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Sample records for genomic instability

  1. 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.)

  2. 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...

  3. 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)

  4. 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)

  5. 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

  6. 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

  7. 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.

  8. 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.

  9. 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.

  10. 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.

  11. 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.

  12. 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).

  13. 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)

  14. 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...

  15. 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...

  16. 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

  17. 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

  18. 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

  19. 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.

  20. 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.

  1. 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

  2. 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...

  3. 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

  4. 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.

  5. 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.

  6. Instability of plastid DNA in the nuclear genome.

    Directory of Open Access Journals (Sweden)

    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.

  7. 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.

  8. 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

  9. 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

  10. 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)

  11. 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

  12. 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.

  13. 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.

  14. 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

  15. 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

  16. 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.

  17. 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.

  18. 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 ...

  19. 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

  20. 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...

  1. 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

  2. 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.

  3. 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.

  4. 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.

  5. 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

  6. 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.

  7. 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

  8. 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

  9. 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

  10. 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

  11. 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

  12. 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)

  13. 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

  14. 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

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

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    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.

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

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

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    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

  18. Genomic and epigenetic instability in chordoma: current insights

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    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

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

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    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.

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

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    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.

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

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    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.

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

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    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.

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

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    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.

  5. 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)

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

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    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.

  7. 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

  8. 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)

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

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    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.

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

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    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

  11. 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.

  12. 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

  13. 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.

  14. 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.

  15. 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.

  16. 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

  17. 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.

  18. 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.

  19. 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

  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. 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.

  3. 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.

  4. 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

  5. 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

  6. 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.

  7. 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

  8. 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.

  9. 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

  10. 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.

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

    Directory of Open Access Journals (Sweden)

    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

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

    Directory of Open Access Journals (Sweden)

    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.

  13. 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.

  14. 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

  15. 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

    Highlights: • Anesthesiologists exposed to the most commonly used anesthetic gases were evaluated. • No alterations were detected for lymphocyte DNA damage detected by the comet assay. • Decreased frequencies of basal cells were detected in exfoliated buccal cells (BMCyt). • Increased frequencies of micronucleus and cytotoxicity were observed in BMCyt assay. • Anesthesiologists have genomic instability due to occupational exposure. - Abstract: Data on the genotoxic and mutagenic effects of occupational exposure to the most frequently used volatile anesthetics are limited and controversial. The current study is the first to evaluate genomic instability, cell death and proliferative index in exfoliated buccal cells (EBC) from anesthesiologists. We also evaluated DNA damage and determined the concentrations of the anesthetic gases most commonly used in operating rooms. This study was conducted on physicians who were allocated into two groups: the exposed group, which consisted of anesthesiologists who had been exposed to waste anesthetic gases (isoflurane, sevoflurane, desflurane and nitrous oxide − N 2 O) for at least two years; and the control group, which consisted of non-exposed physicians matched for age, sex and lifestyle with the exposed group. Venous blood and EBC samples were collected from all participants. Basal DNA damage was evaluated in lymphocytes by the comet assay, whereas the buccal micronucleus (MN) cytome (BMCyt) assay was applied to evaluate genotoxic and cytotoxic effects. The concentrations of N 2 O and anesthetics were measured via a portable infrared spectrophotometer. The average concentration of waste gases was greater than 5 parts per million (ppm) for all of the halogenated anesthetics and was more than 170 ppm for N 2 O, expressed as a time-weighted average. There was no significant difference between the groups in relation to lymphocyte DNA damage. The exposed group had higher frequencies of MN, karyorrhexis and pyknosis, and

  16. 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

    Highlights: • Anesthesiologists exposed to the most commonly used anesthetic gases were evaluated. • No alterations were detected for lymphocyte DNA damage detected by the comet assay. • Decreased frequencies of basal cells were detected in exfoliated buccal cells (BMCyt). • Increased frequencies of micronucleus and cytotoxicity were observed in BMCyt assay. • Anesthesiologists have genomic instability due to occupational exposure. - Abstract: Data on the genotoxic and mutagenic effects of occupational exposure to the most frequently used volatile anesthetics are limited and controversial. The current study is the first to evaluate genomic instability, cell death and proliferative index in exfoliated buccal cells (EBC) from anesthesiologists. We also evaluated DNA damage and determined the concentrations of the anesthetic gases most commonly used in operating rooms. This study was conducted on physicians who were allocated into two groups: the exposed group, which consisted of anesthesiologists who had been exposed to waste anesthetic gases (isoflurane, sevoflurane, desflurane and nitrous oxide − N{sub 2}O) for at least two years; and the control group, which consisted of non-exposed physicians matched for age, sex and lifestyle with the exposed group. Venous blood and EBC samples were collected from all participants. Basal DNA damage was evaluated in lymphocytes by the comet assay, whereas the buccal micronucleus (MN) cytome (BMCyt) assay was applied to evaluate genotoxic and cytotoxic effects. The concentrations of N{sub 2}O and anesthetics were measured via a portable infrared spectrophotometer. The average concentration of waste gases was greater than 5 parts per million (ppm) for all of the halogenated anesthetics and was more than 170 ppm for N{sub 2}O, expressed as a time-weighted average. There was no significant difference between the groups in relation to lymphocyte DNA damage. The exposed group had higher frequencies of MN, karyorrhexis and

  17. 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.

  18. 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.

  19. 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.

  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. 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.

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

    Directory of Open Access Journals (Sweden)

    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.

  3. 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.

  4. 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.

  5. 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.)

  6. 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

  7. 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.

  8. 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

  9. 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

  10. 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

  11. 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

  12. 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

  13. 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.

  14. [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

  15. 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.

  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. 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

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

    Directory of Open Access Journals (Sweden)

    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.

  20. 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.

  1. 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.

  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. 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

  4. 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.

  5. [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.

  6. 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)

  7. 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.

  8. 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.

  9. 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.

  10. 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.

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

    Directory of Open Access Journals (Sweden)

    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

  12. 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.

  13. 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.

  14. 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.

  15. 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

  16. 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.

  17. 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.

  18. 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

  19. 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.

  20. 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

  1. 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

  2. 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.

  3. 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.

  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. 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

  7. 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.

  8. 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.

  9. 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)

  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. 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.

  12. 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.

  13. 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

  14. 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

  15. 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...

  16. 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

  17. 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.

  18. 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.

  19. 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.

  20. 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.

  1. 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.

  2. 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

    The Trp53 gene is clearly associated with increased cancer risk. This, coupled with the broad understanding of its mode of action at the molecular level, makes this gene a good candidate for investigating the relationship between genetic risk factors and spontaneous cancer occurring in a mouse model exposed to low dose radiation. We have shown that adaptive response to chronic low dose radiation could increase cancer latency, as well as overall lifespan. To better understand the molecular processes that influence cellular risk, modern tools in molecular biology were used to evaluate the loss of heterozigozity (LOH) at the Trp53 locus, and chromosomal instability in the cells from mice exposed to chronic low dose radiation. Female mice carrying a single defective copy of the Trp53 gene were irradiated with doses of gamma-radiation delivered at a low dose rate of about 0.7 mGy/hr. Groups of mice (5 irradiated and 5 unexposed) were exposed to 0.33 mGy per day for 15, 30, 45, 60, 67 and 75 weeks equaling total body doses of 2.4, 4.7, 7.2, 9.7, 10.9 and 12.1 cGy, respectively. The presence of a single defective copy of the Trp53 gene increases cancer risk in these mice. However, in vivo exposure to low dose radiation increased cancer latency. We hypothesized that: (1) These mice might have spontaneous chromosome instability, and (2) that this low dose adaptive exposure would reduce the chromosomal instability. This instability was investigated using spectral karyotyping (SKY). Bone marrow cells from 5 irradiated mice (doses of 10.9 and 12.1 cGy) and 5 control mice were collected for metaphase harvest. Briefly, the cells were incubated at 37 C for 4 hours in RPMI containing 25% heat-inactivated FBS and 0.1 mg/ml colcemid, and then given a hypotonic treatment of 0.075M KCl for 20 minutes at 37 C. An average of 100 metaphases per mouse were karyotyped. The Trp53 heterozygous mice do not show apparent structural chromosome instability. From both unexposed and irradiated

  3. 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.

  4. 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.

  5. 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.

  6. 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....

  7. 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.

  8. 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.

  9. 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

  10. 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.

  11. 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.

  12. 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.

  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. 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.

  15. 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.

  16. 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.

  17. 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

  18. 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

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

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    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.

  20. 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.

  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. 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

  3. 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.

  4. 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

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

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    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.

  6. 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.

  7. 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

  8. 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

  9. 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.

  10. 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.

  11. 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

  12. 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.

  13. 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

  14. 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.

  15. 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

  16. 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.

  17. 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

  18. 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

  19. 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.

  20. 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.

  1. 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.)

  2. 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...

  3. 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.

  4. 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.)

  5. 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.)

  6. 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

  7. 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

  8. 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...

  9. 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.)

  10. 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

  11. 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.)

  12. 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.

  13. 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

  14. 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

  15. 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.

  16. 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

  17. Instabilities in inhomogeneous plasma

    International Nuclear Information System (INIS)

    Mikhailovsky, A.B.

    1983-01-01

    The plasma inhomogeneity across the magnetic field causes a wide class of instabilities which are called instabilities of an inhomogeneous plasma or gradient instabilities. The instabilities that can be studied in the approximation of a magnetic field with parallel straight field lines are treated first, followed by a discussion of the influence of shear on these instabilities. The instabilities of a weakly inhomogeneous plasma with the Maxwellian velocity distribution of particles caused by the density and temperature gradients are often called drift instabilities, and the corresponding types of perturbations are the drift waves. An elementary theory of drift instabilities is presented, based on the simplest equations of motion of particles in the field of low-frequency and long-wavelength perturbations. Following that is a more complete theory of inhomogeneous collisionless plasma instabilities which uses the permittivity tensor and, in the case of electrostatic perturbations, the scalar of permittivity. The results are used to study the instabilities of a strongly inhomogeneous plasma. The instabilities of a plasma in crossed fields are discussed and the electromagnetic instabilities of plasma with finite and high pressure are described. (Auth.)

  18. 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

  19. 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.

  20. 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.

  1. Hydrodynamic instabilities in inertial fusion

    International Nuclear Information System (INIS)

    Hoffman, N.M.

    1994-01-01

    This report discusses topics on hydrodynamics instabilities in inertial confinement: linear analysis of Rayleigh-Taylor instability; ablation-surface instability; bubble rise in late-stage Rayleigh-Taylor instability; and saturation and multimode interactions in intermediate-stage Rayleigh-Taylor instability

  2. Chromosomal Instability in Gastric Cancer Biology

    Directory of Open Access Journals (Sweden)

    Saffiyeh Saboor Maleki

    2017-05-01

    Full Text Available Gastric cancer (GC is the fifth most common cancer in the world and accounts for 7% of the total cancer incidence. The prognosis of GC is dismal in Western countries due to late diagnosis: approximately 70% of the patients die within 5 years following initial diagnosis. Recently, integrative genomic analyses led to the proposal of a molecular classification of GC into four subtypes, i.e.,microsatellite-instable, Epstein-Barr virus–positive, chromosomal-instable (CIN, and genomically stable GCs. Molecular classification of GC advances our knowledge of the biology of GC and may have implications for diagnostics and patient treatment. Diagnosis of microsatellite-instable GC and Epstein-Barr virus–positive GC is more or less straightforward. Microsatellite instability can be tested by immunohistochemistry (MLH1, PMS2, MSH2, and MSH6 and/or molecular-biological analysis. Epstein-Barr virus–positive GC can be tested by in situ hybridization (Epstein-Barr virus encoded small RNA. However, with regard to CIN, testing may be more complicated and may require a more in-depth knowledge of the underlying mechanism leading to CIN. In addition, CIN GC may not constitute a distinct subgroup but may rather be a compilation of a more heterogeneous group of tumors. In this review, we aim to clarify the definition of CIN and to point out the molecular mechanisms leading to this molecular phenotype and the challenges faced in characterizing this type of cancer.

  3. Tearing instabilities in turbulence

    International Nuclear Information System (INIS)

    Ishizawa, A.; Nakajima, N.

    2009-01-01

    Full text: Effects of micro-turbulence on tearing instabilities are investigated by numerically solving a reduced set of two-fluid equations. Micro-turbulence excites both large-scale and small-scale Fourier modes through energy transfer due to nonlinear mode coupling. The energy transfer to large scale mode does not directly excite tearing instability but it gives an initiation of tearing instability. When tearing instability starts to grow, the excited small scale mode plays an important role. The mixing of magnetic flux by micro-turbulence is the dominant factor of non-ideal MHD effect at the resonant surface and it gives rise to magnetic reconnection which causes tearing instability. Tearing instabilities were investigated against static equilibrium or flowing equilibrium so far. On the other hand, the recent progress of computer power allows us to investigate interactions between turbulence and coherent modes such as tearing instabilities in magnetically confined plasmas by means of direct numerical simulations. In order to investigate effects of turbulence on tearing instabilities we consider a situation that tearing mode is destabilized in a quasi-equilibrium including micro-turbulence. We choose an initial equilibrium that is unstable against kinetic ballooning modes and tearing instabilities. Tearing instabilities are current driven modes and thus they are unstable for large scale Fourier modes. On the other hand kinetic ballooning modes are unstable for poloidal Fourier modes that are characterized by ion Larmor radius. The energy of kinetic ballooning modes spreads over wave number space through nonlinear Fourier mode coupling. We present that micro-turbulence affects tearing instabilities in two different ways by three-dimensional numerical simulation of a reduced set of two-fluid equations. One is caused by energy transfer to large scale modes, the other is caused by energy transfer to small scale modes. The former is the excitation of initial

  4. 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

  5. Character of decay instability

    International Nuclear Information System (INIS)

    Polovin, R.V.; Demutskii, V.P.

    1981-01-01

    If the initial wave is unstable in the upper half plane Im ω>0 and there are no branch points of the quasiwave number, or if waves traveling in the same direction coalesce at a branch point, the instability is convective. On the other hand, if a branch point k(ω) does exist in the upper half-plane Im ω>0, and not all the waves that merge at this point travel in the same direction, the instability is absolute. A Green's function that describes the evolution of the perturbations of the initial wave in space and in time is constructed. The growth rates of the decay instability of the harmonics are determined. The produced waves are richer in harmonics than the initial waves. It is shown that the decay instability of an Alfven wave is absolute

  6. Spondylolisthesis and Posterior Instability

    International Nuclear Information System (INIS)

    Niggemann, P.; Beyer, H.K.; Frey, H.; Grosskurth, D.; Simons, P.; Kuchta, J.

    2009-01-01

    We present the case of a patient with a spondylolisthesis of L5 on S1 due to spondylolysis at the level L5/S1. The vertebral slip was fixed and no anterior instability was found. Using functional magnetic resonance imaging (MRI) in an upright MRI scanner, posterior instability at the level of the spondylolytic defect of L5 was demonstrated. A structure, probably the hypertrophic ligament flava, arising from the spondylolytic defect was displaced toward the L5 nerve root, and a bilateral contact of the displaced structure with the L5 nerve root was shown in extension of the spine. To our knowledge, this is the first case described of posterior instability in patients with spondylolisthesis. The clinical implications of posterior instability are unknown; however, it is thought that this disorder is common and that it can only be diagnosed using upright MRI

  7. Spondylolisthesis and Posterior Instability

    Energy Technology Data Exchange (ETDEWEB)

    Niggemann, P.; Beyer, H.K.; Frey, H.; Grosskurth, D. (Privatpraxis fuer Upright MRT, Koeln (Germany)); Simons, P.; Kuchta, J. (Media Park Klinik, Koeln (Germany))

    2009-04-15

    We present the case of a patient with a spondylolisthesis of L5 on S1 due to spondylolysis at the level L5/S1. The vertebral slip was fixed and no anterior instability was found. Using functional magnetic resonance imaging (MRI) in an upright MRI scanner, posterior instability at the level of the spondylolytic defect of L5 was demonstrated. A structure, probably the hypertrophic ligament flava, arising from the spondylolytic defect was displaced toward the L5 nerve root, and a bilateral contact of the displaced structure with the L5 nerve root was shown in extension of the spine. To our knowledge, this is the first case described of posterior instability in patients with spondylolisthesis. The clinical implications of posterior instability are unknown; however, it is thought that this disorder is common and that it can only be diagnosed using upright MRI.

  8. Streaming gravity mode instability

    International Nuclear Information System (INIS)

    Wang Shui.

    1989-05-01

    In this paper, we study the stability of a current sheet with a sheared flow in a gravitational field which is perpendicular to the magnetic field and plasma flow. This mixing mode caused by a combined role of the sheared flow and gravity is named the streaming gravity mode instability. The conditions of this mode instability are discussed for an ideal four-layer model in the incompressible limit. (author). 5 refs

  9. 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)

  10. Plasma physics and instabilities

    International Nuclear Information System (INIS)

    Lashmore-Davies, C.N.

    1981-01-01

    These lectures procide an introduction to the theory of plasmas and their instabilities. Starting from the Bogoliubov, Born, Green, Kirkwood, and Yvon (BBGKY) hierarchy of kinetic equations, the additional concept of self-consistent fields leads to the fundamental Vlasov equation and hence to the warm two-fluid model and the one-fluid MHD, or cold, model. The properties of small-amplitude waves in magnetized (and unmagnetized) plasmas, and the instabilities to which they give rise, are described in some detail, and a complete chapter is devoted to Landau damping. The linear theory of plasma instabilities is illustrated by the current-driven electrostatic kind, with descriptions of the Penrose criterion and the energy principle of ideal MHD. There is a brief account of the application of feedback control. The non-linear theory is represented by three examples: quasi-linear velocity-space instabilities, three-wave instabilities, and the stability of an arbitrarily largeamplitude wave in a plasma. (orig.)

  11. 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)

  12. Fingerprints of dynamical instabilities

    International Nuclear Information System (INIS)

    Chomaz, Ph.; Colonna, M.; Guarnera, A.

    1993-01-01

    It is explained why any reduced descriptions, such as mean field approximation, are stochastic in nature. It is shown that the introduction of this stochastic dynamics leads to a predictive theory in a statistical sens whatever the individual trajectories are characterized by the occurrence of bifurcations, instabilities or phase transitions. Concerning nuclear matter, the spinodal instability is discussed. In such a critical situation, the possibility to replace the stochastic part of the collision integral in the Boltzmann-Langevin model by the numerical noise associated with the finite number of test particles in ordinary BUU treatment is studied. It is shown that the fingerprints of these instabilities are kept during the evolution because of the relatively long recombination time compared with the typical time scales imposed by the Coulomb repulsion and the possible collective expansion. (author) 5 refs., 12 figs

  13. Instability and star evolution

    International Nuclear Information System (INIS)

    Mirzoyan, L.V.

    1981-01-01

    The observational data are discussed which testify that the phenomena of dynamical instability of stars and stellar systems are definite manifestations of their evolution. The study of these phenomena has shown that the instability is a regular phase of stellar evolution. It has resulted in the recognition of the most important regularities of the process of star formation concerning its nature. This became possible due to the discovery in 1947 of stellar associations in our Galaxy. The results of the study of the dynamical instability of stellar associations contradict the predictions of classical hypothesis of stellar condensation. These data supplied a basis for a new hypothesis on the formation of stars and nebulae by the decay of superdense protostars [ru

  14. The Quiescent Cellular State is Arf/p53-Dependent and Associated with H2AX Downregulation and Genome Stability

    Directory of Open Access Journals (Sweden)

    Mitsuko Masutani

    2012-05-01

    Full Text Available Cancer is a disease associated with genomic instability and mutations. Excluding some tumors with specific chromosomal translocations, most cancers that develop at an advanced age are characterized by either chromosomal or microsatellite instability. However, it is still unclear how genomic instability and mutations are generated during the process of cellular transformation and how the development of genomic instability contributes to cellular transformation. Recent studies of cellular regulation and tetraploidy development have provided insights into the factors triggering cellular transformation and the regulatory mechanisms that protect chromosomes from genomic instability.

  15. Instabilities and nonequilibrium structures

    International Nuclear Information System (INIS)

    Tirapegui, E.; Villarroel, D.

    1987-01-01

    Physical systems can be studied both near to and far from equilibrium where instabilities appear. The behaviour in these two regions is reviewed in this book, from both the theoretical and application points of view. The influence of noise in these situations is an essential feature which cannot be ignored. It is therefore discussed using phenomenological and theoretical approaches for the numerous problems which still remain in the field. This volume should appeal to mathematicians and physicists interested in the areas of instability, bifurcation theory, dynamical systems, pattern formation, nonequilibrium structures and statistical mechanics. (Auth.)

  16. RINGED ACCRETION DISKS: INSTABILITIES

    Energy Technology Data Exchange (ETDEWEB)

    Pugliese, D.; Stuchlík, Z., E-mail: d.pugliese.physics@gmail.com, E-mail: zdenek.stuchlik@physics.cz [Institute of Physics and Research Centre of Theoretical Physics and Astrophysics, Faculty of Philosophy and Science, Silesian University in Opava, Bezručovo náměstí 13, CZ-74601 Opava (Czech Republic)

    2016-04-01

    We analyze the possibility that several instability points may be formed, due to the Paczyński mechanism of violation of mechanical equilibrium, in the orbiting matter around a supermassive Kerr black hole. We consider a recently proposed model of a ringed accretion disk, made up by several tori (rings) that can be corotating or counter-rotating relative to the Kerr attractor due to the history of the accretion process. Each torus is governed by the general relativistic hydrodynamic Boyer condition of equilibrium configurations of rotating perfect fluids. We prove that the number of the instability points is generally limited and depends on the dimensionless spin of the rotating attractor.

  17. Chromosomal instability drives metastasis through a cytosolic DNA response.

    Science.gov (United States)

    Bakhoum, Samuel F; Ngo, Bryan; Laughney, Ashley M; Cavallo, Julie-Ann; Murphy, Charles J; Ly, Peter; Shah, Pragya; Sriram, Roshan K; Watkins, Thomas B K; Taunk, Neil K; Duran, Mercedes; Pauli, Chantal; Shaw, Christine; Chadalavada, Kalyani; Rajasekhar, Vinagolu K; Genovese, Giulio; Venkatesan, Subramanian; Birkbak, Nicolai J; McGranahan, Nicholas; Lundquist, Mark; LaPlant, Quincey; Healey, John H; Elemento, Olivier; Chung, Christine H; Lee, Nancy Y; Imielenski, Marcin; Nanjangud, Gouri; Pe'er, Dana; Cleveland, Don W; Powell, Simon N; Lammerding, Jan; Swanton, Charles; Cantley, Lewis C

    2018-01-25

    Chromosomal instability is a hallmark of cancer that results from ongoing errors in chromosome segregation during mitosis. Although chromosomal instability is a major driver of tumour evolution, its role in metastasis has not been established. Here we show that chromosomal instability promotes metastasis by sustaining a tumour cell-autonomous response to cytosolic DNA. Errors in chromosome segregation create a preponderance of micronuclei whose rupture spills genomic DNA into the cytosol. This leads to the activation of the cGAS-STING (cyclic GMP-AMP synthase-stimulator of interferon genes) cytosolic DNA-sensing pathway and downstream noncanonical NF-κB signalling. Genetic suppression of chromosomal instability markedly delays metastasis even in highly aneuploid tumour models, whereas continuous chromosome segregation errors promote cellular invasion and metastasis in a STING-dependent manner. By subverting lethal epithelial responses to cytosolic DNA, chromosomally unstable tumour cells co-opt chronic activation of innate immune pathways to spread to distant organs.

  18. 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)

  19. Elbow joint instability

    DEFF Research Database (Denmark)

    Olsen, Bo Sanderhoff; Henriksen, M G; Søjbjerg, Jens Ole

    1994-01-01

    The effect of simultaneous ulnar and radial collateral ligament division on the kinematics of the elbow joint is studied in a cadaveric model. Severance of the anterior part of the ulnar collateral ligament and the annular ligament led to significant elbow joint instability in valgus and varus...

  20. Structural and Material Instability

    DEFF Research Database (Denmark)

    Cifuentes, Gustavo Cifuentes

    This work is a small contribution to the general problem of structural and material instability. In this work, the main subject is the analysis of cracking and failure of structural elements made from quasi-brittle materials like concrete. The analysis is made using the finite element method. Three...

  1. Agricultural Markets Instability

    NARCIS (Netherlands)

    Garrido, A.; Brümmer, B.; M'Barek, R.; Gielen-Meuwissen, M.P.M.; Morales-Opazo, C.

    2016-01-01

    Since the financial and food price crises of 2007, market instability has been a topic of major concern to agricultural economists and policy professionals. This volume provides an overview of the key issues surrounding food prices volatility, focusing primarily on drivers, long-term implications of

  2. Comment on critical instability

    International Nuclear Information System (INIS)

    King, S.F.; Suzuki, Mahiko

    1992-01-01

    We discuss the problem of the mass splitting between top and bottom quarks, within the context of Nambu-Jona-Lasinio type models involving top and bottom quark condensates. We interpret the phenomenon of 'critical instability' recently proposed to account for such a mass splitting as the fine-tuning of two vacuum expectation values in a composite two-Higgs doublet model. (orig.)

  3. Tracking Code for Microwave Instability

    International Nuclear Information System (INIS)

    Heifets, S.; SLAC

    2006-01-01

    To study microwave instability the tracking code is developed. For bench marking, results are compared with Oide-Yokoya results [1] for broad-band Q = 1 impedance. Results hint to two possible mechanisms determining the threshold of instability

  4. Instabilities in thin tunnel junctions

    International Nuclear Information System (INIS)

    Konkin, M.K.; Adler, J.G.

    1978-01-01

    Tunnel junctions prepared for inelastic electron tunneling spectroscopy are often plagued by instabilities in the 0-500-meV range. This paper relates the bias at which the instability occurs to the barrier thickness

  5. Nonlinear evolution of MHD instabilities

    International Nuclear Information System (INIS)

    Bateman, G.; Hicks, H.R.; Wooten, J.W.; Dory, R.A.

    1975-01-01

    A 3-D nonlinear MHD computer code was used to study the time evolution of internal instabilities. Velocity vortex cells are observed to persist into the nonlinear evolution. Pressure and density profiles convect around these cells for a weak localized instability, or convect into the wall for a strong instability. (U.S.)

  6. 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.

  7. Instabilities in strongly coupled plasmas

    CERN Document Server

    Kalman, G J

    2003-01-01

    The conventional Vlasov treatment of beam-plasma instabilities is inappropriate when the plasma is strongly coupled. In the strongly coupled liquid state, the strong correlations between the dust grains fundamentally affect the conditions for instability. In the crystalline state, the inherent anisotropy couples the longitudinal and transverse polarizations, and results in unstable excitations in both polarizations. We summarize analyses of resonant and non-resonant, as well as resistive instabilities. We consider both ion-dust streaming and dust beam-plasma instabilities. Strong coupling, in general, leads to an enhancement of the growth rates. In the crystalline phase, a resonant transverse instability can be excited.

  8. Orphans and political instability.

    Science.gov (United States)

    Breuning, Marijke; Ishiyama, John

    2011-01-01

    This study investigates the security implications of growing orphan populations, particularly in Sub-Saharan Africa. Little has been written about the security implications of this especially vulnerable group of children. Are growing orphan populations associated with increases in political instability as has been suggested? Using data from several sources, we employ regression analysis to test whether Sub-Saharan African countries with larger proportions of orphans and those with increasing orphan populations experience higher rates of political instability. We find that the increase in the orphan population is related to an increasing incidence of civil conflict, but do not find a similar relationship for the proportion of orphans. In addition, we find that the causes of orphanhood matter. We conclude that increases in orphan populations (rather than simple proportions) are destabilizing. We suggest possible avenues for mediating the security risks posed by growing orphan populations.

  9. A trickle instability

    Science.gov (United States)

    Bossa, Benjamin

    2005-11-01

    We address the problem of the free fall of a long, horizontal and narrow liquid layer squeezed in a vertical open Hele-Shaw cell. The layer destabilizes as it falls down, evolving into a series of liquid blobs linked together by thin bridges, which ultimately break, leaving the initially connex fluid layer as a set a disjointed drops. The mechanism of this instability is the onset of a vertical pressure gradient due to the curvature difference of the moving contact line between the advancing interface and the rear interface. This instability, whose growth rate scales with a non-trivial power of the capillary number, amplifies indifferently a broad band of wavenumbers because of the flat shape of its dispersion relation in the thin layer limit. We will finally comment on the nature of the final fragmentation process and drop size distributions.

  10. Instability and internet design

    Directory of Open Access Journals (Sweden)

    Sandra Braman

    2016-09-01

    Full Text Available Instability - unpredictable but constant change in one’s environment and the means with which one deals with it - has replaced convergence as the focal problem for telecommunications policy in general and internet policy in particular. Those who designed what we now call the internet during the first decade of the effort (1969-1979, who in essence served simultaneously as its policy-makers, developed techniques for coping with instability of value for network designers today and for those involved with any kind of large-scale sociotechnical infrastructure. Analysis of the technical document series that was medium for and record of that design process reveals coping techniques that began with defining the problem and went on to include conceptual labour, social practices, and technical approaches.

  11. Imaging of patellofemoral instability

    International Nuclear Information System (INIS)

    Waldt, S.; Rummeny, E.J.

    2012-01-01

    Patellofemoral instability remains a diagnostic and therapeutic challenge due to its multifactorial genesis. The purpose of imaging is to systematically analyze predisposing factors, such as trochlear dysplasia, patella alta, tibial tuberosity-trochlear groove (TT-TG) distance, rotational deformities of the lower limb and patellar tilt. In order to evaluate anatomical abnormalities with a sufficient diagnostic accuracy, standardized measurement methods and implementation of various imaging modalities are necessary. Diagnosis of acute and often overlooked lateral patellar dislocation can be established with magnetic resonance imaging (MRI) because of its characteristic patterns of injury. Damage to the medial patellofemoral ligament (MPFL) has a significance just as high as the predisposing risk factors in relation to the cause of chronic instability. (orig.) [de

  12. Linear waves and instabilities

    International Nuclear Information System (INIS)

    Bers, A.

