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Sample records for genomic instabilities caused

  1. Causes of genome instability

    DEFF Research Database (Denmark)

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

    2015-01-01

    , 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......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...... 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...

  2. 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.

  3. Dicamba causes genomic instability in Phaseolus vulgaris seedlings

    Science.gov (United States)

    Aydin, Murat; Taşpınar, Mahmut Sinan; Arslan, Esra; Yaǧci, Semra; Aǧar, Güleray

    2017-04-01

    The herbicide 3,6-dichloro-2-methoxybenzoic acid (dicamba) is principally used widely agriculture today. The widely use of dicamba in agriculture may represent a potential toxic risks to some crops. Thus, the present study aimed to evaluate the genotoxic effects of dicamba by using randomly amplified polymorphic DNA (RAPD) in Phaseolus vulgaris seedlings. The results showed that persistent DNA damage and decreased genomic template stability (GTS) induced by dicamba (0,2, 0,4 and 0,6 ppm).

  4. PCNA Retention on DNA into G2/M Phase Causes Genome Instability in Cells Lacking Elg1

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    Catherine Johnson

    2016-07-01

    Full Text Available Loss of the genome maintenance factor Elg1 causes serious genome instability that leads to cancer, but the underlying mechanism is unknown. Elg1 forms the major subunit of a replication factor C-like complex, Elg1-RLC, which unloads the ring-shaped polymerase clamp PCNA from DNA during replication. Here, we show that prolonged retention of PCNA on DNA into G2/M phase is the major cause of genome instability in elg1Δ yeast. Overexpression-induced accumulation of PCNA on DNA causes genome instability. Conversely, disassembly-prone PCNA mutants that relieve PCNA accumulation rescue the genome instability of elg1Δ cells. Covalent modifications to the retained PCNA make only a minor contribution to elg1Δ genome instability. By engineering cell-cycle-regulated ELG1 alleles, we show that abnormal accumulation of PCNA on DNA during S phase causes moderate genome instability and its retention through G2/M phase exacerbates genome instability. Our results reveal that PCNA unloading by Elg1-RLC is critical for genome maintenance.

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

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    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.

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

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    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.

  7. Radiation Induced Genomic Instability

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    Morgan, William F.

    2011-03-01

    Radiation induced genomic instability can be observed in the progeny of irradiated cells multiple generations after irradiation of parental cells. The phenotype is well established both in vivo (Morgan 2003) and in vitro (Morgan 2003), and may be critical in radiation carcinogenesis (Little 2000, Huang et al. 2003). Instability can be induced by both the deposition of energy in irradiated cells as well as by signals transmitted by irradiated (targeted) cells to non-irradiated (non-targeted) cells (Kadhim et al. 1992, Lorimore et al. 1998). Thus both targeted and non-targeted cells can pass on the legacy of radiation to their progeny. However the radiation induced events and cellular processes that respond to both targeted and non-targeted radiation effects that lead to the unstable phenotype remain elusive. The cell system we have used to study radiation induced genomic instability utilizes human hamster GM10115 cells. These cells have a single copy of human chromosome 4 in a background of hamster chromosomes. Instability is evaluated in the clonal progeny of irradiated cells and a clone is considered unstable if it contains three or more metaphase sub-populations involving unique rearrangements of the human chromosome (Marder and Morgan 1993). Many of these unstable clones have been maintained in culture for many years and have been extensively characterized. As initially described by Clutton et al., (Clutton et al. 1996) many of our unstable clones exhibit persistently elevated levels of reactive oxygen species (Limoli et al. 2003), which appear to be due dysfunctional mitochondria (Kim et al. 2006, Kim et al. 2006). Interestingly, but perhaps not surprisingly, our unstable clones do not demonstrate a “mutator phenotype” (Limoli et al. 1997), but they do continue to rearrange their genomes for many years. The limiting factor with this system is the target – the human chromosome. While some clones demonstrate amplification of this chromosome and thus lend

  8. 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

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

    DEFF Research Database (Denmark)

    Galanos, Panagiotis; Vougas, Konstantinos; Walter, David

    2016-01-01

    cells strongly expressing p21 showed proliferation features. This occurred predominantly in p53-mutant human cancers, suggesting p53-independent upregulation of p21 selectively in more aggressive tumour cells. Multifaceted phenotypic and genomic analyses of p21-inducible, p53-null, cancerous and near...

  10. 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

  11. Rac2-MRC-cIII-generated ROS cause genomic instability in chronic myeloid leukemia stem cells and primitive progenitors.

    Science.gov (United States)

    Nieborowska-Skorska, Margaret; Kopinski, Piotr K; Ray, Regina; Hoser, Grazyna; Ngaba, Danielle; Flis, Sylwia; Cramer, Kimberly; Reddy, Mamatha M; Koptyra, Mateusz; Penserga, Tyrone; Glodkowska-Mrowka, Eliza; Bolton, Elisabeth; Holyoake, Tessa L; Eaves, Connie J; Cerny-Reiterer, Sabine; Valent, Peter; Hochhaus, Andreas; Hughes, Timothy P; van der Kuip, Heiko; Sattler, Martin; Wiktor-Jedrzejczak, Wieslaw; Richardson, Christine; Dorrance, Adrienne; Stoklosa, Tomasz; Williams, David A; Skorski, Tomasz

    2012-05-03

    Chronic myeloid leukemia in chronic phase (CML-CP) is induced by BCR-ABL1 oncogenic tyrosine kinase. Tyrosine kinase inhibitors eliminate the bulk of CML-CP cells, but fail to eradicate leukemia stem cells (LSCs) and leukemia progenitor cells (LPCs) displaying innate and acquired resistance, respectively. These cells may accumulate genomic instability, leading to disease relapse and/or malignant progression to a fatal blast phase. In the present study, we show that Rac2 GTPase alters mitochondrial membrane potential and electron flow through the mitochondrial respiratory chain complex III (MRC-cIII), thereby generating high levels of reactive oxygen species (ROS) in CML-CP LSCs and primitive LPCs. MRC-cIII-generated ROS promote oxidative DNA damage to trigger genomic instability, resulting in an accumulation of chromosomal aberrations and tyrosine kinase inhibitor-resistant BCR-ABL1 mutants. JAK2(V617F) and FLT3(ITD)-positive polycythemia vera cells and acute myeloid leukemia cells also produce ROS via MRC-cIII. In the present study, inhibition of Rac2 by genetic deletion or a small-molecule inhibitor and down-regulation of mitochondrial ROS by disruption of MRC-cIII, expression of mitochondria-targeted catalase, or addition of ROS-scavenging mitochondria-targeted peptide aptamer reduced genomic instability. We postulate that the Rac2-MRC-cIII pathway triggers ROS-mediated genomic instability in LSCs and primitive LPCs, which could be targeted to prevent the relapse and malignant progression of CML.

  12. 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

  13. 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

  14. In situ quantification of genomic instability in breast cancer progression

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    Ortiz de Solorzano, Carlos; Chin, Koei; Gray, Joe W.; Lockett, Stephen J.

    2003-05-15

    Genomic instability is a hallmark of breast and other solid cancers. Presumably caused by critical telomere reduction, GI is responsible for providing the genetic diversity required in the multi-step progression of the disease. We have used multicolor fluorescence in situ hybridization and 3D image analysis to quantify genomic instability cell-by-cell in thick, intact tissue sections of normal breast epithelium, preneoplastic lesions (usual ductal hyperplasia), ductal carcinona is situ or invasive carcinoma of the breast. Our in situ-cell by cell-analysis of genomic instability shows an important increase of genomic instability in the transition from hyperplasia to in situ carcinoma, followed by a reduction of instability in invasive carcinoma. This pattern suggests that the transition from hyperplasia to in situ carcinoma corresponds to telomere crisis and invasive carcinoma is a consequence of telomerase reactivation afertelomere crisis.

  15. Separase prevents genomic instability by controlling replication fork speed

    Science.gov (United States)

    Cucco, Francesco; Palumbo, Elisa; Camerini, Serena; D’Alessio, Barbara; Quarantotti, Valentina; Casella, Maria Luisa; Rizzo, Ilaria Maria; Cukrov, Dubravka; Delia, Domenico; Russo, Antonella; Crescenzi, Marco

    2018-01-01

    Abstract Proper chromosome segregation is crucial for preserving genomic integrity, and errors in this process cause chromosome mis-segregation, which may contribute to cancer development. Sister chromatid separation is triggered by Separase, an evolutionary conserved protease that cleaves the cohesin complex, allowing the dissolution of sister chromatid cohesion. Here we provide evidence that Separase participates in genomic stability maintenance by controlling replication fork speed. We found that Separase interacted with the replication licensing factors MCM2–7, and genome-wide data showed that Separase co-localized with MCM complex and cohesin. Unexpectedly, the depletion of Separase increased the fork velocity about 1.5-fold and caused a strong acetylation of cohesin's SMC3 subunit and altered checkpoint response. Notably, Separase silencing triggered genomic instability in both HeLa and human primary fibroblast cells. Our results show a novel mechanism for fork progression mediated by Separase and thus the basis for genomic instability associated with tumorigenesis. PMID:29165708

  16. 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.

  17. 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.

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

    African Journals Online (AJOL)

    The primer detectability on genomic instability in 12 samples ranged from 25% with primer OPA-01 to 66% with OPA-08. Case 2 showed the highest genomic instability (80%). The lowest genomic instabamility was (10%) case 6. The results determined numbers of genomic instabilities among hypospadias patients.

  19. 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.

  20. 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...

  1. 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.

  2. c-MYC-Induced Genomic Instability

    Science.gov (United States)

    Kuzyk, Alexandra; Mai, Sabine

    2014-01-01

    MYC dysregulation initiates a dynamic process of genomic instability that is linked to tumor initiation. Early studies using MYC-carrying retroviruses showed that these viruses were potent transforming agents. Cell culture models followed that addressed the role of MYC in transformation. With the advent of MYC transgenic mice, it became obvious that MYC deregulation alone was sufficient to initiate B-cell neoplasia in mice. More than 70% of all tumors have some form of c-MYC gene dysregulation, which affects gene regulation, microRNA expression profiles, large genomic amplifications, and the overall organization of the nucleus. These changes set the stage for the dynamic genomic rearrangements that are associated with cellular transformation. PMID:24692190

  3. Separase prevents genomic instability by controlling replication fork speed.

    Science.gov (United States)

    Cucco, Francesco; Palumbo, Elisa; Camerini, Serena; D'Alessio, Barbara; Quarantotti, Valentina; Casella, Maria Luisa; Rizzo, Ilaria Maria; Cukrov, Dubravka; Delia, Domenico; Russo, Antonella; Crescenzi, Marco; Musio, Antonio

    2018-01-09

    Proper chromosome segregation is crucial for preserving genomic integrity, and errors in this process cause chromosome mis-segregation, which may contribute to cancer development. Sister chromatid separation is triggered by Separase, an evolutionary conserved protease that cleaves the cohesin complex, allowing the dissolution of sister chromatid cohesion. Here we provide evidence that Separase participates in genomic stability maintenance by controlling replication fork speed. We found that Separase interacted with the replication licensing factors MCM2-7, and genome-wide data showed that Separase co-localized with MCM complex and cohesin. Unexpectedly, the depletion of Separase increased the fork velocity about 1.5-fold and caused a strong acetylation of cohesin's SMC3 subunit and altered checkpoint response. Notably, Separase silencing triggered genomic instability in both HeLa and human primary fibroblast cells. Our results show a novel mechanism for fork progression mediated by Separase and thus the basis for genomic instability associated with tumorigenesis. © The Author(s) 2017. Published by Oxford University Press on behalf of Nucleic Acids Research.

  4. One-hit wonders of genomic instability

    Directory of Open Access Journals (Sweden)

    Strunnikov Alexander V

    2010-05-01

    Full Text Available Abstract Recent data show that cells from many cancers exhibit massive chromosome instability. The traditional view is that the gradual accumulation of mutations in genes involved in transcriptional regulation and cell cycle controls results in tumor development. This, however, does not exclude the possibility that some mutations could be more potent than others in destabilizing the genome by targeting both chromosomal integrity and corresponding checkpoint mechanisms simultaneously. Three such examples of "single-hit" lesions potentially leading to heritable genome destabilization are discussed. They include: failure to release sister chromatid cohesion due to the incomplete proteolytic cleavage of cohesin; massive merotelic kinetochore misattachments upon condensin depletion; and chromosome under-replication. In all three cases, cells fail to detect potential chromosomal bridges before anaphase entry, indicating that there is a basic cell cycle requirement to maintain a degree of sister chromatid bridging that is not recognizable as chromosomal damage.

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

    African Journals Online (AJOL)

    DIRECTOR

    2011-05-16

    May 16, 2011 ... The results determined numbers of genomic instabilities among hypospadias patients. In addition, the RAPD-PCR technique is a powerful tool for detection of genomic instability in hypospadias patients. Further larger studies are needed, which include low and high grade of patients to: 1) Obtain RAPD ...

  6. 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

  7. The Role of Telomere Dysfunction in Driving Genomic Instability

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    Robert L Ullrich; Susan Bailey

    2008-01-17

    The mechanistic role of radiation-induced genomic instability in radiation carcinogenesis is an attractive hypothesis that remains to be rigorously tested. There are few in vivo studies on which to base judgments, but work in our laboratory with mouse models of radiogenic mammary neoplasia provided the first indications that certain forms of genetically predisposed radiation-induced genomic instability may contribute to tumor development. The central goal of this research project is to more firmly establish the mechanistic basis of this radiation-associated genomic instability and, from this, to assess whether such induced instability might play a major role in tumorigenesis at low doses of low LET radiation. In the case of mouse mammary tumors, susceptibility to induced instability is expressed as an autosomal recessive trait in mammary epithelial cells and is manifest largely as excess chromatid damage. Recently published studies associate this form of instability with DNA repair deficiency, polymorphic variation in the gene encoding DNA-PKcs (Prkdc), and mammary associated susceptibility. The underlying hypothesis being tested in this project is that tumor-associated genomic instability is preferentially expressed in certain recombinogenic genomic domains and that these may be cell lineage/individual-specific.

  8. Pathways and Mechanisms that Prevent Genome Instability in Saccharomyces cerevisiae

    Science.gov (United States)

    Putnam, Christopher D.; Kolodner, Richard D.

