despite their having several kinds of clinical and pathological features in common. (author)

  7. APC/C Dysfunction Limits Excessive Cancer Chromosomal Instability.

    Science.gov (United States)

    Sansregret, Laurent; Patterson, James O; Dewhurst, Sally; López-García, Carlos; Koch, André; McGranahan, Nicholas; Chao, William Chong Hang; Barry, David J; Rowan, Andrew; Instrell, Rachael; Horswell, Stuart; Way, Michael; Howell, Michael; Singleton, Martin R; Medema, René H; Nurse, Paul; Petronczki, Mark; Swanton, Charles

    2017-02-01

    Intercellular heterogeneity, exacerbated by chromosomal instability (CIN), fosters tumor heterogeneity and drug resistance. However, extreme CIN correlates with improved cancer outcome, suggesting that karyotypic diversity required to adapt to selection pressures might be balanced in tumors against the risk of excessive instability. Here, we used a functional genomics screen, genome editing, and pharmacologic approaches to identify CIN-survival factors in diploid cells. We find partial anaphase-promoting complex/cyclosome (APC/C) dysfunction lengthens mitosis, suppresses pharmacologically induced chromosome segregation errors, and reduces naturally occurring lagging chromosomes in cancer cell lines or following tetraploidization. APC/C impairment caused adaptation to MPS1 inhibitors, revealing a likely resistance mechanism to therapies targeting the spindle assembly checkpoint. Finally, CRISPR-mediated introduction of cancer somatic mutations in the APC/C subunit cancer driver gene CDC27 reduces chromosome segregation errors, whereas reversal of an APC/C subunit nonsense mutation increases CIN. Subtle variations in mitotic duration, determined by APC/C activity, influence the extent of CIN, allowing cancer cells to dynamically optimize fitness during tumor evolution. We report a mechanism whereby cancers balance the evolutionary advantages associated with CIN against the fitness costs caused by excessive genome instability, providing insight into the consequence of CDC27 APC/C subunit driver mutations in cancer. Lengthening of mitosis through APC/C modulation may be a common mechanism of resistance to cancer therapeutics that increase chromosome segregation errors. Cancer Discov; 7(2); 218-33. ©2017 AACR.See related commentary by Burkard and Weaver, p. 134This article is highlighted in the In This Issue feature, p. 115. ©2017 American Association for Cancer Research.

  8. Path from schizophrenia genomics to biology: gene regulation and perturbation in neurons derived from induced pluripotent stem cells and genome editing.

    Science.gov (United States)

    Duan, Jubao

    2015-02-01

    Schizophrenia (SZ) is a devastating mental disorder afflicting 1% of the population. Recent genome-wide association studies (GWASs) of SZ have identified >100 risk loci. However, the causal variants/genes and the causal mechanisms remain largely unknown, which hinders the translation of GWAS findings into disease biology and drug targets. Most risk variants are noncoding, thus likely regulate gene expression. A major mechanism of transcriptional regulation is chromatin remodeling, and open chromatin is a versatile predictor of regulatory sequences. MicroRNA-mediated post-transcriptional regulation plays an important role in SZ pathogenesis. Neurons differentiated from patient-specific induced pluripotent stem cells (iPSCs) provide an experimental model to characterize the genetic perturbation of regulatory variants that are often specific to cell type and/or developmental stage. The emerging genome-editing technology enables the creation of isogenic iPSCs and neurons to efficiently characterize the effects of SZ-associated regulatory variants on SZ-relevant molecular and cellular phenotypes involving dopaminergic, glutamatergic, and GABAergic neurotransmissions. SZ GWAS findings equipped with the emerging functional genomics approaches provide an unprecedented opportunity for understanding new disease biology and identifying novel drug targets.

  9. Aeroelastic instability problems for wind turbines

    DEFF Research Database (Denmark)

    Hansen, Morten Hartvig

    2007-01-01

    This paper deals with the aeroelostic instabilities that have occurred and may still occur for modem commercial wind turbines: stall-induced vibrations for stall-turbines, and classical flutter for pitch-regulated turbines. A review of previous works is combined with derivations of analytical...... stiffness and chordwise position of the center of gravity along the blades are the main parameters for flutter. These instability characteristics are exemplified by aeroelastic stability analyses of different wind turbines. The review of each aeroelastic instability ends with a list of current research...... issues that represent unsolved aeroelostic instability problems for wind turbines. Copyright (c) 2007 John Wiley & Sons, Ltd....