    1975-01-01

    The electrodynamic equations for small-amplitude waves and their dispersion relation in a homogeneous plasma are outlined. For such waves, energy and momentum, and their flow and transformation, are described. Perturbation theory of waves is treated and applied to linear coupling of waves, and the resulting instabilities from such interactions between active and passive waves. Linear stability analysis in time and space is described where the time-asymptotic, time-space Green's function for an arbitrary dispersion relation is developed. The perturbation theory of waves is applied to nonlinear coupling, with particular emphasis on pump-driven interactions of waves. Details of the time--space evolution of instabilities due to coupling are given. (U.S.)

  13. Cosmic ray driven instability

    International Nuclear Information System (INIS)

    Dorfi, E.A.; Drury, L.O.

    1985-01-01

    The interaction between energetic charged particles and thermal plasma, which forms the basis of diffusive shock acceleration, leads also to interesting dynamical phenomena. For a compressional mode propagating in a system with homoeneous energetic particle pressure it is well known that friction with the energetic particles leads to damping. The linear theory of this effect has been analyzed in detail by Ptuskin. Not so obvious is that a non-uniform energetic particle pressure can in addition amplify compressional disturbances. If the pressure gradient is sufficiently steep this growth can dominate the frictional damping and lead to an instability. It is important to not that this effect results from the collective nature of the interaction between the energetic particles and the gas and is not connected with the Parker instability, nor with the resonant amplification of Alfven waves

  14. Instability in dynamic fracture

    Science.gov (United States)

    Fineberg, J.; Marder, M.

    1999-05-01

    The fracture of brittle amorphous materials is an especially challenging problem, because the way a large object shatters is intimately tied to details of cohesion at microscopic scales. This subject has been plagued by conceptual puzzles, and to make matters worse, experiments seemed to contradict the most firmly established theories. In this review, we will show that the theory and experiments fit within a coherent picture where dynamic instabilities of a crack tip play a crucial role. To accomplish this task, we first summarize the central results of linear elastic dynamic fracture mechanics, an elegant and powerful description of crack motion from the continuum perspective. We point out that this theory is unable to make predictions without additional input, information that must come either from experiment, or from other types of theories. We then proceed to discuss some of the most important experimental observations, and the methods that were used to obtain the them. Once the flux of energy to a crack tip passes a critical value, the crack becomes unstable, and it propagates in increasingly complicated ways. As a result, the crack cannot travel as quickly as theory had supposed, fracture surfaces become rough, it begins to branch and radiate sound, and the energy cost for crack motion increases considerably. All these phenomena are perfectly consistent with the continuum theory, but are not described by it. Therefore, we close the review with an account of theoretical and numerical work that attempts to explain the instabilities. Currently, the experimental understanding of crack tip instabilities in brittle amorphous materials is fairly detailed. We also have a detailed theoretical understanding of crack tip instabilities in crystals, reproducing qualitatively many features of the experiments, while numerical work is beginning to make the missing connections between experiment and theory.

  15. Relativistic centrifugal instability

    Science.gov (United States)

    Gourgouliatos, Konstantinos N.; Komissarov, Serguei S.

    2018-03-01

    Near the central engine, many astrophysical jets are expected to rotate about their axis. Further out they are expected to go through the processes of reconfinement and recollimation. In both these cases, the flow streams along a concave surface and hence, it is subject to the centrifugal force. It is well known that such flows may experience the centrifugal instability (CFI), to which there are many laboratory examples. The recent computer simulations of relativistic jets from active galactic nuclei undergoing the process of reconfinement show that in such jets CFI may dominate over the Kelvin-Helmholtz instability associated with velocity shear (Gourgouliatos & Komissarov). In this letter, we generalize the Rayleigh criterion for CFI in rotating fluids to relativistic flows using a heuristic analysis. We also present the results of computer simulations which support our analytic criterion for the case of an interface separating two uniformly rotating cylindrical flows. We discuss the difference between CFI and the Rayleigh-Taylor instability in flows with curved streamlines.

  16. Analyses of MHD instabilities

    International Nuclear Information System (INIS)

    Takeda, Tatsuoki

    1985-01-01

    In this article analyses of the MHD stabilities which govern the global behavior of a fusion plasma are described from the viewpoint of the numerical computation. First, we describe the high accuracy calculation of the MHD equilibrium and then the analysis of the linear MHD instability. The former is the basis of the stability analysis and the latter is closely related to the limiting beta value which is a very important theoretical issue of the tokamak research. To attain a stable tokamak plasma with good confinement property it is necessary to control or suppress disruptive instabilities. We, next, describe the nonlinear MHD instabilities which relate with the disruption phenomena. Lastly, we describe vectorization of the MHD codes. The above MHD codes for fusion plasma analyses are relatively simple though very time-consuming and parts of the codes which need a lot of CPU time concentrate on a small portion of the codes, moreover, the codes are usually used by the developers of the codes themselves, which make it comparatively easy to attain a high performance ratio on the vector processor. (author)

  17. Ion temperature gradient instability

    International Nuclear Information System (INIS)

    1989-01-01

    Anomalous ion thermal conductivity remains an open physics issue for the present generation of high temperature Tokamaks. It is generally believed to be due to Ion Temperature Gradient Instability (η i mode). However, it has been difficult, if not impossible to identify this instability and study the anomalous transport due to it, directly. Therefore the production and identification of the mode is pursued in the simpler and experimentally convenient configuration of the Columbia Linear Machine (CLM). CLM is a steady state machine which already has all the appropriate parameters, except η i . This parameter is being increased to the appropriate value of the order of 1 by 'feathering' a tungsten screen located between the plasma source and the experimental cell to flatten the density profile and appropriate redesign of heating antennas to steepen the ion temperature profile. Once the instability is produced and identified, a thorough study of the characteristics of the mode can be done via a wide range of variation of all the critical parameters: η i , parallel wavelength, etc

  18. Ionising radiation and trans-generational instability

    International Nuclear Information System (INIS)

    Vrhovac, I.; Niksic, G.

    2007-01-01

    Indirect monitoring of the impact posed by ionising radiation to the genome instability of the descendants, consequent to the irradiation of one of their parents, boils down to the investigation of changes occurring exclusively in the mini-satellite loci of the cells constituting the gametal developmental line. The resultant mini-satellite mutations are expressed in their percentages, and equal to the ratio of the number of mutated alleles in that particular generation over the total number of alleles present. The impact of ionising radiation to the irradiated parent's offspring was first noticed on haematopoietic mouse stem-cells. Even though an irradiated cell of a female parent lacks any mutations whatsoever, daughter cells present with the increased mutation rates. The observed phenomenon of the so called trans-generational instability has been defined as the occurrence of mutations in the genome of individuals originating from the irradiated ancestors. Due to the aforementioned, one can conclude that these mutations need not be present in the irradiated parental cells, and do not necessarily vanish in the next few generations, but may result in the increase in mutation rates observed in the latter. The results of the investigations performed on the animal model, as well as of those carried out in human population, point to the occurrence of significant changes to be found on mini-satellite loci of the descending generation, while the mechanism underlying those changes hasn't been completely clarified yet, and, therefore, calls for the further investigation. (author)

  19. 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

  20. Instability of warped discs

    Science.gov (United States)

    Doǧan, S.; Nixon, C. J.; King, A. R.; Pringle, J. E.

    2018-05-01

    Accretion discs are generally warped. If a warp in a disc is too large, the disc can `break' apart into two or more distinct planes, with only tenuous connections between them. Further, if an initially planar disc is subject to a strong differential precession, then it can be torn apart into discrete annuli that precess effectively independently. In previous investigations, torque-balance formulae have been used to predict where and when the disc breaks into distinct parts. In this work, focusing on discs with Keplerian rotation and where the shearing motions driving the radial communication of the warp are damped locally by turbulence (the `diffusive' regime), we investigate the stability of warped discs to determine the precise criterion for an isolated warped disc to break. We find and solve the dispersion relation, which, in general, yields three roots. We provide a comprehensive analysis of this viscous-warp instability and the emergent growth rates and their dependence on disc parameters. The physics of the instability can be understood as a combination of (1) a term that would generally encapsulate the classical Lightman-Eardley instability in planar discs (given by ∂(νΣ)/∂Σ < 0) but is here modified by the warp to include ∂(ν1|ψ|)/∂|ψ| < 0, and (2) a similar condition acting on the diffusion of the warp amplitude given in simplified form by ∂(ν2|ψ|)/∂|ψ| < 0. We discuss our findings in the context of discs with an imposed precession, and comment on the implications for different astrophysical systems.

  1. System Detects Vibrational Instabilities

    Science.gov (United States)

    Bozeman, Richard J., Jr.

    1990-01-01

    Sustained vibrations at two critical frequencies trigger diagnostic response or shutdown. Vibration-analyzing electronic system detects instabilities of combustion in rocket engine. Controls pulse-mode firing of engine and identifies vibrations above threshold amplitude at 5.9 and/or 12kHz. Adapted to other detection and/or control schemes involving simultaneous real-time detection of signals above or below preset amplitudes at two or more specified frequencies. Potential applications include rotating machinery and encoders and decoders in security systems.

  2. Evaporation and Antievaporation Instabilities

    Directory of Open Access Journals (Sweden)

    Andrea Addazi

    2017-10-01

    Full Text Available We review (antievaporation phenomena within the context of quantum gravity and extended theories of gravity. The (antievaporation effect is an instability of the black hole horizon discovered in many different scenarios: quantum dilaton-gravity, f ( R -gravity, f ( T -gravity, string-inspired black holes, and brane-world cosmology. Evaporating and antievaporating black holes seem to have completely different thermodynamical features compared to standard semiclassical black holes. The purpose of this review is to provide an introduction to conceptual and technical aspects of (antievaporation effects, while discussing problems that are still open.

  3. Resonant Drag Instabilities in protoplanetary disks: the streaming instability and new, faster-growing instabilities

    Science.gov (United States)

    Squire, Jonathan; Hopkins, Philip F.

    2018-04-01

    We identify and study a number of new, rapidly growing instabilities of dust grains in protoplanetary disks, which may be important for planetesimal formation. The study is based on the recognition that dust-gas mixtures are generically unstable to a Resonant Drag Instability (RDI), whenever the gas, absent dust, supports undamped linear modes. We show that the "streaming instability" is an RDI associated with epicyclic oscillations; this provides simple interpretations for its mechanisms and accurate analytic expressions for its growth rates and fastest-growing wavelengths. We extend this analysis to more general dust streaming motions and other waves, including buoyancy and magnetohydrodynamic oscillations, finding various new instabilities. Most importantly, we identify the disk "settling instability," which occurs as dust settles vertically into the midplane of a rotating disk. For small grains, this instability grows many orders of magnitude faster than the standard streaming instability, with a growth rate that is independent of grain size. Growth timescales for realistic dust-to-gas ratios are comparable to the disk orbital period, and the characteristic wavelengths are more than an order of magnitude larger than the streaming instability (allowing the instability to concentrate larger masses). This suggests that in the process of settling, dust will band into rings then filaments or clumps, potentially seeding dust traps, high-metallicity regions that in turn seed the streaming instability, or even overdensities that coagulate or directly collapse to planetesimals.

  4. Feedback stabilization of plasma instabilities

    International Nuclear Information System (INIS)

    Cap, F.F.

    1977-01-01

    This paper reviews the theoretical and experimental aspects of feedback stabilization. After giving an outline of a general theoretical model for electrostatic instabilities the author provides a theoretical analysis of the suppression of various types of instability. Experiments which have been carried out on the feedback stabilization of various types of plasma instability are reported. An extensive list of references is given. (B.R.H.)

  5. Thermal Shrinkage for Shoulder Instability

    OpenAIRE

    Toth, Alison P.; Warren, Russell F.; Petrigliano, Frank A.; Doward, David A.; Cordasco, Frank A.; Altchek, David W.; O’Brien, Stephen J.

    2010-01-01

    Thermal capsular shrinkage was popular for the treatment of shoulder instability, despite a paucity of outcomes data in the literature defining the indications for this procedure or supporting its long-term efficacy. The purpose of this study was to perform a clinical evaluation of radiofrequency thermal capsular shrinkage for the treatment of shoulder instability, with a minimum 2-year follow-up. From 1999 to 2001, 101 consecutive patients with mild to moderate shoulder instability underwent...

  6. Political Instability and Economic Growth

    OpenAIRE

    Alberto Alesina; Sule Ozler; Nouriel Roubini; Phillip Swagel

    1992-01-01

    This paper investigates the relationship between political instability and per capita GDP growth in a sample of 113 countries for the period 1950-1982. We define ?political instability? as the propensity of a government collapse, and we estimate a model in which political instability and economic growth are jointly determined. The main result of this paper is that in countries and time periods with a high propensity of government collapse, growth is significantly lower than otherwise. This ef...

  7. Instabilities in mimetic matter perturbations

    Energy Technology Data Exchange (ETDEWEB)

    Firouzjahi, Hassan; Gorji, Mohammad Ali [School of Astronomy, Institute for Research in Fundamental Sciences (IPM), P.O. Box 19395-5531, Tehran (Iran, Islamic Republic of); Mansoori, Seyed Ali Hosseini, E-mail: firouz@ipm.ir, E-mail: gorji@ipm.ir, E-mail: shosseini@shahroodut.ac.ir, E-mail: shossein@ipm.ir [Physics Department, Shahrood University of Technology, P.O. Box 3619995161 Shahrood (Iran, Islamic Republic of)

    2017-07-01

    We study cosmological perturbations in mimetic matter scenario with a general higher derivative function. We calculate the quadratic action and show that both the kinetic term and the gradient term have the wrong sings. We perform the analysis in both comoving and Newtonian gauges and confirm that the Hamiltonians and the associated instabilities are consistent with each other in both gauges. The existence of instabilities is independent of the specific form of higher derivative function which generates gradients for mimetic field perturbations. It is verified that the ghost instability in mimetic perturbations is not associated with the higher derivative instabilities such as the Ostrogradsky ghost.

  8. Transcription as a Threat to Genome Integrity.

    Science.gov (United States)

    Gaillard, Hélène; Aguilera, Andrés

    2016-06-02

    Genomes undergo different types of sporadic alterations, including DNA damage, point mutations, and genome rearrangements, that constitute the basis for evolution. However, these changes may occur at high levels as a result of cell pathology and trigger genome instability, a hallmark of cancer and a number of genetic diseases. In the last two decades, evidence has accumulated that transcription constitutes an important natural source of DNA metabolic errors that can compromise the integrity of the genome. Transcription can create the conditions for high levels of mutations and recombination by its ability to open the DNA structure and remodel chromatin, making it more accessible to DNA insulting agents, and by its ability to become a barrier to DNA replication. Here we review the molecular basis of such events from a mechanistic perspective with particular emphasis on the role of transcription as a genome instability determinant.

  9. Instability characteristics of fluidelastic instability of tube rows in crossflow

    International Nuclear Information System (INIS)

    Chen, S.S.; Jendrzejczyk, J.A.

    1986-04-01

    An experimental study is reported to investigate the jump phenomenon in critical flow velocities for tube rows with different pitch-to-diameter ratios and the excited and intrinsic instabilities for a tube row with a pitch-to-diameter ratio of 1.75. The experimental data provide additional insights into the instability phenomena of tube arrays in crossflow. 9 refs., 10 figs

  10. Kinetic instabilities in relativistic plasmas: the Harris instability revisited

    International Nuclear Information System (INIS)

    Tautz, R.C.

    2008-01-01

    Plasma instabilities that generate aperiodic fluctuations are of outstanding importance in the astrophysical context. Two prominent examples are the electromagnetic Weibel instability and the electrostatic Harris instability, which operate in initially non-magnetized and magnetized plasmas, respectively. In this talk, the original formulation of the Harris instability will be reviewed and generalizations will be presented such as the inclusion of (1) relativistic effects, (2) ion effects, and (3) mode coupling. It will be shown that, with these modifications, a powerful method has been developed for the determination of both the existence and the growth rate of low-frequency instabilities. Applications can be found in astrophysical jets, where the rest frame can be used and so no parallel motion is present. At the end of the talk, how the particle composition of gamma-ray burst jets can be predicted using the Harris technique. (author)

  11. Superoxide dismutase 1-mediated production of ethanol- and DNA-derived radicals in yeasts challenged with hydrogen peroxide: molecular insights into the genome instability of peroxiredoxin-null strains.

    Science.gov (United States)

    Ogusucu, Renata; Rettori, Daniel; Netto, Luis E S; Augusto, Ohara

    2009-02-27

    Peroxiredoxins are receiving increasing attention as defenders against oxidative damage and sensors of hydrogen peroxide-mediated signaling events. In the yeast Saccharomyces cerevisiae, deletion of one or more isoforms of the peroxiredoxins is not lethal but compromises genome stability by mechanisms that remain under scrutiny. Here, we show that cytosolic peroxiredoxin-null cells (tsa1Deltatsa2Delta) are more resistant to hydrogen peroxide than wild-type (WT) cells and consume it faster under fermentative conditions. Also, tsa1Deltatsa2Delta cells produced higher yields of the 1-hydroxyethyl radical from oxidation of the glucose metabolite ethanol, as proved by spin-trapping experiments. A major role for Fenton chemistry in radical formation was excluded by comparing WT and tsa1Deltatsa2Delta cells with respect to their levels of total and chelatable metal ions and of radical produced in the presence of chelators. The main route for 1-hydroxyethyl radical formation was ascribed to the peroxidase activity of Cu,Zn-superoxide dismutase (Sod1), whose expression and activity increased approximately 5- and 2-fold, respectively, in tsa1Deltatsa2Delta compared with WT cells. Accordingly, overexpression of human Sod1 in WT yeasts led to increased 1-hydroxyethyl radical production. Relevantly, tsa1Deltatsa2Delta cells challenged with hydrogen peroxide contained higher levels of DNA-derived radicals and adducts as monitored by immuno-spin trapping and incorporation of (14)C from glucose into DNA, respectively. The results indicate that part of hydrogen peroxide consumption by tsa1Deltatsa2Delta cells is mediated by induced Sod1, which oxidizes ethanol to the 1-hydroxyethyl radical, which, in turn, leads to increased DNA damage. Overall, our studies provide a pathway to account for the hypermutability of peroxiredoxin-null strains.

  12. Instabilities in the aether

    International Nuclear Information System (INIS)

    Carroll, Sean M.; Dulaney, Timothy R.; Gresham, Moira I.; Tam, Heywood

    2009-01-01

    We investigate the stability of theories in which Lorentz invariance is spontaneously broken by fixed-norm vector 'aether' fields. Models with generic kinetic terms are plagued either by ghosts or by tachyons, and are therefore physically unacceptable. There are precisely three kinetic terms that are not manifestly unstable: a sigma model (∂ μ A ν ) 2 , the Maxwell Lagrangian F μν F μν , and a scalar Lagrangian (∂ μ A μ ) 2 . The timelike sigma-model case is well defined and stable when the vector norm is fixed by a constraint; however, when it is determined by minimizing a potential there is necessarily a tachyonic ghost, and therefore an instability. In the Maxwell and scalar cases, the Hamiltonian is unbounded below, but at the level of perturbation theory there are fewer degrees of freedom and the models are stable. However, in these two theories there are obstacles to smooth evolution for certain choices of initial data.

  13. Posterolateral elbow joint instability

    DEFF Research Database (Denmark)

    Olsen, Bo Sanderhoff; Søjbjerg, Jens Ole; Nielsen, K K

    1998-01-01

    Thirty-five osteoligamentous elbows were included in a study on the kinematics of posterolateral elbow joint instability during the pivot shift test (PST) before and after separate ligament cuttings in the lateral collateral ligament complex (LCLC). Division of the annular ligament or the lateral...... ulnar collateral ligament caused no laxity during the PST. Division of the lateral collateral ligament caused maximal laxity of 4 degrees and 23 degrees during forced PST in valgus and external rotation (supination), respectively. Cutting of the LCLC at the ulnar or the humeral insertion was necessary...... for any PST stressed elbow joint laxity to occur. Total division of the LCLC induced a maximal laxity of 7.9 degrees and 37 degrees during forced PST in valgus and external rotation (supination), respectively. This study suggests the lateral collateral ligament to be the primary soft tissue constraint...

  14. Instabilities in electromagnetic quasilevitation.

    Science.gov (United States)

    Spragg, Kirk; Letout, Sebastien; Ernst, R; Sneyd, Alfred; Fautrelle, Yves

    2014-05-01

    We investigate free-surface instabilities occurring in various industrial processes involving liquid metal. Of particular interest is the behavior of the free surface of a pool of liquid metal when it is submitted to an alternating magnetic field. Experimentally, we study the effect of a vertical alternating medium-frequency magnetic field on an initially circular pool. We observe various types of behavior according to magnetic field amplitude, e.g., axisymmetric deformations, azimuthal mode structures, slow radial oscillation of the pool perimeter, and random rotation of the pool around its center. Drop rotation could be attributed to nonsymmetric shape deformations. The effect of oxidation leads to drastic changes in pool behavior. The experimental results are then compared to a linear stability analysis of the free surface of a circular liquid drop.

  15. From instabilities to multifragmentation

    International Nuclear Information System (INIS)

    Chomaz, P.; Jacquot, B.; Colonna, M.; Guarnera, A.

    1994-01-01

    The main purpose of this article is to show that, in many physical situations, the spinodal decomposition of unstable systems can be correctly described by stochastic mean-field approaches. Such theories predict that the occurrence of spinodal instability leading the multifragmentation of an expended nuclear system, can be signed through the observation of time scales for the fragment formation of the order of 100 fm/c and of typical fragment size around A=20. We will finally discuss the fact that these fragments are formed at finite temperature and so can subsequently decay in flight. Finally, we will give some hints about possible experimental signals of such first order phase transitions. (authors). 12 refs., 5 figs

  16. From instabilities to multifragmentation

    Energy Technology Data Exchange (ETDEWEB)

    Chomaz, P.; Jacquot, B. [Grand Accelerateur National d`Ions Lourds (GANIL), 14 - Caen (France); Colonna, M.; Guarnera, A. [Grand Accelerateur National d`Ions Lourds (GANIL), 14 - Caen (France)]|[Istituto Nazionale di Fisica Nucleare, Bologna (Italy)

    1994-12-31

    The main purpose of this article is to show that, in many physical situations, the spinodal decomposition of unstable systems can be correctly described by stochastic mean-field approaches. Such theories predict that the occurrence of spinodal instability leading the multifragmentation of an expended nuclear system, can be signed through the observation of time scales for the fragment formation of the order of 100 fm/c and of typical fragment size around A=20. We will finally discuss the fact that these fragments are formed at finite temperature and so can subsequently decay in flight. Finally, we will give some hints about possible experimental signals of such first order phase transitions. (authors). 12 refs., 5 figs.

  17. Saturation of equatorial inertial instability

    NARCIS (Netherlands)

    Kloosterziel, R.C.; Orlandi, P.; Carnevale, G.F.

    2015-01-01

    Inertial instability in parallel shear flows and circular vortices in a uniformly rotating system ( $f$f-plane) redistributes absolute linear momentum or absolute angular momentum in such a way as to neutralize the instability. In previous studies we showed that, in the absence of other

  18. Internal rotor friction instability

    Science.gov (United States)

    Walton, J.; Artiles, A.; Lund, J.; Dill, J.; Zorzi, E.

    1990-01-01

    The analytical developments and experimental investigations performed in assessing the effect of internal friction on rotor systems dynamic performance are documented. Analytical component models for axial splines, Curvic splines, and interference fit joints commonly found in modern high speed turbomachinery were developed. Rotor systems operating above a bending critical speed were shown to exhibit unstable subsynchronous vibrations at the first natural frequency. The effect of speed, bearing stiffness, joint stiffness, external damping, torque, and coefficient of friction, was evaluated. Testing included material coefficient of friction evaluations, component joint quantity and form of damping determinations, and rotordynamic stability assessments. Under conditions similar to those in the SSME turbopumps, material interfaces experienced a coefficient of friction of approx. 0.2 for lubricated and 0.8 for unlubricated conditions. The damping observed in the component joints displayed nearly linear behavior with increasing amplitude. Thus, the measured damping, as a function of amplitude, is not represented by either linear or Coulomb friction damper models. Rotordynamic testing of an axial spline joint under 5000 in.-lb of static torque, demonstrated the presence of an extremely severe instability when the rotor was operated above its first flexible natural frequency. The presence of this instability was predicted by nonlinear rotordynamic time-transient analysis using the nonlinear component model developed under this program. Corresponding rotordynamic testing of a shaft with an interference fit joint demonstrated the presence of subsynchronous vibrations at the first natural frequency. While subsynchronous vibrations were observed, they were bounded and significantly lower in amplitude than the synchronous vibrations.

  19. Dynamical Instability and Soliton Concept

    International Nuclear Information System (INIS)

    Kartavenko, V.G.

    1994-01-01

    The problem of dynamical instability and clustering (stable fragments formation) in a breakup of excited nuclear systems are considered from the points of view of the soliton concept. It is noted that the volume (spinodal) instability can be associated with nonlinear terms, and the surface (Rayleigh-Taylor type) instability, with the dispersion terms in the evolution equations. The spinodal instability and the Rayleigh-Taylor instability may compensate each other and lead to stable quasi-soliton type objects. The simple analytical model is presented to illustrate this physical picture. The time evolution of an initially compressed cold nuclear system is analysed in the framework of the inverse mean-field method. It is demonstrated that the nonlinearity and dispersion terms of the evolution equations can lead to clusterization in the final channel. 8 p

  20. Beam instability Workshop - plenary sessions

    International Nuclear Information System (INIS)

    2001-01-01

    The purpose of this workshop was to provide a review of the mechanisms of limiting beam instabilities, their cures, including feedback, and beam measurement for synchrotron radiation light sources. 12 plenary sessions took place whose titles are: 1) challenging brilliance and lifetime issues with increasing currents; 2) limiting instabilities in multibunch; 3) experience from high currents in B factories; 4) longitudinal dynamics in high intensity/bunch; 5) Transverse instabilities for high intensity/bunch; 6) working group introduction from ESRF experience; 7) impedance modelling: simulations, minimization; 8) report on the broadband impedance measurements and modelling workshop; 9) feedback systems for synchrotron light sources; 10) beam instabilities diagnostics; 11) harmonic cavities: the pros and cons; and 12) experimental study of fast beam-ion instabilities at PLS. This document gathers the 12 articles that were presented during these sessions

  1. Beam instability Workshop - plenary sessions

    Energy Technology Data Exchange (ETDEWEB)

    NONE

    2001-07-01

    The purpose of this workshop was to provide a review of the mechanisms of limiting beam instabilities, their cures, including feedback, and beam measurement for synchrotron radiation light sources. 12 plenary sessions took place whose titles are: 1) challenging brilliance and lifetime issues with increasing currents; 2) limiting instabilities in multibunch; 3) experience from high currents in B factories; 4) longitudinal dynamics in high intensity/bunch; 5) Transverse instabilities for high intensity/bunch; 6) working group introduction from ESRF experience; 7) impedance modelling: simulations, minimization; 8) report on the broadband impedance measurements and modelling workshop; 9) feedback systems for synchrotron light sources; 10) beam instabilities diagnostics; 11) harmonic cavities: the pros and cons; and 12) experimental study of fast beam-ion instabilities at PLS. This document gathers the 12 articles that were presented during these sessions.

  2. Electron/electron acoustic instability

    International Nuclear Information System (INIS)

    Gary, S.P.

    1987-01-01

    The electron acoustic wave becomes a normal mode of an unmagnetized collisionless plasma in the presence of two electron components with similar densities, but strongly disparate temperatures. The characteristic frequency of this mode is the plasma frequency of the cooler electron component. If these two electron components have a relative drift speed several times the thermal speed of the cooler component, the electron/electron acoustic instability may arise. This paper describes the parametric dependences of the threshold drift speed and maximum growth rate of this instability, and compares these with the same properties of the electron/ion acoustic instability. Under the condition of zero current, the electron/ion acoustic instability typically has the lower threshold drift speed, so that observation of the electron/electron acoustic instability is a strong indication of the presence of an electrical current in the plasma

  3. Gravitational Instabilities in Circumstellar Disks

    Science.gov (United States)

    Kratter, Kaitlin; Lodato, Giuseppe

    2016-09-01

    Star and planet formation are the complex outcomes of gravitational collapse and angular momentum transport mediated by protostellar and protoplanetary disks. In this review, we focus on the role of gravitational instability in this process. We begin with a brief overview of the observational evidence for massive disks that might be subject to gravitational instability and then highlight the diverse ways in which the instability manifests itself in protostellar and protoplanetary disks: the generation of spiral arms, small-scale turbulence-like density fluctuations, and fragmentation of the disk itself. We present the analytic theory that describes the linear growth phase of the instability supplemented with a survey of numerical simulations that aim to capture the nonlinear evolution. We emphasize the role of thermodynamics and large-scale infall in controlling the outcome of the instability. Despite apparent controversies in the literature, we show a remarkable level of agreement between analytic predictions and numerical results. In the next part of our review, we focus on the astrophysical consequences of the instability. We show that the disks most likely to be gravitationally unstable are young and relatively massive compared with their host star, Md/M*≥0.1. They will develop quasi-stable spiral arms that process infall from the background cloud. Although instability is less likely at later times, once infall becomes less important, the manifestations of the instability are more varied. In this regime, the disk thermodynamics, often regulated by stellar irradiation, dictates the development and evolution of the instability. In some cases the instability may lead to fragmentation into bound companions. These companions are more likely to be brown dwarfs or stars than planetary mass objects. Finally, we highlight open questions related to the development of a turbulent cascade in thin disks and the role of mode-mode coupling in setting the maximum angular

  4. Thermal shrinkage for shoulder instability.

    Science.gov (United States)

    Toth, Alison P; Warren, Russell F; Petrigliano, Frank A; Doward, David A; Cordasco, Frank A; Altchek, David W; O'Brien, Stephen J

    2011-07-01

    Thermal capsular shrinkage was popular for the treatment of shoulder instability, despite a paucity of outcomes data in the literature defining the indications for this procedure or supporting its long-term efficacy. The purpose of this study was to perform a clinical evaluation of radiofrequency thermal capsular shrinkage for the treatment of shoulder instability, with a minimum 2-year follow-up. From 1999 to 2001, 101 consecutive patients with mild to moderate shoulder instability underwent shoulder stabilization surgery with thermal capsular shrinkage using a monopolar radiofrequency device. Follow-up included a subjective outcome questionnaire, discussion of pain, instability, and activity level. Mean follow-up was 3.3 years (range 2.0-4.7 years). The thermal capsular shrinkage procedure failed due to instability and/or pain in 31% of shoulders at a mean time of 39 months. In patients with unidirectional anterior instability and those with concomitant labral repair, the procedure proved effective. Patients with multidirectional instability had moderate success. In contrast, four of five patients with isolated posterior instability failed. Thermal capsular shrinkage has been advocated for the treatment of shoulder instability, particularly mild to moderate capsular laxity. The ease of the procedure makes it attractive. However, our retrospective review revealed an overall failure rate of 31% in 80 patients with 2-year minimum follow-up. This mid- to long-term cohort study adds to the literature lacking support for thermal capsulorrhaphy in general, particularly posterior instability. The online version of this article (doi:10.1007/s11420-010-9187-7) contains supplementary material, which is available to authorized users.