    2017-01-01

    Genome rearrangements result in mutations that underlie many human diseases, and ongoing genome instability likely contributes to the development of many cancers. The tools for studying genome instability in mammalian cells are limited, whereas model organisms such as Saccharomyces cerevisiae are more amenable to these studies. Here, we discuss the many genetic assays developed to measure the rate of occurrence of Gross Chromosomal Rearrangements (called GCRs) in S. cerevisiae. These genetic assays have been used to identify many types of GCRs, including translocations, interstitial deletions, and broken chromosomes healed by de novo telomere addition, and have identified genes that act in the suppression and formation of GCRs. Insights from these studies have contributed to the understanding of pathways and mechanisms that suppress genome instability and how these pathways cooperate with each other. Integrated models for the formation and suppression of GCRs are discussed. PMID:28684602

  9. Industrialization and the increasing risk of genome instability in developing countries: nutrigenomics as a promising antidote.

    Science.gov (United States)

    Anetor, J I

    2010-12-01

    Increased reliance on chemicals in the industrializing developing countries places new demands on them, as they have limited resources to adequately regulate exposure to these chemicals. Majority of the chemicals cause mutation in DNA among others. The consequences of increased exposure to chemicals on the genome and their mitigation by Nutrigenomics, a science concerned with the prevention of genome damage by nutritional factors is poorly recognized in these countries. Growing evidence indicates that genome instability in the absence of overt exposure to genotoxicants is a sensitive marker of nutritional deficiency. Therefore, the increasing prevalence of chemicals in these countries which contribute to genome disturbances and the widespread nutritional deficiency, at least double the risk of genome instability.Environmental pollutants such polychlorobiphenyls, metal fumes, and fly ash, common in these countries are known to increase urinary level of 8-hydroxy deoxyguanosine (8-OHdG), a marker of oxidative DNA damage, precursor of genome instability.Increasing evidence emphasizes the importance of zinc in both genetic stability and function. Zinc deficiency has been linked with oxidative stress, DNA damage and impairment of repair mechanisms as well as risk of cancer. Zinc plays an important role in vitamin A metabolism from which the retinoids are derived. Zinc is also an important component of the p53 protein, a DNA damage sensor which prevents genetic lesions contributing to genome instability.Zinc deficiency ranks among the top 10 leading causes of death in developing countries. A large proportion of the population in these countries ingests less than 50% of the RDA for Zn.This makes this genome protective nutrient among others grossly inadequate. Folate now also recognized for its role in genome stability, is among the nutrients frequently cited as critical to genome stability. Folate deficiency of sub- clinical degree is common. Reduced folate intake causes

  10. Genome instability in blood cells of a BRCA1+ breast cancer family

    International Nuclear Information System (INIS)

    Xiao, Fengxia; Lynch, Henry; Wang, San Ming; Kim, Yeong C; Snyder, Carrie; Wen, Hongxiu; Chen, Pei Xian; Luo, Jiangtao; Becirovic, Dina; Downs, Bradley; Cowan, Kenneth H

    2014-01-01

    BRCA1 plays an essential role in maintaining genome stability. Inherited BRCA1 germline mutation (BRCA1+) is a determined genetic predisposition leading to high risk of breast cancer. While BRCA1+ induces breast cancer by causing genome instability, most of the knowledge is known about somatic genome instability in breast cancer cells but not germline genome instability. Using the exome-sequencing method, we analyzed the genomes of blood cells in a typical BRCA1+ breast cancer family with an exon 13-duplicated founder mutation, including six breast cancer-affected and two breast cancer unaffected members. We identified 23 deleterious mutations in the breast cancer-affected family members, which are absent in the unaffected members. Multiple mutations damaged functionally important and breast cancer-related genes, including transcriptional factor BPTF and FOXP1, ubiquitin ligase CUL4B, phosphorylase kinase PHKG2, and nuclear receptor activator SRA1. Analysis of the mutations between the mothers and daughters shows that most mutations were germline mutation inherited from the ancestor(s) while only a few were somatic mutation generated de novo. Our study indicates that BRCA1+ can cause genome instability with both germline and somatic mutations in non-breast cells

  11. 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

  12. 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 ...

  13. DNA repair defects and genome instability in Hutchinson-Gilford Progeria Syndrome

    OpenAIRE

    Gonzalo, Susana; Kreienkamp, Ray

    2015-01-01

    The integrity of the nuclear lamina has emerged as an important factor in the maintenance of genome stability. In particular, mutations in the LMNA gene, encoding A-type lamins (lamin A/C), alter nuclear morphology and function, and cause genomic instability. LMNA gene mutations are associated with a variety of degenerative diseases and devastating premature aging syndromes such as Hutchinson-Gilford Progeria Syndrome (HGPS) and Restrictive Dermopathy (RD). HGPS is a severe laminopathy, with ...

  14. 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

  15. Acquired genomic aberrations associated with methotrexate resistance vary with background genomic instability

    Czech Academy of Sciences Publication Activity Database

    Snijders, A.M.; Hermsen, M.A.; Baughman, J.; Buffart, T.E.; Huey, B.; Jirsová, Pavla; Roydasgupta, R.; Tokuyasu, T.; Meijer, G.A.; Fridlyand, J.; Albertson, D. G.

    2008-01-01

    Roč. 47, č. 1 (2008), s. 71-83 ISSN 1045-2257 Institutional research plan: CEZ:AV0Z50040507; CEZ:AV0Z50040702 Keywords : genomic instability * array comparative genomic hybridization * methotrexate Subject RIV: BO - Biophysics Impact factor: 3.925, year: 2008

  16. Does Femoroacetabular Impingement Cause Hip Instability? A Systematic Review.

    Science.gov (United States)

    Canham, Colin D; Yen, Yi-Meng; Giordano, Brian D

    2016-01-01

    To determine whether femoroacetabular impingement (FAI) is associated with hip instability. A systematic search examining FAI and hip instability was conducted according to Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines. Clinical and basic science studies were included. Instability had to be documented with either a clinical or imaging examination. Studies were excluded if they did not define diagnostic criteria for FAI, involved prosthetic hips, were not in English, were review articles, or reported Level V evidence (case reports, expert opinion). Rates of FAI morphologic features in patients with documented hip instability were determined. Mechanisms and rates of FAI-induced hip subluxation were examined in basic science studies. The search yielded 1,630 relevant studies. Seven studies (4 clinical and 3 basic science) met inclusion criteria. Four studies investigated an association between FAI and hip instability in 92 patients with an average age of 31 years. Seventy-six patients experienced frank dislocations and 16 experienced posterior subluxation events. The prevalence of FAI was documented in 89 patients with hip instability. The rates of cam and pincer morphologic characteristics were 74% and 64%, respectively. The average lateral center edge angle and prevalence of acetabular retroversion were 30° and 70%, respectively (n = 76 patients). All 3 basic science studies had real-time visualization of FAI-induced hip subluxations. High rates of FAI morphologic characteristics are present in patients with hip instability. FAI morphologic characteristics may predispose the hip to instability through anatomic conflict caused by pincer or cam lesions (or both) levering the femoral head posteriorly. Level IV, systematic review of Level III, Level IV, and non-clinical studies. Copyright © 2016 Arthroscopy Association of North America. Published by Elsevier Inc. All rights reserved.

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

    Directory of Open Access Journals (Sweden)

    Joshua C Saldivar

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

  18. 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

  19. Genome instability and chromosomal rearrangements in a heterothallic wine yeast.

    Science.gov (United States)

    Miklos, I; Varga, T; Nagy, A; Sipiczki, M

    1997-01-01

    Wine strains of Saccharomyces cerevisiae are usually homothallic diploids and show chromosome length polymorphism. We describe the analysis of a heterothallic strain heterozygous for the mating types a and alpha. Surveying cultures of the strain, we found a remarkable degree of heterogeneity in ploidy and in electrophoretic karyotype. The CHEF analysis of tetrads and dyads revealed an enormous variability of band patterns hampering the analysis of chromosome segregation. We propose that the instability of ploidy and chromosome polymorphism might be due to heterothallism that precludes the process "genome renewal" (MORTIMER et al. 1994) by selfdiploidization of spore clones.

  20. Genomic instability in children born from the Chernobyl accident victims

    International Nuclear Information System (INIS)

    Komar, V.; Koliubaeva, S.; Monakhov, V.; Bejenar, V.

    1997-01-01

    It seems in all probability that the radiation exposure induces a persistent destabilization of cell genome. Evidence has been presented in the previous reports of our laboratory that a chromosome instability could be found out in liquidators of the Chernobyl accident and in children from the regions with a high radiation level. Data on a chromosome instability in children born from the Chernobyl victims are presented in this paper. We investigated women in 1986 within the limits of 30 km zone around the Chernobyl nuclear power station. Children born from these women were a main subject of our studies. In some cases an examination of their fathers was also carried out. It seems to us that a genetic instability transmitted from the parents is realized as an increased sensitivity to the different environmental factors, including an enhanced radiation level, chemical mutagens et al. Latent hereditary disturbances in these children probably appear later as a result of their contact with mutagens of a different nature. (authors)

  1. Bystander effects in radiation-induced genomic instability

    Science.gov (United States)

    Morgan, William F.; Hartmann, Andreas; Limoli, Charles L.; Nagar, Shruti; Ponnaiya, Brian

    2002-01-01

    Exposure of GM10115 hamster-human hybrid cells to X-rays can result in the induction of chromosomal instability in the progeny of surviving cells. This instability manifests as the dynamic production of novel sub-populations of cells with unique cytogenetic rearrangements involving the "marker" human chromosome. We have used the comet assay to investigate whether there was an elevated level of endogenous DNA breaks in chromosomally unstable clones that could provide a source for the chromosomal rearrangements and thus account for the persistent instability observed. Our results indicate no significant difference in comet tail measurement between non-irradiated and radiation-induced chromosomally unstable clones. Using two-color fluorescence in situ hybridization we also investigated whether recombinational events involving the interstitial telomere repeat-like sequences in GM10115 cells were involved at frequencies higher than random processes would otherwise predict. Nine of 11 clones demonstrated a significantly higher than expected involvement of these interstitial telomere repeat-like sequences at the recombination junction between the human and hamster chromosomes. Since elevated levels of endogenous breaks were not detected in unstable clones we propose that epigenetic or bystander effects (BSEs) lead to the activation of recombinational pathways that perpetuate the unstable phenotype. Specifically, we expand upon the hypothesis that radiation induces conditions and/or factors that stimulate the production of reactive oxygen species (ROS). These reactive intermediates then contribute to a chronic pro-oxidant environment that cycles over multiple generations, promoting chromosomal recombination and other phenotypes associated with genomic instability.

  2. Separase prevents genomic instability by controlling replication fork speed

    OpenAIRE

    Cucco, Francesco; Palumbo, Elisa; Camerini, Serena; D’Alessio, Barbara; Quarantotti, Valentina; Casella, Maria Luisa; Rizzo, Ilaria Maria; Cukrov, Dubravka; Delia, Domenico; Russo, Antonella; Crescenzi, Marco; Musio, Antonio

    2017-01-01

    Abstract Proper chromosome segregation is crucial for preserving genomic integrity, and errors in this process cause chromosome mis-segregation, which may contribute to cancer development. Sister chromatid separation is triggered by Separase, an evolutionary conserved protease that cleaves the cohesin complex, allowing the dissolution of sister chromatid cohesion. Here we provide evidence that Separase participates in genomic stability maintenance by controlling replication fork speed. We fou...

  3. β-Catenin induces T-cell transformation by promoting genomic instability

    OpenAIRE

    Dose, Marei; Emmanuel, Akinola Olumide; Chaumeil, Julie; Zhang, Jiangwen; Sun, Tianjiao; Germar, Kristine; Aghajani, Katayoun; Davis, Elizabeth M.; Keerthivasan, Shilpa; Bredemeyer, Andrea L.; Sleckman, Barry P.; Rosen, Steven T.; Skok, Jane A.; Le Beau, Michelle M.; Georgopoulos, Katia

    2013-01-01

    Understanding molecular mechanisms that underlie genomic instability will remove a major obstacle to effective treatment of cancer. Here we characterize a unique animal model that allows insight into mechanisms of genomic instability leading to oncogenic translocations. We show that thymocyte-specific activation of β-catenin induces genomically unstable lymphomas with Tcra/Myc translocations, reminiscent of human leukemia. Tcf-1, the partner of β-catenin, colocalized throughout the genome wit...

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

    Directory of Open Access Journals (Sweden)

    Philpott Michael P

    2010-02-01

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

  5. 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

  6. 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)

  7. A Signature of Genomic Instability Resulting from Deficient Replication Licensing.

    Directory of Open Access Journals (Sweden)

    Steven C Pruitt

    2017-01-01

    Full Text Available Insufficient licensing of DNA replication origins has been shown to result in genome instability, stem cell deficiency, and cancers. However, it is unclear whether the DNA damage resulting from deficient replication licensing occurs generally or if specific sites are preferentially affected. To map locations of ongoing DNA damage in vivo, the DNAs present in red blood cell micronuclei were sequenced. Many micronuclei are the product of DNA breaks that leave acentromeric remnants that failed to segregate during mitosis and should reflect the locations of breaks. To validate the approach we show that micronuclear sequences identify known common fragile sites under conditions that induce breaks at these locations (hydroxyurea. In MCM2 deficient mice a different set of preferred breakage sites is identified that includes the tumor suppressor gene Tcf3, which is known to contribute to T-lymphocytic leukemias that arise in these mice, and the 45S rRNA gene repeats.

  8. 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

  9. 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

  10. 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...... clusters differed with respect to chemotherapy resistance, and the extent of LOH correlated with PFS. LOH burden may indicate vulnerability to treatment targeting DNA repair, such as PARP1 inhibitors. Clin Cancer Res; 18(20); 5806–15. ©2012 AACR....... into two subgroups. The second group contained remarkably less LOH. BRCA1 promoter methylation was associated with the major group. LOH clusters were reproducible when validated in two independent HGSC datasets. LOH burden in the major cluster of HGSC was similar to triple-negative, and distinct from other...