  10. Coordinated Changes in Mutation and Growth Rates Induced by Genome Reduction

    Directory of Open Access Journals (Sweden)

    Issei Nishimura

    2017-07-01

    Full Text Available Genome size is determined during evolution, but it can also be altered by genetic engineering in laboratories. The systematic characterization of reduced genomes provides valuable insights into the cellular properties that are quantitatively described by the global parameters related to the dynamics of growth and mutation. In the present study, we analyzed a small collection of W3110 Escherichia coli derivatives containing either the wild-type genome or reduced genomes of various lengths to examine whether the mutation rate, a global parameter representing genomic plasticity, was affected by genome reduction. We found that the mutation rates of these cells increased with genome reduction. The correlation between genome length and mutation rate, which has been reported for the evolution of bacteria, was also identified, intriguingly, for genome reduction. Gene function enrichment analysis indicated that the deletion of many of the genes encoding membrane and transport proteins play a role in the mutation rate changes mediated by genome reduction. Furthermore, the increase in the mutation rate with genome reduction was highly associated with a decrease in the growth rate in a nutrition-dependent manner; thus, poorer media showed a larger change that was of higher significance. This negative correlation was strongly supported by experimental evidence that the serial transfer of the reduced genome improved the growth rate and reduced the mutation rate to a large extent. Taken together, the global parameters corresponding to the genome, growth, and mutation showed a coordinated relationship, which might be an essential working principle for balancing the cellular dynamics appropriate to the environment.

  11. SUMO E3 ligase Mms21 prevents spontaneous DNA damage induced genome rearrangements.

    Directory of Open Access Journals (Sweden)

    Jason Liang

    2018-03-01

    Full Text Available Mms21, a subunit of the Smc5/6 complex, possesses an E3 ligase activity for the Small Ubiquitin-like MOdifier (SUMO. Here we show that the mms21-CH mutation, which inactivates Mms21 ligase activity, causes increased accumulation of gross chromosomal rearrangements (GCRs selected in the dGCR assay. These dGCRs are formed by non-allelic homologous recombination between divergent DNA sequences mediated by Rad52-, Rrm3- and Pol32-dependent break-induced replication. Combining mms21-CH with sgs1Δ caused a synergistic increase in GCRs rates, indicating the distinct roles of Mms21 and Sgs1 in suppressing GCRs. The mms21-CH mutation also caused increased rates of accumulating uGCRs mediated by breakpoints in unique sequences as revealed by whole genome sequencing. Consistent with the accumulation of endogenous DNA lesions, mms21-CH mutants accumulate increased levels of spontaneous Rad52 and Ddc2 foci and had a hyper-activated DNA damage checkpoint. Together, these findings support that Mms21 prevents the accumulation of spontaneous DNA lesions that cause diverse GCRs.

  12. Genome Editing in Induced Pluripotent Stem Cells using CRISPR/Cas9.

    Science.gov (United States)

    Ben Jehuda, Ronen; Shemer, Yuval; Binah, Ofer

    2018-06-01

    The development of the reprogramming technology led to generation of induced Pluripotent Stem Cells (iPSC) from a variety of somatic cells. Ever since, fast growing knowledge of different efficient protocols enabled the differentiation of these iPSCs into different cells types utilized for disease modeling. Indeed, iPSC-derived cells have been increasingly used for investigating molecular and cellular pathophysiological mechanisms underlying inherited diseases. However, a major barrier in the field of iPSC-based disease modeling relies on discriminating between the effects of the causative mutation and the genetic background of these cells. In the past decade, researchers have made great improvement in genome editing techniques, with one of the latest being CRISPR/Cas9. Using a single non-sequence specific protein combined with a small guiding RNA molecule, this state-of-the-art approach enables modifications of genes with high efficiency and accuracy. By so doing, this technique enables the generation of isogenic controls or isogenic mutated cell lines in order to focus on the pathologies caused by a specific mutation. In this article, we review the latest studies combining iPSC and CRISPR/Cas9 technologies for the investigation of the molecular and cellular mechanisms underlying inherited diseases including immunological, metabolic, hematological, neurodegenerative and cardiac diseases.