  5. Instability timescale for the inclination instability in the solar system

    Science.gov (United States)

    Zderic, Alexander; Madigan, Ann-Marie; Fleisig, Jacob

    2018-04-01

    The gravitational influence of small bodies is often neglected in the study of solar system dynamics. However, this is not always an appropriate assumption. For example, mutual secular torques between low mass particles on eccentric orbits can result in a self-gravity instability (`inclination instability'; Madigan & McCourt 2016). During the instability, inclinations increase exponentially, eccentricities decrease (detachment), and orbits cluster in argument of perihelion. In the solar system, the orbits of the most distant objects show all three of these characteristics (high inclination: Volk & Malhotra (2017), detachment: Delsanti & Jewitt (2006), and argument of perihelion clustering: Trujillo & Sheppard (2014)). The inclination instability is a natural explanation for these phenomena.Unfortunately, full N-body simulations of the solar system are unfeasible (N ≈ O(1012)), and the behavior of the instability depends on N, prohibiting the direct application of lower N simulations. Here we present the instability timescale's functional dependence on N, allowing us to extrapolate our simulation results to that appropriate for the solar system. We show that ~5 MEarth of small icy bodies in the Sedna region is sufficient for the inclination instability to occur in the outer solar system.

  6. 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.

  7. Non-random distribution of instability-associated chromosomal rearrangement breakpoints in human lymphoblastoid cells

    International Nuclear Information System (INIS)

    Moore, Stephen R.; Papworth, David; Grosovsky, Andrew J.

    2006-01-01

    Genomic instability is observed in tumors and in a large fraction of the progeny surviving irradiation. One of the best-characterized phenotypic manifestations of genomic instability is delayed chromosome aberrations. Our working hypothesis for the current study was that if genomic instability is in part attributable to cis mechanisms, we should observe a non-random distribution of chromosomes or sites involved in instability-associated rearrangements, regardless of radiation quality, dose, or trans factor expression. We report here the karyotypic examination of 296 instability-associated chromosomal rearrangement breaksites (IACRB) from 118 unstable TK6 human B lymphoblast, and isogenic derivative, clones. When we tested whether IACRB were distributed across the chromosomes based on target size, a significant non-random distribution was evident (p < 0.00001), and three IACRB hotspots (chromosomes 11, 12, and 22) and one IACRB coldspot (chromosome 2) were identified. Statistical analysis at the chromosomal band-level identified four IACRB hotspots accounting for 20% of all instability-associated breaks, two of which account for over 14% of all IACRB. Further, analysis of independent clones provided evidence within 14 individual clones of IACRB clustering at the chromosomal band level, suggesting a predisposition for further breaks after an initial break at some chromosomal bands. All of these events, independently, or when taken together, were highly unlikely to have occurred by chance (p < 0.000001). These IACRB band-level cluster hotspots were observed independent of radiation quality, dose, or cellular p53 status. The non-random distribution of instability-associated chromosomal rearrangements described here significantly differs from the distribution that was observed in a first-division post-irradiation metaphase analysis (p = 0.0004). Taken together, these results suggest that genomic instability may be in part driven by chromosomal cis mechanisms

  8. Functional Instability of the Ankle Joint: Etiopathogenesis

    Directory of Open Access Journals (Sweden)

    Aydan ÖRSÇELİK

    2016-09-01

    Full Text Available Ankle sprain is one of the most common sports injuries. Chronic ankle instability is a common complication of ankle sprains. Two causes of chronic ankle instability are mechanical instability and functional instability. It is important to understand functional instability etiopathogenesis of the ankle joint in order to guide diagnosis and treatment. This article aims to understand the etiopathogenesis of functional ankle instability.

  9. Size effects on cavitation instabilities

    DEFF Research Database (Denmark)

    Niordson, Christian Frithiof; Tvergaard, Viggo

    2006-01-01

    growth is here analyzed for such cases. A finite strain generalization of a higher order strain gradient plasticity theory is applied for a power-law hardening material, and the numerical analyses are carried out for an axisymmetric unit cell containing a spherical void. In the range of high stress...... triaxiality, where cavitation instabilities are predicted by conventional plasticity theory, such instabilities are also found for the nonlocal theory, but the effects of gradient hardening delay the onset of the instability. Furthermore, in some cases the cavitation stress reaches a maximum and then decays...... as the void grows to a size well above the characteristic material length....

  10. Resistive instabilities in tokamaks

    International Nuclear Information System (INIS)

    Rutherford, P.H.

    1985-10-01

    Low-m tearing modes constitute the dominant instability problem in present-day tokamaks. In this lecture, the stability criteria for representative current profiles with q(0)-values slightly less than unit are reviewed; ''sawtooth'' reconnection to q(0)-values just at, or slightly exceeding, unity is generally destabilizing to the m = 2, n = 1 and m = 3, n = 2 modes, and severely limits the range of stable profile shapes. Feedback stabilization of m greater than or equal to 2 modes by rf heating or current drive, applied locally at the magnetic islands, appears feasible; feedback by island current drive is much more efficient, in terms of the radio-frequency power required, then feedback by island heating. Feedback stabilization of the m = 1 mode - although yielding particularly beneficial effects for resistive-tearing and high-beta stability by allowing q(0)-values substantially below unity - is more problematical, unless the m = 1 ideal-MHD mode can be made positively stable by strong triangular shaping of the central flux surfaces. Feedback techniques require a detectable, rotating MHD-like signal; the slowing of mode rotation - or the excitation of non-rotating modes - by an imperfectly conducting wall is also discussed

  11. Sheared Electroconvective Instability

    Science.gov (United States)

    Kwak, Rhokyun; Pham, Van Sang; Lim, Kiang Meng; Han, Jongyoon

    2012-11-01

    Recently, ion concentration polarization (ICP) and related phenomena draw attention from physicists, due to its importance in understanding electrochemical systems. Researchers have been actively studying, but the complexity of this multiscale, multiphysics phenomenon has been limitation for gaining a detailed picture. Here, we consider electroconvective(EC) instability initiated by ICP under pressure-driven flow, a scenario often found in electrochemical desalinations. Combining scaling analysis, experiment, and numerical modeling, we reveal unique behaviors of sheared EC: unidirectional vortex structures, its size selection and vortex propagation. Selected by balancing the external pressure gradient and the electric body force, which generates Hagen-Poiseuille(HP) flow and vortical EC, the dimensionless EC thickness scales as (φ2 /UHP)1/3. The pressure-driven flow(or shear) suppresses unfavorably-directed vortices, and simultaneously pushes favorably-directed vortices with constant speed, which is linearly proportional to the total shear of HP flow. This is the first systematic characterization of sheared EC, which has significant implications on the optimization of electrodialysis and other electrochemical systems.

  12. Environmental and molecular characterization of systems which affect genome alteration in pseudomonas aeruginosa

    International Nuclear Information System (INIS)

    Miller, R.V.; Kokjohn, T.A.; Sayler, G.S.

    1990-01-01

    Pseudomonas aeruginosa is used as a model organism to study genome alteration in freshwater microbial populations and horizontal gene transmission by both transduction and conjugation has been demonstrated. The studies have also provided data which suggest that intracellular genome instability may be increased in the aquatic environment as a result of stresses encountered by the cell in this habitat. The role of the P. aeruginosa recA analog in regulating genome instability is also addressed

  13. Tunnelling instability via perturbation theory

    Energy Technology Data Exchange (ETDEWEB)

    Graffi, S. (Bologna Univ. (Italy). Dip. di Matematica); Grecchi, V. (Moderna Univ. (Italy). Dip. di Matematica); Jona-Lasinio, G. (Paris-11 Univ., 91 - Orsay (France). Lab. de Physique Theorique et Hautes Energies)

    1984-10-21

    The semiclassical limit of low lying states in a multiwell potential is studied by rigorous perturbative techniques. In particular tunnelling instability and localisation of wave functions is obtained in a simple way under small deformations of symmetric potentials.

  14. Fluctuations and Instability in Sedimentation

    KAUST Repository

    Guazzelli, É lisabeth; Hinch, John

    2011-01-01

    This review concentrates on the fluctuations of the velocities of sedimenting spheres, and on the structural instability of a suspension of settling fibers. For many years, theoretical estimates and numerical simulations predicted the fluctuations

  15. 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.

  16. Instability of ties in compression

    DEFF Research Database (Denmark)

    Buch-Hansen, Thomas Cornelius

    2013-01-01

    Masonry cavity walls are loaded by wind pressure and vertical load from upper floors. These loads results in bending moments and compression forces in the ties connecting the outer and the inner wall in a cavity wall. Large cavity walls are furthermore loaded by differential movements from...... the temperature gradient between the outer and the inner wall, which results in critical increase of the bending moments in the ties. Since the ties are loaded by combined compression and moment forces, the loadbearing capacity is derived from instability equilibrium equations. Most of them are iterative, since...... exact instability solutions are complex to derive, not to mention the extra complexity introducing dimensional instability from the temperature gradients. Using an inverse variable substitution and comparing an exact theory with an analytical instability solution a method to design tie...

  17. Summary of longitudinal instabilities workshop

    Energy Technology Data Exchange (ETDEWEB)

    Chasman, R.

    1976-01-01

    A five-day ISABELLE workshop on longitudinal instabilities was held at Brookhaven, August 9-13, 1976. About a dozen outside accelerator experts, both from Europe and the U.S.A., joined the local staff for discussions of longitudinal instabilities in ISABELLE. An agenda of talks was scheduled for the first day of the workshop. Later during the week, a presentation was given on the subject ''A more rigorous treatment of Landau damping in longitudinal beam instabilities''. A few progress meetings were held in which disagreements regarding calculations of coupling impedances were clarified. A summary session was held on the last day. Heavy emphasis was put on single bunched beam instabilities in the microwave region extending above the cut-off frequency of the ISABELLE vacuum chamber.

  18. Predicting Catastrophic BGP Routing Instabilities

    National Research Council Canada - National Science Library

    Nguyen, Lien

    2004-01-01

    .... Currently, this critical function is performed by the Border Gateway Protocol (BGP) version 4 RF01771. Like all routing protocols, BGP is vulnerable to instabilities that reduce its effectiveness...

  19. WELLBORE INSTABILITY: CAUSES AND CONSEQUENCES

    Directory of Open Access Journals (Sweden)

    Borivoje Pašić

    2007-12-01

    Full Text Available Wellbore instability is one of the main problems that engineers meet during drilling. The causes of wellbore instability are often classified into either mechanical (for example, failure of the rock around the hole because of high stresses, low rock strength, or inappropriate drilling practice or chemical effects which arise from damaging interaction between the rock, generally shale, and the drilling fluid. Often, field instances of instability are a result of a combination of both chemical and mechanical. This problem might cause serious complication in well and in some case can lead to expensive operational problems. The increasing demand for wellbore stability analyses during the planning stage of a field arise from economic considerations and the increasing use of deviated, extended reach and horizontal wells. This paper presents causes, indicators and diagnosing of wellbore instability as well as the wellbore stresses model.

  20. Aerodynamic instability: A case history

    Science.gov (United States)

    Eisenmann, R. C.

    1985-01-01

    The identification, diagnosis, and final correction of complex machinery malfunctions typically require the correlation of many parameters such as mechanical construction, process influence, maintenance history, and vibration response characteristics. The progression is reviewed of field testing, diagnosis, and final correction of a specific machinery instability problem. The case history presented addresses a unique low frequency instability problem on a high pressure barrel compressor. The malfunction was eventually diagnosed as a fluidic mechanism that manifested as an aerodynamic disturbance to the rotor assembly.

  1. Surgical treatment of chest instability

    International Nuclear Information System (INIS)

    Kitka, M.; Masek, M.

    2015-01-01

    Fractures of the ribs is the most common thoracic injury after blunt trauma. Chest wall instability (flail chest) is a common occurrence in the presence of multiple ribs fracture. Unilateral or bilateral fractures more ribs anteriorly or posteriorly will produce enough instability that paradoxical respiratory motion results in hypoventilation of an unacceptable degree. Open approach and surgical stabilisation of the chest preserved pulmonary function, improved pain control, minimized posttraumatic deformities and shorter back to work time. (author)

  2. Beam Instabilities in Hadron Synchrotrons

    CERN Document Server

    Métral, E; Bartosik, H; Biancacci, N; Buffat, X; Esteban Muller, J F; Herr, W; Iadarola, G; Lasheen, A; Li, K; Oeftiger, A; Pieloni, T; Quartullo, D; Rumolo, G; Salvant, B; Schenk, M; Shaposhnikova, E; Tambasco, C; Timko, H; Zannini, C; Burov, A; Banfi, D; Barranco, J; Mounet, N; Boine-Frankenheim, O; Niedermayer, U; Kornilov, V; White, S

    2016-01-01

    Beam instabilities cover a wide range of effects in particle accelerators and they have been the subjects of intense research for several decades. As the machines performance was pushed new mechanisms were revealed and nowadays the challenge consists in studying the interplays between all these intricate phenomena, as it is very often not possible to treat the different effects separately. The aim of this paper is to review the main mechanisms, discussing in particular the recent developments of beam instability theories and simulations.

  3. Microsatellite instability in bladder cancer

    DEFF Research Database (Denmark)

    Gonzalez-Zulueta, M; Ruppert, J M; Tokino, K

    1993-01-01

    Somatic instability at microsatellite repeats was detected in 6 of 200 transitional cell carcinomas of the bladder. Instabilities were apparent as changes in (GT)n repeat lengths on human chromosome 9 for four tumors and as alterations in a (CAG)n repeat in the androgen receptor gene on the X...... or larger (> 2 base pairs) alterations in repeat length. All six tumors were low stage (Ta-T1), suggesting that these alterations can occur early in bladder tumorigenesis....

  4. Waves and instabilities in plasmas

    International Nuclear Information System (INIS)

    Chen, L.

    1987-01-01

    The contents of this book are: Plasma as a Dielectric Medium; Nyquist Technique; Absolute and Convective Instabilities; Landau Damping and Phase Mixing; Particle Trapping and Breakdown of Linear Theory; Solution of Viasov Equation via Guilding-Center Transformation; Kinetic Theory of Magnetohydrodynamic Waves; Geometric Optics; Wave-Kinetic Equation; Cutoff and Resonance; Resonant Absorption; Mode Conversion; Gyrokinetic Equation; Drift Waves; Quasi-Linear Theory; Ponderomotive Force; Parametric Instabilities; Problem Sets for Homework, Midterm and Final Examinations

  5. Instability following total knee arthroplasty.

    Science.gov (United States)

    Rodriguez-Merchan, E Carlos

    2011-10-01

    Background Knee prosthesis instability (KPI) is a frequent cause of failure of total knee arthroplasty. Moreover, the degree of constraint required to achieve immediate and long-term stability in total knee arthroplasty (TKA) is frequently debated. Questions This review aims to define the problem, analyze risk factors, and review strategies for prevention and treatment of KPI. Methods A PubMed (MEDLINE) search of the years 2000 to 2010 was performed using two key words: TKA and instability. One hundred and sixty-five initial articles were identified. The most important (17) articles as judged by the author were selected for this review. The main criteria for selection were that the articles addressed and provided solutions to the diagnosis and treatment of KPI. Results Patient-related risk factors predisposing to post-operative instability include deformity requiring a large surgical correction and aggressive ligament release, general or regional neuromuscular pathology, and hip or foot deformities. KPI can be prevented in most cases with appropriate selection of implants and good surgical technique. When ligament instability is anticipated post-operatively, the need for implants with a greater degree of constraint should be anticipated. In patients without significant varus or valgus malalignment and without significant flexion contracture, the posterior cruciate ligament (PCL) can be retained. However, the PCL should be sacrificed when deformity exists particularly in patients with rheumatoid arthritis, previous patellectomy, previous high tibial osteotomy or distal femoral osteotomy, and posttraumatic osteoarthritis with disruption of the PCL. In most cases, KPI requires revision surgery. Successful outcomes can only be obtained if the cause of KPI is identified and addressed. Conclusions Instability following TKA is a common cause of the need for revision. Typically, knees with deformity, rheumatoid arthritis, previous patellectomy or high tibial osteotomy, and

  6. Instability of enclosed horizons

    Science.gov (United States)

    Kay, Bernard S.

    2015-03-01

    We point out that there are solutions to the scalar wave equation on dimensional Minkowski space with finite energy tails which, if they reflect off a uniformly accelerated mirror due to (say) Dirichlet boundary conditions on it, develop an infinite stress-energy tensor on the mirror's Rindler horizon. We also show that, in the presence of an image mirror in the opposite Rindler wedge, suitable compactly supported arbitrarily small initial data on a suitable initial surface will develop an arbitrarily large stress-energy scalar near where the two horizons cross. Also, while there is a regular Hartle-Hawking-Israel-like state for the quantum theory between these two mirrors, there are coherent states built on it for which there are similar singularities in the expectation value of the renormalized stress-energy tensor. We conjecture that in other situations with analogous enclosed horizons such as a (maximally extended) Schwarzschild black hole in equilibrium in a (stationary spherical) box or the (maximally extended) Schwarzschild-AdS spacetime, there will be similar stress-energy singularities and almost-singularities—leading to instability of the horizons when gravity is switched on and matter and gravity perturbations are allowed for. All this suggests it is incorrect to picture a black hole in equilibrium in a box or a Schwarzschild-AdS black hole as extending beyond the past and future horizons of a single Schwarzschild (/Schwarzschild-AdS) wedge. It would thus provide new evidence for 't Hooft's brick wall model while seeming to invalidate the picture in Maldacena's ` Eternal black holes in AdS'. It would thereby also support the validity of the author's matter-gravity entanglement hypothesis and of the paper ` Brick walls and AdS/CFT' by the author and Ortíz.

  7. History of shoulder instability surgery.

    Science.gov (United States)

    Randelli, Pietro; Cucchi, Davide; Butt, Usman

    2016-02-01

    The surgical management of shoulder instability is an expanding and increasingly complex area of study within orthopaedics. This article describes the history and evolution of shoulder instability surgery, examining the development of its key principles, the currently accepted concepts and available surgical interventions. A comprehensive review of the available literature was performed using PubMed. The reference lists of reviewed articles were also scrutinised to ensure relevant information was included. The various types of shoulder instability including anterior, posterior and multidirectional instability are discussed, focussing on the history of surgical management of these topics, the current concepts and the results of available surgical interventions. The last century has seen important advancements in the understanding and treatment of shoulder instability. The transition from open to arthroscopic surgery has allowed the discovery of previously unrecognised pathologic entities and facilitated techniques to treat these. Nevertheless, open surgery still produces comparable results in the treatment of many instability-related conditions and is often required in complex or revision cases, particularly in the presence of bone loss. More high-quality research is required to better understand and characterise this spectrum of conditions so that successful evidence-based management algorithms can be developed. IV.

  8. Ionospheric modification and parametric instabilities

    International Nuclear Information System (INIS)

    Fejer, J.A.

    1979-01-01

    Thresholds and linear growth rates for stimulated Brillouin and Raman scattering and for the parametric decay instability are derived by using arguments of energy transfer. For this purpose an expression for the ponderomotive force is derived. Conditions under which the partial pressure force due to differential dissipation exceeds the ponderomotive force are also discussed. Stimulated Brillouin and Raman scattering are weakly excited by existing incoherent backscatter radars. The parametric decay instability is strongly excited in ionospheric heating experiments. Saturation theories of the parametric decay instability are therefore described. After a brief discussion of the purely growing instability the effect of using several pumps is discussed as well as the effects of inhomogenicity. Turning to detailed theories of ionospheric heating, artificial spread F is discussed in terms of a purely growing instability where the nonlinearity is due to dissipation. Field-aligned short-scale striations are explained in terms of dissipation of the parametrically excited Langmuir waves (plasma oscillations): they might be further amplified by an explosive instability (except the magnetic equator). Broadband absorption is probably responsible for the 'overshoot' effect: the initially observed level of parametrically excited Langmuir waves is much higher than the steady state level

  9. 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

  10. Extreme genomes

    OpenAIRE

    DeLong, Edward F

    2000-01-01

    The complete genome sequence of Thermoplasma acidophilum, an acid- and heat-loving archaeon, has recently been reported. Comparative genomic analysis of this 'extremophile' is providing new insights into the metabolic machinery, ecology and evolution of thermophilic archaea.

  11. Neutron star pulsations and instabilities

    International Nuclear Information System (INIS)

    Lindblom, L.

    2001-01-01

    Gravitational radiation (GR) drives an instability in certain modes of rotating stars. This instability is strong enough in the case of the r-modes to cause their amplitudes to grow on a timescale of tens of seconds in rapidly rotating neutron stars. GR emitted by these modes removes angular momentum from the star at a rate which would spin it down to a relatively small angular velocity within about one year, if the dimensionless amplitude of the mode grows to order unity. A pedagogical level discussion is given here on the mechanism of GR instability in rotating stars, on the relevant properties of the r-modes, and on our present understanding of the dissipation mechanisms that tend to suppress this instability in neutron stars. The astrophysical implications of this GR driven instability are discussed for young neutron stars, and for older systems such as low mass x-ray binaries. Recent work on the non-linear evolution of the r-modes is also presented. (author)

  12. Kinetic theory of tearing instabilities

    International Nuclear Information System (INIS)

    Drake, J.F.; Lee, Y.C.

    1977-01-01

    The transition of the tearing instability from the collisional to the collisionless regime is investigated kinetically using a Fokker--Planck collision operator to represent electron-ion collisions. As a function of the collisionality of the plasma, the tearing instability falls into three regions, which are referred to as collisionless, semi-collisional, and collisional. The width Δ of the singular layer around kxB 0 =0 is limited by electron thermal motion along B 0 in the collisional and semi-collisional regimes and is typically smaller than rho/sub i/, the ion Larmor radius. Previously accepted theories, which are based on the assumption Δvery-much-greater-thanrho/sub i/, are found to be valid only in the collisional regime. The effects of density and temperature gradients on the instabilities are also studied. The tearing instability is only driven by the temperature gradient in the collisional and semi-collisional regimes. Numerical calculations indicate that the semi-collisional tearing instability is particularly relevant to present day high temperature tokamak discharges

  13. 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.

  14. Grass genomes

    OpenAIRE

    Bennetzen, Jeffrey L.; SanMiguel, Phillip; Chen, Mingsheng; Tikhonov, Alexander; Francki, Michael; Avramova, Zoya

    1998-01-01

    For the most part, studies of grass genome structure have been limited to the generation of whole-genome genetic maps or the fine structure and sequence analysis of single genes or gene clusters. We have investigated large contiguous segments of the genomes of maize, sorghum, and rice, primarily focusing on intergenic spaces. Our data indicate that much (>50%) of the maize genome is composed of interspersed repetitive DNAs, primarily nested retrotransposons that in...

  15. DNA mismatch repair, genome instability and cancer in zebrafish

    NARCIS (Netherlands)

    Feitsma, H.

    2008-01-01

    The objective of this study was to find out whether the zebrafish can be an appropriate model for studying DNA repair and cancer. For this purpose three fish lines were used that lack components of an important mechanism for the repair of small DNA damage: DNA mismatch repair. These fish are

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

    Science.gov (United States)

    2014-03-01

    repair defects asso- ciated with downstream mediators of the HR reaction (e.g., XRCC2, BRCA2, or PALB2) (Bouwman et al., 2010; Bowman- Colin et al., 2013...and BRCA-mutated breast cancers. Nat. Struct. Mol. Biol. 17, 688–695. Bowman- Colin , C., Xia, B., Bunting, S., Klijn, C., Drost, R., Bouwman, P., Fine...chromosomes. It is thus surprising that cells use ‘quick and dirty ’ repair by NHEJ rather than the slower, more accurate repair by homologous recombination

  17. Synthetic Genetic Targeting of Genome Instability in Cancer

    International Nuclear Information System (INIS)

    Sajesh, Babu V.; Guppy, Brent J.; McManus, Kirk J.

    2013-01-01

    Cancer is a leading cause of death throughout the World. A limitation of many current chemotherapeutic approaches is that their cytotoxic effects are not restricted to cancer cells, and adverse side effects can occur within normal tissues. Consequently, novel strategies are urgently needed to better target cancer cells. As we approach the era of personalized medicine, targeting the specific molecular defect(s) within a given patient’s tumor will become a more effective treatment strategy than traditional approaches that often target a given cancer type or sub-type. Synthetic genetic interactions are now being examined for their therapeutic potential and are designed to target the specific genetic and epigenetic phenomena associated with tumor formation, and thus are predicted to be highly selective. In general, two complementary approaches have been employed, including synthetic lethality and synthetic dosage lethality, to target aberrant expression and/or function associated with tumor suppressor genes and oncogenes, respectively. Here we discuss the concepts of synthetic lethality and synthetic dosage lethality, and explain three general experimental approaches designed to identify novel genetic interactors. We present examples and discuss the merits and caveats of each approach. Finally, we provide insight into the subsequent pre-clinical work required to validate novel candidate drug targets

  18. 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.

  19. RAPD-based detection of genomic instability in cucumber plants ...

    African Journals Online (AJOL)

    STORAGESEVER

    2009-07-20

    Jul 20, 2009 ... 2School of biology and Environmental Sciences, Belfield, Dublin 4, ... detectable differences between the somatic embryo derived plants compared to their F1 parents in the. Random Amplified Polymorphic DNA (RAPD) test using five primers ... The mixture was allowed to thaw and ice-cold polyvinyl-.

  20. Final Technical Report - Mechanisms and pathways controlling genomic instability

    Energy Technology Data Exchange (ETDEWEB)

    Dynan, William S. [Georgia Regents Univ., Augusta, GA (United States)

    2013-05-31

    This project used model organisms, the zebrafish and the Japanese medaka fish to investigate the effects of low-dose radiation exposure on the vertebrate embryo. Endpoints measured included apoptotic cell death, aging, and oxidative stress.

  1. Comparative analysis of genome maintenance genes in naked mole rat, mouse, and human

    NARCIS (Netherlands)

    S.L. Macrae (Sheila L.); Q. Zhang (Quanwei); C. Lemetre (Christophe); I. Seim (Inge); R.B. Calder (Robert B.); J.H.J. Hoeijmakers (Jan); Y. Suh (Yousin); V.N. Gladyshev (Vadim N.); A. Seluanov (Andrei); V. Gorbunova (Vera); J. Vijg (Jan); Z.D. Zhang (Zhengdong D.)

    2015-01-01

    textabstractGenome maintenance (GM) is an essential defense system against aging and cancer, as both are characterized by increased genome instability. Here, we compared the copy number variation and mutation rate of 518 GM-associated genes in the naked mole rat (NMR), mouse, and human genomes. GM

  2. Cancer genomics

    DEFF Research Database (Denmark)

    Norrild, Bodil; Guldberg, Per; Ralfkiær, Elisabeth Methner

    2007-01-01

    Almost all cells in the human body contain a complete copy of the genome with an estimated number of 25,000 genes. The sequences of these genes make up about three percent of the genome and comprise the inherited set of genetic information. The genome also contains information that determines whe...

  3. Kinetic theory of tearing instability

    International Nuclear Information System (INIS)

    Hazeltine, R.D.; Dobrott, D.; Wang, T.S.

    1975-01-01

    The guiding-center kinetic equation with Fokker-Planck collision term is used to study, in cylindrical geometry, a class of dissipative instabilities of which the classical tearing mode is an archetype. Variational solution of the kinetic equation obviates the use of an approximate Ohm's law or adiabatic assumption, as used in previous studies, and it provides a dispersive relation which is uniformly valid for any ratio of wave frequency to collision frequency. One result of using the rigorous collision operator is the prediction of a new instability. This instability, driven by the electron temperature gradient, is predicted to occur under the long mean-free path conditions of present tokamak experiments, and has significant features in common with the kink-like oscillations observed in such experiments

  4. Hydrodynamick instabilities on ICF capsules

    International Nuclear Information System (INIS)

    Haan, S.W.

    1991-01-01

    This article summarizes our current understanding of hydrodynamic instabilities as relevant to ICF. First we discuss classical, single mode Rayleigh-Taylor instability, and nonlinear effects in the evolution of a single mode. Then we discuss multimode systems, considering: (1) the onset of nonlinearity; (2) a second order mode coupling theory for weakly nonlinear effects, and (3) the fully nonlinear regime. Two stabilization mechanisms relevant to ICF are described next: gradient scale length and convective stabilization. Then we describe a model which is meant to estimate the weakly nonlinear evolution of multi-mode systems as relevant to ICF, given the short-wavelength stabilization. Finally, we discuss the relevant code simulation capability, and experiments. At this time we are quite optimistic about our ability to estimate instability growth on ICF capsules, but further experiments and simulations are needed to verify the modeling. 52 refs

  5. [Patellar instability : diagnosis and treatment].

    Science.gov (United States)

    Ngo, Trieu Hoai Nam; Martin, Robin

    2017-12-13

    The aim of this paper is to present recent advances in surgical management of patellar instability. Several anatomical factors were reported to promote instability. We propose to classify them in two groups. Extra articular factors are valgus and torsion deformity. Articular factors include trochlea and patella dysplasia, tibial tubercle lateralization and medial patellofemoral ligament (MPFL) insufficiency. Acute patellar dislocations are treated conservatively, with exception for osteochondral and MPFL avulsion fractures that require acute reinsertion. Surgery is considered for recurrent instability. As we aim for a correction of all contributing elements, we prefer a two stages approach. Extra articular factors are treated first by osteotomy, followed by articular factors after 4-6 months. This allows separate rehabilitation protocols.

  6. Pierce instability and bifurcating equilibria

    International Nuclear Information System (INIS)

    Godfrey, B.B.