  11. Genetic predisposition and genomic instability: studies with mouse embryos

    Energy Technology Data Exchange (ETDEWEB)

    Streffer, C. [Universitaetsklinikum Essen (Germany). Inst. fuer Medizinische Strahlenbiologie

    1999-07-01

    The preimplantation mouse embryo is a useful system for radiobiological studies. Chromosomal aberrations were determined after exposure to X-rays and neutrons during the zygote (1-cell stage). New aberrations developed and were expressed during the 2nd and 3rd mitosis after irradiation. These later aberration developed from DNA damage which was originally not a DSB. Further chromosomal aberrations were studied in fibroblasts of fetuses 19 days post conception. A significant increase of chromosome aberrations was found in the fetuses which were irradiated in the 1-cell stage and which had developed a malformation. These data can only be explained by the induction of a genome instability through the radiation exposure which had been performed many cell generations earlier. Until recently it was generally accepted that an exposure to ionizing radiation during the preimplantation period of mammalian development will not induce malformations. However, recently it could be shown that certain sensitive mouse strains exist in which malformations are induced by exposure to X-rays and neutrons during the preimplantation period. It was further demonstrated that this effect can be suppressed if the sensitive mouse strain is crossbred with mice from a resistant mouse strain. These data show that this radiation effect is due to a genetic phenomenon with a recessive trait. Studies on protein patterns in normal fetuses and in fetuses with the malformation showed that characteristic changes occur. There are proteins which are no longer expressed in the malformed fetuses and new proteins may appear. Certain changes in glycoproteins and phosphoproteins were found not only in liver of malformed fetuses but also in skin and kidney of these organisms. The analysis of the genome of these malformed fetuses have given evidence that changes in two or three genes are responsible for the radiation-induced malformation. It was possible to localize 1 gene on chromosome 13 and another gene on

  12. Radiation induced genome instability: multiscale modelling and data analysis

    Science.gov (United States)

    Andreev, Sergey; Eidelman, Yuri

    2012-07-01

    Genome instability (GI) is thought to be an important step in cancer induction and progression. Radiation induced GI is usually defined as genome alterations in the progeny of irradiated cells. The aim of this report is to demonstrate an opportunity for integrative analysis of radiation induced GI on the basis of multiscale modelling. Integrative, systems level modelling is necessary to assess different pathways resulting in GI in which a variety of genetic and epigenetic processes are involved. The multilevel modelling includes the Monte Carlo based simulation of several key processes involved in GI: DNA double strand breaks (DSBs) generation in cells initially irradiated as well as in descendants of irradiated cells, damage transmission through mitosis. Taking the cell-cycle-dependent generation of DNA/chromosome breakage into account ensures an advantage in estimating the contribution of different DNA damage response pathways to GI, as to nonhomologous vs homologous recombination repair mechanisms, the role of DSBs at telomeres or interstitial chromosomal sites, etc. The preliminary estimates show that both telomeric and non-telomeric DSB interactions are involved in delayed effects of radiation although differentially for different cell types. The computational experiments provide the data on the wide spectrum of GI endpoints (dicentrics, micronuclei, nonclonal translocations, chromatid exchanges, chromosome fragments) similar to those obtained experimentally for various cell lines under various experimental conditions. The modelling based analysis of experimental data demonstrates that radiation induced GI may be viewed as processes of delayed DSB induction/interaction/transmission being a key for quantification of GI. On the other hand, this conclusion is not sufficient to understand GI as a whole because factors of DNA non-damaging origin can also induce GI. Additionally, new data on induced pluripotent stem cells reveal that GI is acquired in normal mature

  13. 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.

  14. 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.

  15. CAUSES OF INSTABILITY IN CEREAL PRODUCTION IN ETHIOPIA

    OpenAIRE

    Alemu, Zerihun Gudeta

    2005-01-01

    In Ethiopia, average cereal production between the period 1990 and 2000 did not change significantly compared to the period between 1974 and 1990. However, cereal production between the period 1990 and 2000 was characterized by significant instability. This study reviews literature on factors with potential impact on instability in cereal production in Ethiopia and applies descriptive and variance decomposition procedures to determine the sources of increased instability in cereal production....

  16. BLM protein mitigates formaldehyde-induced genomic instability.

    Science.gov (United States)

    Kumari, Anuradha; Owen, Nichole; Juarez, Eleonora; McCullough, Amanda K

    2015-04-01

    Formaldehyde is a reactive aldehyde that has been classified as a class I human carcinogen by the International Agency for Cancer Research. There are growing concerns over the possible adverse health effects related to the occupational and environmental human exposures to formaldehyde. Although formaldehyde-induced DNA and protein adducts have been identified, the genomic instability mechanisms and the cellular tolerance pathways associated with formaldehyde exposure are not fully characterized. This study specifically examines the role of a genome stability protein, Bloom (BLM) in limiting formaldehyde-induced cellular and genetic abnormalities. Here, we show that in the absence of BLM protein, formaldehyde-treated cells exhibited increased cellular sensitivity, an immediate cell cycle arrest, and an accumulation of chromosome radial structures. In addition, live-cell imaging experiments demonstrated that formaldehyde-treated cells are dependent on BLM for timely segregation of daughter cells. Both wild-type and BLM-deficient formaldehyde-treated cells showed an accumulation of 53BP1 and γH2AX foci indicative of DNA double-strand breaks (DSBs); however, relative to wild-type cells, the BLM-deficient cells exhibited delayed repair of formaldehyde-induced DSBs. In response to formaldehyde exposure, we observed co-localization of 53BP1 and BLM foci at the DSB repair site, where ATM-dependent accumulation of formaldehyde-induced BLM foci occurred after the recruitment of 53BP1. Together, these findings highlight the significance of functional interactions among ATM, 53BP1, and BLM proteins as responders associated with the repair and tolerance mechanisms induced by formaldehyde. Copyright © 2015 Elsevier B.V. All rights reserved.

  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. The Dual Roles of MYC in Genomic Instability and Cancer Chemoresistance

    Science.gov (United States)

    Kumari, Alpana; Folk, Watson P.; Sakamuro, Daitoku

    2017-01-01

    Cancer is associated with genomic instability and aging. Genomic instability stimulates tumorigenesis, whereas deregulation of oncogenes accelerates DNA replication and increases genomic instability. It is therefore reasonable to assume a positive feedback loop between genomic instability and oncogenic stress. Consistent with this premise, overexpression of the MYC transcription factor increases the phosphorylation of serine 139 in histone H2AX (member X of the core histone H2A family), which forms so-called γH2AX, the most widely recognized surrogate biomarker of double-stranded DNA breaks (DSBs). Paradoxically, oncogenic MYC can also promote the resistance of cancer cells to chemotherapeutic DNA-damaging agents such as cisplatin, clearly implying an antagonistic role of MYC in genomic instability. In this review, we summarize the underlying mechanisms of the conflicting functions of MYC in genomic instability and discuss when and how the oncoprotein exerts the contradictory roles in induction of DSBs and protection of cancer-cell genomes. PMID:28590415

  19. Predisposition and genome instability: studies with mouse embryos

    Energy Technology Data Exchange (ETDEWEB)

    Streffer, C. [Essen Universitatsklinikum, (Germany). Institut fur Medizinische Strahlenbiologie

    1997-03-01

    The preimplantation mouse embryo is a useful system for radiobiological studies. Chromosomal aberrations were determined after exposure to X-rays and neutrons during the zygote (1-cell stage). New aberrations developed and were expressed during the 2. and 3. mitosis after irradiation. These later aberration developed from DNA damage which was originally not a DSB. Further chromosomal aberrations were studied in fibroblasts of fetuses 19 days post conception. A significant increase of chromosome aberrations was found in the fetuses which were irradiated in the 1-cell stage and which had developed a malformation. These data can only be explained by the induction of a genome instability through the radiation exposure which had been performed many cell generations earlier. Until recently is was generally accepted that an exposure which had been performed many cell generations earlier. Until recently it was generally accepted that an exposure to ionizing radiation during the preimplantation period of mammalian development will not induce malformations. However, recently it could be shown that certain sensitive mouse strains exist in which malformations are induced by exposure to X-rays and neutrons during the preimplantation period. It was further demonstrated that this effect can be suppressed if the sensitive mouse strain is crossbred with mice from a resistant mouse train. These data show that this radiation effect is due to a genetic phenomenon with a recessive trait. Studies on protein patterns in normal fetuses and in fetuses with the malformation showed that characteristic changes occur. There are proteins which are no longer expressed in the malformed fetuses nd new proteins may appear. Certain changes in glycoproteins and phosphoproteins were found not only in liver of malformed fetuses but also in skin and kidney of these organisms. The analysis of the genome of these malformed fetuses have given evidence that changes in two or three genes are responsible for

  20. 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.

  1. IS INCREASED INSTABILITY IN CEREAL PRODUCTION IN ETHIOPIA CAUSED BY POLICY CHANGES?

    OpenAIRE

    Alemu, Zerihun Gudeta; Oosthuizen, Klopper; van Schalkwyk, Herman D.

    2003-01-01

    In Ethiopia, growth in cereal production is accompanied by a more than proportionate increase in the standard deviation of production. This study applies descriptive and variance decomposition procedures to determine the sources of increased instability in cereal production in order to show whether they are caused by policy changes. It was found that production instability was caused more by increased yield instability. Considering the fact that use of high-powered inputs is limited to a smal...

  2. Ultradeep sequencing of a human ultraconserved region reveals somatic and constitutional genomic instability.

    Directory of Open Access Journals (Sweden)

    Anna De Grassi

    2010-01-01

    Full Text Available Early detection of cancer-associated genomic instability is crucial, particularly in tumour types in which this instability represents the essential underlying mechanism of tumourigenesis. Currently used methods require the presence of already established neoplastic cells because they only detect clonal mutations. In principle, parallel sequencing of single DNA filaments could reveal the early phases of tumour initiation by detecting low-frequency mutations, provided an adequate depth of coverage and an effective control of the experimental error. We applied ultradeep sequencing to estimate the genomic instability of individuals with hereditary non-polyposis colorectal cancer (HNPCC. To overcome the experimental error, we used an ultraconserved region (UCR of the human genome as an internal control. By comparing the mutability outside and inside the UCR, we observed a tendency of the ultraconserved element to accumulate significantly fewer mutations than the flanking segments in both neoplastic and nonneoplastic HNPCC samples. No difference between the two regions was detectable in cells from healthy donors, indicating that all three HNPCC samples have mutation rates higher than the healthy genome. This is the first, to our knowledge, direct evidence of an intrinsic genomic instability of individuals with heterozygous mutations in mismatch repair genes, and constitutes the proof of principle for the development of a more sensitive molecular assay of genomic instability.

  3. Essays on political instability : Measurement, causes and consequences

    NARCIS (Netherlands)

    Jong-A-Pin, R.

    2008-01-01

    In political economy, the concept of political instability plays a prominent role as it raises uncertainty with respect to future institutions and economic policies, thereby affecting the incentives of e.g. households, firms, and politicians. This dissertation contains four quantitative studies on

  4. UV-C-irradiated Arabidopsis and tobacco emit volatiles that trigger genomic instability in neighboring plants.

    Science.gov (United States)

    Yao, Youli; Danna, Cristian H; Zemp, Franz J; Titov, Viktor; Ciftci, Ozan Nazim; Przybylski, Roman; Ausubel, Frederick M; Kovalchuk, Igor

    2011-10-01

    We have previously shown that local exposure of plants to stress results in a systemic increase in genome instability. Here, we show that UV-C-irradiated plants produce a volatile signal that triggers an increase in genome instability in neighboring nonirradiated Arabidopsis thaliana plants. This volatile signal is interspecific, as UV-C-irradiated Arabidopsis plants transmit genome destabilization to naive tobacco (Nicotiana tabacum) plants and vice versa. We report that plants exposed to the volatile hormones methyl salicylate (MeSA) or methyl jasmonate (MeJA) exhibit a similar level of genome destabilization as UV-C-irradiated plants. We also found that irradiated Arabidopsis plants produce MeSA and MeJA. The analysis of mutants impaired in the synthesis and/or response to salicylic acid (SA) and/or jasmonic acid showed that at least one other volatile compound besides MeSA and MeJA can communicate interplant genome instability. The NONEXPRESSOR OF PATHOGENESIS-RELATED GENES1 (npr1) mutant, defective in SA signaling, is impaired in both the production and the perception of the volatile signals, demonstrating a key role for NPR1 as a central regulator of genome stability. Finally, various forms of stress resulting in the formation of necrotic lesions also generate a volatile signal that leads to genomic instability.

  5. Genomic instability during reprogramming by nuclear transfer is DNA replication dependent.

    Science.gov (United States)

    Chia, Gloryn; Agudo, Judith; Treff, Nathan; Sauer, Mark V; Billing, David; Brown, Brian D; Baer, Richard; Egli, Dieter

    2017-04-01

    Somatic cells can be reprogrammed to a pluripotent state by nuclear transfer into oocytes, yet developmental arrest often occurs. While incomplete transcriptional reprogramming is known to cause developmental failure, reprogramming also involves concurrent changes in cell cycle progression and nuclear structure. Here we study cellular reprogramming events in human and mouse nuclear transfer embryos prior to embryonic genome activation. We show that genetic instability marked by frequent chromosome segregation errors and DNA damage arise prior to, and independent of, transcriptional activity. These errors occur following transition through DNA replication and are repaired by BRCA1. In the absence of mitotic nuclear remodelling, DNA replication is delayed and errors are exacerbated in subsequent mitosis. These results demonstrate that independent of gene expression, cell-type-specific features of cell cycle progression constitute a barrier sufficient to prevent the transition from one cell type to another during reprogramming.

  6. 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.

  7. 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.

  8. Genomic instability in pancreatic adenocarcinoma: a new step towards precision medicine and novel therapeutic approaches.

    Science.gov (United States)

    Sahin, Ibrahim H; Lowery, Maeve A; Stadler, Zsofia K; Salo-Mullen, Erin; Iacobuzio-Donahue, Christine A; Kelsen, David P; O'Reilly, Eileen M

    2016-08-01

    Pancreatic cancer is one of the most challenging cancers. Whole genome sequencing studies have been conducted to elucidate the underlying fundamentals underscoring disease behavior. Studies have identified a subgroup of pancreatic cancer patients with distinct molecular and clinical features. Genetic fingerprinting of these tumors is consistent with an unstable genome and defective DNA repair pathways, which creates unique susceptibility to agents inducing DNA damage. BRCA1/2 mutations, both germline and somatic, which lead to impaired DNA repair, are found to be important biomarkers of genomic instability as well as of response to DNA damaging agents. Recent studies have elucidated that PARP inhibitors and platinum agents may be effective to induce tumor regression in solid tumors bearing an unstable genome including pancreatic cancer. In this review we discuss the characteristics of genomic instability in pancreatic cancer along with its clinical implications and the utility of DNA targeting agents particularly PARP inhibitors as a novel treatment approach.

  9. 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

  10. 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

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

    African Journals Online (AJOL)

    ... test using five primers OP-C10, OP-G14, OP-H05, OP-Y03 and OP-AT01. The results indicate the usefulness of RAPD markers to detect genetic instability in cucumber primary regenerant plants derived from somatic embryogenesis, and as a certification tool for monitoring genetic stability during the generation process.