  13. Integrated Genomic Analysis of Diverse Induced Pluripotent Stem Cells from the Progenitor Cell Biology Consortium.

    Science.gov (United States)

    Salomonis, Nathan; Dexheimer, Phillip J; Omberg, Larsson; Schroll, Robin; Bush, Stacy; Huo, Jeffrey; Schriml, Lynn; Ho Sui, Shannan; Keddache, Mehdi; Mayhew, Christopher; Shanmukhappa, Shiva Kumar; Wells, James; Daily, Kenneth; Hubler, Shane; Wang, Yuliang; Zambidis, Elias; Margolin, Adam; Hide, Winston; Hatzopoulos, Antonis K; Malik, Punam; Cancelas, Jose A; Aronow, Bruce J; Lutzko, Carolyn

    2016-07-12

    The rigorous characterization of distinct induced pluripotent stem cells (iPSC) derived from multiple reprogramming technologies, somatic sources, and donors is required to understand potential sources of variability and downstream potential. To achieve this goal, the Progenitor Cell Biology Consortium performed comprehensive experimental and genomic analyses of 58 iPSC from ten laboratories generated using a variety of reprogramming genes, vectors, and cells. Associated global molecular characterization studies identified functionally informative correlations in gene expression, DNA methylation, and/or copy-number variation among key developmental and oncogenic regulators as a result of donor, sex, line stability, reprogramming technology, and cell of origin. Furthermore, X-chromosome inactivation in PSC produced highly correlated differences in teratoma-lineage staining and regulator expression upon differentiation. All experimental results, and raw, processed, and metadata from these analyses, including powerful tools, are interactively accessible from a new online portal at https://www.synapse.org to serve as a reusable resource for the stem cell community. Copyright © 2016 The Authors. Published by Elsevier Inc. All rights reserved.

  14. Genome wide transcriptional response of Saccharomyces cerevisiae to stress-induced perturbations

    Directory of Open Access Journals (Sweden)

    Hilal eTaymaz-Nikerel

    2016-02-01

    Full Text Available Cells respond to environmental and/or genetic perturbations in order to survive and proliferate. Characterization of the changes after various stimuli at different -omics levels is crucial to comprehend the adaptation of cells to changing conditions. Genome wide quantification and analysis of transcript levels, the genes affected by perturbations, extends our understanding of cellular metabolism by pointing out the mechanisms that play role in sensing the stress caused by those perturbations and related signaling pathways, and in this way guides us to achieve endeavors such as rational engineering of cells or interpretation of disease mechanisms. Saccharomyces cerevisiae as a model system has been studied in response to different perturbations and corresponding transcriptional profiles were followed either statically or/and dynamically, short- and long- term. This review focuses on response of yeast cells to diverse stress inducing perturbations including nutritional changes, ionic stress, salt stress, oxidative stress, osmotic shock, as well as to genetic interventions such as deletion and over-expression of genes. It is aimed to conclude on common regulatory phenomena that allow yeast to organize its transcriptomic response after any perturbation under different external conditions.

  15. Mode-locking via dissipative Faraday instability.

    Science.gov (United States)

    Tarasov, Nikita; Perego, Auro M; Churkin, Dmitry V; Staliunas, Kestutis; Turitsyn, Sergei K

    2016-08-09

    Emergence of coherent structures and patterns at the nonlinear stage of modulation instability of a uniform state is an inherent feature of many biological, physical and engineering systems. There are several well-studied classical modulation instabilities, such as Benjamin-Feir, Turing and Faraday instability, which play a critical role in the self-organization of energy and matter in non-equilibrium physical, chemical and biological systems. Here we experimentally demonstrate the dissipative Faraday instability induced by spatially periodic zig-zag modulation of a dissipative parameter of the system-spectrally dependent losses-achieving generation of temporal patterns and high-harmonic mode-locking in a fibre laser. We demonstrate features of this instability that distinguish it from both the Benjamin-Feir and the purely dispersive Faraday instability. Our results open the possibilities for new designs of mode-locked lasers and can be extended to other fields of physics and engineering.