    1981-01-01

    The report investigates the connection between equilibrium bifurcations and occurrence of the Pierce instability. Electrons flowing from one ground plane to a second through an ion background possess a countable infinity of static equilibria, of which only one is uniform and force-free. Degeneracy of the uniform and simplest non-uniform equilibria at a certain ground plan separation marks the onset of the Pierce instability, based on a newly derived dispersion relation appropriate to all the equilibria. For large ground plane separations the uniform equilibrium is unstable and the non-uniform equilibrium is stable, the reverse of their stability properties at small separations. Onset of the Pierce instability at the first bifurcation of equilibria persists in more complicated geometries, providing a general criterion for marginal stability. It seems probable that bifurcation analysis can be a useful tool in the overall study of stable beam generation in diodes and transport in finite cavities

  7. Performance through Deformation and Instability

    Science.gov (United States)

    Bertoldi, Katia

    2015-03-01

    Materials capable of undergoing large deformations like elastomers and gels are ubiquitous in daily life and nature. An exciting field of engineering is emerging that uses these compliant materials to design active devices, such as actuators, adaptive optical systems and self-regulating fluidics. Compliant structures may significantly change their architecture in response to diverse stimuli. When excessive deformation is applied, they may eventually become unstable. Traditionally, mechanical instabilities have been viewed as an inconvenience, with research focusing on how to avoid them. Here, I will demonstrate that these instabilities can be exploited to design materials with novel, switchable functionalities. The abrupt changes introduced into the architecture of soft materials by instabilities will be used to change their shape in a sudden, but controlled manner. Possible and exciting applications include materials with unusual properties such negative Poisson's ratio, phononic crystals with tunable low-frequency acoustic band gaps and reversible encapsulation systems.

  8. Telomere dysfunction and chromosome instability

    Energy Technology Data Exchange (ETDEWEB)

    Murnane, John P., E-mail: jmurnane@radonc.ucsf.edu [Department of Radiation Oncology, University of California San Francisco, 2340 Sutter Street, San Francisco, CA 94143-1331 (United States)

    2012-02-01

    The ends of chromosomes are composed of a short repeat sequence and associated proteins that together form a cap, called a telomere, that keeps the ends from appearing as double-strand breaks (DSBs) and prevents chromosome fusion. The loss of telomeric repeat sequences or deficiencies in telomeric proteins can result in chromosome fusion and lead to chromosome instability. The similarity between chromosome rearrangements resulting from telomere loss and those found in cancer cells implicates telomere loss as an important mechanism for the chromosome instability contributing to human cancer. Telomere loss in cancer cells can occur through gradual shortening due to insufficient telomerase, the protein that maintains telomeres. However, cancer cells often have a high rate of spontaneous telomere loss despite the expression of telomerase, which has been proposed to result from a combination of oncogene-mediated replication stress and a deficiency in DSB repair in telomeric regions. Chromosome fusion in mammalian cells primarily involves nonhomologous end joining (NHEJ), which is the major form of DSB repair. Chromosome fusion initiates chromosome instability involving breakage-fusion-bridge (B/F/B) cycles, in which dicentric chromosomes form bridges and break as the cell attempts to divide, repeating the process in subsequent cell cycles. Fusion between sister chromatids results in large inverted repeats on the end of the chromosome, which amplify further following additional B/F/B cycles. B/F/B cycles continue until the chromosome acquires a new telomere, most often by translocation of the end of another chromosome. The instability is not confined to a chromosome that loses its telomere, because the instability is transferred to the chromosome donating a translocation. Moreover, the amplified regions are unstable and form extrachromosomal DNA that can reintegrate at new locations. Knowledge concerning the factors promoting telomere loss and its consequences is

  9. Instabilities of higher dimensional compactifications

    International Nuclear Information System (INIS)

    Accetta, F.S.

    1987-02-01

    Various schemes for cosmological compactification of higher dimensional theories are considered. Possible instabilities which drive the ground state with static internal space to de Sitter-like expansion of all dimensions are discussed. These instabilities are due to semiclassical barrier penetration and classical thermal fluctuations. For the case of the ten dimensional Chapline-Manton action, it is possible to avoid such difficulties by balancing one-loop Casimir corrections against monopole contributions from the field strength H/sub MNP/ and fermionic condensates. 10 refs

  10. Taming Instabilities in Plasma Discharges

    International Nuclear Information System (INIS)

    Klinger, T.; Krahnstover, N. O.; Mausbach, T.; Piel, A.

    2000-01-01

    Recent experimental work on taming instabilities in plasma discharges is discussed. Instead of suppressing instabilities, it is desired to achieve control over their dynamics, done by perturbing appropriately the current flow in the external circuit of the discharge. Different discrete and continuous feedback as well as open-loop control schemes are applied. Chaotic oscillations in plasma diodes are controlled using the OGY discrete feedback scheme. This is demonstrated both in experiment and computer simulation. Weakly developed ionization wave turbulence is tamed by continuous feedback control. Open-loop control of stochastic fluctuations - stochastic resonance - is demonstrated in a thermionic plasma diode. (author)

  11. Helical instability in film blowing process: Analogy to buckling instability

    Science.gov (United States)

    Lee, Joo Sung; Kwon, Ilyoung; Jung, Hyun Wook; Hyun, Jae Chun

    2017-12-01

    The film blowing process is one of the most important polymer processing operations, widely used for producing bi-axially oriented film products in a single-step process. Among the instabilities observed in this film blowing process, i.e., draw resonance and helical motion occurring on the inflated film bubble, the helical instability is a unique phenomenon portraying the snake-like undulation motion of the bubble, having the period on the order of few seconds. This helical instability in the film blowing process is commonly found at the process conditions of a high blow-up ratio with too low a freezeline position and/or too high extrusion temperature. In this study, employing an analogy to the buckling instability for falling viscous threads, the compressive force caused by the pressure difference between inside and outside of the film bubble is introduced into the simulation model along with the scaling law derived from the force balance between viscous force and centripetal force of the film bubble. The simulation using this model reveals a close agreement with the experimental results of the film blowing process of polyethylene polymers such as low density polyethylene and linear low density polyethylene.

  12. 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.

  13. Lending sociodynamics and economic instability

    Science.gov (United States)

    Hawkins, Raymond J.

    2011-11-01

    We show how the dynamics of economic instability and financial crises articulated by Keynes in the General Theory and developed by Minsky as the Financial Instability Hypothesis can be formalized using Weidlich’s sociodynamics of opinion formation. The model addresses both the lending sentiment of a lender in isolation as well as the impact on that lending sentiment of the behavior of other lenders. The risk associated with lending is incorporated through a stochastic treatment of loan dynamics that treats prepayment and default as competing risks. With this model we are able to generate endogenously the rapid changes in lending opinion that attend slow changes in lending profitability and find these dynamics to be consistent with the rise and collapse of the non-Agency mortgage-backed securities market in 2007/2008. As the parameters of this model correspond to well-known phenomena in cognitive and social psychology, we can both explain why economic instability has proved robust to advances in risk measurement and suggest how policy for reducing economic instability might be formulated in an experimentally sound manner.

  14. Kinetic theory of Jeans instability

    NARCIS (Netherlands)

    Trigger, S.A.; Ershkovic, A.I.; Heijst, van G.J.F.; Schram, P.P.J.M.

    2004-01-01

    Kinetic treatment of the Jeans gravitational instability, with collisions taken into account, is presented. The initial-value problem for the distribution function which obeys the kinetic equation, with the collision integral conserving the number of particles, is solved. Dispersion relation is

  15. Cinerama sickness and postural instability.

    Science.gov (United States)

    Bos, Jelte E; Ledegang, Wietse D; Lubeck, Astrid J A; Stins, John F

    2013-01-01

    Motion sickness symptoms and increased postural instability induced by motion pictures have been reported in a laboratory, but not in a real cinema. We, therefore, carried out an observational study recording sickness severity and postural instability in 19 subjects before, immediately and 45 min after watching a 1 h 3D aviation documentary in a cinema. Sickness was significantly larger right after the movie than before, and in a lesser extent still so after 45 min. The average standard deviation of the lateral centre of pressure excursions was significantly larger only right afterwards. When low-pass filtered at 0.1 Hz, lateral and for-aft excursions were both significantly larger right after the movie, while for-aft excursions then remained larger even after 45 min. Speculating on previous findings, we predict more sickness and postural instability in 3D than in 2D movies, also suggesting a possible, but yet unknown risk for work-related activities and vehicle operation. Watching motion pictures may be sickening and posturally destabilising, but effects in a cinema are unknown. We, therefore, carried out an observational study showing that sickness then is mainly an issue during the exposure while postural instability is an issue afterwards.

  16. Faraday instability in deformable domains

    International Nuclear Information System (INIS)

    Pucci, G.

    2013-01-01

    Hydrodynamical instabilities are usually studied either in bounded regions or free to grow in space. In this article we review the experimental results of an intermediate situation, in which an instability develops in deformable domains. The Faraday instability, which consists in the formation of surface waves on a liquid experiencing a vertical forcing, is triggered in floating liquid lenses playing the role of deformable domains. Faraday waves deform the lenses from the initial circular shape and the mutual adaptation of instability patterns with the lens boundary is observed. Two archetypes of behaviour have been found. In the first archetype a stable elongated shape is reached, the wave vector being parallel to the direction of elongation. In the second archetype the waves exceed the response of the lens border and no equilibrium shape is reached. The lens stretches and eventually breaks into fragments that have a complex dynamics. The difference between the two archetypes is explained by the competition between the radiation pressure the waves exert on the lens border and its response due to surface tension.

  17. 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

  18. Nonlinear behavior of the radiative condensation instability

    International Nuclear Information System (INIS)

    McCarthy, D.; Drake, J.F.

    1991-01-01

    An investigation of the nonlinear behavior of the radiative condensation instability is presented in a simple one-dimensional magnetized plasma. It is shown that the radiative condensation is typically a nonlinear instability---the growth of the instability is stronger once the disturbance reaches finite amplitude. Moreover, classical parallel thermal conduction is insufficient by itself to saturate the instability. Radiative collapse continues until the temperature in the high density condensation falls sufficiently to reduce the radiation rate

  19. Dynamic ultrasound of peroneal tendon instability.

    Science.gov (United States)

    Pesquer, Lionel; Guillo, Stéphane; Poussange, Nicolas; Pele, Eric; Meyer, Philippe; Dallaudière, Benjamin

    2016-07-01

    Ankle snapping may be caused by peroneal tendon instability. Anterior instability occurs after traumatic superior peroneal retinaculum injury, whereas peroneal tendon intrasheath subluxation is atraumatic. Whereas subluxation is mainly dynamic, ultrasound allows for the diagnosis and classification of peroneal instability because it allows for real-time exploration. The purpose of this review is to describe the anatomic and physiologic bases for peroneal instability and to heighten the role of dynamic ultrasound in the diagnosis of snapping.

  20. A general approach to optomechanical parametric instabilities

    International Nuclear Information System (INIS)

    Evans, M.; Barsotti, L.; Fritschel, P.

    2010-01-01

    We present a simple feedback description of parametric instabilities which can be applied to a variety of optical systems. Parametric instabilities are of particular interest to the field of gravitational-wave interferometry where high mechanical quality factors and a large amount of stored optical power have the potential for instability. In our use of Advanced LIGO as an example application, we find that parametric instabilities, if left unaddressed, present a potential threat to the stability of high-power operation.

  1. Observation of Parametric Instability in Advanced LIGO.

    Science.gov (United States)

    Evans, Matthew; Gras, Slawek; Fritschel, Peter; Miller, John; Barsotti, Lisa; Martynov, Denis; Brooks, Aidan; Coyne, Dennis; Abbott, Rich; Adhikari, Rana X; Arai, Koji; Bork, Rolf; Kells, Bill; Rollins, Jameson; Smith-Lefebvre, Nicolas; Vajente, Gabriele; Yamamoto, Hiroaki; Adams, Carl; Aston, Stuart; Betzweiser, Joseph; Frolov, Valera; Mullavey, Adam; Pele, Arnaud; Romie, Janeen; Thomas, Michael; Thorne, Keith; Dwyer, Sheila; Izumi, Kiwamu; Kawabe, Keita; Sigg, Daniel; Derosa, Ryan; Effler, Anamaria; Kokeyama, Keiko; Ballmer, Stefan; Massinger, Thomas J; Staley, Alexa; Heinze, Matthew; Mueller, Chris; Grote, Hartmut; Ward, Robert; King, Eleanor; Blair, David; Ju, Li; Zhao, Chunnong

    2015-04-24

    Parametric instabilities have long been studied as a potentially limiting effect in high-power interferometric gravitational wave detectors. Until now, however, these instabilities have never been observed in a kilometer-scale interferometer. In this Letter, we describe the first observation of parametric instability in a gravitational wave detector, and the means by which it has been removed as a barrier to progress.

  2. Multifragmentation: Surface instabilities or statistical decay

    International Nuclear Information System (INIS)

    Moretto, L.G.; Tso, K.; Delis, D.; Colonna, N.; Wozniak, G.J.

    1992-11-01

    Boltzmann-Nordheim-Vlasov calculations show multifragmentation that seems to originate from surface instabilities. These instabilities are traced to a sheet instability caused by the proximity interaction. Experimental data, on the other hand, suggest that multifragmentation may be dominated by phase space

  3. Multifragmentation: surface instabilities or statistical decay?

    International Nuclear Information System (INIS)

    Moretto, L.G.; Tso, K.; Delis, D.; Colonna, N.; Wozniak, G.J.

    1993-01-01

    Boltzmann-Nordheim-Vlasov calculations show multifragmentation that seems to originate from surface instabilities. These instabilities are traced to a sheet instability caused by the proximity interaction. Experimental data, on the other hand, suggest that multifragmentation may be dominated by phase space. (author)

  4. Casimir effect and thermodynamics of horizon instabilities

    International Nuclear Information System (INIS)

    Hartnoll, Sean A.

    2004-01-01

    We propose a dual thermodynamic description of a classical instability of generalized black hole spacetimes. From a thermodynamic perspective, the instability is due to negative compressibility in regions where the Casimir pressure is large. The argument indicates how the correspondence between thermodynamic and classical instability for horizons may be extended to cases without translational invariance

  5. Generalized laser filamentation instability coupled to cooling instability

    International Nuclear Information System (INIS)

    Liang, E.P.; Wong, J.; Garrison, J.

    1984-01-01

    We consider the propagation of laser light in an initially slightly nonuniform plasma. The classical dispersion relation for the laser filamentation growth rate (see e.g., B. Langdon, in the 1980 Lawrence Livermore National Laboratory Laser Program Annual Report, pp. 3-56, UCRL-50021-80, 1981) can be generalized to include other acoustical effects. For example, we find that the inclusion of potential imbalances in the heating and cooling rates of the ambient medium due to density and temperature perturbations can cause the laser filamentation mode to bifurcate into a cooling instability mode at long acoustic wavelengths. We also attempt to study semi-analytically the nonlinear evolution of this and related instabilities. These results have wide applications to a variety of chemical gas lasers and phenomena related to laser-target interactions (e.g., jet-like behavior)

  6. Effect of Hecogenin on DNA instability

    Directory of Open Access Journals (Sweden)

    Marina Sampaio Cruz

    Full Text Available Hecogenin is a sapogenin found in Agave species in high quantities and is responsible for the many therapeutic effects of these medicinal plants. In addition, this compound is also widely used in the pharmaceutical industry as a precursor for the synthesis of steroidal hormones and anti-inflammatory drugs. Despite Hecogenin being widely used, little is known about its toxicological properties. Therefore, the present study aimed to investigate the cytotoxic, genotoxic and mutagenic effects of Hecogenin on HepG2 cells. Cytotoxicity was analyzed using the MTT test. Then, genotoxic and mutagenic potentials were assessed by comet assay and cytokinesis-block micronucleus assay, respectively. Cytotoxic effect was observed only when cells were exposed to concentrations of Hecogenin equal or higher than 100 μM. Although a lower concentration of Hecogenin caused DNA damage, a reduction on nuclear mutagenic markers in HepG2 cells was observed. The results indicated that Hecogenin treatment generated DNA damage, but in fact it would be repaired, avoiding dissemination of the damage throughout the cell division. Further studies need to be performed to confirm the observed protective effect of Hecogenin against genomic instability. Keywords: Hecogenin, CBMN, Genotoxicity, Comet assay

  7. The DNA-instability test as a specific marker of malignancy and its application to detect cancer clones in borderline malignancy

    Directory of Open Access Journals (Sweden)

    M Fukuda

    2009-06-01

    Full Text Available Recent progress in cytogenetic and biochemical mutator assay technologies has enabled us to detect single gene alterations and gross chromosomal rearrangements, and it became clear that all cancer cells are genetically unstable. In order to detect the genome-wide instability of cancer cells, a new simple method, the DNA-instability test, was developed. The methods to detect genomic instability so far reported have only demonstrated the presence of qualitative and quantitative alterations in certain specific genomic loci. In contrast to these commonly used methods to reveal the genomic instability at certain specific DNA regions, the newly introduced DNA-instability test revealed the presence of physical DNA-instability in the entire DNA molecule of a cancer cell nucleus as revealed by increased liability to denature upon HCl hydrolysis or formamide exposure. When this test was applied to borderline malignancies, cancer clones were detected in all cases at an early-stage of cancer progression. We proposed a new concept of “procancer” clones to define those cancer clones with “functional atypia” showing positivities for various cancer markers, as well as DNA-instability testing, but showing no remarkable ordinary “morphological atypia” which is commonly used as the basis of histopathological diagnosis of malignancy.

  8. 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

  9. 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

  10. History and Physical Examination for Shoulder Instability.

    Science.gov (United States)

    Haley, Col Chad A

    2017-09-01

    Glenohumeral instability frequently occurs in young active individuals especially those engaged in athletic and military activities. With advanced imaging and arthroscopic evaluation, our understanding of the injury patterns associated with instability has significantly improved. The majority of instability results from a traumatic anterior event which presents with common findings in the history, examination, and imaging studies. As such, a comprehensive evaluation of the patient is important to correctly diagnose the instability patterns and thus provide appropriate treatment intervention. With the correct diagnosis and improved surgical techniques, the majority of patients with instability can return to preinjury levels.

  11. Electromagnetic theory of the radiative Pierce instability

    International Nuclear Information System (INIS)

    Klochkov, D.N.; Rukhadze, A.A.

    1997-01-01

    A study is made of the radiative Pierce instability of a relativistic electron beam propagating in a waveguide in the presence of an infinitely strong magnetic field. The perturbation theory is used to find the growth rates and conditions of instability over a broad range of the beam current. It is shown that, under the Pierce boundary conditions, the instability is Raman in nature, and there is no current threshold for the instability. This allows the instability saturation level to be accurately determined from the condition for the violation of the Cherenkov resonance and the radiation efficiency to be estimated

  12. Single bunch fast longitudinal instability

    International Nuclear Information System (INIS)

    Wang, J.M.; Pellegrini, C.

    1979-01-01

    Single bunch longitudinal instability producing an increase of the bunch area have been observed in proton synchrotron and storage rings. Signals at microwave frequencies are observed during the bunch blow-up and because of this the effect has been called the microwave instability. A similar increase in bunch area is observed also in electron storage rings, where it is usually referred to as the bunch lengthening effect. This paper is an attempt to obtain a more general theory of this effect. Here we describe the model used and the method of calculation, together with some general results. More detailed results will be given in another paper. The main result is the derivation of a condition for the existence of a fast longitudinal bunch blow-up. This condition is a generalized threshold formula, showing explicitly the dependence on the bunch energy spread and length. This condition is qualitatively in agreement with Boussard's suggestion

  13. Feedback control of resistive instabilities

    International Nuclear Information System (INIS)

    White, R.B.; Rutherford, P.H.; Furth, H.P.; Park, W.; Liu Chen

    1986-01-01

    Resistive instabilities are responsible for much of the global behavior and the determination of the possible domains of operation of Tokamaks. Their successful control could have definite advantages, even making available new regimes of operation. Elimination of sawtoothing might allow operation with higher currents and more peaked current profiles, with q on axis well below unity. In this work different feedback schemes are explored. Simple analytical derivations of the effects of local heating and current drive feedback are presented. Although control of modes with m ≥ 2 is fairly straighforward, the control of the m = 1 mode is more difficult because of its proximity to ideal instability. The most promising scheme utilizes high energy trapped particles

  14. Instability after total hip arthroplasty

    Science.gov (United States)

    Werner, Brian C; Brown, Thomas E

    2012-01-01

    Instability following total hip arthroplasty (THA) is an unfortunately frequent and serious problem that requires thorough evaluation and preoperative planning before surgical intervention. Prevention through optimal index surgery is of great importance, as the management of an unstable THA is challenging even for an experienced joints surgeon. However, even after well-planned surgery, a significant incidence of recurrent instability still exists. Non-operative management is often successful if the components are well-fixed and correctly positioned in the absence of neurocognitive disorders. If conservative management fails, surgical options include revision of malpositioned components; exchange of modular components such as the femoral head and acetabular liner; bipolar arthroplasty; tripolar arthroplasty; use of a larger femoral head; use of a constrained liner; soft tissue reinforcement and advancement of the greater trochanter. PMID:22919568

  15. Feedback control of resistive instabilities

    International Nuclear Information System (INIS)

    White, R.B.; Rutherford, P.H.; Furth, H.P.; Park, W.; Chen, L.

    1985-12-01

    Resistive instabilities are responsible for much of the global behavior and the determination of the possible domains of operation of tokamaks. Their successful control could have definite advantages, even making available new regimes of operation. Elimination of sawtoothing might allow operation with higher currents and more peaked current profiles, with q on axis well below unity. In this work different feedback schemes are explored. Simple analytical derivations of the effects of local heating and current drive feedback are presented. Although control of modes with m greater than or equal to 2 is fairly straightforward, the control of the m = 1 mode is more difficult because of its proximity to ideal instability. The most promising scheme utilizes high energy trapped particles. 20 refs., 3 figs

  16. Fluctuations and Instability in Sedimentation

    KAUST Repository

    Guazzelli, Élisabeth

    2011-01-21

    This review concentrates on the fluctuations of the velocities of sedimenting spheres, and on the structural instability of a suspension of settling fibers. For many years, theoretical estimates and numerical simulations predicted the fluctuations of the velocities of spheres to increase with the size of the container, whereas experiments found no such variation. Two ideas have increased our understanding. First, the correlation length of the velocity fluctuations was found experimentally to be 20 interparticle separations. Second, in dilute suspensions, a vertical variation in the concentration due to the spreading of the front with the clear fluid can inhibit the velocity fluctuations. In a very dilute regime, a homogeneous suspension of fibers suffers a spontaneous instability in which fast descending fiber-rich columns are separated by rising fiber-sparse columns. In a semidilute regime, the settling is hindered, more so than for spheres. © 2011 by Annual Reviews. All rights reserved.

  17. A cosmic ray driven instability

    Science.gov (United States)

    Dorfi, E. A.; Drury, L. O.

    1985-01-01

    The interaction between energetic charged particles and thermal plasma which forms the basis of diffusive shock acceleration leads also to interesting dynamical phenomena. For a compressional mode propagating in a system with homogeneous energetic particle pressure it is well known that friction with the energetic particles leads to damping. The linear theory of this effect has been analyzed in detail by Ptuskin. Not so obvious is that a non-uniform energetic particle pressure can addition amplify compressional disturbances. If the pressure gradient is sufficiently steep this growth can dominate the frictional damping and lead to an instability. It is important to not that this effect results from the collective nature of the interaction between the energetic particles and the gas and is not connected with the Parker instability, nor with the resonant amplification of Alfven waves.

  18. Modulational instability of coupled waves

    International Nuclear Information System (INIS)

    McKinstrie, C.J.; Bingham, R.

    1989-01-01

    The collinear propagation of an arbitrary number of finite-amplitude waves is modeled by a system of coupled nonlinear Schroedinger equations; one equation for each complex wave amplitude. In general, the waves are modulationally unstable with a maximal growth rate larger than the modulational growth rate of any wave alone. Moreover, waves that are modulationally stable by themselves can be driven unstable by the nonlinear coupling. The general theory is then applied to the relativistic modulational instability of two laser beams in a beat-wave accelerator. For parameters typical of a proposed beat-wave accelerator, this instability can seriously distort the incident laser pulse shapes on the particle-acceleration time scale, with detrimental consequences for particle acceleration

  19. Single bunch fast longitudinal instability

    International Nuclear Information System (INIS)

    Wang, J.M.; Pellegrini, C.

    1979-01-01

    Single bunch longitudinal instability producing an increase of the bunch areas has been observed in proton synchrotron and storage rings. Singals at microwave frequencies are observed during the bunch blow-up and because of this the effect has been called the microwave instability. A similar increase in bunch area is observed also in electron storage rings, where it is usually referred to as the bunch lengthening effect. This paper is an attempt to obtain a more general theory of this effect. Here we describe the model used and the method of calculation, together with some general results. The main result of this paper is the derivation of a condition for the existence of a fast longitudinal bunch blow-up. This condition is a generalized threshold formula, showing explicitly the dependence on the bunch energy spread and length

  20. Genome Imprinting

    Indian Academy of Sciences (India)

    the cell nucleus (mitochondrial and chloroplast genomes), and. (3) traits governed ... tively good embryonic development but very poor development of membranes and ... Human homologies for the type of situation described above are naturally ..... imprint; (b) New modifications of the paternal genome in germ cells of each ...

  1. Baculovirus Genomics

    NARCIS (Netherlands)

    Oers, van M.M.; Vlak, J.M.

    2007-01-01

    Baculovirus genomes are covalently closed circles of double stranded-DNA varying in size between 80 and 180 kilobase-pair. The genomes of more than fourty-one baculoviruses have been sequenced to date. The majority of these (37) are pathogenic to lepidopteran hosts; three infect sawflies

  2. Genomic Testing

    Science.gov (United States)

    ... this database. Top of Page Evaluation of Genomic Applications in Practice and Prevention (EGAPP™) In 2004, the Centers for Disease Control and Prevention launched the EGAPP initiative to establish and test a ... and other applications of genomic technology that are in transition from ...

  3. Ancient genomes

    OpenAIRE

    Hoelzel, A Rus

    2005-01-01

    Ever since its invention, the polymerase chain reaction has been the method of choice for work with ancient DNA. In an application of modern genomic methods to material from the Pleistocene, a recent study has instead undertaken to clone and sequence a portion of the ancient genome of the cave bear.

  4. Laser driven hydrodynamic instability experiments

    International Nuclear Information System (INIS)

    Remington, B.A.; Weber, S.V.; Haan, S.W.; Kilkenny, J.D.; Glendinning, S.G.; Wallace, R.J.; Goldstein, W.H.; Wilson, B.G.; Nash, J.K.

    1993-01-01

    An extensive series of experiments has been conducted on the Nova laser to measure hydrodynamic instabilities in planar foils accelerated by x-ray ablation. Single mode experiments allow a measurement of the fundamental growth rates from the linear well into the nonlinear regime. Two-mode foils allow a first direct observation of mode coupling. Surface-finish experiments allow a measurement of the evolution of a broad spectrum of random initial modes

  5. Finite temperature instability for compactification

    International Nuclear Information System (INIS)

    Accetta, F.S.; Kolb, E.W.

    1986-03-01

    We consider finite temperature effects upon theories with extra dimensions compactified via vacuum stress energy (Casimir) effects. For sufficiently high temperature, a static configuration for the internal space is impossible. At somewhat lower temperatures, there is an instability due to thermal fluctuations of radius of the compact dimensions. For both cases, the Universe can evolve to a de Sitter-like expansion of all dimensions. Stability to late times constrains the initial entropy of the universe. 28 refs., 1 fig., 2 tabs

  6. Instability of colliding metastable strings

    Energy Technology Data Exchange (ETDEWEB)

    Hiramatsu, Takashi [Kyoto Univ. (Japan). Yukawa Inst. for Theoretical Physics; Eto, Minoru [Yamagata Univ. (Japan). Dept. of Physics; Kamada, Kohei [Deutsches Elektronen-Synchrotron (DESY), Hamburg (Germany); Kobayashi, Tatsuo [Kyoto Univ. (Japan). Dept. of Physics; Ookouchi, Yutaka [Kyoto Univ. (Japan). Dept. of Physics; Kyoto Univ. (Japan). The Hakubi Center for Advanced Research

    2013-04-15

    We investigate the collision dynamics of two metastable strings which can be viewed as tube-like domain walls with winding numbers interpolating a false vacuum and a true vacuum. We find that depending on the relative angle and speed of two strings, instability of strings increases and the false vacuum is filled out by rapid expansion of the strings or of a remnant of the collision.

  7. Combustion instability modeling and analysis

    Energy Technology Data Exchange (ETDEWEB)

    Santoro, R.J.; Yang, V.; Santavicca, D.A. [Pennsylvania State Univ., University Park, PA (United States); Sheppard, E.J. [Tuskeggee Univ., Tuskegee, AL (United States). Dept. of Aerospace Engineering

    1995-12-31

    It is well known that the two key elements for achieving low emissions and high performance in a gas turbine combustor are to simultaneously establish (1) a lean combustion zone for maintaining low NO{sub x} emissions and (2) rapid mixing for good ignition and flame stability. However, these requirements, when coupled with the short combustor lengths used to limit the residence time for NO formation typical of advanced gas turbine combustors, can lead to problems regarding unburned hydrocarbons (UHC) and carbon monoxide (CO) emissions, as well as the occurrence of combustion instabilities. The concurrent development of suitable analytical and numerical models that are validated with experimental studies is important for achieving this objective. A major benefit of the present research will be to provide for the first time an experimentally verified model of emissions and performance of gas turbine combustors. The present study represents a coordinated effort between industry, government and academia to investigate gas turbine combustion dynamics. Specific study areas include development of advanced diagnostics, definition of controlling phenomena, advancement of analytical and numerical modeling capabilities, and assessment of the current status of our ability to apply these tools to practical gas turbine combustors. The present work involves four tasks which address, respectively, (1) the development of a fiber-optic probe for fuel-air ratio measurements, (2) the study of combustion instability using laser-based diagnostics in a high pressure, high temperature flow reactor, (3) the development of analytical and numerical modeling capabilities for describing combustion instability which will be validated against experimental data, and (4) the preparation of a literature survey and establishment of a data base on practical experience with combustion instability.

  8. Instability of colliding metastable strings

    International Nuclear Information System (INIS)

    Hiramatsu, Takashi; Kobayashi, Tatsuo; Ookouchi, Yutaka; Kyoto Univ.