  12. Nutritional treatment of genome instability: a paradigm shift in disease prevention and in the setting of recommended dietary allowances.

    Science.gov (United States)

    Fenech, Michael

    2003-06-01

    The link between genome instability and adverse health outcomes during the various stages of life, such as infertility, fetal development and cancer, is briefly reviewed against a background of evidence indicating that genome instability, in the absence of overt exposure to genotoxins, is itself a sensitive marker of nutritional deficiency. The latter is illustrated with cross-sectional and dietary intervention data obtained using the micronucleus assay, an efficient biomarker for diagnosing genome instability and nutritional deficiency. The concept of recommended dietary allowances for genome stability and how this could be achieved is discussed together with the emerging field of nutritional genomics for genome stability. The review concludes with a vision for a disease-prevention strategy based on the diagnosis and nutritional treatment of genome instability, i.e. 'Genome Health Clinics'.

  13. 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.

  14. 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

  15. 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

  16. Lack of Major Genome Instability in Tumors of p53 Null Rats

    NARCIS (Netherlands)

    Hermsen, Roel; Toonen, Pim; Kuijk, Ewart|info:eu-repo/dai/nl/304834459; Youssef, Sameh A.; Kuiper, Raoul; van Heesch, Sebastiaan; de Bruin, Alain; Cuppen, Edwin|info:eu-repo/dai/nl/183050487; Simonis, Marieke

    2015-01-01

    Tumorigenesis is often associated with loss of tumor suppressor genes (such as TP53), genomic instability and telomere lengthening. Previously, we generated and characterized a rat p53 knockout model in which the homozygous rats predominantly develop hemangiosarcomas whereas the heterozygous rats

  17. Lerner's theory on the genetic relationship between heterozygosity, genomic co-adaptation, and developmental instability revisited

    DEFF Research Database (Denmark)

    Pertoldi, Cino; Sorensen, Jesper G.; David, Jean R.

    2006-01-01

    inbreeding is likely to have purged the genome of some of its genetic load and its most deleterious variants. The greater developmental instability in the parthenogenetic and inbred strains implies a non-linear relationship between heritability (h(2)) and additive genetic variance (sigma(2)(a)) (which...

  18. 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)

  19. 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.

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

    Directory of Open Access Journals (Sweden)

    Mulder Chris JJ

    2011-01-01

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

  1. 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

  2. The causes of replication stress and their consequences on genome stability and cell fate.

    Science.gov (United States)

    Magdalou, Indiana; Lopez, Bernard S; Pasero, Philippe; Lambert, Sarah A E

    2014-06-01

    Alterations of the dynamics of DNA replication cause genome instability. These alterations known as "replication stress" have emerged as a major source of genomic instability in pre-neoplasic lesions, contributing to cancer development. The concept of replication stress covers a wide variety of events that distort the temporal and spatial DNA replication program. These events have endogenous or exogenous origins and impact globally or locally on the dynamics of DNA replication. They may arise within a short window of time (acute stress) or during each S phase (chronic stress). Here, we review the known situations in which the dynamics of DNA replication is distorted. We have united them in four main categories: (i) inadequate firing of replication origins (deficiency or excess), (ii) obstacles to fork progression, (iii) conflicts between replication and transcription and (iv) DNA replication under inappropriate metabolic conditions (unbalanced DNA replication). Because the DNA replication program is a process tightly regulated by many factors, replication stress often appears as a cascade of events. A local stress may prevent the completion of DNA replication at a single locus and subsequently compromise chromosome segregation in mitosis and therefore have a global effect on genome integrity. Finally, we discuss how replication stress drives genome instability and to what extent it is relevant to cancer biology. Copyright © 2014 Elsevier Ltd. All rights reserved.

  3. Numerical study of coupled-bunch instability caused by an electron cloud

    Directory of Open Access Journals (Sweden)

    S. S. Win

    2005-09-01

    Full Text Available An electron cloud induces a wake force on a charged particle beam which creates correlations between bunches—i.e., a small displacement of a bunch creates a perturbation of the electron cloud, which affects the motions of the following bunches, with the result that a coupled-bunch instability is caused. The coupling mode of the instability is determined by the motion of the electrons in the cloud—that is, it depends on which electrons, moving in a drift space, a weak solenoid field or a strong bending field, are dominant for the instability. We discuss the coupled-bunch instability focusing on the relation between the mode spectrum and the electron motion.

  4. Lack of major genome instability in tumors of p53 null rats.

    Directory of Open Access Journals (Sweden)

    Roel Hermsen

    Full Text Available Tumorigenesis is often associated with loss of tumor suppressor genes (such as TP53, genomic instability and telomere lengthening. Previously, we generated and characterized a rat p53 knockout model in which the homozygous rats predominantly develop hemangiosarcomas whereas the heterozygous rats mainly develop osteosarcomas. Using genome-wide analyses, we find that the tumors that arise in the heterozygous and homozygous Tp53C273X mutant animals are also different in their genomic instability profiles. While p53 was fully inactivated in both heterozygous and homozygous knockout rats, tumors from homozygous animals show very limited aneuploidy and low degrees of somatic copy number variation as compared to the tumors from heterozygous animals. In addition, complex structural rearrangements such as chromothripsis and breakage-fusion-bridge cycles were never found in tumors from homozygous animals, while these were readily detectable in tumors from heterozygous animals. Finally, we measured telomere length and telomere lengthening pathway activity and found that tumors of homozygous animals have longer telomeres but do not show clear telomerase or alternative lengthening of telomeres (ALT activity differences as compared to the tumors from heterozygous animals. Taken together, our results demonstrate that host p53 status in this rat p53 knockout model has a large effect on both tumor type and genomic instability characteristics, where full loss of functional p53 is not the main driver of large-scale structural variations. Our results also suggest that chromothripsis primarily occurs under p53 heterozygous rather than p53 null conditions.

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

    Energy Technology Data Exchange (ETDEWEB)

    Aghajanyan, Anna, E-mail: ann-aghajanyan@yandex.ru [Cytogenetics Laboratory, FSI Russian Scientific Center of Roentgenology and Radiology, Profsoyuznaya 86, GSP-7, Moscow, 117997 (Russian Federation); Suskov, Igor [Laboratory of Ecological Genetics, N.I. Vavilov Institute of General Genetics Russian Academy of Sciences, Gybkin st. 3, Moscow 119991 (Russian Federation)

    2009-12-01

    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 < 0.01), but also in their children born after the accident (n = 159, p < 0.05). This is an indicative of the phenomenon of transgenerational genomic instability. To elucidate this phenomenon, experiments were undertaken to model genomic instability by using single and fractional in vitro {gamma}-irradiation ({sup 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.

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

    Energy Technology Data Exchange (ETDEWEB)

    Schild, David; Wiese, Claudia

    2009-10-15

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

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

    Energy Technology Data Exchange (ETDEWEB)

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

    2016-11-14

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

  8. 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.

  9. 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.

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

    Directory of Open Access Journals (Sweden)

    Sonia Chadha

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

  11. Kelvin-Helmholtz instability as a possible cause of edge localized modes

    International Nuclear Information System (INIS)

    Strauss, H.R.

    1992-01-01

    Edge localized modes may be a Kelvin-Helmholtz instability caused by the sheared rotation of H-mode plasmas. The Kelvin-Helmholtz instability is stabilized by coupling to Alfven waves. There is a critical velocity gradient, of the order of the Alfven velocity divided by the magnetic shear length. This is verified in a numerical simulation. The critical velocity shear is consistent with experiment. A non-linear simulation shows how the Kelvin-Helmholtz mode can cause oscillations of the velocity profile. (author). Letter-to-the-editor. 13 refs, 6 figs

  12. Genetic predisposition and genomic instability in murine stem cells exposed to low LET radiation

    International Nuclear Information System (INIS)

    Macdonald, D.A.; Bowler, D.A.; Moore, S.R.; Papworth, D.; Kadhim, M.A.; Goodhead, D.T.

    2003-01-01

    Full text: The contribution of genetic factors to the initiation of radiation-induced genomic instability remains poorly understood. Studies with high LET α-particles and very high doses of low LET radiation have described several common mouse strains that differ in their sensitivity to the induction of genomic instability and apoptosis. The aim here was to investigate whether low doses of low LET radiation would elucidate a similar genetic predisposition. To assess the influence of genetic factors on the initiation of genomic instability by low doses of low LET radiation, we irradiated stem cells from two mouse strains known to differ in susceptibility to radiation-induced delayed chromosomal instability. The frequency of delayed chromosomal aberrations was measured in bone marrow cells from CBA/H and C57BL/6 mice after exposure to 0.1 - 2 Gy of 250 kV X-rays. The yield of both chromosomal and chromatid-type aberrations were assessed 13-15 cell divisions post-irradiation in the clonal descendents of surviving stem cells. The apoptotic index of these surviving clones was scored as morphological changes by electron microscopy. At low doses, the frequency of cells with aberrations increased significantly in both strains, contrary to the strain differences observed with high LET α-particles in earlier studies (Watson et al. 1997). The percentage of apoptotic cells was similar between the strains at low doses, with both showing comparable levels of cells with aberrations and apoptotic cells. However, at higher doses, strain differences became evident: CBA/H cells had a substantially higher fraction of cells with aberrations to apoptotic cells, while the converse was true for C57/Bl/6. This data indicates that low doses may be insufficient to initiate the apoptotic pathway, while still resulting in significant induction of delayed chromosomal instability. Overall, these observations have important implications for low dose low LET radiation risk assessment and human

  13. Baicalin hydrate inhibits cancer progression in nasopharyngeal carcinoma by affecting genome instability and splicing.

    Science.gov (United States)

    Lai, Weiwei; Jia, Jiantao; Yan, Bin; Jiang, Yiqun; Shi, Ying; Chen, Ling; Mao, Chao; Liu, Xiaoli; Tang, Haosheng; Gao, Menghui; Cao, Ya; Liu, Shuang; Tao, Yongguang

    2018-01-02

    Baicalin hydrate (BH), a natural compound, has been investigated for many years because of its traditional medicinal properties. However, the anti-tumor activities of BH and its epigenetic role in NPC have not been elucidated. In this study, we identified that BH inhibits NPC cell growth in vivo and in vitro by inducing apoptosis and cell cycle arrest. BH epigenetically regulated genome instability by up-regulating the expression of satellite 2 (Sat2), alpha satellite (α-Sat), and major satellite (Major-Sat). BH also increased the level of IKKα, Suv39H1, and H3K9me3 and decreased LSH expression. Interestingly, BH promoted the splicing of Suv39H1 via the enhancement of m6A RNA methylation, rather than DNA methylation. Taken together, our results demonstrated that BH has an anti-tumor role in NPC and revealed a unique role of BH in genome instability and splicing in response to DNA damage.

  14. Is delayed genomic instability specifically induced by high-LET particles?

    Science.gov (United States)

    Testard, Isabelle; Sabatier, Laure

    1998-12-01

    Ionizing radiation can induce a large variety of damages in the DNA. The processing or repair of this damage occurs in the first minutes up to several hours after irradiation. Afterwhile the remaining lesions are fixed in an irreparable state. However, in recent years, data have accumulated to suggest that genomic instability can manifest in the progeny of irradiated cells leading to accumulation of damage through cell generations. Different biological endpoints were described: delayed cell death, delayed mutations, de novo chromosomal instability. The question regarding the ability of sparsely ionizing X-or γ-rays to induce such phenomenon is still unclear for normal cells. In most of the reports, high linear energy transfer (LET) particles are able to induce genomic instability but not low-LET particles. The mechanisms underlying this phenomenon are still unknown. In human fibroblasts irradiated by heavy ions in a large range of LETs, we showed that the chromosomal instability is characterized by telomeric associations (TAS) involving specific chromosomes. The same instability is observed during the senescence process and during the first passages after viral transfection. The specific chromosomal instability that we observed after irradiation would not be a direct consequence of irradiation but would be a natural phenomenon occurring after many cell divisions. The effect of the irradiation would lie on the bypass of the senescence process that would permit cells with end to end fusions to survive and be transmitted through cell generations, accumulating chromosome rearrangements and chromosome imbalances. Research on molecular mechanisms of chromosomal instability is focused on the role of telomeres in end to end fusions. Such observations could contribute to understand why chromosomal instability is not a dose dependant phenomenon. Why high-LET particles would be so potent in inducing delayed instability? The answer might lie in the study of primary effects of

  15. Genome of a chronic osteitis-causing Clostridium tetani.

    Science.gov (United States)

    Fournier, P-E; Levy, P-Y; Million, M; Croce, O; Blanc-Tailleur, C; Brouqui, P; Raoult, D

    2014-01-01

    We sequenced the genome of a Clostridium tetani strain that caused chronic tibial osteitis without any clinical sign of tetanus in a 26-year-old man previously vaccinated against this disease. The genome contained a plasmid that harboured the tetX-tetR tetanospasmin operon, and was highly similar to that of a tetanus-causing strain.

  16. Genome of a chronic osteitis-causing Clostridium tetani

    Directory of Open Access Journals (Sweden)

    P.-E. Fournier

    2014-01-01

    Full Text Available We sequenced the genome of a Clostridium tetani strain that caused chronic tibial osteitis without any clinical sign of tetanus in a 26-year-old man previously vaccinated against this disease. The genome contained a plasmid that harboured the tetX-tetR tetanospasmin operon, and was highly similar to that of a tetanus-causing strain.

  17. 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.

  18. Cyclooxygenase-2 expression induces genomic instability in MCF10A breast epithelial cells.

    Science.gov (United States)

    Singh, Balraj; Vincent, Laura; Berry, Jacob A; Multani, Asha S; Lucci, Anthony

    2007-06-15

    Cyclooxygenase-2 (COX-2) is induced in many breast cancers and COX-2 expression correlates with a worse outcome in the clinic. We hypothesized that the induction of genomic instability is a major mechanism through which COX-2 contributes to breast cancer progression. We transfected a normal immortalized breast epithelial cell line of Basal B subtype, MCF10A, with the pSG5-COX-2 vector and established the stably transfected cell line MCF10A/COX-2. We analyzed the genomic instability phenotype by chromosomal analysis of metaphase-arrested MCF10A and MCF10A/COX-2 cells after Giemsa staining. Groups were compared using chi(2) tests. To investigate the DNA damage checkpoint signaling, we analyzed the phosphorylation status of CHK1 protein with a phospho-specific antibody. Cytogenetic analysis of early passage transfected cells showed that COX-2 expression increased genomic instability compared with the MCF10A cells transfected with a luciferase vector alone. COX-2 overexpression was associated with a significant increase in chromosomal aberrations (fusions, breaks, and tetraploidy). There was a statistically significant increase in the number of polyploid cells in the COX-2 transfected cells versus the control (P=0.004). We also found that an inhibitory CHK1 phosphorylation at Ser-280 was dramatically increased upon COX-2 overexpression in MCF10A cells, thus explaining the mechanism of inactivation of an important cell cycle checkpoint. Further analysis of the MCF10A/COX-2 cells showed that these cells have acquired a premalignant phenotype characterized by a morphological transformation, a resistance to anoikis, a reduced requirement of epidermal growth factor for growth in culture, but their inability to establish tumors in a nude mouse model of malignancy. We found that COX-2 expression in MCF10A breast epithelial cells confers a premalignant phenotype that includes enhanced genomic instability and altered cell-cycle regulation.