  16. Fungal-induced cell cycle impairment, chromosome instability and apoptosis via differential activation of NF-κB.

    Directory of Open Access Journals (Sweden)

    Mariem Ben-Abdallah

    Full Text Available Microbial pathogens have developed efficient strategies to compromise host immune responses. Cryptococcus neoformans is a facultative intracellular pathogen, recognised as the most common cause of systemic fungal infections leading to severe meningoencephalitis, mainly in immunocompromised patients. This yeast is characterized by a polysaccharide capsule, which inhibits its phagocytosis. Whereas phagocytosis escape and macrophage intracellular survival have been intensively studied, extracellular survival of this yeast and restraint of host innate immune response are still poorly understood. In this study, we have investigated whether C. neoformans affected macrophage cell viability and whether NF-κB (nuclear factor-κB, a key regulator of cell growth, apoptosis and inflammation, was involved. Using wild-type (WT as well as mutant strains of C. neoformans for the pathogen side, and WT and mutant cell lines with altered NF-κB activity or signalling as well as primary macrophages for the host side, we show that C. neoformans manipulated NF-κB-mediated signalling in a unique way to regulate macrophage cell fate and viability. On the one hand, serotype A strains reduced macrophage proliferation in a capsule-independent fashion. This growth decrease, which required a critical dosage of NF-κB activity, was caused by cell cycle disruption and aneuploidy, relying on fungal-induced modification of expression of several cell cycle checkpoint regulators in S and G2/M phases. On the other hand, C. neoformans infection induced macrophage apoptosis in a capsule-dependent manner with a differential requirement of the classical and alternative NF-κB signalling pathways, the latter one being essential. Together, these findings shed new light on fungal strategies to subvert host response through uncoupling of NF-κB activity in pathogen-controlled apoptosis and impairment of cell cycle progression. They also provide the first demonstration of induction of

  17. Direct and inverted repeats elicit genetic instability by both exploiting and eluding DNA double-strand break repair systems in mycobacteria.

    Directory of Open Access Journals (Sweden)

    Ewelina A Wojcik

    Full Text Available Repetitive DNA sequences with the potential to form alternative DNA conformations, such as slipped structures and cruciforms, can induce genetic instability by promoting replication errors and by serving as a substrate for DNA repair proteins, which may lead to DNA double-strand breaks (DSBs. However, the contribution of each of the DSB repair pathways, homologous recombination (HR, non-homologous end-joining (NHEJ and single-strand annealing (SSA, to this sort of genetic instability is not fully understood. Herein, we assessed the genome-wide distribution of repetitive DNA sequences in the Mycobacterium smegmatis, Mycobacterium tuberculosis and Escherichia coli genomes, and determined the types and frequencies of genetic instability induced by direct and inverted repeats, both in the presence and in the absence of HR, NHEJ, and SSA. All three genomes are strongly enriched in direct repeats and modestly enriched in inverted repeats. When using chromosomally integrated constructs in M. smegmatis, direct repeats induced the perfect deletion of their intervening sequences ~1,000-fold above background. Absence of HR further enhanced these perfect deletions, whereas absence of NHEJ or SSA had no influence, suggesting compromised replication fidelity. In contrast, inverted repeats induced perfect deletions only in the absence of SSA. Both direct and inverted repeats stimulated excision of the constructs from the attB integration sites independently of HR, NHEJ, or SSA. With episomal constructs, direct and inverted repeats triggered DNA instability by activating nucleolytic activity, and absence of the DSB repair pathways (in the order NHEJ>HR>SSA exacerbated this instability. Thus, direct and inverted repeats may elicit genetic instability in mycobacteria by 1 directly interfering with replication fidelity, 2 stimulating the three main DSB repair pathways, and 3 enticing L5 site-specific recombination.

  18. Direct and inverted repeats elicit genetic instability by both exploiting and eluding DNA double-strand break repair systems in mycobacteria.

    Science.gov (United States)

    Wojcik, Ewelina A; Brzostek, Anna; Bacolla, Albino; Mackiewicz, Pawel; Vasquez, Karen M; Korycka-Machala, Malgorzata; Jaworski, Adam; Dziadek, Jaroslaw