    2013-04-01

    We investigate the collision dynamics of two metastable strings which can be viewed as tube-like domain walls with winding numbers interpolating a false vacuum and a true vacuum. We find that depending on the relative angle and speed of two strings, instability of strings increases and the false vacuum is filled out by rapid expansion of the strings or of a remnant of the collision.

  9. 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.

  10. 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.

  11. 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.

  12. Telomeres and viruses: common themes of genome maintenance

    Science.gov (United States)

    Deng, Zhong; Wang, Zhuo; Lieberman, Paul M.

    2012-01-01

    Genome maintenance mechanisms actively suppress genetic instability associated with cancer and aging. Some viruses provoke genetic instability by subverting the host’s control of genome maintenance. Viruses have their own specialized strategies for genome maintenance, which can mimic and modify host cell processes. Here, we review some of the common features of genome maintenance utilized by viruses and host chromosomes, with a particular focus on terminal repeat (TR) elements. The TRs of cellular chromosomes, better known as telomeres, have well-established roles in cellular chromosome stability. Cellular telomeres are themselves maintained by viral-like mechanisms, including self-propagation by reverse transcription, recombination, and retrotransposition. Viral TR elements, like cellular telomeres, are essential for viral genome stability and propagation. We review the structure and function of viral repeat elements and discuss how they may share telomere-like structures and genome protection functions. We consider how viral infections modulate telomere regulatory factors for viral repurposing and can alter normal host telomere structure and chromosome stability. Understanding the common strategies of viral and cellular genome maintenance may provide new insights into viral–host interactions and the mechanisms driving genetic instability in cancer. PMID:23293769

  13. Fanconi anemia: causes and consequences of genetic instability.

    Science.gov (United States)

    Kalb, R; Neveling, K; Nanda, I; Schindler, D; Hoehn, H

    2006-01-01

    Fanconi anemia (FA) is a rare recessive disease that reflects the cellular and phenotypic consequences of genetic instability: growth retardation, congenital malformations, bone marrow failure, high risk of neoplasia, and premature aging. At the cellular level, manifestations of genetic instability include chromosomal breakage, cell cycle disturbance, and increased somatic mutation rates. FA cells are exquisitely sensitive towards oxygen and alkylating drugs such as mitomycin C or diepoxybutane, pointing to a function of FA genes in the defense against reactive oxygen species and other DNA damaging agents. FA is caused by biallelic mutations in at least 12 different genes which appear to function in the maintenance of genomic stability. Eight of the FA proteins form a nuclear core complex with a catalytic function involving ubiquitination of the central FANCD2 protein. The posttranslational modification of FANCD2 promotes its accumulation in nuclear foci, together with known DNA maintenance proteins such as BRCA1, BRCA2, and the RAD51 recombinase. Biallelic mutations in BRCA2 cause a severe FA-like phenotype, as do biallelic mutations in FANCD2. In fact, only leaky or hypomorphic mutations in this central group of FA genes appear to be compatible with life birth and survival. The newly discovered FANCJ (= BRIP1) and FANCM (= Hef ) genes correspond to known DNA-maintenance genes (helicase resp. helicase-associated endonuclease for fork-structured DNA). These genes provide the most convincing evidence to date of a direct involvement of FA genes in DNA repair functions associated with the resolution of DNA crosslinks and stalled replication forks. Even though genetic instability caused by mutational inactivation of the FANC genes has detrimental effects for the majority of FA patients, around 20% of patients appear to benefit from genetic instability since genetic instability also increases the chance of somatic reversion of their constitutional mutations. Intragenic

  14. Modes of storage ring coherent instabilities

    Energy Technology Data Exchange (ETDEWEB)

    Wang, J.M.

    1986-12-01

    Longitudinal impedance in a beam and various modes of longitudinal coherent instabilities are discussed. The coasting beam coherent instability, microwave instability, and single-bunch longitudinal coherent instabilities are considered. The Vlasov equation is formulated, and a method of solving it is developed. The synchrotron modes are treated, which take the possible bunch shape distortion fully into consideration. A method of treating the synchrotron mode coupling in the case of a small bunch is discussed which takes advantage of the fact that only a few of the synchrotron modes can contribute in such a case. The effect of many bunches on the coherent motion of the beam and the longitudinal symmetric coupled bunch modes are discussed. The transverse impedance is then introduced, and the transverse coasting beam instability is discussed. Various bunched beam instabilities are discussed, including both single bunch instabilities and coupled bunch instabilities. The Vlasov equation for transverse as well as longitudinal motion of particles is introduced as well as a method of solving it within a linear approximation. Head-tail modes and short bunch instabilities and strong coupling instabilities in the long bunch case are covered. (LEW)

  15. Modes of storage ring coherent instabilities

    International Nuclear Information System (INIS)

    Wang, J.M.

    1986-12-01

    Longitudinal impedance in a beam and various modes of longitudinal coherent instabilities are discussed. The coasting beam coherent instability, microwave instability, and single-bunch longitudinal coherent instabilities are considered. The Vlasov equation is formulated, and a method of solving it is developed. The synchrotron modes are treated, which take the possible bunch shape distortion fully into consideration. A method of treating the synchrotron mode coupling in the case of a small bunch is discussed which takes advantage of the fact that only a few of the synchrotron modes can contribute in such a case. The effect of many bunches on the coherent motion of the beam and the longitudinal symmetric coupled bunch modes are discussed. The transverse impedance is then introduced, and the transverse coasting beam instability is discussed. Various bunched beam instabilities are discussed, including both single bunch instabilities and coupled bunch instabilities. The Vlasov equation for transverse as well as longitudinal motion of particles is introduced as well as a method of solving it within a linear approximation. Head-tail modes and short bunch instabilities and strong coupling instabilities in the long bunch case are covered

  16. Microbunch Instability Theory and Simulations

    Energy Technology Data Exchange (ETDEWEB)

    Stupakov, G.

    2005-01-26

    Over the last years there have been several reports of quasiperiodic bursts of coherent synchrotron radiation (CSR) in electron rings in the microwave and far-infrared range. The observations were made on synchrotron radiation light sources which include the Synchrotron Ultraviolet Radiation Facility SURF II [1], the VUV ring at the National Synchrotron Light Source at BNL [2, 3], second generation light sources MAX-I [4], BESSY II [5], and ALS [6]. General features of those observations can be summarized as follows. Above a threshold current, there is a strongly increased radiation of the beam in the range of wavelengths shorter than the bunch length, {lambda} < {sigma}{sub 2}. At large currents, this radiation is observed as a sequence of random bursts. In the bursting regime, intensity of the radiation scales approximately as square of the number of particles in the bunch, indicating a coherent nature of the phenomenon. It is generally accepted that the source of this radiation is related to the microbunching of the beam arising from development of a microwave instability caused by the coherent synchrotron radiation of the beam. A relativistic electron beam moving in a circular orbit in free space can radiate coherently if the wavelength of the synchrotron radiation exceeds the length of the bunch. In accelerators coherent radiation of the bunch is usually suppressed by the shielding effect of the conducting walls of the vacuum chamber [7-9], which gives an exponential cutoff of wavelengths greater than a certain threshold. However, an initial density fluctuation with a characteristic length much shorter than the shielding threshold would radiate coherently. If the radiation reaction force is such that it results in the growth of the initial fluctuation one can expect an instability that leads to micro-bunching of the beam and an increased coherent radiation at short wavelengths. A possibility of CSR instability was pointed out in Refs. [10, 11].

  17. Herbarium genomics

    DEFF Research Database (Denmark)

    Bakker, Freek T.; Lei, Di; Yu, Jiaying

    2016-01-01

    Herbarium genomics is proving promising as next-generation sequencing approaches are well suited to deal with the usually fragmented nature of archival DNA. We show that routine assembly of partial plastome sequences from herbarium specimens is feasible, from total DNA extracts and with specimens...... up to 146 years old. We use genome skimming and an automated assembly pipeline, Iterative Organelle Genome Assembly, that assembles paired-end reads into a series of candidate assemblies, the best one of which is selected based on likelihood estimation. We used 93 specimens from 12 different...... correlation between plastome coverage and nuclear genome size (C value) in our samples, but the range of C values included is limited. Finally, we conclude that routine plastome sequencing from herbarium specimens is feasible and cost-effective (compared with Sanger sequencing or plastome...

  18. Elastocapillary Instability in Mitochondrial Fission

    Science.gov (United States)

    Gonzalez-Rodriguez, David; Sart, Sébastien; Babataheri, Avin; Tareste, David; Barakat, Abdul I.; Clanet, Christophe; Husson, Julien

    2015-08-01

    Mitochondria are dynamic cell organelles that constantly undergo fission and fusion events. These dynamical processes, which tightly regulate mitochondrial morphology, are essential for cell physiology. Here we propose an elastocapillary mechanical instability as a mechanism for mitochondrial fission. We experimentally induce mitochondrial fission by rupturing the cell's plasma membrane. We present a stability analysis that successfully explains the observed fission wavelength and the role of mitochondrial morphology in the occurrence of fission events. Our results show that the laws of fluid mechanics can describe mitochondrial morphology and dynamics.

  19. Laser driven hydrodynamic instability experiments

    International Nuclear Information System (INIS)

    Remington, B.A.; Weber, S.V.; Haan, S.W.; Kilkenny, J.D.; Glendinning, S.G.; Wallace, R.J.; Goldstein, W.H.; Wilson, B.G.; Nash, J.K.

    1992-01-01

    We have conducted an extensive series of experiments on the Nova laser to measure hydrodynamic instabilities in planar foils accelerated by x-ray ablation. Single mode experiments allow a measurement of the fundamental growth rates from the linear well into the nonlinear regime; multimode foils allow an assessment of the degree of mode coupling; and surface-finish experiments allow a measurement of the evolution of a broad spectrum of random initial modes. Experimental results and comparisons with theory and simulations are presented

  20. Longitudinal single-bunch instabilities

    International Nuclear Information System (INIS)

    Migliorati, M.; Palumbo, L.; Rome Univ. La Sapienza, Rome

    2001-02-01

    After introducing the concepts of longitudinal wakefield and coupling impedance, it is reviewed the theory of longitudinal single-bunch collective effects in storage rings. From the Fokker-Planck equation it is first derived the stationary solution describing the natural single-bunch regime, and then treat the problem of microwave instability, showing the different approaches used for estimating the threshold current. The lecture is ended with the semi-empirical laws that allow everyone to obtain the single-bunch behaviour above threshold, and with a description of the simulation codes that are now reliable tools for investigating all these effects

  1. Sheet Beam Klystron Instability Analysis

    International Nuclear Information System (INIS)

    Bane, K.

    2009-01-01

    Using the principle of energy balance we develop a 2D theory for calculating growth rates of instability in a two-cavity model of a sheet beam klystron. An important ingredient is a TE-like mode in the gap that also gives a longitudinal kick to the beam. When compared with a self-consistent particle-in-cell calculation, with sheet beam klystron-type parameters, agreement is quite good up to half the design current, 65 A; at full current, however, other, current-dependent effects come in and the results deviate significantly

  2. Chromosomal instability determines taxane response

    DEFF Research Database (Denmark)

    Swanton, C.; Nicke, B.; Schuett, M.

    2009-01-01

    chromosomal instability (CIN). Silencing 22/50 of these genes, many of which are involved in DNA repair, caused cancer cell death, suggesting that these genes are involved in the survival of aneuploid cells. Overexpression of these "CIN-survival'' genes is associated with poor outcome in estrogen receptor......-positive breast cancer and occurs frequently in basal-like and Her2-positive cases. In diploid cells, but not in chromosomally unstable cells, paclitaxel causes repression of CIN-survival genes, followed by cell death. In the OV01 ovarian cancer clinical trial, a high level of CIN was associated with taxane...

  3. Spatiotemporal chaos involving wave instability.

    Science.gov (United States)

    Berenstein, Igal; Carballido-Landeira, Jorge

    2017-01-01

    In this paper, we investigate pattern formation in a model of a reaction confined in a microemulsion, in a regime where both Turing and wave instability occur. In one-dimensional systems, the pattern corresponds to spatiotemporal intermittency where the behavior of the systems alternates in both time and space between stationary Turing patterns and traveling waves. In two-dimensional systems, the behavior initially may correspond to Turing patterns, which then turn into wave patterns. The resulting pattern also corresponds to a chaotic state, where the system alternates in both space and time between standing wave patterns and traveling waves, and the local dynamics may show vanishing amplitude of the variables.

  4. Risk bubbles and market instability

    Science.gov (United States)

    Marsili, Matteo; Raffaelli, Giacomo

    2006-10-01

    We discuss a simple model of correlated assets capturing the feedback effects induced by portfolio investment in the covariance dynamics. This model predicts an instability when the volume of investment exceeds a critical value. Close to the critical point the model exhibits dynamical correlations very similar to those observed in real markets. Maximum likelihood estimates of the model's parameter for empirical data indeed confirms this conclusion. We show that this picture is confirmed by the empirical analysis for different choices of the time horizon.

  5. Chromosomal instability as a prognostic marker in cervical cancer

    International Nuclear Information System (INIS)

    How, Christine; Bruce, Jeff; So, Jonathan; Pintilie, Melania; Haibe-Kains, Benjamin; Hui, Angela; Clarke, Blaise A; Hedley, David W; Hill, Richard P; Milosevic, Michael; Fyles, Anthony; Liu, Fei-Fei

    2015-01-01

    Cervical cancer is the third most common cancer in women globally, and despite treatment, distant metastasis and nodal recurrence will still develop in approximately 30% of patients. The ability to predict which patients are likely to experience distant relapse would allow clinicians to better tailor treatment. Previous studies have investigated the role of chromosomal instability (CIN) in cancer, which can promote tumour initiation and growth; a hallmark of human malignancies. In this study, we sought to examine the published CIN70 gene signature in a cohort of cervical cancer patients treated at the Princess Margaret (PM) Cancer Centre and an independent cohort of The Cancer Genome Atlas (TCGA) cervical cancer patients, to determine if this CIN signature associated with patient outcome. Cervical cancer samples were collected from 79 patients, treated between 2000–2007 at the PM, prior to undergoing curative chemo-radiation. Total RNA was extracted from each patient sample and analyzed using the GeneChip Human Genome U133 Plus 2.0 array (Affymetrix). High CIN70 scores were significantly related to increased chromosomal alterations in TCGA cervical cancer patients, including a higher percentage of genome altered and a higher number of copy number alterations. In addition, this same CIN70 signature was shown to be predictive of para-aortic nodal relapse in the PM Cancer Centre cohort. These findings demonstrate that chromosomal instability plays an important role in cervical cancer, and is significantly associated with patient outcome. For the first time, this CIN70 gene signature provided prognostic value for patients with cervical cancer

  6. 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.

  7. How does political instability affect economic growth?

    OpenAIRE

    Aisen, Ari; Veiga, Francisco José

    2011-01-01

    The purpose of this paper is to empirically determine the effects of political instability on economic growth. Using the system-GMM estimator for linear dynamic panel data models on a sample covering up to 169 countries, and 5-year periods from 1960 to 2004, we find that higher degrees of political instability are associated with lower growth rates of GDP per capita. Regarding the channels of transmission, we find that political instability adversely affects growth by lowering the rates of pr...

  8. Surface instabilities during straining of anisotropic materials

    DEFF Research Database (Denmark)

    Legarth, Brian Nyvang; Richelsen, Ann Bettina

    2006-01-01

    The development of instabilities in traction-free surfaces is investigated numerically using a unit cell model. Full finite strain analyses are conducted using isotropic as well as anisotropic yield criteria and both plane strain tension and compression are considered. In the load range of tensio...... of principal overall strain. For other orientations surface instabilities are seen when non-associated plastic flow is taken into account. Compared to tension, smaller compressive deformations are needed in order to initiate a surface instability....

  9. Secondary instabilities of hypersonic stationary crossflow waves

    Science.gov (United States)

    Edelman, Joshua B.

    A sharp, circular 7° half-angle cone was tested in the Boeing/AFOSR Mach-6 Quiet Tunnel at 6° angle of attack. Using a variety of roughness configurations, measurements were made using temperature-sensitive paint (TSP) and fast pressure sensors. High-frequency secondary instabilities of the stationary crossflow waves were detected near the aft end of the cone, from 110° to 163° from the windward ray. At least two frequency bands of the secondary instabilities were measured. The secondary instabilities have high coherence between upstream and downstream sensor pairs. In addition, the amplitudes of the instabilities increase with the addition of roughness elements near the nose of the cone. Two of the measured instabilities were captured over a range of axial Reynolds numbers of about 1 - 2 million, with amplitudes ranging from low to turbulent breakdown. For these instabilities, the wave speed and amplitude growth can be calculated. The wave speeds were all near the edge velocity. Measured growth before breakdown for the two instabilities are between e3 and e4 from background noise levels. The initial linear growth rates for the instabilities are near 50 /m. Simultaneous measurement of two frequency bands of the secondary instabilities was made during a single run. It was found that each mode was spatially confined within a small azimuthal region, and that the regions of peak amplitude for one mode correspond to regions of minimal amplitude for the other.

  10. Pearling Instabilities of a Viscoelastic Thread

    Science.gov (United States)

    Deblais, A.; Velikov, K. P.; Bonn, D.

    2018-05-01

    Pearling instabilities of slender viscoelastic threads have received much attention, but remain incompletely understood. We study the instabilities in polymer solutions subject to uniaxial elongational flow. Two distinctly different instabilites are observed: beads on a string and blistering. The beads-on-a-string structure arises from a capillary instability whereas the blistering instability has a different origin: it is due to a coupling between stress and polymer concentration. By varying the temperature to change the solution properties we elucidate the interplay between flow and phase separation.

  11. Review of two-phase instabilities

    Energy Technology Data Exchange (ETDEWEB)

    Kang, Han Ok; Seo, Han Ok; Kang, Hyung Suk; Cho, Bong Hyun; Lee, Doo Jeong

    1997-06-01

    KAERI is carrying out a development of the design for a new type of integral reactors. The once-through helical steam generator is important design features. The study on designs and operating conditions which prevent flow instability should precede the introduction of one-through steam generator. Experiments are currently scheduled to understand two-phase instability, evaluate the effect of each design parameter on the critical point, and determine proper inlet throttling for the prevention of instability. This report covers general two-phase instability with review of existing studies on this topics. The general classification of two phase flow instability and the characteristics of each type of instability are first described. Special attention is paid to BWR core flow instability and once-through steam generator instability. The reactivity feedback and the effect of system parameters are treated mainly for BWR. With relation to once-through steam generators, the characteristics of convective heating and dryout point oscillation are first investigated and then the existing experimental studies are summarized. Finally chapter summarized the proposed correlations for instability boundary conditions. (author). 231 refs., 5 tabs., 47 figs

  12. Gravitational instability in isotropic MHD plasma waves

    Science.gov (United States)

    Cherkos, Alemayehu Mengesha

    2018-04-01

    The effect of compressive viscosity, thermal conductivity and radiative heat-loss functions on the gravitational instability of infinitely extended homogeneous MHD plasma has been investigated. By taking in account these parameters we developed the six-order dispersion relation for magnetohydrodynamic (MHD) waves propagating in a homogeneous and isotropic plasma. The general dispersion relation has been developed from set of linearized basic equations and solved analytically to analyse the conditions of instability and instability of self-gravitating plasma embedded in a constant magnetic field. Our result shows that the presence of viscosity and thermal conductivity in a strong magnetic field substantially modifies the fundamental Jeans criterion of gravitational instability.

  13. Fringe instability in constrained soft elastic layers.

    Science.gov (United States)

    Lin, Shaoting; Cohen, Tal; Zhang, Teng; Yuk, Hyunwoo; Abeyaratne, Rohan; Zhao, Xuanhe

    2016-11-04

    Soft elastic layers with top and bottom surfaces adhered to rigid bodies are abundant in biological organisms and engineering applications. As the rigid bodies are pulled apart, the stressed layer can exhibit various modes of mechanical instabilities. In cases where the layer's thickness is much smaller than its length and width, the dominant modes that have been studied are the cavitation, interfacial and fingering instabilities. Here we report a new mode of instability which emerges if the thickness of the constrained elastic layer is comparable to or smaller than its width. In this case, the middle portion along the layer's thickness elongates nearly uniformly while the constrained fringe portions of the layer deform nonuniformly. When the applied stretch reaches a critical value, the exposed free surfaces of the fringe portions begin to undulate periodically without debonding from the rigid bodies, giving the fringe instability. We use experiments, theory and numerical simulations to quantitatively explain the fringe instability and derive scaling laws for its critical stress, critical strain and wavelength. We show that in a force controlled setting the elastic fingering instability is associated with a snap-through buckling that does not exist for the fringe instability. The discovery of the fringe instability will not only advance the understanding of mechanical instabilities in soft materials but also have implications for biological and engineered adhesives and joints.

  14. Electromagnetic theory of the radiative Pierce instability

    International Nuclear Information System (INIS)

    Klochkov, D.N.; Rukhadze, A.A.

    1997-01-01

    The radiative Pierce instability of a relativistic electron beam in a waveguide stabilized by an infinite strong magnetic field is considered. the increment and conditions for instability development in a wide interval of the beam currents are determined on the basis of the perturbation theory. It is shown that the instability has always the Raman character and is threshold less in current for the Pierce boundary conditions. It permits sufficiently strictly to define the instability saturation level from breaking the resonance condition and to estimate the radiation efficiency

  15. Systems and methods for controlling flame instability

    KAUST Repository

    Cha, Min Suk

    2016-07-21

    A system (62) for controlling flame instability comprising: a nozzle (66) coupled to a fuel supply line (70), an insulation housing (74) coupled to the nozzle, a combustor (78) coupled to the nozzle via the insulation housing, where the combustor is grounded (80), a pressure sensor (82) coupled to the combustor and configured to detect pressure in the combustor, and an instability controlling assembly coupled to the pressure sensor and to an alternating current power supply (86), where, the instability controlling assembly can control flame instability of a flame in the system based on pressure detected by the pressure sensor.

  16. 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....

  17. Analysis of fluid structural instability in water

    International Nuclear Information System (INIS)

    Piccirillo, N.

    1997-02-01

    Recent flow testing of stainless steel hardware in a high pressure/high temperature water environment produced an apparent fluid-structural instability. The source of instability was investigated by studying textbook theory and by performing NASTRAN finite element analyses. The modal analyses identified the mode that was being excited, but the flutter instability analysis showed that the design is stable if minimal structural damping is present. Therefore, it was suspected that the test hardware was the root cause of the instability. Further testing confirmed this suspicion

  18. Instabilities in the plasma focus

    International Nuclear Information System (INIS)

    Kaeppeler, H.J.

    1975-03-01

    The plasma focus was studied by many research teams in view of a possible approach to controlled thermonuclear fusion. Though it is questionable whether the plasma focus will ever lead to a fusion reactor, it nevertheless constitutes a strong source of neutron, X- and gamma radiation for simulating fusion reactor conditions. Furthermore, the plasma focus yields very high temperatures (10 7 K) and densities (> 10 19 cm -3 ) and thus provides interesting conditions for the study of high density plasmas. This review paper starts with a description of the compression stage of the focussing plasma, using a snow-plough model. It is shown that sophisticated MHD calculations substantiate the snowplough theory, but are not suited to describe the phenomena in the final compressed stage. For this purpose, a particle-in-cell calculation is employed, yielding a beam-beam collision model for the neutron production. Experimental evidence indicates that neutron production is associated with the appearence of m = O instabilities and is the direct result of collisions between anomalously accelerated ions. One of the mechanisms of ion acceleration are strong local electric fields. Another possible mechanism can bee seen in beam-plasma instabilities caused by runaway electrons. The analytical derivation of the dispersion relation for plasma focus conditions including runaway effect is discussed (orig.) [de

  19. Combustion instability modeling and analysis

    Energy Technology Data Exchange (ETDEWEB)

    Santoro, R.J.; Yang, V.; Santavicca, D.A. [Pennsylvania State Univ., University Park, PA (United States)] [and others

    1995-10-01

    It is well known that the two key elements for achieving low emissions and high performance in a gas turbine combustor are to simultaneously establish (1) a lean combustion zone for maintaining low NO{sub x} emissions and (2) rapid mixing for good ignition and flame stability. However, these requirements, when coupled with the short combustor lengths used to limit the residence time for NO formation typical of advanced gas turbine combustors, can lead to problems regarding unburned hydrocarbons (UHC) and carbon monoxide (CO) emissions, as well as the occurrence of combustion instabilities. Clearly, the key to successful gas turbine development is based on understanding the effects of geometry and operating conditions on combustion instability, emissions (including UHC, CO and NO{sub x}) and performance. The concurrent development of suitable analytical and numerical models that are validated with experimental studies is important for achieving this objective. A major benefit of the present research will be to provide for the first time an experimentally verified model of emissions and performance of gas turbine combustors.

  20. 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

  1. Adhesional instabilities and gecko locomotion

    Science.gov (United States)

    Williams, John A.

    2015-01-01

    Geckos possess a remarkable ability to run rapidly on both walls and ceilings and in recent years the mechanisms that underlie this facility have come under close scrutiny. It is now generally agreed that one of the principal mechanisms of adhesion relies on the action of van der Waal forces acting between the final extremely fine structure of the gecko toe and the underlying substrate. High speed video analysis shows that adhesive contact is both made and broken in intervals of less than 20 ms and this suggests that the mechanism of detachment is one of adhesive instability rather than steady-state peeling. By considering the gecko seta/spatula as a Euler-Bernoulli cantilever it is possible to model this instability in non-dimensional terms and thus to test the analysis at a much larger scale with more conventional engineering materials. When applied to the scale and material combination appropriate to a gecko spatula, the predicted critical load, of around 10 nN, is close to values that have been observed using and AFM cantilever and a single detached spatula.

  2. Adhesional instabilities and gecko locomotion

    International Nuclear Information System (INIS)

    Williams, John A

    2015-01-01

    Geckos possess a remarkable ability to run rapidly on both walls and ceilings and in recent years the mechanisms that underlie this facility have come under close scrutiny. It is now generally agreed that one of the principal mechanisms of adhesion relies on the action of van der Waal forces acting between the final extremely fine structure of the gecko toe and the underlying substrate. High speed video analysis shows that adhesive contact is both made and broken in intervals of less than 20 ms and this suggests that the mechanism of detachment is one of adhesive instability rather than steady-state peeling. By considering the gecko seta/spatula as a Euler–Bernoulli cantilever it is possible to model this instability in non-dimensional terms and thus to test the analysis at a much larger scale with more conventional engineering materials. When applied to the scale and material combination appropriate to a gecko spatula, the predicted critical load, of around 10 nN, is close to values that have been observed using and AFM cantilever and a single detached spatula. (paper)

  3. Option price and market instability

    Science.gov (United States)

    Baaquie, Belal E.; Yu, Miao

    2017-04-01

    An option pricing formula, for which the price of an option depends on both the value of the underlying security as well as the velocity of the security, has been proposed in Baaquie and Yang (2014). The FX (foreign exchange) options price was empirically studied in Baaquie et al., (2014), and it was found that the model in general provides an excellent fit for all strike prices with a fixed model parameters-unlike the Black-Scholes option price Hull and White (1987) that requires the empirically determined implied volatility surface to fit the option data. The option price proposed in Baaquie and Cao Yang (2014) did not fit the data during the crisis of 2007-2008. We make a hypothesis that the failure of the option price to fit data is an indication of the market's large deviation from its near equilibrium behavior due to the market's instability. Furthermore, our indicator of market's instability is shown to be more accurate than the option's observed volatility. The market prices of the FX option for various currencies are studied in the light of our hypothesis.

  4. Maintaining Genome Stability: The Role of Helicases and Deaminases

    Science.gov (United States)

    2008-07-01

    Errors in duplicating DNA can result in genomic instability, leading to various human diseases, such as cancer, immune system disorder, muscle dystrophy ...as cancer, immune system disorder, muscle dystrophy , and neurodegenerations. Thus, maintaining genomic integrity is vital to the normal growth of...31–38. Eberharter, A., R. Ferreira and P. Becker , 2005 Dynamic chro- matin: concerted nucleosome remodelling and acetylation. Biol. Chem. 386: 745

  5. Shoulder instability in professional football players.

    Science.gov (United States)

    Leclere, Lance E; Asnis, Peter D; Griffith, Matthew H; Granito, David; Berkson, Eric M; Gill, Thomas J

    2013-09-01

    Shoulder instability is a common problem in American football players entering the National Football League (NFL). Treatment options include nonoperative and surgical stabilization. This study evaluated how the method of treatment of pre-NFL shoulder instability affects the rate of recurrence and the time elapsed until recurrence in players on 1 NFL team. Retrospective cohort. Medical records from 1980 to 2008 for 1 NFL team were reviewed. There were 328 players included in the study who started their career on the team and remained on the team for at least 2 years (mean, 3.9 years; range, 2-14 years). The history of instability prior to entering the NFL and the method of treatment were collected. Data on the occurrence of instability while in the NFL were recorded to determine the rate and timing of recurrence. Thirty-one players (9.5%) had a history of instability prior to entering the NFL. Of the 297 players with no history of instability, 39 (13.1%) had a primary event at a mean of 18.4 ± 22.2 months (range, 0-102 months) after joining the team. In the group of players with prior instability treated with surgical stabilization, there was no statistical difference in the rate of recurrence (10.5%) or the timing to the instability episode (mean, 26 months) compared with players with no history of instability. Twelve players had shoulder instability treated nonoperatively prior to the NFL. Five of these players (41.7%) had recurrent instability at a mean of 4.4 ± 7.0 months (range, 0-16 months). The patients treated nonoperatively had a significantly higher rate of recurrence (P = 0.02) and an earlier time of recurrence (P = 0.04). The rate of contralateral instability was 25.8%, occurring at a mean of 8.6 months. Recurrent shoulder instability is more common in NFL players with a history of nonoperative treatment. Surgical stabilization appears to restore the rate and timing of instability to that of players with no prior history of instability.

  6. Testing the gravitational instability hypothesis?

    Science.gov (United States)

    Babul, Arif; Weinberg, David H.; Dekel, Avishai; Ostriker, Jeremiah P.