  19. Genome Instability in Childhood Obesity – a potential role for bariatric surgery in cancer prevention?

    OpenAIRE

    Usman, M.; Volpi, E.

    2017-01-01

    Severe paediatric obesity is associated with a range of metabolic complications and is characterised by a chronic meta-inflammatory state. It is postulated that this inflammatory response may result in an excess of systemic reactive oxygen species (ROS) that are well known for inducing DNA damage and reducing the capability of DNA synthesis and repair enzymes. Consequently, chronic inflammation in obesity may promote an accumulation of deleterious DNA mutations, leading to genome instability ...

  20. Development of genomic instability after irradiation; Entwicklung einer genomischen Instabilitaet nach Bestrahlung

    Energy Technology Data Exchange (ETDEWEB)

    Streffer, C. [Essen Univ. (Gesamthochschule) (Germany). Universitaetsklinikum

    2001-07-01

    It has been shown for various endpoints, both in vitro and in vivo, that genomic instability can be induced by low as well as by high LET radiation. Genomic instability in this case is not limited to a specific chromosome or gene. It can be passed on over many cell generations and in mammals can even be inherited to the next generation. It is capable of being induced in gametes. A dose dependence of the development of genomic instability has been found to exist in the range from 0.5 to 2.0 Gy. However, there are no data available in the low dose range. The mechanisms by which genomic instability is induced are still not understood at present. Various possibilities have been suggested. An understanding of these mechanisms will contribute to developing a deepened knowledge of processes such as stochastic radiation effects with multi-step mutation processes, and in particular carcinogenesis. It will facilitate the evaluation of radiation risks in the low-dose range. [German] Die Induktion einer genomischen Instabilitaet durch niedrige ebenso wie Hoch-LET-Strahlung ist fuer verschiedene Endpunkte gezeigt worden. Dieses ist sowohl in vitro als auch in vivo beobachtet worden. Die genomische Instabilitaet ist nicht auf ein spezifisches Chromosom oder Gen begrenzt. Sie kann ueber viele Zellgenerationen weitergegeben und auf die naechste Generation bei Saeugetieren vererbt werden. Eine Induktion in Keimzellen ist moeglich. Eine Dosisabhaengigkeit der Entwicklung genomischer Instabilitaet ist fuer den Dosisbereich von 0,5-2,0 Gy beobachtet worden. Daten im niedrigen Dosisbereich fehlen. Die Mechanismen der Induktion der genomischen Instabilitaet werden bisher nicht verstanden. Eine Anzahl verschiedener Moeglichkeiten ist vorgeschlagen worden. Die genomische Instabilitaet und das Verstaendnis der Mechanismen wird helfen, ein besseres Wissen ueber die Prozesse, wie stochastische Strahleneffekte mit Mehrschrittmutationsprozessen, besonders die Karzinogenese, zu entwickeln

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

    Science.gov (United States)

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

    2016-01-01

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

  2. 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)

  3. Causes of Marital Instability in the Port-Harcourt Municipality, Nigeria

    African Journals Online (AJOL)

    Over the years marriage instability has affected the growth and development of many Nigerian homes and children. Several factors could be responsible for this ugly situation. The study therefore focused on identifying some of these causes. A sample size of 150 subjects was thus interviewed in the Port Harcourt ...

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

    Directory of Open Access Journals (Sweden)

    Love Brad

    2008-10-01

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

  5. Electron heating caused by the ion-acoustic decay instability in a finite-length system

    International Nuclear Information System (INIS)

    Rambo, P.W.; Woo, W.; DeGroot, J.S.; Mizuno, K.

    1984-01-01

    The ion-acoustic decay instability is investigated for a finite-length plasma with density somewhat below the cutoff density of the electromagnetic driver (napprox.0.7n/sub c/). For this regime, the heating in a very long system can overpopulate the electron tail and cause linear saturation of the low phase velocity electron plasma waves. For a short system, the instability is nonlinearly saturated at larger amplitude by ion trapping. Absorption can be significantly increased by the large-amplitude ion waves. These results compare favorably with microwave experiments

  6. 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

  7. Fast Transverse Beam Instability Caused by Electron Cloud Trapped in Combined Function Magnets

    Energy Technology Data Exchange (ETDEWEB)

    Antipov, Sergey [Univ. of Chicago, IL (United States)

    2017-03-01

    Electron cloud instabilities affect the performance of many circular high-intensity particle accelerators. They usually have a fast growth rate and might lead to an increase of the transverse emittance and beam loss. A peculiar example of such an instability is observed in the Fermilab Recycler proton storage ring. Although this instability might pose a challenge for future intensity upgrades, its nature had not been completely understood. The phenomena has been studied experimentally by comparing the dynamics of stable and unstable beam, numerically by simulating the build-up of the electron cloud and its interaction with the beam, and analytically by constructing a model of an electron cloud driven instability with the electrons trapped in combined function dipoles. Stabilization of the beam by a clearing bunch reveals that the instability is caused by the electron cloud, trapped in beam optics magnets. Measurements of microwave propagation confirm the presence of the cloud in the combined function dipoles. Numerical simulations show that up to 10$^{-2}$ of the particles can be trapped by their magnetic field. Since the process of electron cloud build-up is exponential, once trapped this amount of electrons significantly increases the density of the cloud on the next revolution. In a combined function dipole this multi-turn accumulation allows the electron cloud reaching final intensities orders of magnitude greater than in a pure dipole. The estimated fast instability growth rate of about 30 revolutions and low mode frequency of 0.4 MHz are consistent with experimental observations and agree with the simulations. The created instability model allows investigating the beam stability for the future intensity upgrades.

  8. Induction of Genomic Instability In Vivo by Low Doses of 137Cs gamma rays

    International Nuclear Information System (INIS)

    Rithidech, Kanokporn; Simon, Sanford R.; Whorton, Elbert B.

    2006-01-01

    The overall goal of this project is to determine if low doses (below or equal to the level traditionally requiring human radiation protection, i.e. less than or equal to 10 cGy) of low LET radiation can induce genomic instability. The magnitude of genomic instability was measured as delayed chromosome instability in bone marrow cells of exposed mice with different levels of endogenous DNA-dependent protein kinase catalytic subunit (DNA-PKcs) activity, i.e. high (C57BL/6J mice), intermediate (BALB/cJ mice), and extremely low (Scid mice). In addition, at early time points (1 and 4 hrs) following irradiation, levels of activation of nuclear factor-kappa B (NF-κB), a transcription factor known to be involved in regulating the expression of genes responsible for cell protection following stimuli, were measured in these cells. Bone marrow cells were collected at different times following irradiation, i.e. 1 hr, 4 hrs, 1 month, and 6 months. A total of five mice per dose per strain were sacrificed at each time point for sample collection. As a result, a total of 80 mice from each strain were used. The frequency and the type of metaphase chromosome aberrations in bone marrow cells collected from exposed mice at different times following irradiation were used as markers for radiation-induced genomic instability. A three-color fluorescence in situ hybridization (FISH) protocol for mouse chromosomes 1, 2, and 3 was used for the analysis of delayed stable chromosomal aberrations in metaphase cells. All other visible chromatid-type aberrations and gross structural abnormalities involving non-painted chromosomes were also evaluated on the same metaphase cells used for scoring the stable chromosomal aberrations of painted chromosomes. Levels of nuclear factor-kappa B (NF-κB) activation were also determined in cells at 1 and 4 hrs following irradiation (indicative of early responses)

  9. Genomic strategies to understand causes of keratoconus

    OpenAIRE

    Karolak, Justyna A.; Gajecka, Marzena

    2016-01-01

    Keratoconus (KTCN) is a degenerative disorder of the eye characterized by the conical shape and thinning of the cornea. The abnormal structure of KTCN-affected cornea results in loss of visual acuity. While many studies examine how environmental factors influence disease development, finding the genetic triggers has been a major emphasis of KTCN research. This paper focuses on genomic strategies that were implemented for finding candidate genes, including linkage and association studies, and ...

  10. LONG-TERM RESULTS OF ARTHROSCOPIC TREATMENT FOR INSTABILITY AT RECURRENT SHOULDER JOINT, CAUSES OF FAILURE

    Directory of Open Access Journals (Sweden)

    R. M. Tikhilov

    2011-01-01

    Full Text Available The authors analyse the results of the performance of arthroscopy stitch on the injured capsule with the use of anchor on 46 patients with anterior recurring instability of the shoulder joint within a period of time from 6 months to 4 years. When assessing the results of the given treatment, functional scales, clinical examination methods and radiological methods have been used. The article presents the results of arthroscopy diagnosis of the interior joint damage accompanying the recurring instability of the shoulder joint. The effectiveness of the conducted operations was 93,5%. The occurrence of postoperative relapses of joint instability (reoccurring dislocations in 3 patients (6,5% was caused by the presence of significant damage of bone formations in the shoulder joint – the shoulder-blade joint socket and the shoulder-bone head as well as the reduction of the strength and elasticity of the soft-tissue structures.

  11. Macroeconomic instability: its causes and consequences for the economy of Ukraine

    Directory of Open Access Journals (Sweden)

    Natalia SKOROBOGATOVA

    2016-06-01

    Full Text Available The article deals with the concepts of appearance and elimination of macroeconomic instability, and the Keynesian approach for overcoming issues in Ukraine’s macroeconomic instability. Based on the Ukraine Statistics Service and World Bank data, Ukraine's economy tendencies have been defined: the country has not reached the pre-crisis economic level. The article identifies the reasons of negative balance payments and budget deficit: a decrease in production value, negative trade balance, growth of foreign creditor’s debt, currency instability, an increase in budget spending. The dynamics of income and expenditure within Ukraine budget has been analyzed, and also the destructiveness of existing approaches for the main financial documents has been grounded. Considering Ukraine’s economic and political situation, the main causes of macroeconomic instability are systematized. Government-implemented approaches for overcoming the macroeconomic instability have been suggested. The article introduces an approach for minimizing the negative effects on businesses, based on the timely identification of macroeconomic risks in terms of internal and external management. The possible negative impacts in case the timely decisions are not implemented have been assessed.

  12. 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

  13. Genomic strategies to understand causes of keratoconus.

    Science.gov (United States)

    Karolak, Justyna A; Gajecka, Marzena

    2017-04-01

    Keratoconus (KTCN) is a degenerative disorder of the eye characterized by the conical shape and thinning of the cornea. The abnormal structure of KTCN-affected cornea results in loss of visual acuity. While many studies examine how environmental factors influence disease development, finding the genetic triggers has been a major emphasis of KTCN research. This paper focuses on genomic strategies that were implemented for finding candidate genes, including linkage and association studies, and presents different approaches of mutation screening. The advantages and limitations of particular tools are discussed based on literature and personal experience. Since etiology underlying KTCN is complex, numerous findings indicating heterogeneity of genetic factors involved KTCN etiology are presented.

  14. Formaldehyde-Induced Genome Instability is Suppressed by an XPF-dependent Pathway

    Science.gov (United States)

    Kumari, Anuradha; Lim, Yun Xin; Newell, Amy Hanlon; Olson, Susan B.; McCullough, Amanda K.

    2011-01-01

    Formaldehyde is a reactive chemical that is commonly used in the production of industrial, laboratory, household, and cosmetic products. The causal association between formaldehyde exposure and increased incidence of cancer led the International Agency for Research on Cancer to classify formaldehyde as a carcinogen. Formaldehyde-induced DNA-protein crosslinks (DPCs) elicit responses involving nucleotide excision repair (NER) and homologous recombination (HR) repair pathways; however, little is known about the cellular and genetic changes that subsequently lead to formaldehyde-induced genotoxic and cytotoxic effects. Herein, investigations of genes that modulate the cytotoxic effects of formaldehyde exposure revealed that of five NER-deficient Chinese Hamster Ovary (CHO) cell lines tested, XPF- and ERCC1-deficient cells were most sensitive to formaldehyde treatment as compared to wild-type cells. Cell cycle analyses revealed that formaldehyde-treated XPF-deficient cells exhibited an immediate G2/M arrest that was associated with altered cell ploidy and apoptosis. Additionally, an elevated number of DNA double-strand breaks (DSBs), chromosomal breaks and radial formation were also observed in XPF-deficient cells following formaldehyde treatment. Formaldehyde-induced DSBs occurred in a replication-dependent, but an XPF-independent manner. However, delayed DSB repair was observed in the absence of XPF function. Collectively, our findings highlight the role of an XPF-dependent pathway in mitigating the sensitivity to formaldehyde-induced DNA damage as evidenced by the increased genomic instability and reduced cell viability in an XPF-deficient background. In addition, centrosome and microtubule abnormalities, as well as enlarged nuclei, caused by formaldehyde exposure are also demonstrated in a repair-proficient cell line. PMID:22186232

  15. PARP Inhibitors in Clinical Use Induce Genomic Instability in Normal Human Cells.

    Directory of Open Access Journals (Sweden)

    Shuhei Ito

    Full Text Available Poly(ADP-ribose polymerases (PARPs are the first proteins involved in cellular DNA repair pathways to be targeted by specific inhibitors for clinical benefit. Tumors harboring genetic defects in homologous recombination (HR, a DNA double-strand break (DSB repair pathway, are hypersensitive to PARP inhibitors (PARPi. Early phase clinical trials with PARPi have been promising in patients with advanced BRCA1 or BRCA2-associated breast, ovary and prostate cancer and have led to limited approval for treatment of BRCA-deficient ovary cancer. Unlike HR-defective cells, HR-proficient cells manifest very low cytotoxicity when exposed to PARPi, although they mount a DNA damage response. However, the genotoxic effects on normal human cells when agents including PARPi disturb proficient cellular repair processes have not been substantially investigated. We quantified cytogenetic alterations of human cells, including primary lymphoid cells and non-tumorigenic and tumorigenic epithelial cell lines, exposed to PARPi at clinically relevant doses by both sister chromatid exchange (SCE assays and chromosome spreading. As expected, both olaparib and veliparib effectively inhibited poly-ADP-ribosylation (PAR, and caused marked hypersensitivity in HR-deficient cells. Significant dose-dependent increases in SCEs were observed in normal and non-tumorigenic cells with minimal residual PAR activity. Clinically relevant doses of the FDA-approved olaparib led to a marked increase of SCEs (5-10-fold and chromatid aberrations (2-6-fold. Furthermore, olaparib potentiated SCE induction by cisplatin in normal human cells. Our data have important implications for therapies with regard to sustained genotoxicity to normal cells. Genomic instability arising from PARPi warrants consideration, especially if these agents will be used in people with early stage cancers, in prevention strategies or for non-oncologic indications.