    2012-01-01

    Repetitive DNA sequences with the potential to form alternative DNA conformations, such as slipped structures and cruciforms, can induce genetic instability by promoting replication errors and by serving as a substrate for DNA repair proteins, which may lead to DNA double-strand breaks (DSBs). However, the contribution of each of the DSB repair pathways, homologous recombination (HR), non-homologous end-joining (NHEJ) and single-strand annealing (SSA), to this sort of genetic instability is not fully understood. Herein, we assessed the genome-wide distribution of repetitive DNA sequences in the Mycobacterium smegmatis, Mycobacterium tuberculosis and Escherichia coli genomes, and determined the types and frequencies of genetic instability induced by direct and inverted repeats, both in the presence and in the absence of HR, NHEJ, and SSA. All three genomes are strongly enriched in direct repeats and modestly enriched in inverted repeats. When using chromosomally integrated constructs in M. smegmatis, direct repeats induced the perfect deletion of their intervening sequences ~1,000-fold above background. Absence of HR further enhanced these perfect deletions, whereas absence of NHEJ or SSA had no influence, suggesting compromised replication fidelity. In contrast, inverted repeats induced perfect deletions only in the absence of SSA. Both direct and inverted repeats stimulated excision of the constructs from the attB integration sites independently of HR, NHEJ, or SSA. With episomal constructs, direct and inverted repeats triggered DNA instability by activating nucleolytic activity, and absence of the DSB repair pathways (in the order NHEJ>HR>SSA) exacerbated this instability. Thus, direct and inverted repeats may elicit genetic instability in mycobacteria by 1) directly interfering with replication fidelity, 2) stimulating the three main DSB repair pathways, and 3) enticing L5 site-specific recombination.

  19. Electron beam instabilities in gyrotron beam tunnels

    International Nuclear Information System (INIS)

    Pedrozzi, M.; Alberti, S.; Hogge, J.P.; Tran, M.Q.; Tran, T.M.

    1997-10-01

    Electron beam instabilities occurring in a gyrotron electron beam can induce an energy spread which might significantly deteriorate the gyrotron efficiency. Three types of instabilities are considered to explain the important discrepancy found between the theoretical and experimental efficiency in the case of quasi-optical gyrotrons (QOG): the electron cyclotron maser instability, the Bernstein instability and the Langmuir instability. The low magnetic field gradient in drift tubes of QOG makes that the electron cyclotron maser instability can develop in the drift tube at very low electron beam currents. Experimental measurements show that with a proper choice of absorbing structures in the beam tunnel, this instability can be suppressed. At high beam currents, the electrostatic Bernstein instability can induce a significant energy spread at the entrance of the interaction region. The induced energy spread scales approximately linearly with the electron beam density and for QOG one observes that the beam density is significantly higher than the beam density of an equivalent cylindrical cavity gyrotron. (author) figs., tabs., refs

  20. Scintillator based detector for fast-ion losses induced by magnetohydrodynamic instabilities in the ASDEX upgrade tokamak.

    Science.gov (United States)

    García-Muñoz, M; Fahrbach, H-U; Zohm, H

    2009-05-01

    A scintillator based detector for fast-ion losses has been designed and installed on the ASDEX upgrade (AUG) tokamak [A. Herrmann and O. Gruber, Fusion Sci. Technol. 44, 569 (2003)]. The detector resolves in time the energy and pitch angle of fast-ion losses induced by magnetohydrodynamics (MHD) fluctuations. The use of a novel scintillator material with a very short decay time and high quantum efficiency allows to identify the MHD fluctuations responsible for the ion losses through Fourier analysis. A Faraday cup (secondary scintillator plate) has been embedded behind the scintillator plate for an absolute calibration of the detector. The detector is mounted on a manipulator to vary its radial position with respect to the plasma. A thermocouple on the inner side of the graphite protection enables the safety search for the most adequate radial position. To align the scintillator light pattern with the light detectors a system composed by a lens and a vacuum-compatible halogen lamp has been allocated within the detector head. In this paper, the design of the scintillator probe, as well as the new technique used to analyze the data through spectrograms will be described. A last section is devoted to discuss the diagnosis prospects of this method for ITER [M. Shimada et al., Nucl. Fusion 47, S1 (2007)].

  1. Genome-wide high-resolution mapping of UV-induced mitotic recombination events in Saccharomyces cerevisiae.

    Directory of Open Access Journals (Sweden)

    Yi Yin

    2013-10-01

    Full Text Available In the yeast Saccharomyces cerevisiae and most other eukaryotes, mitotic recombination is important for the repair of double-stranded DNA breaks (DSBs. Mitotic recombination between homologous chromosomes can result in loss of heterozygosity (LOH. In this study, LOH events induced by ultraviolet (UV light are mapped throughout the genome to a resolution of about 1 kb using single-nucleotide polymorphism (SNP microarrays. UV doses that have little effect on the viability of diploid cells stimulate crossovers more than 1000-fold in wild-type cells. In addition, UV stimulates recombination in G1-synchronized cells about 10-fold more efficiently than in G2-synchronized cells. Importantly, at high doses of UV, most conversion events reflect the repair of two sister chromatids that are broken at approximately the same position whereas at low doses, most conversion events reflect the repair of a single broken chromatid. Genome-wide mapping of about 380 unselected crossovers, break-induced replication (BIR events, and gene conversions shows that UV-induced recombination events occur throughout the genome without pronounced hotspots, although the ribosomal RNA gene cluster has a significantly lower frequency of crossovers.