    1994-01-01

    We challenge a widely accepted assumption of observational cosmology: that successful reconstruction of observed galaxy density fields from measured galaxy velocity fields (or vice versa), using the methods of gravitational instability theory, implies that the observed large-scale structures and large-scale flows were produced by the action of gravity. This assumption is false, in that there exist nongravitational theories that pass the reconstruction tests and gravitational theories with certain forms of biased galaxy formation that fail them. Gravitational instability theory predicts specific correlations between large-scale velocity and mass density fields, but the same correlations arise in any model where (a) structures in the galaxy distribution grow from homogeneous initial conditions in a way that satisfies the continuity equation, and (b) the present-day velocity field is irrotational and proportional to the time-averaged velocity field. We demonstrate these assertions using analytical arguments and N-body simulations. If large-scale structure is formed by gravitational instability, then the ratio of the galaxy density contrast to the divergence of the velocity field yields an estimate of the density parameter Omega (or, more generally, an estimate of beta identically equal to Omega(exp 0.6)/b, where b is an assumed constant of proportionality between galaxy and mass density fluctuations. In nongravitational scenarios, the values of Omega or beta estimated in this way may fail to represent the true cosmological values. However, even if nongravitational forces initiate and shape the growth of structure, gravitationally induced accelerations can dominate the velocity field at late times, long after the action of any nongravitational impulses. The estimated beta approaches the true value in such cases, and in our numerical simulations the estimated beta values are reasonably accurate for both gravitational and nongravitational models. Reconstruction tests

  7. Interfacial instabilities in vibrated fluids

    Science.gov (United States)

    Porter, Jeff; Laverón-Simavilla, Ana; Tinao Perez-Miravete, Ignacio; Fernandez Fraile, Jose Javier

    2016-07-01

    Vibrations induce a range of different interfacial phenomena in fluid systems depending on the frequency and orientation of the forcing. With gravity, (large) interfaces are approximately flat and there is a qualitative difference between vertical and horizontal forcing. Sufficient vertical forcing produces subharmonic standing waves (Faraday waves) that extend over the whole interface. Horizontal forcing can excite both localized and extended interfacial phenomena. The vibrating solid boundaries act as wavemakers to excite traveling waves (or sloshing modes at low frequencies) but they also drive evanescent bulk modes whose oscillatory pressure gradient can parametrically excite subharmonic surface waves like cross-waves. Depending on the magnitude of the damping and the aspect ratio of the container, these locally generated surfaces waves may interact in the interior resulting in temporal modulation and other complex dynamics. In the case where the interface separates two fluids of different density in, for example, a rectangular container, the mass transfer due to vertical motion near the endwalls requires a counterflow in the interior region that can lead to a Kelvin-Helmholtz type instability and a ``frozen wave" pattern. In microgravity, the dominance of surface forces favors non-flat equilibrium configurations and the distinction between vertical and horizontal applied forcing can be lost. Hysteresis and multiplicity of solutions are more common, especially in non-wetting systems where disconnected (partial) volumes of fluid can be established. Furthermore, the vibrational field contributes a dynamic pressure term that competes with surface tension to select the (time averaged) shape of the surface. These new (quasi-static) surface configurations, known as vibroequilibria, can differ substantially from the hydrostatic state. There is a tendency for the interface to orient perpendicular to the vibrational axis and, in some cases, a bulge or cavity is induced

  8. Cephalopod genomics

    DEFF Research Database (Denmark)

    Albertin, Caroline B.; Bonnaud, Laure; Brown, C. Titus

    2012-01-01

    The Cephalopod Sequencing Consortium (CephSeq Consortium) was established at a NESCent Catalysis Group Meeting, ``Paths to Cephalopod Genomics-Strategies, Choices, Organization,'' held in Durham, North Carolina, USA on May 24-27, 2012. Twenty-eight participants representing nine countries (Austria......, Australia, China, Denmark, France, Italy, Japan, Spain and the USA) met to address the pressing need for genome sequencing of cephalopod mollusks. This group, drawn from cephalopod biologists, neuroscientists, developmental and evolutionary biologists, materials scientists, bioinformaticians and researchers...... active in sequencing, assembling and annotating genomes, agreed on a set of cephalopod species of particular importance for initial sequencing and developed strategies and an organization (CephSeq Consortium) to promote this sequencing. The conclusions and recommendations of this meeting are described...

  9. A comparison of 100 human genes using an alu element-based instability model.

    Directory of Open Access Journals (Sweden)

    George W Cook

    Full Text Available The human retrotransposon with the highest copy number is the Alu element. The human genome contains over one million Alu elements that collectively account for over ten percent of our DNA. Full-length Alu elements are randomly distributed throughout the genome in both forward and reverse orientations. However, full-length widely spaced Alu pairs having two Alus in the same (direct orientation are statistically more prevalent than Alu pairs having two Alus in the opposite (inverted orientation. The cause of this phenomenon is unknown. It has been hypothesized that this imbalance is the consequence of anomalous inverted Alu pair interactions. One proposed mechanism suggests that inverted Alu pairs can ectopically interact, exposing both ends of each Alu element making up the pair to a potential double-strand break, or "hit". This hypothesized "two-hit" (two double-strand breaks potential per Alu element was used to develop a model for comparing the relative instabilities of human genes. The model incorporates both 1 the two-hit double-strand break potential of Alu elements and 2 the probability of exon-damaging deletions extending from these double-strand breaks. This model was used to compare the relative instabilities of 50 deletion-prone cancer genes and 50 randomly selected genes from the human genome. The output of the Alu element-based genomic instability model developed here is shown to coincide with the observed instability of deletion-prone cancer genes. The 50 cancer genes are collectively estimated to be 58% more unstable than the randomly chosen genes using this model. Seven of the deletion-prone cancer genes, ATM, BRCA1, FANCA, FANCD2, MSH2, NCOR1 and PBRM1, were among the most unstable 10% of the 100 genes analyzed. This algorithm may lay the foundation for comparing genetic risks posed by structural variations that are unique to specific individuals, families and people groups.

  10. A comparison of 100 human genes using an alu element-based instability model.

    Science.gov (United States)

    Cook, George W; Konkel, Miriam K; Walker, Jerilyn A; Bourgeois, Matthew G; Fullerton, Mitchell L; Fussell, John T; Herbold, Heath D; Batzer, Mark A

    2013-01-01

    The human retrotransposon with the highest copy number is the Alu element. The human genome contains over one million Alu elements that collectively account for over ten percent of our DNA. Full-length Alu elements are randomly distributed throughout the genome in both forward and reverse orientations. However, full-length widely spaced Alu pairs having two Alus in the same (direct) orientation are statistically more prevalent than Alu pairs having two Alus in the opposite (inverted) orientation. The cause of this phenomenon is unknown. It has been hypothesized that this imbalance is the consequence of anomalous inverted Alu pair interactions. One proposed mechanism suggests that inverted Alu pairs can ectopically interact, exposing both ends of each Alu element making up the pair to a potential double-strand break, or "hit". This hypothesized "two-hit" (two double-strand breaks) potential per Alu element was used to develop a model for comparing the relative instabilities of human genes. The model incorporates both 1) the two-hit double-strand break potential of Alu elements and 2) the probability of exon-damaging deletions extending from these double-strand breaks. This model was used to compare the relative instabilities of 50 deletion-prone cancer genes and 50 randomly selected genes from the human genome. The output of the Alu element-based genomic instability model developed here is shown to coincide with the observed instability of deletion-prone cancer genes. The 50 cancer genes are collectively estimated to be 58% more unstable than the randomly chosen genes using this model. Seven of the deletion-prone cancer genes, ATM, BRCA1, FANCA, FANCD2, MSH2, NCOR1 and PBRM1, were among the most unstable 10% of the 100 genes analyzed. This algorithm may lay the foundation for comparing genetic risks posed by structural variations that are unique to specific individuals, families and people groups.

  11. 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...

  12. Prognostic value of partial genetic instability in Neuroblastoma with ? 50% neuroblastic cell content.

    OpenAIRE

    2011-01-01

    Abstract Aims. Better understanding of neuroblastoma genetics will improve with genome-wide techniques. However it is not adequated to perform these analyses in samples with less than 60% neuroblastic cell content. We evaluated the utility of FISH on tissue microarrays (TMA) in detecting partial genetic instability (PGI), focussing on samples with ? 50% neuroblastic cells. Methods and results. Alterations of 11q and 17q were detected by FISH on 369 neuroblastic samples included...

  13. RADIATIVE RAYLEIGH-TAYLOR INSTABILITIES

    International Nuclear Information System (INIS)

    Jacquet, Emmanuel; Krumholz, Mark R.

    2011-01-01

    We perform analytic linear stability analyses of an interface separating two stratified media threaded by a radiation flux, a configuration relevant in several astrophysical contexts. We develop a general framework for analyzing such systems and obtain exact stability conditions in several limiting cases. In the optically thin, isothermal regime, where the discontinuity is chemical in nature (e.g., at the boundary of a radiation pressure-driven H II region), radiation acts as part of an effective gravitational field, and instability arises if the effective gravity per unit volume toward the interface overcomes that away from it. In the optically thick a diabaticregime where the total (gas plus radiation) specific entropy of a Lagrangian fluid element is conserved, for example at the edge of radiation pressure-driven bubble around a young massive star, we show that radiation acts like a modified equation of state and derive a generalized version of the classical Rayleigh-Taylor stability condition.

  14. Perturbative instabilities in Horava gravity

    International Nuclear Information System (INIS)

    Bogdanos, Charalampos; Saridakis, Emmanuel N

    2010-01-01

    We investigate the scalar and tensor perturbations in Horava gravity, with and without detailed balance, around a flat background. Once both types of perturbations are taken into account, it is revealed that the theory is plagued by ghost-like scalar instabilities in the range of parameters which would render it power-counting renormalizable, that cannot be overcome by simple tricks such as analytic continuation. Implementing a consistent flow between the UV and IR limits seems thus more challenging than initially presumed, regardless of whether the theory approaches general relativity at low energies or not. Even in the phenomenologically viable parameter space, the tensor sector leads to additional potential problems, such as fine-tunings and super-luminal propagation.

  15. Instability of expanding bacterial droplets.

    Science.gov (United States)

    Sokolov, Andrey; Rubio, Leonardo Dominguez; Brady, John F; Aranson, Igor S

    2018-04-03

    Suspensions of motile bacteria or synthetic microswimmers, termed active matter, manifest a remarkable propensity for self-organization, and formation of large-scale coherent structures. Most active matter research deals with almost homogeneous in space systems and little is known about the dynamics of strongly heterogeneous active matter. Here we report on experimental and theoretical studies on the expansion of highly concentrated bacterial droplets into an ambient bacteria-free fluid. The droplet is formed beneath a rapidly rotating solid macroscopic particle inserted in the suspension. We observe vigorous instability of the droplet reminiscent of a violent explosion. The phenomenon is explained in terms of continuum first-principle theory based on the swim pressure concept. Our findings provide insights into the dynamics of active matter with strong density gradients and significantly expand the scope of experimental and analytic tools for control and manipulation of active systems.

  16. Instability of vortex pair leapfrogging

    DEFF Research Database (Denmark)

    Tophøj, Laust; Aref, Hassan

    2013-01-01

    Leapfrogging is a periodic solution of the four-vortex problem with two positive and two negative point vortices all of the same absolute circulation arranged as co-axial vortex pairs. The set of co-axial motions can be parameterized by the ratio 0 vortex pair sizes at the time when one...... pair passes through the other. Leapfrogging occurs for α > σ2, where is the silver ratio. The motion is known in full analytical detail since the 1877 thesis of Gröbli and a well known 1894 paper by Love. Acheson ["Instability of vortex leapfrogging," Eur. J. Phys.21, 269-273 (2000...... pairs fly off to infinity, and a "walkabout" mode, where the vortices depart from leapfrogging but still remain within a finite distance of one another. We show numerically that this transition is more gradual, a result that we relate to earlier investigations of chaotic scattering of vortex pairs [L...

  17. Filament instability under constant loads

    Science.gov (United States)

    Monastra, A. G.; Carusela, M. F.; D’Angelo, M. V.; Bruno, L.

    2018-04-01

    Buckling of semi-flexible filaments appears in different systems and scales. Some examples are: fibers in geophysical applications, microtubules in the cytoplasm of eukaryotic cells and deformation of polymers freely suspended in a flow. In these examples, instabilities arise when a system’s parameter exceeds a critical value, being the Euler force the most known. However, the complete time evolution and wavelength of buckling processes are not fully understood. In this work we solve analytically the time evolution of a filament under a constant compressive force in the small amplitude approximation. This gives an insight into the variable force scenario in terms of normal modes. The evolution is highly sensitive to the initial configuration and to the magnitude of the compressive load. This model can be a suitable approach to many different real situations.

  18. Hydromagnetic instability in a stellarator

    Energy Technology Data Exchange (ETDEWEB)

    Kruskal, M D; Gottlieb, M B; Johnson, J L; Goldman, L M [Project Matterhorn, Princeton University, Princeton, NJ (United States)

    1958-07-01

    It was noted that when there is a uniform externally imposed longitudinal field much larger than the field of the discharge current, one should expect instabilities in the form of a lateral displacement of the plasma column into a helix of large pitch. At the wavelength of fastest growth the e-folding time approximates the time it takes a sound wave in the plasma to traverse the radius of the plasma column. This problem has been re-examines under the conditions which might be expected to occur in the stellarator during ohmic heating, including the presence of external conductors. The theory is applied to the stellarator; and it is shown that the external conductors are in fact unimportant. The important effects due to the finite length of the Machine are discussed and the effects of more general current distributions are considered. The results from the experiments are given.

  19. Hose instability at arbitrary conductivity

    International Nuclear Information System (INIS)

    Lee, E.P.

    1975-01-01

    A model is developed for studying the dynamics of a low-current, highly relativistic beam propagating in a conducting medium. Here the conductivity (sigma) is of arbitrary magnitude, the usual assumption being that the scale beam radius (a) is small compared with the magnetic skin length (4 π sigma a 2 /c). A dispersion formula for the hose instability is derived for the case of uniform sigma and Bennett current profile J/sub b/(r) varies as (a 2 + r 2 ) -2 . The peak growth rate at fixed laboratory position, maximized with respect to sigma as well as driver frequency, is approximately 0.465 c/a. This growth rate is realized when 4 π sigma a/c = √12/5. (U.S.)

  20. Parametric instabilities in inhomogeneous plasma

    International Nuclear Information System (INIS)

    Nicholson, D.R.

    1975-01-01

    The nonlinear coupling of three waves in a plasma is considered. One of the waves is assumed large and constant; its amplitude is the parameter of the parametric instability. The spatial-temporal evolution of the other two waves is treated theoretically, in one dimension, by analytic methods and by direct numerical integration of the basic equations. Various monotonic forms of inhomogeneity are considered; agreement with previous work is found and new results are established. Nonmonotonic inhomogeneities are considered, in the form of turbulence and, as a model problem, in the form of a simple sinusoidal modulation. Relatively small amounts of nonmonotonic inhomogeneity, in the presence of a linear density gradient, are found to destabilize the well-known convective saturation, absolute growth occurring instead. (U.S.)

  1. Ion-cyclotron instability in magnetic mirrors

    International Nuclear Information System (INIS)

    Pearlstein, L.D.

    1987-01-01

    This report reviews the role of ion-cyclotron frequency instability in magnetic mirrors. The modes discussed here are loss-cone or anisotropy driven. The discussion includes quasilinear theory, explosive instabilities of 3-wave interaction and non-linear Landau damping, and saturation due to non-linear orbits

  2. On viscoelastic instability in polymeric filaments

    DEFF Research Database (Denmark)

    Rasmussen, Henrik Koblitz; Hassager, Ole

    1999-01-01

    The 3D Lagrangian Integral Method is used to simulate the effects of surface tension on the viscoelastic end-plate instability, occuring in the rapid extension of some polymeric filaments between parallel plates. It is shovn that the surface tension delays the onset of the instability. Furthermore...

  3. The short circuit instability in protoplanetary disks

    DEFF Research Database (Denmark)

    Hubbard, A.; McNally, C.P.; Mac Low, M.M.

    2013-01-01

    We introduce a magneto-hydrodynamic instability which occurs, among other locations, in the inner, hot regions of protoplanetary disks, and which alters the way in which resistive dissipation of magnetic energy into heat proceeds. This instability can be likened to both an electrical short circui...

  4. Cultural diversity, economic development and societal instability

    Science.gov (United States)

    Nettle, D.; Grace, J.B.; Choisy, M.; Cornell, H.V.; Guegan, J.-F.; Hochberg, M.E.

    2007-01-01

    Background. Social scientists have suggested that cultural diversity in a nation leads to societal instability. However, societal instability may be affected not only by within-nation on ?? diversity, but also diversity between a nation and its neighbours or ?? diversity. It is also necessary to distinguish different domains of diversity, namely linguistic, ethnic and religious, and to distinguish between the direct effects of diversity on societal instability, and effects that are mediated by economic conditions. Methodology/Principal Findings. We assembled a large cross-national dataset with information on ?? and ?? cultural diversity, economic conditions, and indices of societal instability. Structural equation modeling was used to evaluate the direct and indirect effects of cultural diversity on economics and societal stability. Results show that different type and domains of diversity have interacting effects. As previously documented, linguistic ?? diversity has a negative effect on economic performance, and we show that it is largely through this economic mechanism that it affects societal instability. For ?? diversity, the higher the linguistic diversity among nations in a region, the less stable the nation. But, religious ?? diversity has the opposite effect, reducing instability, particularly in the presence of high linguistic diversity. Conclusions. Within-nation linguistic diversity is associated with reduced economic performance, which, in turn, increases societal instability. Nations which differ linguistically from their neighbors are also less stable. However, religious diversity between, neighboring nations has the opposite effect, decreasing societal instability.

  5. Plasma instabilities in high electric fields

    DEFF Research Database (Denmark)

    Morawetz, K.; Jauho, Antti-Pekka

    1994-01-01

    expression is derived for the nonequilibrium dielectric function epsilon(K, omega). For certain values of momenta K and frequency omega, Imepsilon(K, omega) becomes negative, implying a plasma instability. This new instability exists only for strong electric fields, underlining its nonequilibrium origin....

  6. 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

  7. Direct observation of nonequilibrium electroosmotic instability

    NARCIS (Netherlands)

    Rubinstein, S.M.; Manukyan, G.; Staicu, A.D.; Rubinstein, I.; Zaltzman, B.; Lammertink, Rob G.H.; Mugele, Friedrich Gunther; Wessling, Matthias

    2008-01-01

    We present a visualization of the predicted instability in ionic conduction from a binary electrolyte into a charge selective solid. This instability develops when a voltage greater than critical is applied to a thin layer of copper sulfate flanked by a copper anode and a cation selective membrane.

  8. Partnership Instability, School Readiness, and Gender Disparities

    Science.gov (United States)

    Cooper, Carey E.; Osborne, Cynthia A.; Beck, Audrey N.; McLanahan, Sara S.

    2011-01-01

    Trends in family formation during the past several decades have increased children's exposure to mothers' partnership instability, defined as an entrance into or exit from a coresidential union or a dating partnership. Instability, in turn, is associated with negative outcomes for children and adolescents. This study uses data from the Fragile…

  9. Cultural diversity, economic development and societal instability.

    Science.gov (United States)

    Nettle, Daniel; Grace, James B; Choisy, Marc; Cornell, Howard V; Guégan, Jean-François; Hochberg, Michael E

    2007-09-26

    Social scientists have suggested that cultural diversity in a nation leads to societal instability. However, societal instability may be affected not only by within-nation or alpha diversity, but also diversity between a nation and its neighbours or beta diversity. It is also necessary to distinguish different domains of diversity, namely linguistic, ethnic and religious, and to distinguish between the direct effects of diversity on societal instability, and effects that are mediated by economic conditions. We assembled a large cross-national dataset with information on alpha and beta cultural diversity, economic conditions, and indices of societal instability. Structural equation modeling was used to evaluate the direct and indirect effects of cultural diversity on economics and societal stability. Results show that different types and domains of diversity have interacting effects. As previously documented, linguistic alpha diversity has a negative effect on economic performance, and we show that it is largely through this economic mechanism that it affects societal instability. For beta diversity, the higher the linguistic diversity among nations in a region, the less stable the nation. But, religious beta diversity has the opposite effect, reducing instability, particularly in the presence of high linguistic diversity. Within-nation linguistic diversity is associated with reduced economic performance, which, in turn, increases societal instability. Nations which differ linguistically from their neighbors are also less stable. However, religious diversity between neighboring nations has the opposite effect, decreasing societal instability.

  10. Genome Sequencing

    DEFF Research Database (Denmark)

    Sato, Shusei; Andersen, Stig Uggerhøj

    2014-01-01

    The current Lotus japonicus reference genome sequence is based on a hybrid assembly of Sanger TAC/BAC, Sanger shotgun and Illumina shotgun sequencing data generated from the Miyakojima-MG20 accession. It covers nearly all expressed L. japonicus genes and has been annotated mainly based on transcr......The current Lotus japonicus reference genome sequence is based on a hybrid assembly of Sanger TAC/BAC, Sanger shotgun and Illumina shotgun sequencing data generated from the Miyakojima-MG20 accession. It covers nearly all expressed L. japonicus genes and has been annotated mainly based...

  11. Neuromuscular control and ankle instability.

    Science.gov (United States)

    Gutierrez, Gregory M; Kaminski, Thomas W; Douex, Al T

    2009-04-01

    Lateral ankle sprains (LAS) are common injuries in athletics and daily activity. Although most are resolved with conservative treatment, others develop chronic ankle instability (AI)-a condition associated with persistent pain, weakness, and instability-both mechanical (such as ligamentous laxity) and functional (neuromuscular impairment with or without mechanical laxity). The predominant theory in AI is one of articular deafferentation from the injury, affecting closed-loop (feedback/reflexive) neuromuscular control, but recent research has called that theory into question. A considerable amount of attention has been directed toward understanding the underlying causes of this pathology; however, little is known concerning the neuromuscular mechanisms behind the development of AI. The purpose of this review is to summarize the available literature on neuromuscular control in uninjured individuals and individuals with AI. Based on available research and reasonable speculation, it seems that open-loop (feedforward/anticipatory) neuromuscular control may be more important for the maintenance of dynamic joint stability than closed-loop control systems that rely primarily on proprioception. Therefore, incorporating perturbation activities into patient rehabilitation schemes may be of some benefit in enhancing these open-loop control mechanisms. Despite the amount of research conducted in this area, analysis of individuals with AI during dynamic conditions is limited. Future work should aim to evaluate dynamic perturbations in individuals with AI, as well as subjects who have a history of at least one LAS and never experienced recurrent symptoms. These potential findings may help elucidate some compensatory mechanisms, or more appropriate neuromuscular control strategies after an LAS event, thus laying the groundwork for future intervention studies that can attempt to reduce the incidence and severity of acute and chronic lateral ankle injury.

  12. Treatment of the subject of tearing instability

    International Nuclear Information System (INIS)

    Paris, P.C.

    1977-07-01

    A simple approach is taken to the mechanics of potential instability associated with the steady tearing portion of J-Integral R-curves. The analysis is developed from simple examples of structural component (or test specimen) configurations with cracks, examining their instability possibilities individually, in order to draw more general conclusions about elastic-plastic cracking instability as contrasted to linear-elastic behavior. Finally, an attempt is made to model a more local cleavage-like instability for material in the fracture process zone just ahead of a crack tip. Results are then presented of a testing program which clearly demonstrates the appropriateness of the tearing instability analysis and which illustrates its broad potential for future application, as well as presenting guidelines for its further development. The material selected for analysis was Ni-Cr-Mo-V rotor steel

  13. Taylor instability in rhyolite lava flows

    Science.gov (United States)

    Baum, B. A.; Krantz, W. B.; Fink, J. H.; Dickinson, R. E.

    1989-01-01

    A refined Taylor instability model is developed to describe the surface morphology of rhyolite lava flows. The effect of the downslope flow of the lava on the structures resulting from the Taylor instability mechanism is considered. Squire's (1933) transformation is developed for this flow in order to extend the results to three-dimensional modes. This permits assessing why ridges thought to arise from the Taylor instability mechanism are preferentially oriented transverse to the direction of lava flow. Measured diapir and ridge spacings for the Little and Big Glass Mountain rhyolite flows in northern California are used in conjunction with the model in order to explore the implications of the Taylor instability for flow emplacement. The model suggests additional lava flow features that can be measured in order to test whether the Taylor instability mechanism has influenced the flows surface morphology.

  14. 3-D nonlinear evolution of MHD instabilities

    International Nuclear Information System (INIS)

    Bateman, G.; Hicks, H.R.; Wooten, J.W.

    1977-03-01

    The nonlinear evolution of ideal MHD internal instabilities is investigated in straight cylindrical geometry by means of a 3-D initial-value computer code. These instabilities are characterized by pairs of velocity vortex cells rolling off each other and helically twisted down the plasma column. The cells persist until the poloidal velocity saturates at a few tenths of the Alfven velocity. The nonlinear phase is characterized by convection around these essentially fixed vortex cells. For example, the initially centrally peaked temperature profile is convected out and around to form an annulus of high temperature surrounding a small region of lower temperature. Weak, centrally localized instabilities do not alter the edge of the plasma. Strong, large-scale instabilities, resulting from a stronger longitudinal equilibrium current, drive the plasma against the wall. After three examples of instability are analyzed in detail, the numerical methods and their verification are discussed

  15. A statistical model for instable thermodynamical systems

    International Nuclear Information System (INIS)

    Sommer, Jens-Uwe

    2003-01-01

    A generic model is presented for statistical systems which display thermodynamic features in contrast to our everyday experience, such as infinite and negative heat capacities. Such system are instable in terms of classical equilibrium thermodynamics. Using our statistical model, we are able to investigate states of instable systems which are undefined in the framework of equilibrium thermodynamics. We show that a region of negative heat capacity in the adiabatic environment, leads to a first order like phase transition when the system is coupled to a heat reservoir. This phase transition takes place without a phase coexistence. Nevertheless, all intermediate states are stable due to fluctuations. When two instable system are brought in thermal contact, the temperature of the composed system is lower than the minimum temperature of the individual systems. Generally, the equilibrium states of instable system cannot be simply decomposed into equilibrium states of the individual systems. The properties of instable system depend on the environment, ensemble equivalence is broken

  16. Role of microsatellite instability in colon cancer

    Directory of Open Access Journals (Sweden)

    M. Yu. Fedyanin

    2012-01-01

    Full Text Available Coloncancer is among leading causes of cancer morbidity and mortality both inRussiaand worldwide. Development of molecular biology lead to decoding of carcinogenesis and tumor progression mechanisms. These processes require accumulation of genetic and epigenetic alterations in a tumor cell.Coloncancer carcinogenesis is characterized by mutations cumulation in genes controlling growth and differentiation of epithelial cells, which leads to their genetic instability. Microsatellite instability is a type of genetic instability characterized by deterioration of mismatch DNA repair. This leads to faster accumulation of mutations in DNA. Loss of mismatch repair mechanism can easily be diagnosed by length of DNA microsatellites. These alterations are termed microsatellite instability. They can be found both in hereditary and sporadic colon cancers. This review covers the questions of microsatellite instability, its prognostic and predictive value in colon cancer.

  17. Resistive hose instability in the Bennet beam

    International Nuclear Information System (INIS)

    Nadezhdin, E.R.; Sorokin, G.A.

    1983-01-01

    Development of resistive hose instability of a relativistic electron beam with the Bennet current density distribution in a homogeneous unlimited plasma in the range of a high, 4πσ 0 a/c >> 1, and a low, 4πσ 0 a/c 0 =conductivity, c=light velocity, a = equilibrium beam radius) has been cansidered. Spatial and temporal increments of the instability development are calculated. In both cases the instability is of a convective nature. At 4πσ 0 a/c >> 1 the instability is shifted to the region of low frequencies as compared with the previously considered case of the Bennet profile of the plasma conductivity, σ(r)=σ 0 /(1+r 2 /a 2 ) 2 . It is shown that in an unlimited plasma a considerable decrease in the spatial and especially temporal increment of the instability development takes place

  18. Gravitational waves from instabilities in relativistic stars

    International Nuclear Information System (INIS)

    Andersson, Nils

    2003-01-01

    This paper provides an overview of stellar instabilities as sources of gravitational waves. The aim is to put recent work on secular and dynamical instabilities in compact stars in context, and to summarize the current thinking about the detectability of gravitational waves from various scenarios. As a new generation of kilometre length interferometric detectors is now coming online this is a highly topical theme. The review is motivated by two key questions for future gravitational-wave astronomy: are the gravitational waves from various instabilities detectable? If so, what can these gravitational-wave signals teach us about neutron star physics? Even though we may not have clear answers to these questions, recent studies of the dynamical bar-mode instability and the secular r-mode instability have provided new insights into many of the difficult issues involved in modelling unstable stars as gravitational-wave sources. (topical review)

  19. Comparative Genomics of Methanopyrus sp. SNP6 and KOL6 Revealing Genomic Regions of Plasticity Implicated in Extremely Thermophilic Profiles

    Directory of Open Access Journals (Sweden)

    Zhiliang Yu

    2017-07-01

    Full Text Available Methanopyrus spp. are usually isolated from harsh niches, such as high osmotic pressure and extreme temperature. However, the molecular mechanisms for their environmental adaption are poorly understood. Archaeal species is commonly considered as primitive organism. The evolutional placement of archaea is a fundamental and intriguing scientific question. We sequenced the genomes of Methanopyrus strains SNP6 and KOL6 isolated from the Atlantic and Iceland, respectively. Comparative genomic analysis revealed genetic diversity and instability implicated in niche adaption, including a number of transporter- and integrase/transposase-related genes. Pan-genome analysis also defined the gene pool of Methanopyrus spp., in addition of ~120-Kb genomic region of plasticity impacting cognate genomic architecture. We believe that Methanopyrus genomics could facilitate efficient investigation/recognition of archaeal phylogenetic diverse patterns, as well as improve understanding of biological roles and significance of these versatile microbes.