  16. Cause-Effect relationship of the Laguna Verde BWR power instability by empirical mode decomposition

    International Nuclear Information System (INIS)

    Blazquez, J.; Ruiz, J.; Castillo, R.

    2008-01-01

    The signals coming from natural phenomena are in essence non lineal and not stationary. A recent development, well-known as Empirical Mode Decomposition (EMD) it presents a novel focus that allows to represent in adaptative form non stationary signals as a sum of components of half zero. These components denominated Intrinsic Mode Functions (IMF) they help to the analysis of the frequency composition of unidimensional signals. The use of the EMD followed by the Hilbert transform of the IMFs it allows to carry out an analysis in time-frequency of the non lineal and not stationary data. This technique is known as the Hilbert Huang Transform (HHT). In this work a power instability event occurred in January 24, 1995 in the unit I of the nuclear power station of Laguna Verde (Mexico), corresponding to a BWR/5 is analyzed. When a Nuclear Plant suffers a power instability event, it is required obligatorily to explain to the Regulator Organism the effects and the causes of the event. The effects are described simply; not in vain there is a registration of signals in the Process Computer of where the required information is extracted. But the causes are not always immediate and easy for to identify. The power instability can happen during the start, when the refrigeration flow is relatively low in front to the power. By reason of that the reactivity coefficient by holes is negative, the power oscillates with a very defined frequency, generally of the order of 0.5 Hz. If the oscillations increase progressively of amplitude, we are in an instability event. It is interesting to include in the report the instant in that the began instability and the actions of the operator before and after the same one. As the actions are registered, the investigation is focused toward the instant of the beginning to be able to identify them. In this work the power signal in five empiric ways of Hilbert-Huang and a residual breaks down. The instability is only reflected in the way of smaller

  17. 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.

  18. 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.

  19. 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

  20. G2/M-Phase Checkpoint Adaptation and Micronuclei Formation as Mechanisms That Contribute to Genomic Instability in Human Cells.

    Science.gov (United States)

    Kalsbeek, Danî; Golsteyn, Roy M

    2017-11-06

    One of the most common characteristics of cancer cells is genomic instability. Recent research has revealed that G2/M-phase checkpoint adaptation-entering mitosis with damaged DNA-contributes to genomic changes in experimental models. When cancer cells are treated with pharmacological concentrations of genotoxic agents, they undergo checkpoint adaptation; however, a small number of cells are able to survive and accumulate micronuclei. These micronuclei harbour damaged DNA, and are able to replicate and reincorporate their DNA into the main nucleus. Micronuclei are susceptible to chromothripsis, which is a phenomenon characterised by extensively rearranged chromosomes that reassemble from pulverized chromosomes in one cellular event. These processes contribute to genomic instability in cancer cells that survive a genotoxic anti-cancer treatment. This review provides insight into checkpoint adaptation and its connection to micronuclei and possibly chromothripsis. Knowledge about these mechanisms is needed to improve the poor cancer treatment outcomes that result from genomic instability.

  1. 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

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

    DEFF Research Database (Denmark)

    Germann, Susanne M; Schramke, Vera; Pedersen, Rune Troelsgaard

    2014-01-01

    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......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...

  3. Granulomatosis with polyangiitis (Wegener's granulomatosis) causing atlantoaxial instability: a case report.

    Science.gov (United States)

    Mohapatra, Anand; Khan, Taleef; Diaz, Jason; Brasington, Richard; Zebala, Lukas P

    2016-10-01

    No previous cases of atlantoaxial instability due to granulomatosis with polyangiitis have been reported. The aim of this study was to report a case of granulomatosis with polyangiitis causing atlantoaxial instability. This is a case report. A 45-year-old woman participated in this study. The patient's pain and atlantoaxial instability were resolved. A 45-year-old Caucasian woman with a large ulcerative lesion in her oropharynx initially presented with chronic sinusitis, pharyngitis, and severe odynophagia. Years after her original symptoms began, she developed neck pain radiating into her upper trapezial region and shoulders. Atlantoaxial fusion was performed on the patient, resolving her neck, upper trapezial, and shoulder pain. She was diagnosed with granulomatosis with polyangiitis (formerly Wegener's granulomatosis) and treated with cyclophosphamide. Granulomatosis with polyangiitis should be part of the working differential diagnosis for non-traumatic cervical spine injury. The atlantoaxial instability can be managed with stabilization, and the disease process itself can be treated with cyclophosphamide. Copyright © 2016 Elsevier Inc. All rights reserved.

  4. UV-C–Irradiated Arabidopsis and Tobacco Emit Volatiles That Trigger Genomic Instability in Neighboring Plants[W

    Science.gov (United States)

    Yao, Youli; Danna, Cristian H.; Zemp, Franz J.; Titov, Viktor; Ciftci, Ozan Nazim; Przybylski, Roman; Ausubel, Frederick M.; Kovalchuk, Igor

    2011-01-01

    We have previously shown that local exposure of plants to stress results in a systemic increase in genome instability. Here, we show that UV-C–irradiated plants produce a volatile signal that triggers an increase in genome instability in neighboring nonirradiated Arabidopsis thaliana plants. This volatile signal is interspecific, as UV-C–irradiated Arabidopsis plants transmit genome destabilization to naive tobacco (Nicotiana tabacum) plants and vice versa. We report that plants exposed to the volatile hormones methyl salicylate (MeSA) or methyl jasmonate (MeJA) exhibit a similar level of genome destabilization as UV-C–irradiated plants. We also found that irradiated Arabidopsis plants produce MeSA and MeJA. The analysis of mutants impaired in the synthesis and/or response to salicylic acid (SA) and/or jasmonic acid showed that at least one other volatile compound besides MeSA and MeJA can communicate interplant genome instability. The NONEXPRESSOR OF PATHOGENESIS-RELATED GENES1 (npr1) mutant, defective in SA signaling, is impaired in both the production and the perception of the volatile signals, demonstrating a key role for NPR1 as a central regulator of genome stability. Finally, various forms of stress resulting in the formation of necrotic lesions also generate a volatile signal that leads to genomic instability. PMID:22028460

  5. 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.

  6. CMTX1 patients' cells present genomic instability corrected by CamKII inhibitors.

    Science.gov (United States)

    Mones, Saleh; Gess, Burkhardt; Bordignon, Benoit; Altié, Alexandre; Young, Peter; Bihel, Frederic; Fraterno, Marc; Peiretti, Franck; Fontes, Michel; Saleh, Mones; Burkhardt, Gess; Benoit, Bordignon; Alexandre, Altié; Peter, Young; Frederic, Bihel; Marc, Fraterno; Franck, Peiretti; Michel, Fontes

    2015-05-07

    We previously described that fibroblasts from animal models of CMTX1 present genomic instability and poor connexon activity. In vivo, these transgenic mice present motor deficits. This phenotype could be significantly reverted by treatment with (CamKII) inhibitors. The objective of this study is to translate our findings to patients. We cultured fibroblasts from skin biopsies of CMTX1 patients and analyzed cells for genomic instabilty, connexon activity, and potential correction by CamKII inhibitors. The phenotypic analysis of these cells confirmed strong similarities between the GJB1 transgenic mouse cell lines and CMTX1 patient fibroblast cell lines. Both present mitotic anomalies, centrosome overduplication, and connexon activity deficit. This phenotype is corrected by CamKII inhibitors. Our data demonstrate that fibroblasts from CMTX1 patients present a phenotype similar to transgenic lines that can be corrected by CamKII inhibitors. This presents a track to develop therapeutic strategies for CMTX1 treatment.

  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. 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

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

    Energy Technology Data Exchange (ETDEWEB)

    Gorman, Sheeona; Tosetto, Miriam [Centre for Colorectal Disease, St. Vincent' s University Hospital, Elm Park, Dublin 4 (Ireland); Lyng, Fiona; Howe, Orla [Radiation and Environmental Science Centre, Dublin Institute of Technology and St. Luke' s Hospital, Dublin (Ireland); Sheahan, Kieran; O' Donoghue, Diarmuid; Hyland, John; Mulcahy, Hugh [Centre for Colorectal Disease, St. Vincent' s University Hospital, Elm Park, Dublin 4 (Ireland); O' Sullivan, Jacintha, E-mail: jacintha.osullivan@ucd.ie [Centre for Colorectal Disease, St. Vincent' s University Hospital, Elm Park, Dublin 4 (Ireland)

    2009-10-02

    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 2 Gy, 5 Gy, 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 (0 Gy) at 24 h. There was no significant difference between 2 Gy and 5 Gy treatments, or between effects elicited by tumor versus matched normal tissue. Bystander cells exposed to media from 2 Gy 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

  10. 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

  11. Separase phosphosite mutation leads to genome instability and primordial germ cell depletion during oogenesis.

    Directory of Open Access Journals (Sweden)

    Juan Xu

    Full Text Available To ensure equal chromosome segregation and the stability of the genome during cell division, Separase is strictly regulated primarily by Securin binding and inhibitory phosphorylation. By generating a mouse model that contained a mutation to the inhibitory phosphosite of Separase, we demonstrated that mice of both sexes are infertile. We showed that Separase deregulation leads to chromosome mis-segregation, genome instability, and eventually apoptosis of primordial germ cells (PGCs during embryonic oogenesis. Although the PGCs of mutant male mice were completely depleted, a population of PGCs from mutant females survived Separase deregulation. The surviving PGCs completed oogenesis but produced deficient initial follicles. These results indicate a sexual dimorphism effect on PGCs from Separase deregulation, which may be correlated with a gender-specific discrepancy of Securin. Our results reveal that Separase phospho-regulation is critical for genome stability in oogenesis. Furthermore, we provided the first evidence of a pre-zygotic mitotic chromosome segregation error resulting from Separase deregulation, whose sex-specific differences may be a reason for the sexual dimorphism of aneuploidy in gametogenesis.

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

    Science.gov (United States)

    Chen, Edwin; Ahn, Jong Sook; Sykes, David B; Breyfogle, Lawrence J; Godfrey, Anna L; Nangalia, Jyoti; Ko, Amy; DeAngelo, Daniel J; Green, Anthony R; Mullally, Ann

    2015-12-22

    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. Copyright © 2015 The Authors. Published by Elsevier Inc. All rights reserved.

  14. The contribution of co-transcriptional RNA:DNA hybrid structures to DNA damage and genome instability.

    Science.gov (United States)

    Hamperl, Stephan; Cimprich, Karlene A

    2014-07-01

    Accurate DNA replication and DNA repair are crucial for the maintenance of genome stability, and it is generally accepted that failure of these processes is a major source of DNA damage in cells. Intriguingly, recent evidence suggests that DNA damage is more likely to occur at genomic loci with high transcriptional activity. Furthermore, loss of certain RNA processing factors in eukaryotic cells is associated with increased formation of co-transcriptional RNA:DNA hybrid structures known as R-loops, resulting in double-strand breaks (DSBs) and DNA damage. However, the molecular mechanisms by which R-loop structures ultimately lead to DNA breaks and genome instability is not well understood. In this review, we summarize the current knowledge about the formation, recognition and processing of RNA:DNA hybrids, and discuss possible mechanisms by which these structures contribute to DNA damage and genome instability in the cell. Copyright © 2014 Elsevier B.V. All rights reserved.

  15. 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.

  16. Lateral-Torsional Buckling Instability Caused by Individuals Walking on Wood Composite I-Joists

    Science.gov (United States)

    Villasenor Aguilar, Jose Maria

    Recent research has shown that a significant number of the falls from elevation occur when laborers are working on unfinished structures. Workers walking on wood I-joists on roofs and floors are prone to fall hazards. Wood I-joists have been replacing dimension lumber for many floor systems and a substantial number of roof systems in light-frame construction. Wood I-joists are designed to resist axial stresses on the flanges and shear stresses on the web while minimizing material used. However, wood I-joists have poor resistance to applied lateral and torsional loads and are susceptible to lateral-torsional buckling instability. Workers walking on unbraced or partially braced wood I-joists can induce axial and lateral forces as well as twist. Experimental testing demonstrated that workers cause lateral-torsional buckling instability in wood I-joists. However, no research was found related to the lateral-torsional buckling instability induced by individuals walking on the wood I-joists. Furthermore, no research was found considering the effects of the supported end conditions and partial bracing in the lateral-torsional buckling instability of wood I-joists. The goal of this research was to derive mathematical models to predict the dynamic lateral-torsional buckling instability of wood composite I-joists loaded by individuals walking considering different supported end conditions and bracing system configurations. The dynamic lateral-torsional buckling instability was analyzed by linearly combining the static lateral-torsional buckling instability with the lateral bending motion of the wood Ijoists. Mathematical models were derived to calculate the static critical loads for the simply supported end condition and four wood I-joist hanger supported end conditions. Additionally, mathematical models were derived to calculate the dynamic maximum lateral displacements and positions of the individual walking on the wood Ijoists for the same five different supported end

  17. Chronic inflammation-associated genomic instability paves the way for human esophageal carcinogenesis

    Science.gov (United States)

    Tian, Dongping; Lei, Zhijin; Chen, Donglin; Xu, Zexin; Su, Min

    2016-01-01

    Chronic inflammation is associated with increased risk of cancer development, whereas the link between chronic inflammation and esophageal carcinogenesis is still obscure heretofore. This study aimed to investigate the relationship between chronic inflammation and DNA damage, as well as the possible role of DNA damage in esophageal carcinogenic process. Endoscopic esophageal biopsies from 109 individuals from Chaoshan littoral, a high-risk region for esophageal squamous cell carcinoma (ESCC), were examined to evaluate the association between chronic inflammation and histological severity, while additional 204 esophageal non-tumor samples from patients with ESCC were collected. Immunohistochemistry was performed to detect the oxidative DNA damage and DNA double-strand breaks (DSBs). Significantly positive correlation was observed between degree of chronic inflammation and esophageal precursor lesions (rs = 0.37, P inflammation (rs = 0.21, P inflammation degree (P inflammation-associated genomic instability with esophageal carcinogenesis and suggest possibilities for early detection and intervention of esophageal carcinogenesis. PMID:27028857

  18. 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.