  2. Cavitation instabilities in hydraulic machines

    International Nuclear Information System (INIS)

    Tsujimoto, Y

    2013-01-01

    Cavitation instabilities in hydraulic machines, hydro turbines and turbopump inducers, are reviewed focusing on the cause of instabilities. One-dimensional model of hydro turbine system shows that the overload surge is caused by the diffuser effect of the draft tube. Experiments show that this effect also causes the surge mode oscillations at part load. One dimensional model of a cavitating turbopump inducer shows that the mass flow gain factor, representing the cavity volume increase caused by the incidence angle increase is the cause of cavitation surge and rotating cavitation. Two dimensional model of a cavitating turbopump inducer shows that various modes of cavitation instabilities start to occur when the cavity length becomes about 65% of the blade spacing. This is caused by the interaction of the local flow near the cavity trailing edge with the leading edge of the next blade. It was shown by a 3D CFD that this is true also for real cases with tip cavitation. In all cases, it was shown that cavitation instabilities are caused by the fundamental characteristics of cavities that the cavity volume increases with the decrease of ambient pressure or the increase of the incidence angle

  3. tigaR: integrative significance analysis of temporal differential gene expression induced by genomic abnormalities

    NARCIS (Netherlands)

    Miok, V.; Wilting, S.M.; van de Wiel, M.A.; Jaspers, A.; van Noort, P.I.; Brakenhoff, R.H.; Snijders, P.J.F.; Steenbergen, R.D.M.; van Wieringen, W.N.

    2014-01-01

    Background: To determine which changes in the host cell genome are crucial for cervical carcinogenesis, a longitudinal in vitro model system of HPV-transformed keratinocytes was profiled in a genome-wide manner. Four cell lines affected with either HPV16 or HPV18 were assayed at 8 sequential time

  4. Anisotropic gravitational instability

    International Nuclear Information System (INIS)

    Polyachenko, V.L.; Fridman, A.M.

    1988-01-01

    Exact solutions of stability problems are obtained for two anisotropic gravitational systems of different geometries - a layer of finite thickness at rest and a rotating cylinder of finite radius. It is shown that the anisotropic gravitational instability which develops in both cases is of Jeans type. However, in contrast to the classical aperiodic Jeans instability, this instability is oscillatory. The physics of the anisotropic gravitational instability is investigated. It is shown that in a gravitating layer this instability is due, in particular, to excitation of previously unknown interchange-Jeans modes. In the cylinder, the oscillatory Jeans instability is associated with excitation of a rotational branch, this also being responsible for the beam gravitational instability. This is the reason why this instability and the anisotropic gravitational instability have so much in common

  5. Ddx19 links mRNA nuclear export with progression of transcription and replication and suppresses genomic instability upon DNA damage in proliferating cells.

    Science.gov (United States)

    Hodroj, Dana; Serhal, Kamar; Maiorano, Domenico

    2017-09-03

    The DEAD-box Helicase 19 (Ddx19) gene codes for an RNA helicase involved in both mRNA (mRNA) export from the nucleus into the cytoplasm and in mRNA translation. In unperturbed cells, Ddx19 localizes in the cytoplasm and at the cytoplasmic face of the nuclear pore. Here we review recent findings related to an additional Ddx19 function in the nucleus in resolving RNA:DNA hybrids (R-loops) generated during collision between transcription and replication, and upon DNA damage. Activation of a DNA damage response pathway dependent upon the ATR kinase, a major regulator of replication fork progression, stimulates translocation of the Ddx19 protein from the cytoplasm into the nucleus. Only nuclear Ddx19 is competent to resolve R-loops, and down regulation of Ddx19 expression induces DNA double strand breaks only in proliferating cells. Overall these observations put forward Ddx19 as an important novel mediator of the crosstalk between transcription and replication.