  20. Comparative Genomics

    Indian Academy of Sciences (India)

    Home; Journals; Resonance – Journal of Science Education; Volume 11; Issue 8. Comparative Genomics - A Powerful New Tool in Biology. Anand K Bachhawat. General Article Volume 11 Issue 8 August 2006 pp 22-40. Fulltext. Click here to view fulltext PDF. Permanent link:

  1. Characterizing the Prevalence of Chromosome Instability in Interval Colorectal Cancer

    Directory of Open Access Journals (Sweden)

    A.L. Cisyk

    2015-03-01

    Full Text Available A substantial proportion of colorectal cancers (CRCs are interval CRCs (I-CRCs; i.e., CRCs diagnosed soon after a colonoscopy. Chromosomal instability (CIN is defined as an increase in the rate of which whole chromosomes/large chromosomal fragments are gained or lost and is observed in 85% of non-hereditary CRCs. The contribution of CIN to the etiology of I-CRCs remains unknown. We established a fluorescence in situ hybridization (FISH approach to characterize CIN by enumerating specific chromosomes and determined the prevalence of numerical CIN in a population-based cohort of I-CRCs and control (sporadic CRCs. Using the population-based Manitoba Health administrative databases and Manitoba Cancer Registry, we identified an age, sex, and colonic site of CRC matched cohort of I-CRCs and controls and retrieved their archived paraffin-embedded tumor samples. FISH chromosome enumeration probes specifically recognizing the pericentric regions of chromosomes 8, 11, and 17 were first used on cell lines and then CRC tissue microarrays to detect aneusomy, which was then used to calculate a CIN score (CS. The 15th percentile CS for control CRC was used to define CIN phenotype. Mean CSs were similar in the control CRCs and I-CRCs; 82% of I-CRCs exhibited a CIN phenotype, which was similar to that in the control CRCs. This study suggests that CIN is the most prevalent contributor to genomic instability in I-CRCs. Further studies should evaluate CIN and microsatellite instability (MSI in the same cohort of I-CRCs to corroborate our findings and to further assess concomitant contribution of CIN and MSI to I-CRCs.

  2. Genomic hypomethylation in the human germline associates with selective structural mutability in the human genome.

    Directory of Open Access Journals (Sweden)

    Jian Li

    Full Text Available The hotspots of structural polymorphisms and structural mutability in the human genome remain to be explained mechanistically. We examine associations of structural mutability with germline DNA methylation and with non-allelic homologous recombination (NAHR mediated by low-copy repeats (LCRs. Combined evidence from four human sperm methylome maps, human genome evolution, structural polymorphisms in the human population, and previous genomic and disease studies consistently points to a strong association of germline hypomethylation and genomic instability. Specifically, methylation deserts, the ~1% fraction of the human genome with the lowest methylation in the germline, show a tenfold enrichment for structural rearrangements that occurred in the human genome since the branching of chimpanzee and are highly enriched for fast-evolving loci that regulate tissue-specific gene expression. Analysis of copy number variants (CNVs from 400 human samples identified using a custom-designed array comparative genomic hybridization (aCGH chip, combined with publicly available structural variation data, indicates that association of structural mutability with germline hypomethylation is comparable in magnitude to the association of structural mutability with LCR-mediated NAHR. Moreover, rare CNVs occurring in the genomes of individuals diagnosed with schizophrenia, bipolar disorder, and developmental delay and de novo CNVs occurring in those diagnosed with autism are significantly more concentrated within hypomethylated regions. These findings suggest a new connection between the epigenome, selective mutability, evolution, and human disease.

  3. Experimental study on low pressure flow instability

    International Nuclear Information System (INIS)

    Jiang Shengyao; Wu Xinxin; Wu Shaorong; Bo Jinhai; Zhang Youjie

    1997-05-01

    The experiment was performed on the test loop (HRTL-5), which simulates the geometry and system design of the 5 MW reactor. The flow behavior for a wide range of inlet subcooling, in which the flow undergoes from single phase to two phase, is described in a natural circulation system at low pressure (p = 0.1, 0.24 MPa). Several kinds of flow instability, e.g. subcooled boiling instability, subcooled boiling induced flashing instability, pure flashing instability as well as flashing coupled density wave instability and high frequency flow oscillation, are investigated. The mechanism of flashing and flashing concerned flow instability, which has never been studied well in this field, is especially interpreted. The experimental results show that, firstly, for a low pressure natural circulation system the two phase flow is unstable in most of inlet subcooling conditions, the two phase stable flow can only be reached at very low inlet subcooling; secondly, at high inlet subcooling the flow instability is dominated by subcooled boiling in the heated section, and at middle inlet subcooling is dominated by void flashing in the adiabatic long riser; thirdly, in two phase stable flow region the condition for boiling out of the core, namely, single phase flow in the heated section, two phase flow in the riser due to vapor flashing, can be realized. The experimental results are very important for the design and accident analysis of the vessel and swimming pool type natural circulation nuclear heating reactor. (7 refs., 10 figs., 1 tab.)

  4. Numerical study of jets secondary instabilities

    International Nuclear Information System (INIS)

    Brancher, Pierre

    1996-01-01

    The work presented in this dissertation is a contribution to the study of the transition to turbulence in open shear flows. Results from direct numerical simulations are interpreted within the framework of hydrodynamic stability theory. The first chapter is an introduction to the primary and secondary instabilities observed in jets and mixing layers. The numerical method used in the present study is detailed in the second chapter. The dynamics of homogeneous circular jets subjected to stream wise and azimuthal perturbations are investigated in the third chapter. A complete scenario describing the evolution of the jet is proposed with emphasis on the dynamics of vorticity within the flow. In the fourth chapter a parametric study reveals a three-dimensional secondary instability mainly controlled in the linear regime by the Strouhal number of the primary instability. In the nonlinear regime the dynamics of the azimuthal harmonies are described by means of model equations and are linked to the formation of stream wise vortices in the braid. The fifth chapter is dedicated to the convective or absolute nature of the secondary instabilities in plane shear layers. It is shown that there are flow configurations for which the two-dimensional secondary instability (pairing) is absolute even though the primary instability (Kelvin-Helmholtz) is convective. Some preliminary results concerning the three-dimensional secondary instabilities arc presented at the end of this chapter. The last chapter summarizes the main results and examines possible extensions of this work. (author) [fr

  5. Measuring the Levels of Ribonucleotides Embedded in Genomic DNA.

    Science.gov (United States)

    Meroni, Alice; Nava, Giulia M; Sertic, Sarah; Plevani, Paolo; Muzi-Falconi, Marco; Lazzaro, Federico

    2018-01-01

    Ribonucleotides (rNTPs) are incorporated into genomic DNA at a relatively high frequency during replication. They have beneficial effects but, if not removed from the chromosomes, increase genomic instability. Here, we describe a fast method to easily estimate the amounts of embedded ribonucleotides into the genome. The protocol described is performed in Saccharomyces cerevisiae and allows us to quantify altered levels of rNMPs due to different mutations in the replicative polymerase ε. However, this protocol can be easily applied to cells derived from any organism.

  6. Bloom syndrome ortholog HIM-6 maintains genomic stability in C. elegans.

    Science.gov (United States)

    Grabowski, Melissa M; Svrzikapa, Nenad; Tissenbaum, Heidi A

    2005-12-01

    Bloom syndrome is caused by mutation of the Bloom helicase (BLM), a member of the RecQ helicase family. Loss of BLM function results in genomic instability that causes a high incidence of cancer. It has been demonstrated that BLM is important for maintaining genomic stability by playing a role in DNA recombination and repair; however, the exact function of BLM is not clearly understood. To determine the mechanism by which BLM controls genomic stability in vivo, we examined the phenotypes caused by mutation of the C. elegans BLM helicase ortholog, HIM-6. We find that the loss of HIM-6 leads to genomic instability as evidenced by an increased number of genomic insertions and deletions, which results in visible random mutant phenotypes. In addition to the mutator phenotype, him-6 mutants have a low brood size, a high incidence of males, a shortened life span, and an increased amount of germ line apoptosis. Upon exposure to high temperature, him-6 mutants that are serially passed become sterile demonstrating a mortal germ line phenotype. Our data suggest a model in which loss of HIM-6 results in genomic instability due to an increased number of DNA lesions, which either cannot be repaired and/or are introduced by low fidelity recombination events. The increased level of genomic instability that leads to him-6(ok412) mutants having a shortened life span.

  7. Surface instabilities in shock loaded granular media

    Science.gov (United States)

    Kandan, K.; Khaderi, S. N.; Wadley, H. N. G.; Deshpande, V. S.

    2017-12-01

    The initiation and growth of instabilities in granular materials loaded by air shock waves are investigated via shock-tube experiments and numerical calculations. Three types of granular media, dry sand, water-saturated sand and a granular solid comprising PTFE spheres were experimentally investigated by air shock loading slugs of these materials in a transparent shock tube. Under all shock pressures considered here, the free-standing dry sand slugs remained stable while the shock loaded surface of the water-saturated sand slug became unstable resulting in mixing of the shocked air and the granular material. By contrast, the PTFE slugs were stable at low pressures but displayed instabilities similar to the water-saturated sand slugs at higher shock pressures. The distal surfaces of the slugs remained stable under all conditions considered here. Eulerian fluid/solid interaction calculations, with the granular material modelled as a Drucker-Prager solid, reproduced the onset of the instabilities as seen in the experiments to a high level of accuracy. These calculations showed that the shock pressures to initiate instabilities increased with increasing material friction and decreasing yield strain. Moreover, the high Atwood number for this problem implied that fluid/solid interaction effects were small, and the initiation of the instability is adequately captured by directly applying a pressure on the slug surface. Lagrangian calculations with the directly applied pressures demonstrated that the instability was caused by spatial pressure gradients created by initial surface perturbations. Surface instabilities are also shown to exist in shock loaded rear-supported granular slugs: these experiments and calculations are used to infer the velocity that free-standing slugs need to acquire to initiate instabilities on their front surfaces. The results presented here, while in an idealised one-dimensional setting, provide physical understanding of the conditions required to

  8. Personal genomics services: whose genomes?

    Science.gov (United States)

    Gurwitz, David; Bregman-Eschet, Yael

    2009-07-01

    New companies offering personal whole-genome information services over the internet are dynamic and highly visible players in the personal genomics field. For fees currently ranging from US$399 to US$2500 and a vial of saliva, individuals can now purchase online access to their individual genetic information regarding susceptibility to a range of chronic diseases and phenotypic traits based on a genome-wide SNP scan. Most of the companies offering such services are based in the United States, but their clients may come from nearly anywhere in the world. Although the scientific validity, clinical utility and potential future implications of such services are being hotly debated, several ethical and regulatory questions related to direct-to-consumer (DTC) marketing strategies of genetic tests have not yet received sufficient attention. For example, how can we minimize the risk of unauthorized third parties from submitting other people's DNA for testing? Another pressing question concerns the ownership of (genotypic and phenotypic) information, as well as the unclear legal status of customers regarding their own personal information. Current legislation in the US and Europe falls short of providing clear answers to these questions. Until the regulation of personal genomics services catches up with the technology, we call upon commercial providers to self-regulate and coordinate their activities to minimize potential risks to individual privacy. We also point out some specific steps, along the trustee model, that providers of DTC personal genomics services as well as regulators and policy makers could consider for addressing some of the concerns raised below.

  9. Dynamics and instabilities in nuclear fragmentation

    International Nuclear Information System (INIS)

    Colonna, M.; Guarnera, A.; Di Toro, M.; Latora, V.; Smerzi, A.; Catania Univ.

    1993-01-01

    A general procedure to identify instability regions which lead to multifragmentation events is presented. The method covers all possible sources of dynamical instabilities. Informations on the instability point, like the time when the nuclear system enters the critical region, the most unstable modes and the time constant of the exponential growing of the relative variances, are deduced without any numerical bias. Important memory effects in the fragmentation pattern are revealed. Some hints towards a fully dynamical picture of fragmentation processes are finally suggested. (author) 7 refs., 3 figs

  10. Plasma instability of a vacuum arc centrifuge

    International Nuclear Information System (INIS)

    Hole, M.J.; Dallaqua, R.S.; Simpson, S.W.; Del Bosco, E.

    2002-01-01

    Ever since conception of the vacuum arc centrifuge in 1980, periodic fluctuations in the ion saturation current and floating potential have been observed in Langmuir probe measurements in the rotation region of a vacuum arc centrifuge. In this work we develop a linearized theoretical model to describe a range of instabilities in the vacuum arc centrifuge plasma column, and then test the validity of the description through comparison with experiment. We conclude that the observed instability is a 'universal' instability, driven by the density gradient, in a plasma with finite conductivity

  11. New instability strip for hot degenerates

    International Nuclear Information System (INIS)

    Starrfield, S.G.; Cox, A.N.; Hodson, S.W.

    1980-01-01

    A new kind of variable star, designated as PG1159-035 is distinguished not only by the complete lack of hydrogen in its spectrum but also by an effective temperature that exceeds 8 x 10 4 K. The star does not fall near any of the known regions of instability in the HR diagram which suggests that the instability mechanism will not be helium and hydrogen ionization as in the Cepheid variables. The more unusual compositions are examined in order to discover the cause of the instability in PG1159-035

  12. Tearing instability in cylindrical plasma configuration

    International Nuclear Information System (INIS)

    Zelenyj, L.M.

    1979-01-01

    The effect of the neutral-layer cylindrical geometry on the development of the tearing instability has been investigated in detail. The increments of the instability for all the regimes have been found. The influence of cylindrical effects becomes manifesting itself at small, as compared to the layer characteristic thickness, distances from the axis, and, finally, the electron regime of the instability development transforms into an ion one. The results obtained are of interest for studying the plasma stability in the devices of the ''Astron'' type and in magnetospheres of cosmic objects

  13. Reflex muscle contraction in anterior shoulder instability.

    Science.gov (United States)

    Wallace, D A; Beard, D J; Gill, R H; Eng, B; Carr, A J

    1997-01-01

    Reduced proprioception may contribute to recurrent anterior shoulder instability. Twelve patients with unilateral shoulder instability were investigated for evidence of deficient proprioception with an activated pneumatic cylinder and surface electromyography electrodes; the contralateral normal shoulder was used as a control. The latency between onset of movement and the detection of muscle contraction was used as an index of proprioception. No significant difference in muscle contraction latency was detected between the stable and unstable shoulders, suggesting that there was no significant defect in muscular reflex activity. This study does not support the use proprioception-enhancing physiotherapy in the treatment of posttraumatic anterior shoulder instability.

  14. Janus faces of Jeans instabilities

    International Nuclear Information System (INIS)

    Verheest, Frank; Jacobs, Gerald; Cadez, Vladimir M.

    2000-01-01

    Self-gravitating clouds have been shown by Jeans to be unstable to harmonic perturbations whose wavelength exceeds some critical value involving the mass density and some thermal velocity or equivalent information. Based upon the assumption that the unperturbed cloud is initially uniform, the Jeans instability is non-oscillatory and purely growing. However, Newtonian gravitation precludes strictly homogeneous equilibria, but a way out is offered, in theory, by considering local perturbations, small compared to the inhomogeneity scale lengths. While in itself plausible, this procedure can in most cases not be tested for internal consistency, because real knowledge about the equilibrium is lacking, and is therefore called the Jeans swindle. The severe limitations of such an approach lead to an unavoidable dichotomy, and an example of a plasma will be discussed where the computations can be done explicitly, both for the stationary as well as for the perturbed state, showing that the system is stable at all wavelengths compatible with the equilibrium inhomogeneity. Nevertheless, the present state of affairs does not allow self-consistent equilibria to be worked out in more complicated configurations, like in dusty plasmas with external magnetic fields. This typically leads to the Jeans swindle being used a little longer than desirable

  15. Valence instabilities in cerium intermetallics

    International Nuclear Information System (INIS)

    Dijkman, W.H.

    1982-01-01

    The primary purpose of this investigation was to study the magnetic behaviour of cerium in intermetallic compounds, that show an IV behaviour, e.g. CeSn 3 . In the progress of the investigations, it became of interest to study the effect of changes in the lattice of the IV compound by substituting La or Y for Ce, thus constituting the Cesub(1-x)Lasub(x)Sn 3 and Cesub(1-x)Ysub(x)Sn 3 quasibinary systems. A second purpose was to examine the possibility of introducing instabilities in the valency of a trivalent intermetallic cerium compound: CeIn 3 , also by La and Y-substitutions in the lattice. Measurements on the resulting Cesub(1-x)Lasub(x)In 3 and Cesub(1-x)Ysub(x)In 3 quasibinaries are described. A third purpose was to study the (gradual) transition from a trivalent cerium compound into an IV cerium compound. This was done by examining the magnetic properties of the CeInsub(x)Snsub(3-x) and CePbsub(x)Snsub(3-x) systems. Finally a new possibility was investigated: that of the occurrence of IV behaviour in CeSi 2 , CeSi, and in CeGa 2 . (Auth.)

  16. Taylor Instability of Incompressible Liquids

    Science.gov (United States)

    Fermi, E.; von Neumann, J.

    1955-11-01

    A discussion is presented in simplified form of the problem of the growth of an initial ripple on the surface of an incompressible liquid in the presence of an acceleration, g, directed from the outside into the liquid. The model is that of a heavy liquid occupying at t = 0 the half space above the plane z = 0, and a rectangular wave profile is assumed. The theory is found to represent correctly one feature of experimental results, namely the fact that the half wave of the heavy liquid into the vacuum becomes rapidly narrower while the half wave pushing into the heavy liquid becomes more and more blunt. The theory fails to account for the experimental results according to which the front of the wave pushing into the heavy liquid moves with constant velocity. The case of instability at the boundary of 2 fluids of different densities is also explored. Similar results are obtained except that the acceleration of the heavy liquid into the light liquid is reduced.

  17. State of human genome at low-doses ecological influences

    International Nuclear Information System (INIS)

    Mel'nov, S.B.; Rytik, P.G.; Kruchinskij, N.G.; Kovalev, V.A.; Palamar, L.A.; Senyuk, O.F.

    2005-01-01

    The results of analysis of the state of genome (amounts of single strand breaks in DNA) of the persons exposed to influence of complex 'Chernobyl factor' in remote terms after a failure on ChNPP are resulted. Findings allowed to expose the increase of level of single strand breaks in DNA at the chronically irradiated persons mainly carry adaptive character and probably can be related to instability of genome. Thus at organism level growth of mutational pressure and strengthening of instability of cellular genome is related to the change of spectrum of biological characteristics, in particular individual reaction of somatic cells of victims on additional mutagens influences. The indicated changes can testify to existence of potential risk of remote genetic consequences of long-term irradiation influence in low doses

  18. Visualization for genomics: the Microbial Genome Viewer.

    NARCIS (Netherlands)

    Kerkhoven, R.; Enckevort, F.H.J. van; Boekhorst, J.; Molenaar, D; Siezen, R.J.

    2004-01-01

    SUMMARY: A Web-based visualization tool, the Microbial Genome Viewer, is presented that allows the user to combine complex genomic data in a highly interactive way. This Web tool enables the interactive generation of chromosome wheels and linear genome maps from genome annotation data stored in a

  19. Gravitational instability of thermally anisotropic plasma

    International Nuclear Information System (INIS)

    Singh, B.; Kalra, G.L.

    1986-01-01

    The equations of Chew, Goldberger, and Low (1956) modified to include the heat flux vector and self-gravitation are used to study the gravitational instability of unbounded plasma placed in a uniform static magnetic field. The linear stability analysis shows that some of the additional terms which arise as a result of higher moments are of the same order of magnitude as the terms in the original Chew, Goldberger, and Low theory. The influence of these terms on the gravitational instability has been specially examined. It is found that the gravitational instability sets in at a comparatively shorter wavelength and the growth rate is enhanced owing to the inclusion of these terms in the case where the propagation vector is along the magnetic field. The condition for instability is, however, unaltered when the direction of propagation is transverse to the direction of magnetic field. 19 references

  20. Investigation of universal plasma instabilities. Final report

    International Nuclear Information System (INIS)

    Lashinsky, H.

    1977-01-01

    This project was undertaken in order to carry out a comprehensive experimental investigation of universal plasma instabilities under a variety of conditions and a wide range of experimental parameters to scale the results appropriately to make comparisons with plasmas of thermonuclear interest. Of particular importance are the roles played by collisions and resonance particles (Landau damping and excitation) and the various stages in the development of the instabilities i.e., the linear onset of the instability, the quasilinear stage, and the transition to turbulence. General nonlinear effects such as mode locking and mode competition, and the relation of these phenomena to plasma turbulence, are also of great interest and were studied experimentally. The ultimate aim was to measure certain plasma transport coefficients in the plasma under stable and turbulent conditions with the particular view of evaluating the effect of the universal plasma instabilities of plasma confinement in a magnetic field

  1. Systems and methods for controlling flame instability

    KAUST Repository

    Cha, Min; Xiong, Yuan; Chung, Suk-Ho

    2016-01-01

    A system (62) for controlling flame instability comprising: a nozzle (66) coupled to a fuel supply line (70), an insulation housing (74) coupled to the nozzle, a combustor (78) coupled to the nozzle via the insulation housing, where the combustor

  2. Toward a definition of affective instability.

    Science.gov (United States)

    Renaud, Suzane M; Zacchia, Camillo

    2012-01-01

    Affective instability is a psychophysiological symptom observed in some psychopathologies. It is a complex construct that encompasses (1) primary emotions, or affects, and secondary emotions, with each category having its own characteristics, amplitude, and duration, (2) rapid shifting from neutral or valenced affect to intense affect, and (3) dysfunctional modulation of emotions. Affective instability is often confused with mood lability, as in bipolar disorders, as well as with other terms. To clarify the concept, we searched databases for the term affective instability and read related articles on the topic. In this article we situate the term within the current affective nomenclature and human emotional experience, explore its psychophysiological features, and place it within the context of psychopathology. We explain why the term can potentially be confused with mood pathology and then define affective instability as an inherited temperamental trait modulated by developmental experience.

  3. Suppression of instability in rotatory hydromagnetic convection

    Indian Academy of Sciences (India)

    first time by Lord Rayleigh [9] for the idealized case of two free boundaries. Rayleigh's theory shows that the gravity-dominated thermal instability in liquid layer ... suppressed for oscillatory perturbations by the simultaneous application of a ...

  4. On nonlinear development of beam instability

    International Nuclear Information System (INIS)

    Popel', S.I.; Tsytovich, V.N.

    1990-01-01

    Radiation-resonance interactions are taken into account in the problem of dynamics of an electron beam inb plasma. The beam characteristics to be taken into account are determined. Stabilization conditions for beam instability are established

  5. Kelvin-Helmholtz instability in solar spicules

    Directory of Open Access Journals (Sweden)

    H Ebadi

    2016-12-01

    Full Text Available Magneto hydrodynamic waves, propagating along spicules, may become unstable and the expected instability is of Kelvin-Helmholtz type. Such instability can trigger the onset of wave turbulence leading to an effective plasma heating and particle acceleration. In present study, two-dimensional magneto hydrodynamic simulations performed on a Cartesian grid is presented in spicules with different densities, moving at various speeds depending on their environment. Simulations being applied in this study show the onset of Kelvin-Helmholtz type instability and transition to turbulent flow in spicules. Development of Kelvin-Helmholtz instability leads to momentum and energy transport, dissipation, and mixing of fluids. When magnetic fields are involved, field amplification is also possible to take place

  6. Plasma equilibrium and instabilities in tokamaks

    International Nuclear Information System (INIS)

    Caldas, I.L.; Vannucci, A.

    1985-01-01

    A phenomenological introduction of some of the main theoretical and experimental features on equilibrium and instabilities in tokamaks is presented. In general only macroscopic effects are considered, being the plasma described as a fluid. (L.C.) [pt

  7. Single-mode coherent synchrotron radiation instability

    Directory of Open Access Journals (Sweden)

    S. Heifets

    2003-06-01

    Full Text Available The microwave instability driven by the coherent synchrotron radiation (CSR has been previously studied [S. Heifets and G. V. Stupakov, Phys. Rev. ST Accel. Beams 5, 054402 (2002] neglecting effect of the shielding caused by the finite beam pipe aperture. In practice, the unstable mode can be close to the shielding threshold where the spectrum of the radiation in a toroidal beam pipe is discrete. In this paper, the CSR instability is studied in the case when it is driven by a single synchronous mode. A system of equations for the beam-wave interaction is derived and its similarity to the 1D free-electron laser theory is demonstrated. In the linear regime, the growth rate of the instability is obtained and a transition to the case of continuous spectrum is discussed. The nonlinear evolution of the single-mode instability, both with and without synchrotron damping and quantum diffusion, is also studied.

  8. The Growth Effects of Institutional Instability

    DEFF Research Database (Denmark)

    Berggren, Niclas; Bergh, Andreas; Bjørnskov, Christian

     Both institutional quality and institutional stability have been argued to stimulate economic growth. But to improve institutional quality, a country must endure a period of institutional change, which implies at least a little and possibly a lot of institutional instability. We investigate...... the growth effects of institutional quality and instability, using the political risk index from the ICRG in a cross-country study of 132 countries, measuring instability as the coefficient of variation. Using the aggregate index, we find evidence that institutional quality is positively linked to growth....... While institutional instability is negatively related to growth in the baseline case, there are indications that the effect can be positive in rich countries, suggesting that institutional reform is not necessarily costly even during a transition period. Sensitivity analysis, e.g., decomposing...

  9. Jeans instability in a quantum dusty magnetoplasma

    International Nuclear Information System (INIS)

    Salimullah, M.; Jamil, M.; Shah, H. A.; Murtaza, G.

    2009-01-01

    Jeans instability in a homogeneous cold quantum dusty plasma in the presence of the ambient magnetic field and the quantum effect arising through the Bohm potential has been examined using the quantum magnetohydrodynamic model. It is found that the Jeans instability is significantly reduced by the presence of the dust-lower-hybrid wave and the ion quantum effect. The minimum wavenumber for Jeans stability depends clearly on ion quantum effect and the dust-lower-hybrid frequency also.

  10. Bosonic instability of charged black holes

    International Nuclear Information System (INIS)

    Gaina, A.B.; Ternov, I.M.

    1986-01-01

    The processes of spontaneous and induced production and accumulation of charged bosons on quasibound superradiant levels in the field of Kerr-Newman black hole is analysed. It is shown that bosonic instability may be caused exclusively by the rotation of the black hole. Particulary, the Reissner-Nordstrom configuration is stable. In the case of rotating and charged black hole the bosonic instability may cause an increase of charge of the black hole

  11. Topographic-driven instabilities in terrestrial bodies

    Science.gov (United States)

    Vantieghem, S.; Cebron, D.; Herreman, W.; Lacaze, L.

    2013-12-01

    Models of internal planetary fluid layers (core flows, subsurface oceans) commonly assume that these fluid envelopes have a spherical shape. This approximation however entails a serious restriction from the fluid dynamics point of view. Indeed, in the presence of mechanical forcings (precession, libration, nutation or tides) due to gravitational interaction with orbiting partners, boundary topography (e.g. of the core-mantle boundary) may excite flow instabilities and space-filling turbulence. These phenomena may affect heat transport and dissipation at the main order. Here, we focus on instabilities driven by longitudinal libration. Using a suite of theoretical tools and numerical simulations, we are able to discern a parameter range for which instability may be excited. We thereby consider deformations of different azimuthal order. This study gives the first numerical evidence of the tripolar instability. Furthermore, we explore the non-linear regime and investigate the amplitude as well as the dissipation of the saturated instability. Indeed, these two quantities control the torques on the solid layers and the thermal transport. Furthermore, based on this results, we address the issue of magnetic field generation associated with these flows (by induction or by dynamo process). This instability mechanism applies to both synchronized as non-synchronized bodies. As such, our results show that a tripolar instability might be present in various terrestrial bodies (Early Moon, Gallilean moons, asteroids, etc.), where it could participate in dynamo action. Simulation of a libration-driven tripolar instability in a deformed spherical fluid layer: snapshot of the velocity magnitude, where a complex 3D flow pattern is established.

  12. Dorsoradial capsulodesis for trapeziometacarpal joint instability.

    Science.gov (United States)

    Rayan, Ghazi; Do, Viet

    2013-02-01

    We describe an alternative method for treating chronic trapeziometacarpal (TM) joint instability after acute injury or chronic repetitive use of the thumb by performing a dorsoradial capsulodesis procedure. The procedure is done by imbricating the redundant TM joint dorsoradial ligament and capsule after reducing the joint by pronating the thumb. The dorsoradial capsulodesis is a reasonable reconstructive option for chronic TM joint instability and subluxation. Copyright © 2013 American Society for Surgery of the Hand. Published by Elsevier Inc. All rights reserved.

  13. Systematics of shoulder instability; Systematik der Schulterinstabilitaet

    Energy Technology Data Exchange (ETDEWEB)

    Kreitner, K.F.; Maehringer-Kunz, A. [Johannes-Gutenberg-Universitaet Mainz, Klinik und Poliklinik fuer Diagnostische und Interventionelle Radiologie, Mainz (Germany)

    2015-03-01

    Shoulder instability is defined as a symptomatic abnormal motion of the humeral head relative to the glenoid during active shoulder motion. Glenohumeral instabilities are classified according to the causative factors as the pathogenesis of instability plays an important role with respect to treatment options. Instabilities are classified into traumatic and atraumatic instabilities as part of a multidirectional instability syndrome and into microtraumatic instabilities. For diagnostics plain radiographs (''trauma series'') are performed to document shoulder dislocation and its successful repositioning. Direct magnetic resonance (MR) arthrography is the most important imaging modality for delineation of the different injury patterns of the labral-ligamentous complex and bony structures. Monocontrast computed tomography (CT) arthrography with the use of multidetector CT scanners represents an alternative imaging modality; however, MR imaging should be preferred in the work-up of shoulder instabilities due to the mostly younger age of patients. (orig.) [German] Unter einer Schulterinstabilitaet versteht man jede zu Beschwerden fuehrende Translation des Humeruskopfs in Relation zur Gelenkpfanne waehrend einer aktiven Bewegung der Schulter. Glenohumerale Instabilitaeten werden heute nach ihrer Aetiologie eingeteilt, da bei der Wahl der Therapie der Entstehungsmechanismus der Instabilitaet eine wichtige Rolle spielt. Danach unterscheidet man primaer traumatisch von atraumatisch entstandenen Instabilitaeten sowie Mikroinstabilitaeten. Bei der Diagnostik dienen konventionelle Roentgenuebersichtsaufnahmen nur noch zur Dokumentation einer Luxation und zur Beurteilung der Reposition. Die durch eine Instabilitaet hervorgerufenen Verletzungsfolgen am labroligamentaeren Komplex und den knoechernen Strukturen werden heute bevorzugt mit der direkten MR-Arthrographie dargestellt. Hierbei koennen unterschiedliche Verletzungsmuster dargestellt werden. Nach

  14. Beam Instabilities in Circular Particle Accelerators

    CERN Document Server

    AUTHOR|(CDS)2067185

    2017-01-01

    The theory of impedance-induced bunched-beam coherent instabilities is reviewed following Laclare's formalism, adding the effect of an electronic damper in the transverse plane. Both single-bunch and coupled-bunch instabilities are discussed, both low-intensity and high-intensity regimes are analysed, both longitudinal and transverse planes are studied, and both short-bunch and long-bunch regimes are considered. Observables and mitigation measures are also examined.