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

    Science.gov (United States)

    Terasawa, Masahiro; Shinohara, Akira; Shinohara, Miki

    2014-12-01

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

  20. Mutational signatures reveal the role of RAD52 in p53-independent p21-driven genomic instability

    DEFF Research Database (Denmark)

    Galanos, Panagiotis; Pappas, George; Polyzos, Alexander

    2018-01-01

    BACKGROUND: Genomic instability promotes evolution and heterogeneity of tumors. Unraveling its mechanistic basis is essential for the design of appropriate therapeutic strategies. In a previous study, we reported an unexpected oncogenic property of p21WAF1/Cip1, showing that its chronic expressio...

  1. 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.

  2. 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.

  3. Extracellular signaling through the microenvironment: a hypothesis relating carcinogenesis, bystander effects, and genomic instability

    Science.gov (United States)

    Barcellos-Hoff, M. H.; Brooks, A. L.; Chatterjee, A. (Principal Investigator)

    2001-01-01

    Cell growth, differentiation and death are directed in large part by extracellular signaling through the interactions of cells with other cells and with the extracellular matrix; these interactions are in turn modulated by cytokines and growth factors, i.e. the microenvironment. Here we discuss the idea that extracellular signaling integrates multicellular damage responses that are important deterrents to the development of cancer through mechanisms that eliminate abnormal cells and inhibit neoplastic behavior. As an example, we discuss the action of transforming growth factor beta (TGFB1) as an extracellular sensor of damage. We propose that radiation-induced bystander effects and genomic instability are, respectively, positive and negative manifestations of this homeostatic process. Bystander effects exhibited predominantly after a low-dose or a nonhomogeneous radiation exposure are extracellular signaling pathways that modulate cellular repair and death programs. Persistent disruption of extracellular signaling after exposure to relatively high doses of ionizing radiation may lead to the accumulation of aberrant cells that are genomically unstable. Understanding radiation effects in terms of coordinated multicellular responses that affect decisions regarding the fate of a cell may necessitate re-evaluation of radiation dose and risk concepts and provide avenues for intervention.

  4. Decrease in Lymphoid Specific Helicase and 5-hydroxymethylcytosine Is Associated with Metastasis and Genome Instability.

    Science.gov (United States)

    Jia, Jiantao; Shi, Ying; Chen, Ling; Lai, Weiwei; Yan, Bin; Jiang, Yiqun; Xiao, Desheng; Xi, Sichuan; Cao, Ya; Liu, Shuang; Cheng, Yan; Tao, Yongguang

    2017-01-01

    DNA methylation is an important epigenetic modification as a hallmark in cancer. Conversion of 5-methylcytosine (5-mC) to 5-hydroxymethylcytosine (5-hmC) by ten-eleven translocation (TET) family enzymes plays an important biological role in embryonic stem cells, development, aging and disease. Lymphoid specific helicase (LSH), a chromatin remodeling factor, is regarded as a reader of 5-hmC. Recent reports show that the level of 5-hmC is altered in various types of cancers. However, the change in 5-hmC levels in cancer and associated metastasis is not well defined. We report that the level of 5-hmC was decreased in metastatic tissues of nasopharyngeal carcinoma, breast cancer, and colon cancer relative to that in non-metastasis tumor tissues. Furthermore, our data show that TET2, but not TET3, interacted with LSH, whereas LSH increased TET2 expression through silencing miR-26b-5p and miR-29c-5p. Finally, LSH promoted genome stability by silencing satellite expression by affecting 5-hmC levels in pericentromeric satellite repeats, and LSH was resistant to cisplatin-induced DNA damage. Our data indicate that 5-hmC might serve as a metastasis marker for cancer and that the decreased expression of LSH is likely one of the mechanisms of genome instability underlying 5-hmC loss in cancer.

  5. 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.

  6. Buckling Instability Causes Inertial Thrust for Spherical Swimmers at All Scales

    Science.gov (United States)

    Djellouli, Adel; Marmottant, Philippe; Djeridi, Henda; Quilliet, Catherine; Coupier, Gwennou

    2017-12-01

    Microswimmers, and among them aspirant microrobots, generally have to cope with flows where viscous forces are dominant, characterized by a low Reynolds number (Re). This implies constraints on the possible sequences of body motion, which have to be nonreciprocal. Furthermore, the presence of a strong drag limits the range of resulting velocities. Here, we propose a swimming mechanism which uses the buckling instability triggered by pressure waves to propel a spherical, hollow shell. With a macroscopic experimental model, we show that a net displacement is produced at all Re regimes. An optimal displacement caused by nontrivial history effects is reached at intermediate Re. We show that, due to the fast activation induced by the instability, this regime is reachable by microscopic shells. The rapid dynamics would also allow high-frequency excitation with standard traveling ultrasonic waves. Scale considerations predict a swimming velocity of order 1 cm /s for a remote-controlled microrobot, a suitable value for biological applications such as drug delivery.

  7. Wake-field and fast head-tail instability caused by an electron cloud

    CERN Document Server

    Ohmi, K; Zimmermann, Frank

    2002-01-01

    In positron and proton storage rings, electrons produced by photoemission, ionization, and secondary emission accumulate in the vacuum chamber during multibunch operation with close spacing. A positron or proton bunch passing through this "electron cloud" experiences a force similar to a short-range wake field. This effective wake field can cause a transverse-mode-coupling instability, if the electron-cloud density exceeds a threshold value. In this report, we compute the electron-cloud induced wake in a region without external magnetic field both analytically and via computer simulation, for parameters representing the low-energy positron ring of KERB and the LHC proton beam in the CERN SPS. We study the linearity and time dependence of the wake function and its variation with the size of the electron cloud. Using a broadband resonator model for the electron-cloud wake field, we then evaluate theoretical expressions for the transverse-mode-coupling instability based on the linearized Vlasov equation, and for...

  8. Passive compensation of the misalignment instability caused by air convection in thin-disk lasers.

    Science.gov (United States)

    Dietrich, Tom; Piehler, Stefan; Röcker, Christoph; Rumpel, Martin; Abdou Ahmed, Marwan; Graf, Thomas

    2017-09-01

    Wavefront distortions caused by the convection of heated ambient air in front of the laser crystal induce severe pump-power-dependent misalignment in thin-disk laser (TDL) resonators. This effect is particularly pronounced in fundamental mode operation and limits the output power when no realignment of the resonator is possible during operation. In this Letter, we present a new approach to passively compensate for this misalignment instability by exploiting the spectral dispersion of a highly efficient grating-waveguide mirror used as a cavity end-mirror in a Littrow configuration. By this, it was possible to almost triple the output power of a fundamental mode Yb:LuAG TDL pumped at 969 nm.

  9. 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

  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. Comparative Genomics of Escherichia coli Strains Causing Urinary Tract Infections

    DEFF Research Database (Denmark)

    Vejborg, Rebecca Munk; Hancock, Viktoria; Schembri, Mark A.

    2011-01-01

    The virulence determinants of uropathogenic Escherichia coli have been studied extensively over the years, but relatively little is known about what differentiates isolates causing various types of urinary tract infections. In this study, we compared the genomic profiles of 45 strains from a range...... and their disease categories but strong correlation between the genotype and the phylogenetic group association. Also, very few genetic differences may exist between isolates causing symptomatic and asymptomatic infections. Only relatively few genes that could potentially differentiate between the individual...

  12. "Sausage-string" appearance of arteries and arterioles can be caused by an instability of the blood vessel wall

    DEFF Research Database (Denmark)

    Jacobsen, Jens Christian Brings; Beierholm, Ulrik; Mikkelsen, Rene

    2002-01-01

    observed experimentally. Most importantly, it suggests that the "sausaging" phenomenon is neither caused by a mechanical failure of the vessel wall due to a high blood pressure nor is it due to standing pressure waves caused by the beating of the heart. Rather, it is the expression of a general instability...

  13. Topoisomerase I plays a critical role in suppressing genome instability at a highly transcribed G-quadruplex-forming sequence.

    Directory of Open Access Journals (Sweden)

    Puja Yadav

    2014-12-01

    Full Text Available G-quadruplex or G4 DNA is a non-B secondary DNA structure that comprises a stacked array of guanine-quartets. Cellular processes such as transcription and replication can be hindered by unresolved DNA secondary structures potentially endangering genome maintenance. As G4-forming sequences are highly frequent throughout eukaryotic genomes, it is important to define what factors contribute to a G4 motif becoming a hotspot of genome instability. Using a genetic assay in Saccharomyces cerevisiae, we previously demonstrated that a potential G4-forming sequence derived from a guanine-run containing immunoglobulin switch Mu (Sμ region becomes highly unstable when actively transcribed. Here we describe assays designed to survey spontaneous genome rearrangements initiated at the Sμ sequence in the context of large genomic areas. We demonstrate that, in the absence of Top1, a G4 DNA-forming sequence becomes a strong hotspot of gross chromosomal rearrangements and loss of heterozygosity associated with mitotic recombination within the ∼ 20 kb or ∼ 100 kb regions of yeast chromosome V or III, respectively. Transcription confers a critical strand bias since genome rearrangements at the G4-forming Sμ are elevated only when the guanine-runs are located on the non-transcribed strand. The direction of replication and transcription, when in a head-on orientation, further contribute to the elevated genome instability at a potential G4 DNA-forming sequence. The implications of our identification of Top1 as a critical factor in suppression of instability associated with potential G4 DNA-forming sequences are discussed.

  14. Weak oceanic heat transport as a cause of the instability of glacial climates

    Energy Technology Data Exchange (ETDEWEB)

    Colin de Verdiere, Alain [Universite de Bretagne Occidentale, Laboratoire de Physique des Oceans, Alain Colin de Verdiere, Brest 3 (France); Te Raa, L. [Utrecht University, Institute for Marine and Atmospheric Research Utrecht, Utrecht (Netherlands); Netherlands Organisation for Applied Scientific Research TNO, The Hague (Netherlands)

    2010-12-15

    The stability of the thermohaline circulation of modern and glacial climates is compared with the help of a two dimensional ocean - atmosphere - sea ice coupled model. It turns out to be more unstable as less freshwater forcing is required to induce a polar halocline catastrophy in glacial climates. The large insulation of the ocean by the extensive sea ice cover changes the temperature boundary condition and the deepwater formation regions moves much further South. The nature of the instability is of oceanic origin, identical to that found in ocean models under mixed boundary conditions. With similar strengths of the oceanic circulation and rates of deep water formation for warm and cold climates, the loss of stability of the cold climate is due to the weak thermal stratification caused by the cooling of surface waters, the deep water temperatures being regulated by the temperature of freezing. Weaker stratification with similar overturning leads to a weakening of the meridional oceanic heat transport which is the major negative feedback stabilizing the oceanic circulation. Within the unstable regime periodic millennial oscillations occur spontaneously. The climate oscillates between a strong convective thermally driven oceanic state and a weak one driven by large salinity gradients. Both states are unstable. The atmosphere of low thermal inertia is carried along by the oceanic overturning while the variation of sea ice is out of phase with the oceanic heat content. During the abrupt warming events that punctuate the course of a millennial oscillation, sea ice variations are shown respectively to damp (amplify) the amplitude of the oceanic (atmospheric) response. This sensitivity of the oceanic circulation to a reduced concentration of greenhouse gases and to freshwater forcing adds support to the hypothesis that the millennial oscillations of the last glacial period, the so called Dansgaard - Oeschger events, may be internal instabilities of the climate system

  15. Human-specific HERV-K insertion causes genomic variations in the human genome.

    Directory of Open Access Journals (Sweden)

    Wonseok Shin

    Full Text Available Human endogenous retroviruses (HERV sequences account for about 8% of the human genome. Through comparative genomics and literature mining, we identified a total of 29 human-specific HERV-K insertions. We characterized them focusing on their structure and flanking sequence. The results showed that four of the human-specific HERV-K insertions deleted human genomic sequences via non-classical insertion mechanisms. Interestingly, two of the human-specific HERV-K insertion loci contained two HERV-K internals and three LTR elements, a pattern which could be explained by LTR-LTR ectopic recombination or template switching. In addition, we conducted a polymorphic test and observed that twelve out of the 29 elements are polymorphic in the human population. In conclusion, human-specific HERV-K elements have inserted into human genome since the divergence of human and chimpanzee, causing human genomic changes. Thus, we believe that human-specific HERV-K activity has contributed to the genomic divergence between humans and chimpanzees, as well as within the human population.

  16. Genomic instability and bystander effects induced by high-LET radiation.

    Science.gov (United States)

    Hall, Eric J; Hei, Tom K

    2003-10-13

    An understanding of the radiobiological effects of high-linear energy transfer (LET) radiation is essential for radiation protection and human risk assessment. Ever since the discovery of X-rays was made by Röntgen more than a century ago, it has always been accepted that the deleterious effects of ionizing radiation, such as mutation and carcinogenesis, are due mainly to direct damage to DNA. With the availability of a precision single-particle microbeam, it is possible to demonstrate, unequivocally, the presence of a bystander effect with many biological end points. These studies provide clear evidence that irradiated cells can induce a bystander mutagenic response in neighboring cells not directly traversed by alpha-particles, and that cell-cell communication processes play a critical role in mediating the bystander phenomenon. Following exposure to high-LET radiation, immortalized human bronchial (BEP2D) and breast (MCF-10F) cells have been shown to undergo malignant transformation through a series of successive steps, before becoming tumorigenic in nude mice. There is a progressive increase in genomic instability, determined either by gene amplification or allelic imbalance, with the highest incidence observed among established tumor cell lines, relative to transformed, nontumorigenic and control cell lines.

  17. 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.

  18. 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.