  6. Faraday instability on patterned surfaces

    Science.gov (United States)

    Feng, Jie; Rubinstein, Gregory; Jacobi, Ian; Stone, Howard

    2013-11-01

    We show how micro-scale surface patterning can be used to control the onset of the Faraday instability in thin liquid films. It is well known that when a liquid film on a planar substrate is subject to sufficient vibrational accelerations, the free surface destabilizes, exhibiting a family of non-linear standing waves. This instability remains a canonical problem in the study of spontaneous pattern formation, but also has practical uses. For example, the surface waves induced by the Faraday instability have been studied as a means of enhanced damping for mechanical vibrations (Genevaux et al. 2009). Also the streaming within the unstable layer has been used as a method for distributing heterogeneous cell cultures on growth medium (Takagi et al. 2002). In each of these applications, the roughness of the substrate significantly affects the unstable flow field. We consider the effect of patterned substrates on the onset and behavior of the Faraday instability over a range of pattern geometries and feature heights where the liquid layer is thicker than the pattern height. Also, we describe a physical model for the influence of patterned roughness on the destabilization of a liquid layer in order to improve the design of practical systems which exploit the Faraday instability.

  7. Helicobacter pylori infection generates genetic instability in gastric cells

    DEFF Research Database (Denmark)

    Machado, Ana Manuel Dantas; Figueiredo, Céu; Seruca, Raquel

    2010-01-01

    The discovery that Helicobacter pylori is associated with gastric cancer has led to numerous studies that investigate the mechanisms by which H. pylori induces carcinogenesis. Gastric cancer shows genetic instability both in nuclear and mitochondrial DNA, besides impairment of important DNA repair...... of the host, such as oxidative damage, methylation, chromosomal instability, microsatellite instability, and mutations. Interestingly, H. pylori infection generates genetic instability in nuclear and mitochondrial DNA. Based on the reviewed literature we conclude that H. pylori infection promotes gastric...

  8. Hypoxia‐induced alterations of G2 checkpoint regulators

    OpenAIRE

    Hasvold, Grete; Lund-Andersen, Christin; Lando, Malin; Patzke, Sebastian; Hauge, Sissel; Suo, ZhenHe; Lyng, Heidi; Syljuåsen, Randi G.

    2016-01-01

    Hypoxia promotes an aggressive tumor phenotype with increased genomic instability, partially due to downregulation of DNA repair pathways. However, genome stability is also surveilled by cell cycle checkpoints. An important issue is therefore whether hypoxia also can influence the DNA damage‐induced cell cycle checkpoints. Here, we show that hypoxia (24 h 0.2% O2) alters the expression of several G2 checkpoint regulators, as examined by microarray gene expression analysis and immunoblotting o...

  9. Galloping instability to chaos of cables

    CERN Document Server

    Luo, Albert C J

    2017-01-01

    This book provides students and researchers with a systematic solution for fluid-induced structural vibrations, galloping instability and the chaos of cables. They will also gain a better understanding of stable and unstable periodic motions and chaos in fluid-induced structural vibrations. Further, the results presented here will help engineers effectively design and analyze fluid-induced vibrations.

  10. Gene expression profile and genomic alterations in colonic tumours induced by 1,2-dimethylhydrazine (DMH) in rats

    International Nuclear Information System (INIS)

    Femia, Angelo Pietro; Luceri, Cristina; Toti, Simona; Giannini, Augusto; Dolara, Piero; Caderni, Giovanna

    2010-01-01

    Azoxymethane (AOM) or 1,2-dimethylhydrazine (DMH)-induced colon carcinogenesis in rats shares many phenotypical similarities with human sporadic colon cancer and is a reliable model for identifying chemopreventive agents. Genetic mutations relevant to human colon cancer have been described in this model, but comprehensive gene expression and genomic analysis have not been reported so far. Therefore, we applied genome-wide technologies to study variations in gene expression and genomic alterations in DMH-induced colon cancer in F344 rats. For gene expression analysis, 9 tumours (TUM) and their paired normal mucosa (NM) were hybridized on 4 × 44K Whole rat arrays (Agilent) and selected genes were validated by semi-quantitative RT-PCR. Functional analysis on microarray data was performed by GenMAPP/MappFinder analysis. Array-comparative genomic hybridization (a-CGH) was performed on 10 paired TUM-NM samples hybridized on Rat genome arrays 2 × 105K (Agilent) and the results were analyzed by CGH Analytics (Agilent). Microarray gene expression analysis showed that Def