  15. MHD instability studies in ISX-B

    International Nuclear Information System (INIS)

    Pare, V.K.; Dunlap, J.L.; Navarro, A.P.; Burris, R.D.

    1979-01-01

    MHD instabilities in Ohmically and beam heated ISX-B plasmas have been studied using collimated x-ray and Mirnov loop diagnostics. The diagnostic systems will be described and the instability signals will be illustrated for a variety of discharges. The latter will include those observed in connection with low and high β operation, density clamping, pellet injection, and deliberate introduction of toroidal field ripple

  16. Plasma wave instabilities in nonequilibrium graphene

    DEFF Research Database (Denmark)

    Aryal, Chinta M.; Hu, Ben Yu-Kuang; Jauho, Antti-Pekka

    2016-01-01

    We study two-stream instabilities in a nonequilibrium system in which a stream of electrons is injected into doped graphene. As with equivalent nonequilibrium parabolic band systems, we find that the graphene systems can support unstable charge-density waves whose amplitudes grow with time. We...... of the injected electrons that maximizes the growth rate increases with increasing | q |. We compare the range and strength of the instability in graphene to that of two- and three-dimensional parabolic band systems....

  17. Arthroscopic Findings in Anterior Shoulder Instability

    OpenAIRE

    Hantes, Michael; Raoulis, Vasilios

    2017-01-01

    Background: In the last years, basic research and arthroscopic surgery, have improved our understanding of shoulder anatomy and pathology. It is a fact that arthroscopic treatment of shoulder instability has evolved considerably over the past decades. The aim of this paper is to present the variety of pathologies that should be identified and treated during shoulder arthroscopy when dealing with anterior shoulder instability cases. Methods: A review of the current literature regarding arthros...

  18. High-pressure mechanical instability in rocks.

    Science.gov (United States)

    Byerlee, J D; Brace, W F

    1969-05-09

    At a confining pressure of a few kilobars, deformation of many sedimentary rocks, altered mafic rocks, porous volcanic rocks, and sand is ductile, in that instabilities leading to audible elastic shocks are absent. At pressures of 7 to 10 kilobars, however, unstable faulting and stick-slip in certain of these rocks was observed. This high pressure-low temperature instability might be responsible for earthquakes in deeply buried sedimentary or volcanic sequences.

  19. Sectoral Diversification as Insurance against Economic Instability

    OpenAIRE

    Jan Kluge

    2015-01-01

    This paper examines the extent to which sectoral diversification can act as an insurance mechanism against fluctuations in regional gross value added growth rates. I apply portfolio theory to the growth-instability properties of German districts. Furthermore, I define a comprehensive diversification measure and use Stochastic Frontier Analysis in order to estimate whether diversification allows regions to achieve more efficient growth-instability combinations, i.e., greater stability at given...

  20. Damage instability and Earthquake nucleation

    Science.gov (United States)

    Ionescu, I. R.; Gomez, Q.; Campillo, M.; Jia, X.

    2017-12-01

    Earthquake nucleation (initiation) is usually associated to the loss of the stability of the geological structure under a slip-weakening friction acting on the fault. The key parameters involved in the stability of the fault are the stress drop, the critical slip distance but also the elastic stiffness of the surrounding materials (rocks). We want to explore here how the nucleation phenomena are correlated to the material softening during damage accumulation by dynamic and/or quasi-static processes. Since damage models are describing micro-cracks growth, which is generally an unstable phenomenon, it is natural to expect some loss of stability on the associated micro-mechanics based models. If the model accurately captures the material behavior, then this can be due to the unstable nature of the brittle material itself. We obtained stability criteria at the microscopic scale, which are related to a large class of damage models. We show that for a given continuous strain history the quasi-static or dynamic problems are instable or ill-posed (multiplicity of material responses) and whatever the selection rule is adopted, shocks (time discontinuities) will occur. We show that the quasi-static equilibria chosen by the "perfect delay convention" is always stable. These stability criteria are used to analyze how NIC (Non Interacting Crack) effective elasticity associated to "self similar growth" model work in some special configurations (one family of micro-cracks in mode I, II and III and in plane strain or plain stress). In each case we determine a critical crack density parameter and critical micro-crack radius (length) which distinguish between stable and unstable behaviors. This critical crack density depends only on the chosen configuration and on the Poisson ratio.

  1. Centrifugally Driven Rayleigh-Taylor Instability

    Science.gov (United States)

    Scase, Matthew; Hill, Richard

    2017-11-01

    The instability that develops at the interface between two fluids of differing density due to the rapid rotation of the system may be considered as a limit of high-rotation rate Rayleigh-Taylor instability. Previously the authors have considered the effect of rotation on a gravitationally dominated Rayleigh-Taylor instability and have shown that some growth modes of instability may be suppressed completely by the stabilizing effect of rotation (Phys. Rev. Fluids 2:024801, Sci. Rep. 5:11706). Here we consider the case of very high rotation rates and a negligible gravitational field. The initial condition is of a dense inner cylinder of fluid surrounded by a lighter layer of fluid. As the system is rotated about the generating axis of the cylinder, the dense inner fluid moves away from the axis and the familiar bubbles and spikes of Rayleigh-Taylor instability develop at the interface. The system may be thought of as a ``fluid-fluid centrifuge''. By developing a model based on an Orr-Sommerfeld equation, we consider the effects of viscosity, surface tension and interface diffusion on the growth rate and modes of instability. We show that under particular circumstances some modes may be stabilized. School of Mathematical Sciences.

  2. [Capsular retensioning in anterior unidirectional glenohumeral instability].

    Science.gov (United States)

    Benítez Pozos, Leonel; Martínez Molina, Oscar; Castañeda Landa, Ezequiel

    2007-01-01

    To present the experience of the Orthopedics Service PEMEX South Central Hospital in the management of anterior unidirectional shoulder instability with an arthroscopic technique consisting of capsular retensioning either combined with other anatomical repair procedures or alone. Thirty-one patients with anterior unidirectional shoulder instability operated-on between January 1999 and December 2005 were included. Fourteen patients underwent capsular retensioning and radiofrequency, and in 17 patients, capsular retensioning was combined with suture anchors. Patients with a history of relapsing glenohumeral dislocations and subluxations, with anterior instability with or without associated Bankart lesions were selected; all of them were young. The results were assessed considering basically the occurrence of instability during the postoperative follow-up. No cases of recurring instability occurred. Two cases had neuroma and one experienced irritation of the suture site. Six patients had residual limitation of combined lateral rotation and abduction movements, of a mean of 10 degrees compared with the healthy contralateral side. The most frequent incident was the leak of solutions to the soft tissues. Capsular retensioning, whether combined or not with other anatomical repair techniques, has proven to result in a highly satisfactory rate of glenohumeral stabilization in cases of anterior unidirectional instabilities. The arthroscopic approach offers the well-known advantages of causing less damage to the soft tissues, and a shorter time to starting rehabilitation therapy and exercises.

  3. Parametric instabilities in advanced gravitational wave detectors

    International Nuclear Information System (INIS)

    Gras, S; Zhao, C; Blair, D G; Ju, L

    2010-01-01

    As the LIGO interferometric gravitational wave detectors have finished gathering a large observational data set, an intense effort is underway to upgrade these observatories to improve their sensitivity by a factor of ∼10. High circulating power in the arm cavities is required, which leads to the possibility of parametric instability due to three-mode opto-acoustic resonant interactions between the carrier, transverse optical modes and acoustic modes. Here, we present detailed numerical analysis of parametric instability in a configuration that is similar to Advanced LIGO. After examining parametric instability for a single three-mode interaction in detail, we examine instability for the best and worst cases, as determined by the resonance condition of transverse modes in the power and signal recycling cavities. We find that, in the best case, the dual recycling detector is substantially less susceptible to instability than a single cavity, but its susceptibility is dependent on the signal recycling cavity design, and on tuning for narrow band operation. In all cases considered, the interferometer will experience parametric instability at full power operation, but the gain varies from 3 to 1000, and the number of unstable modes varies between 7 and 30 per test mass. The analysis focuses on understanding the detector complexity in relation to opto-acoustic interactions, on providing insights that can enable predictions of the detector response to transient disturbances, and of variations in thermal compensation conditions.

  4. Ancient genomics

    DEFF Research Database (Denmark)

    Der Sarkissian, Clio; Allentoft, Morten Erik; Avila Arcos, Maria del Carmen

    2015-01-01

    throughput of next generation sequencing platforms and the ability to target short and degraded DNA molecules. Many ancient specimens previously unsuitable for DNA analyses because of extensive degradation can now successfully be used as source materials. Additionally, the analytical power obtained...... by increasing the number of sequence reads to billions effectively means that contamination issues that have haunted aDNA research for decades, particularly in human studies, can now be efficiently and confidently quantified. At present, whole genomes have been sequenced from ancient anatomically modern humans...

  5. Marine genomics

    DEFF Research Database (Denmark)

    Oliveira Ribeiro, Ângela Maria; Foote, Andrew David; Kupczok, Anne

    2017-01-01

    Marine ecosystems occupy 71% of the surface of our planet, yet we know little about their diversity. Although the inventory of species is continually increasing, as registered by the Census of Marine Life program, only about 10% of the estimated two million marine species are known. This lag......-throughput sequencing approaches have been helping to improve our knowledge of marine biodiversity, from the rich microbial biota that forms the base of the tree of life to a wealth of plant and animal species. In this review, we present an overview of the applications of genomics to the study of marine life, from...

  6. Genome Sequences of the Oxytetracycline Production Strain Streptomyces rimosus R6-500 and Two Mutants with Chromosomal Rearrangements

    KAUST Repository

    Baranasic, Damir

    2014-07-17

    The genome sequence of Streptomyces rimosus R6-500, an industrially improved strain which produces high titers of the important antibiotic oxytetracycline, is reported, as well as the genome sequences of two derivatives arising due to the genetic instability of the strain.

  7. Genome Sequences of the Oxytetracycline Production Strain Streptomyces rimosus R6-500 and Two Mutants with Chromosomal Rearrangements

    KAUST Repository

    Baranasic, Damir; Zucko, Jurica; Nair, Mridul; Pain, Arnab; Long, Paul F.; Hranueli, Daslav; Cullum, John; Starcevic, Antonio

    2014-01-01

    The genome sequence of Streptomyces rimosus R6-500, an industrially improved strain which produces high titers of the important antibiotic oxytetracycline, is reported, as well as the genome sequences of two derivatives arising due to the genetic instability of the strain.

  8. Instabilities in Interacting Binary Stars

    Science.gov (United States)

    Andronov, I. L.; Andrych, K. D.; Antoniuk, K. A.; Baklanov, A. V.; Beringer, P.; Breus, V. V.; Burwitz, V.; Chinarova, L. L.; Chochol, D.; Cook, L. M.; Cook, M.; Dubovský, P.; Godlowski, W.; Hegedüs, T.; Hoňková, K.; Hric, L.; Jeon, Y.-B.; Juryšek, J.; Kim, C.-H.; Kim, Y.; Kim, Y.-H.; Kolesnikov, S. V.; Kudashkina, L. S.; Kusakin, A. V.; Marsakova, V. I.; Mason, P. A.; Mašek, M.; Mishevskiy, N.; Nelson, R. H.; Oksanen, A.; Parimucha, S.; Park, J.-W.; Petrík, K.; Quiñones, C.; Reinsch, K.; Robertson, J. W.; Sergey, I. M.; Szpanko, M.; Tkachenko, M. G.; Tkachuk, L. G.; Traulsen, I.; Tremko, J.; Tsehmeystrenko, V. S.; Yoon, J.-N.; Zola, S.; Shakhovskoy, N. M.

    2017-07-01

    The types of instability in the interacting binary stars are briefly reviewed. The project “Inter-Longitude Astronomy” is a series of smaller projects on concrete stars or groups of stars. It has no special funds, and is supported from resources and grants of participating organizations, when informal working groups are created. This “ILA” project is in some kind similar and complementary to other projects like WET, CBA, UkrVO, VSOLJ, BRNO, MEDUZA, AstroStatistics, where many of us collaborate. Totally we studied 1900+ variable stars of different types, including newly discovered variables. The characteristic timescale is from seconds to decades and (extrapolating) even more. The monitoring of the first star of our sample AM Her was initiated by Prof. V.P. Tsesevich (1907-1983). Since more than 358 ADS papers were published. In this short review, we present some highlights of our photometric and photo-polarimetric monitoring and mathematical modeling of interacting binary stars of different types: classical (AM Her, QQ Vul, V808 Aur = CSS 081231:071126+440405, FL Cet), asynchronous (BY Cam, V1432 Aql), intermediate (V405 Aql, BG CMi, MU Cam, V1343 Her, FO Aqr, AO Psc, RXJ 2123, 2133, 0636, 0704) polars and magnetic dwarf novae (DO Dra) with 25 timescales corresponding to different physical mechanisms and their combinations (part “Polar”); negative and positive superhumpers in nova-like (TT Ari, MV Lyr, V603 Aql, V795 Her) and many dwarf novae stars (“Superhumper”); eclipsing “non-magnetic” cataclysmic variables(BH Lyn, DW UMa, EM Cyg; PX And); symbiotic systems (“Symbiosis”); super-soft sources (SSS, QR And); spotted (and not spotted) eclipsing variables with (and without) evidence for a current mass transfer (“Eclipser”) with a special emphasis on systems with a direct impact of the stream into the gainer star's atmosphere, which we propose to call “Impactor” (short from “Extreme Direct Impactor”), or V361 Lyr-type stars. Other

  9. Analytic study of resistive instabilities

    Energy Technology Data Exchange (ETDEWEB)

    Svensson, Magnus

    2003-05-01

    In a fusion plasma there is always a small amount of resistivity that may cause instabilities. Although their rather slow growth rates they can be of major importance for fusion plasma confinement. In this work a MAPLE-code was rewritten and simplified to make it possible to analytically solve the linearized MHD-equations with resistivity in an RFP-configuration. By using the MHD-equations and expanding the unknown perturbed quantities u{sub 1r}(r) and B{sub 1r}(r) as Taylor series and solving each coefficient we could get eigenvalues, dispersion relations and a relation between the growth rate and the resistivity. The new code was first used to solve two cases with no resistivity and simple unstable equilibria which after running gave the correct expected results. The difference from running the original code with these two cases was the greater speed of the calculations and the less memory needed. Then by using an ideal MHD-stable equilibrium in a plasma with no resistivity the code gave us solutions which unfortunately were not of the expected kind but the time of the calculations was still very fast. The resistivity was finally added to the code with the ideal MHD-stable equilibrium. The program also this time gave incorrect results. We could, however, see from a relation between the growth rate and the resistivity that the solution may be approximately correct in this domain. Although we did not get all the correct results we have to consider the fact that we got results, that were not possible before. Before this work was carried out we could not get any results at all in the resistive cue because of the very long memory demanding expressions. In future work and studies it is not only possible to get the desired eigenvalues {gamma} as function of {eta} but also possible to get expressions for eigenfunctions, dispersion relations and other significant relations with a number of variable parameters. We could also use the method for any geometry and possibly for

  10. Analytic study of resistive instabilities

    International Nuclear Information System (INIS)

    Svensson, Magnus

    2003-05-01

    In a fusion plasma there is always a small amount of resistivity that may cause instabilities. Although their rather slow growth rates they can be of major importance for fusion plasma confinement. In this work a MAPLE-code was rewritten and simplified to make it possible to analytically solve the linearized MHD-equations with resistivity in an RFP-configuration. By using the MHD-equations and expanding the unknown perturbed quantities u 1r (r) and B 1r (r) as Taylor series and solving each coefficient we could get eigenvalues, dispersion relations and a relation between the growth rate and the resistivity. The new code was first used to solve two cases with no resistivity and simple unstable equilibria which after running gave the correct expected results. The difference from running the original code with these two cases was the greater speed of the calculations and the less memory needed. Then by using an ideal MHD-stable equilibrium in a plasma with no resistivity the code gave us solutions which unfortunately were not of the expected kind but the time of the calculations was still very fast. The resistivity was finally added to the code with the ideal MHD-stable equilibrium. The program also this time gave incorrect results. We could, however, see from a relation between the growth rate and the resistivity that the solution may be approximately correct in this domain. Although we did not get all the correct results we have to consider the fact that we got results, that were not possible before. Before this work was carried out we could not get any results at all in the resistive cue because of the very long memory demanding expressions. In future work and studies it is not only possible to get the desired eigenvalues γ as function of η but also possible to get expressions for eigenfunctions, dispersion relations and other significant relations with a number of variable parameters. We could also use the method for any geometry and possibly for non

  11. Detection of chromosomal instability in α-irradiated and bystander human fibroblasts

    International Nuclear Information System (INIS)

    Ponnaiya, Brian; Jenkins-Baker, Gloria; Bigelow, Alan; Marino, Stephen; Geard, Charles R.

    2004-01-01

    There is increasing evidence biological responses to ionizing radiation are not confined to those cells that are directly hit, but may be seen in the progeny at subsequent generations (genomic instability) and in non-irradiated neighbors of irradiated cells (bystander effects). These so called non-targeted phenomena would have significant contributions to radiation-induced carcinogenesis, especially at low doses where only a limited number of cells in a population are directed hit. Here we present data using a co-culturing protocol examining chromosomal instability in α-irradiated and bystander human fibroblasts BJ1-htert. At the first cell division following exposure to 0.1 and 1 Gy α-particles, irradiated populations demonstrated a dose dependent increase in chromosome-type aberrations. At this time bystander BJ1-htert populations demonstrated elevated chromatid-type aberrations when compared to controls. Irradiated and bystander populations were also analyzed for chromosomal aberrations as a function of time post-irradiation. When considered over 25 doublings, all irradiated and bystander populations had significantly higher frequencies of chromatid aberrations when compared to controls (2-3-fold over controls) and were not dependent on dose. The results presented here support the link between the radiation-induced phenomena of genomic instability and the bystander effect

  12. Intimate partner violence and housing instability.

    Science.gov (United States)

    Pavao, Joanne; Alvarez, Jennifer; Baumrind, Nikki; Induni, Marta; Kimerling, Rachel

    2007-02-01

    The mental and physical health consequences of intimate partner violence (IPV) have been well established, yet little is known about the impact of violence on a woman's ability to obtain and maintain housing. This cross-sectional study examines the relationship between recent IPV and housing instability among a representative sample of California women. It is expected that women who have experienced IPV will be at increased risk for housing instability as evidenced by: (1) late rent or mortgage, (2) frequent moves because of difficulty obtaining affordable housing, and/or (3) without their own housing. Data were taken from the 2003 California Women's Health Survey, a population-based, random-digit-dial, annual probability survey of adult California women (N=3619). Logistic regressions were used to predict housing instability in the past 12 months, adjusting for the following covariates; age, race/ethnicity, education, poverty status, marital status, children in the household, and past year IPV. In the multivariate model, age, race/ethnicity, marital status, poverty, and IPV were significant predictors of housing instability. After adjusting for all covariates, women who experienced IPV in the last year had almost four times the odds of reporting housing instability than women who did not experience IPV (adjusted odds ratio=3.98, 95% confidence interval: 2.94-5.39). This study found that IPV was associated with housing instability among California women. Future prospective studies are needed to learn more about the nature and direction of the relationship between IPV and housing instability and the possible associated negative health consequences.

  13. Critical target and dose and dose-rate responses for the induction of chromosomal instability by ionizing radiation

    Science.gov (United States)

    Limoli, C. L.; Corcoran, J. J.; Milligan, J. R.; Ward, J. F.; Morgan, W. F.

    1999-01-01

    To investigate the critical target, dose response and dose-rate response for the induction of chromosomal instability by ionizing radiation, bromodeoxyuridine (BrdU)-substituted and unsubstituted GM10115 cells were exposed to a range of doses (0.1-10 Gy) and different dose rates (0.092-17.45 Gy min(-1)). The status of chromosomal stability was determined by fluorescence in situ hybridization approximately 20 generations after irradiation in clonal populations derived from single progenitor cells surviving acute exposure. Overall, nearly 700 individual clones representing over 140,000 metaphases were analyzed. In cells unsubstituted with BrdU, a dose response was found, where the probability of observing delayed chromosomal instability in any given clone was 3% per gray of X rays. For cells substituted with 25-66% BrdU, however, a dose response was observed only at low doses (1.0 Gy), the incidence of chromosomal instability leveled off. There was an increase in the frequency and complexity of chromosomal instability per unit dose compared to cells unsubstituted with BrdU. The frequency of chromosomal instability appeared to saturate around approximately 30%, an effect which occurred at much lower doses in the presence of BrdU. Changing the gamma-ray dose rate by a factor of 190 (0.092 to 17.45 Gy min(-1)) produced no significant differences in the frequency of chromosomal instability. The enhancement of chromosomal instability promoted by the presence of the BrdU argues that DNA comprises at least one of the critical targets important for the induction of this end point of genomic instability.

  14. The temporal interplay of self-esteem instability and affective instability in borderline personality disorder patients' everyday lives.

    Science.gov (United States)

    Santangelo, Philip S; Reinhard, Iris; Koudela-Hamila, Susanne; Bohus, Martin; Holtmann, Jana; Eid, Michael; Ebner-Priemer, Ulrich W

    2017-11-01

    Borderline personality disorder (BPD) is defined by a pervasive pattern of instability. Although there is ample empirical evidence that unstable self-esteem is associated with a myriad of BPD-like symptoms, self-esteem instability and its temporal dynamics have received little empirical attention in patients with BPD. Even worse, the temporal interplay of affective instability and self-esteem instability has been neglected completely, although it has been hypothesized recently that the lack of specificity of affective instability in association with BPD might be explained by the highly intertwined temporal relationship between affective and self-esteem instability. To investigate self-esteem instability, its temporal interplay with affective instability, and its association with psychopathology, 60 patients with BPD and 60 healthy controls (HCs) completed electronic diaries for 4 consecutive days during their everyday lives. Participants reported their current self-esteem, valence, and tense arousal levels 12 times a day in approximately one-hr intervals. We used multiple state-of-the-art statistical techniques and graphical approaches to reveal patterns of instability, clarify group differences, and examine the temporal interplay of self-esteem instability and affective instability. As hypothesized, instability in both self-esteem and affect was clearly elevated in the patients with BPD. In addition, self-esteem instability and affective instability were highly correlated. Both types of instability were related to general psychopathology. Because self-esteem instability could not fully explain affective instability and vice versa and neither affective instability nor self-esteem instability was able to explain psychopathology completely, our findings suggest that these types of instability represent unique facets of BPD. (PsycINFO Database Record (c) 2017 APA, all rights reserved).

  15. Kinetic simulations of Rayleigh-Taylor instabilities

    International Nuclear Information System (INIS)

    Sagert, Irina; Bauer, Wolfgang; Colbry, Dirk; Howell, Jim; Staber, Alec; Strother, Terrance

    2014-01-01

    We report on an ongoing project to develop a large scale Direct Simulation Monte Carlo code. The code is primarily aimed towards applications in astrophysics such as simulations of core-collapse supernovae. It has been tested on shock wave phenomena in the continuum limit and for matter out of equilibrium. In the current work we focus on the study of fluid instabilities. Like shock waves these are routinely used as test-cases for hydrodynamic codes and are discussed to play an important role in the explosion mechanism of core-collapse supernovae. As a first test we study the evolution of a single-mode Rayleigh-Taylor instability at the interface of a light and a heavy fluid in the presence of a gravitational acceleration. To suppress small-wavelength instabilities caused by the irregularity in the separation layer we use a large particle mean free path. The latter leads to the development of a diffusion layer as particles propagate from one fluid into the other. For small amplitudes, when the instability is in the linear regime, we compare its position and shape to the analytic prediction. Despite the broadening of the fluid interface we see a good agreement with the analytic solution. At later times we observe the development of a mushroom like shape caused by secondary Kelvin-Helmholtz instabilities as seen in hydrodynamic simulations and consistent with experimental observations.

  16. Tidal instability in exoplanetary systems evolution

    Directory of Open Access Journals (Sweden)

    Le Gal P.

    2011-02-01

    Full Text Available A new element is proposed to play a role in the evolution of extrasolar planetary systems: the tidal (or elliptical instability. It comes from a parametric resonance and takes place in any rotating fluid whose streamlines are (even slightly elliptically deformed. Based on theoretical, experimental and numerical works, we estimate the growth rate of the instability for hot-jupiter systems, when the rotation period of the star is known. We present the physical process, its application to stars, and preliminary results obtained on a few dozen systems, summarized in the form of a stability diagram. Most of the systems are trapped in the so-called "forbidden zone", where the instability cannot grow. In some systems, the tidal instability is able to grow, at short timescales compared to the system evolution. Implications are discussed in the framework of misaligned transiting systems, as the rotational axis of the star would be unstable in systems where this elliptical instability grows.

  17. Coherent Instabilities of ILC Damping Ring

    Energy Technology Data Exchange (ETDEWEB)

    Heifets, S.; Stupakov, G.; Bane, K.; /SLAC

    2006-09-27

    The paper presents the first attempt to estimates the ILC damping ring impedance and compare thresholds of the classical instabilities for several designs initially proposed for the DR. The work was carried out in the spring of 2006. Since then the choice of the DR is narrowed. Nevertheless, the analysis described may be useful for the next iterations of the beam stability. Overall, the conventional instabilities will have little impact on the ring performance provided the careful design of the ring minimizes the impedance below acceptable level indicated above. The only exception is the transverse CB instability. The longitudinal CB is less demanding. However, even the transverse CB instability would have threshold current above nominal provided the aperture in the wigglers is increased from 8 mm to 16 mm. The microwave instability needs more studies. Nevertheless, we should remember that the ILC DR is different from existing high-current machines at least in two respects: absence of the beam-beam tune spread stabilizing beams in colliders, and unusual strict requirements for low emittance. That may cause new problems such as bunch emittance dilution due to high-frequency wakes (BPMs, grooves), etc. Even if such a possibility exists, it probably universal for all machines and ought be addressed in the design of vacuum components rather than have effect on the choice of the machine design.

  18. Magnetohydrodynamic instability in annular linear induction pump

    International Nuclear Information System (INIS)

    Araseki, Hideo; Kirillov, Igor R.; Preslitsky, Gennady V.; Ogorodnikov, Anatoly P.

    2006-01-01

    In the previous work, the authors showed some detailed aspects of the magnetohydrodynamic instability arising in an annular linear induction pump: the instability is accompanied with a low frequency pressure pulsation in the range of 0-10 Hz when the magnetic Reynolds number is larger than unity; the low frequency pressure pulsation is produced by the sodium vortices that come from some azimuthal non-uniformity of the applied magnetic field or of the sodium inlet velocity. In the present work, an experiment and a numerical analysis are carried out to verify the pump winding phase shift that is expected as an effective way to suppress the instability. The experimental data shows that the phase shift suppresses the instability unless the slip value is so high, but brings about a decrease of the developed pressure. The numerical results indicate that the phase shift causes a local decrease of the electromagnetic force, which results in the suppression of the instability and the decrease of the developed pressure. In addition, it is exhibited that the intensity of the double-supply-frequency pressure pulsation is in nearly the same level in the case with and without the phase shift

  19. Inertioelastic Flow Instability at a Stagnation Point

    Science.gov (United States)

    Burshtein, Noa; Zografos, Konstantinos; Shen, Amy Q.; Poole, Robert J.; Haward, Simon J.

    2017-10-01

    A number of important industrial applications exploit the ability of small quantities of high molecular weight polymer to suppress instabilities that arise in the equivalent flow of Newtonian fluids, a particular example being turbulent drag reduction. However, it can be extremely difficult to probe exactly how the polymer acts to, e.g., modify the streamwise near-wall eddies in a fully turbulent flow. Using a novel cross-slot flow configuration, we exploit a flow instability in order to create and study a single steady-state streamwise vortex. By quantitative experiment, we show how the addition of small quantities (parts per million) of a flexible polymer to a Newtonian solvent dramatically affects both the onset conditions for this instability and the subsequent growth of the axial vorticity. Complementary numerical simulations with a finitely extensible nonlinear elastic dumbbell model show that these modifications are due to the growth of polymeric stress within specific regions of the flow domain. Our data fill a significant gap in the literature between the previously reported purely inertial and purely elastic flow regimes and provide a link between the two by showing how the instability mode is transformed as the fluid elasticity is varied. Our results and novel methods are relevant to understanding the mechanisms underlying industrial uses of weakly elastic fluids and also to understanding inertioelastic instabilities in more confined flows through channels with intersections and stagnation points.

  20. Adolescent patellar instability: current concepts review.

    Science.gov (United States)

    Clark, D; Metcalfe, A; Wogan, C; Mandalia, V; Eldridge, J

    2017-02-01

    Patellar instability most frequently presents during adolescence. Congenital and infantile dislocation of the patella is a distinct entity from adolescent instability and measurable abnormalities may be present at birth. In the normal patellofemoral joint an increase in quadriceps angle and patellar height are matched by an increase in trochlear depth as the joint matures. Adolescent instability may herald a lifelong condition leading to chronic disability and arthritis. Restoring normal anatomy by trochleoplasty, tibial tubercle transfer or medial patellofemoral ligament (MPFL) reconstruction in the young adult prevents further instability. Although these techniques are proven in the young adult, they may cause growth arrest and deformity where the physis is open. A vigorous non-operative strategy may permit delay of surgery until growth is complete. Where non-operative treatment has failed a modified MPFL reconstruction may be performed to maintain stability until physeal closure permits anatomical reconstruction. If significant growth remains an extraosseous reconstruction of the MPFL may impart the lowest risk to the physis. If minor growth remains image intensifier guided placement of femoral intraosseous fixation may impart a small, but acceptable, risk to the physis. This paper presents and discusses the literature relating to adolescent instability and provides a framework for management of these patients. Cite this article: Bone Joint J 2017;99-B:159-70. ©2017 The British Editorial Society of Bone & Joint Surgery.