  19. Population genomics and the causes of local differentiation.

    Science.gov (United States)

    Tonsor, Stephen J

    2012-11-01

    Exactly 50 years ago, a revolution in empirical population genetics began with the introduction of methods for detecting allelic variation using protein electrophoresis (Throckmorton 1962; Hubby 1963; Lewontin & Hubby 1966). These pioneering scientists showed that populations are chock-full of genetic variation. This variation was a surprise that required a re-thinking of evolutionary genetic heuristics. Understanding the causes for the maintenance of this variation became and remains a major area of research. In the process of addressing the causes, this same group of scientists documented geographical genetic structure (Prakash et al. 1969), spawning the continued accumulation of what is now a huge case study catalogue of geographical differentiation (e.g. Loveless & Hamrick 1984; Linhart & Grant 1996). Geographical differentiation is clearly quite common. Yet, a truly general understanding of the patterns in and causes of spatial genetic structure across the genome remains elusive. To what extent is spatial structure driven by drift and phylogeography vs. geographical differences in environmental sources of selection? What proportion of the genome participates? A general understanding requires range-wide data on spatial patterning of variation across the entire genome. In this issue of Molecular Ecology, Lasky et al. (2012) make important strides towards addressing these issues, taking advantage of three contemporary revolutions in evolutionary biology. Two are technological: high-throughput sequencing and burgeoning computational power. One is cultural: open access to data from the community of scientists and especially data sets that result from large collaborative efforts. Together, these developments may at last put answers within reach.

  20. Genomic instability in normal human fibroblasts for chronically low-dose radiation in heavy-ion radiation field

    International Nuclear Information System (INIS)

    Suzuki, Masao; Tsuruoka, Chizuru; Uchihori, Yukio; Ishizaki, Kanji; Hayashi, Hiroko; Yamane, Yoshihiro; Nakamura, Hideaki

    2004-01-01

    We have been studying genomic instability of biological effects in normal human fibroblasts exposed to chronic low-dose radiation in heavy-ion radiation field. This year we try to irradiate cells with low-density carbon ions using faint beams. Genomic instability in cellular responses was examined to measure either cell killing or mutation induction in low-dose accumulated cell populations after exposing to X-ray challenging doses. The results showed that there was no enhanced effect on cell killing between the low-dose pretreated and unirradiated cell populations with carbon-ion faint beams after exposing to defined challenging doses of 200 kV X rays. On the other hand, the frequency of mutation induction, which was measured as the induction of a 6-thioguanine resistant clone focused on hprt locus, of the low-dose pretreated cell population was much higher than that of unirradiated cell population. The results suggested that genomic instability was induced in mutagenesis by the pretreatment of low-density carbon ions. (author)

  1. Genomic instability in normal human fibroblasts for chronically low-dose radiation in heavy-ion radiation field

    International Nuclear Information System (INIS)

    Suzuki, Masao; Tsuruoka, Chizuru; Fujitaka, Kazunobu; Ishizaki, Kanji; Hayashi, Hiroko; Yamane, Y.; Nakamura, H.

    2003-01-01

    We have been studying genomic instability of biological effects in normal human fibroblasts exposed to chronically low-dose radiation in heavy-ion radiation field. Cells were cultured in a CO 2 incubator, which was placed in the irradiation room for biological study of heavy ions in the Heavy Ion Medical Accelerator in Chiba (HIMAC) and irradiated with scattered radiations produced with heavy-ion beams throughout the life span of the cell population. Genomic instability in cellular responses was examined to measure either cell killing or mutation induction in low-dose accumulated cell populations after exposing to X-ray challenging doses. The results showed that there was no enhanced effect on cell killing between the low-dose accumulated and non-irradiated cell populations after exposing to defined challenging doses of 200 kV X rays. On the contrary, the mutation frequency, which 2 was measured as the induction of a 6-thioguanine resistant clone focused on hprt locus, of the low-dose accumulated cell population was much higher than that of non-irradiated cell population. The results suggested that genomic instability was induced in mutagenesis by the chronic low-dose irradiations in heavy-ion radiation field. (author)

  2. Long-term persistence of X-ray-induced genomic instability in quiescent normal human diploid cells

    International Nuclear Information System (INIS)

    Suzuki, Keiji; Kashino, Genro; Kodama, Seiji; Watanabe, Masami

    2009-01-01

    Ionizing radiation can induce genomic instability in the progeny of irradiated cells, as was demonstrated in various experimental systems. Most in vitro studies have utilized replicating cells, but it is not clear whether radiation-induced genomic instability persists in quiescent cells. Here we show the induction of X-ray-induced genomic instability in normal human diploid cells irradiated and maintained in a quiescent state for up to 24 months while cells were subcultured approximately once every 2-3 months. Every 12 months, a fraction of the irradiated cell population was stimulated to divide by culturing at a low density, and we found that these cells showed increased frequencies of phosphorylated ATM foci, decreased colony-forming ability, and increased frequency of chromosomal aberrations. No significant increases in ROS levels were detected in long-term cultured cells. These results suggest that there are ROS-independent mechanism(s) induced by radiation, which can generate persistent delayed effects in quiescent cells, and could ultimately contribute to carcinogenesis.

  3. Secondary knee instability caused by fracture of the stabilizing insert in a dual-articular total knee

    DEFF Research Database (Denmark)

    Boesen, Morten P; Jensen, Tim Toftgaard; Husted, Henrik

    2004-01-01

    A case of a fractured polyethylene stabilizing insert causing secondary knee instability in a Dual-articular total knee arthroplasty (TKA) is presented. A 65-year-old woman who underwent surgery with a Dual-articular TKA 4 years earlier had a well-functioning prosthesis until a fall, after which......-articular knee....

  4. QUASI-BIENNIAL OSCILLATIONS IN THE SOLAR TACHOCLINE CAUSED BY MAGNETIC ROSSBY WAVE INSTABILITIES

    International Nuclear Information System (INIS)

    Zaqarashvili, Teimuraz V.; Carbonell, Marc; Oliver, Ramon; Ballester, Jose Luis

    2010-01-01

    Quasi-biennial oscillations (QBOs) are frequently observed in solar activity indices. However, no clear physical mechanism for the observed variations has been suggested so far. Here, we study the stability of magnetic Rossby waves in the solar tachocline using the shallow water magnetohydrodynamic approximation. Our analysis shows that the combination of typical differential rotation and a toroidal magnetic field with a strength of ≥10 5 G triggers the instability of the m = 1 magnetic Rossby wave harmonic with a period of ∼2 years. This harmonic is antisymmetric with respect to the equator and its period (and growth rate) depends on the differential rotation parameters and magnetic field strength. The oscillations may cause a periodic magnetic flux emergence at the solar surface and consequently may lead to the observed QBO in solar activity features. The period of QBOs may change throughout a cycle, and from cycle to cycle, due to variations of the mean magnetic field and differential rotation in the tachocline.

  5. Secondary knee instability caused by fracture of the stabilizing insert in a dual-articular total knee

    DEFF Research Database (Denmark)

    Boesen, Morten P; Jensen, Tim Toftgaard; Husted, Henrik

    2004-01-01

    A case of a fractured polyethylene stabilizing insert causing secondary knee instability in a Dual-articular total knee arthroplasty (TKA) is presented. A 65-year-old woman who underwent surgery with a Dual-articular TKA 4 years earlier had a well-functioning prosthesis until a fall, after which...... she began complaining of an intermittent, audible clicking; pain; and instability. At surgery, a fractured polyethylene peg was discovered, and the tibial insert was replaced. At follow-up, she remains asymptomatic. This is the first description of a fractured stabilizing insert in a Dual......-articular knee....

  6. Genomic instability, bystander effect, cytoplasmic irradiation and other phenomena that may achieve fame without fortune

    Science.gov (United States)

    Hall, E. J.

    2001-01-01

    The possible risk of induced malignancies in astronauts, as a consequence of the radiation environment in space, is a factor of concern for long term missions. Cancer risk estimates for high doses of low LET radiation are available from the epidemiological studies of the A-bomb survivors. Cancer risks at lower doses cannot be detected in epidemiological studies and must be inferred by extrapolation from the high dose risks. The standard setting bodies, such as the ICRP recommend a linear, no-threshold extrapolation of risks from high to low doses, but this is controversial. A study of mechanisms of carcinogenesis may shed some light on the validity of a linear extrapolation. The multi-step nature of carcinogenesis suggests that the role of radiation may be to induce a mutation leading to a mutator phenotype. High energy Fe ions, such as those encountered in space are highly effective in inducing genomic instability. Experiments involving the single particle microbeam have demonstrated a "bystander effect", ie a biological effect in cells not themselves hit, but in close proximity to those that are, as well as the induction of mutations in cells where only the cytoplasm, and not the nucleus, have been traversed by a charged particle. These recent experiments cast doubt on the validity of a simple linear extrapolation, but the data are so far fragmentary and conflicting. More studies are necessary. While mechanistic studies cannot replace epidemiology as a source of quantitative risk estimates, they may shed some light on the shape of the dose response relationship and therefore on the limitations of a linear extrapolation to low doses.

  7. Accumulation of abasic sites induces genomic instability in normal human gastric epithelial cells during Helicobacter pylori infection.

    Science.gov (United States)

    Kidane, D; Murphy, D L; Sweasy, J B

    2014-11-24

    Helicobacter pylori infection of the human stomach is associated with inflammation that leads to the release of reactive oxygen and nitrogen species (RONs), eliciting DNA damage in host cells. Unrepaired DNA damage leads to genomic instability that is associated with cancer. Base excision repair (BER) is critical to maintain genomic stability during RONs-induced DNA damage, but little is known about its role in processing DNA damage associated with H. pylori infection of normal gastric epithelial cells. Here, we show that upon H. pylori infection, abasic (AP) sites accumulate and lead to increased levels of double-stranded DNA breaks (DSBs). In contrast, downregulation of the OGG1 DNA glycosylase decreases the levels of both AP sites and DSBs during H. pylori infection. Processing of AP sites during different phases of the cell cycle leads to an elevation in the levels of DSBs. Therefore, the induction of oxidative DNA damage by H. pylori and subsequent processing by BER in normal gastric epithelial cells has the potential to lead to genomic instability that may have a role in the development of gastric cancer. Our results are consistent with the interpretation that precise coordination of BER processing of DNA damage is critical for the maintenance of genomic stability.

  8. Can Kelvin-Helmholtz Instabilities of Jet-Like Structures and Plumes Cause Solar Wind Fluctuations at 1AU

    Science.gov (United States)

    Parhi, Shyamsundar; Suess, Steven T.; Sulkanen, Martin E.

    1998-01-01

    During its south polar passage in 1994, Ulysses sampled the solar wind emerging from the south polar coronal hole. In analysing these data two types of density fluctuations lasting a few hours have been reported, one characterized by fluctuations in velocity gradients ("microstreams") and the other by magnetic plus thermal-pressure balance structures ("PBS"). Microstreams were both temporal and spatial in nature. At higher frequencies, MHD turbulence was observed and found to be less evolved than in the ecliptic, but essentially independent of heliographic latitude. It is argued here that microstreams, PBS, and MHD turbulence could all be the remnant of shears associated with plumes and other filamentary structures ("jets") which have been reported to exist in coronal holes. The shear between a jet and its ambient can become unstable to the MHD Kelvin-Helmholtz ("KH') instability at 5-10 solar radius and the propagating instability can cause fluctuations like those seen by Ulysses. This motivates us to simulate coronal jets using a 3D MHD ZEUS code. The first 2D results have just started to come and are promising. To study the KH instability the jet is perturbed at the boundary with a linear amplitude and fixed frequency. The jet seems to pass through various distinct phases, one of which Is apparently dominated by KH instabilities. These instabilities drive oblique shocks into the jet as the turbulent eddies contact the jet surface. It is known that KH instabilities and internal shock waves are partially suppressed by magnetic field tension. Hence, in simulating far along the jet the Instability is expected to produce Alfvenic fluctuations like those seen near 1 AU.

  9. Head-tail instability caused by electron cloud in positron storage rings

    CERN Document Server

    Ohmi, K

    2000-01-01

    In positron or proton storage rings with many closely spaced bunches, a large number of electrons can be generated in the vacuum chamber due to photoemission or secondary emission. The density of this `electron cloud' increases along a bunch train, until the growth saturates under the influence of its own space charge field. In this report, we discuss the possibility of a single-bunch two-stream instability driven by the electron cloud, where any initial head-tail perturbation of the bunch is amplified by the coherent motion of cloud electrons near the beam. Depending on the strength of the beam-electron interaction, the chromaticity and the synchrotron oscillation frequency, this instability either resembles a linac beam break up, or a head-tail instability. We present computer simulations of beam break up and head-tail instabilities for the Low Energy Ring of the KEK B factory, and compare the simulation results with analytical estimates.

  10. Gravitational Perturbations as a Possible Cause for Instability in the Measurements of Positron Annihilation

    Directory of Open Access Journals (Sweden)

    Vikin B. P.

    2006-04-01

    Full Text Available The annihilation of positrons is measured in a wide range of studies in the field of physical chemistry. One of the problems in these studies is the instability of the results of measurements. As shown in our research, instability may result from the change of nonregistering gravitational effects related to alteration of the tidal forces upon the change of moon phases and the seasonal changes of the distance between the Earth and the Sun.

  11. Gravitational Perturbations as a Possible Cause for Instability in the Measurements of Positron Annihilation

    Directory of Open Access Journals (Sweden)

    Vikin B. P.

    2006-04-01

    Full Text Available The annihilation of positrons is measured in a wide range of studies in the field of physical chemistry [1, 2]. One of the problems in these studies is the instability of the results of measurements [3–5]. As shown in our research, instability may result from the change of nonregistering gravitational effects related to alteration of the tidal forces upon the change of moon phases and the seasonal changes of the distance between the Earth and the Sun.

  12. 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)

  13. 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.

  14. 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.

  15. Comparative Genomic Analysis of Meningitis- and Bacteremia-Causing Pneumococci Identifies a Common Core Genome.

    Science.gov (United States)

    Kulohoma, Benard W; Cornick, Jennifer E; Chaguza, Chrispin; Yalcin, Feyruz; Harris, Simon R; Gray, Katherine J; Kiran, Anmol M; Molyneux, Elizabeth; French, Neil; Parkhill, Julian; Faragher, Brian E; Everett, Dean B; Bentley, Stephen D; Heyderman, Robert S

    2015-10-01

    Streptococcus pneumoniae is a nasopharyngeal commensal that occasionally invades normally sterile sites to cause bloodstream infection and meningitis. Although the pneumococcal population structure and evolutionary genetics are well defined, it is not clear whether pneumococci that cause meningitis are genetically distinct from those that do not. Here, we used whole-genome sequencing of 140 isolates of S. pneumoniae recovered from bloodstream infection (n = 70) and meningitis (n = 70) to compare their genetic contents. By fitting a double-exponential decaying-function model, we show that these isolates share a core of 1,427 genes (95% confidence interval [CI], 1,425 to 1,435 genes) and that there is no difference in the core genome or accessory gene content from these disease manifestations. Gene presence/absence alone therefore does not explain the virulence behavior of pneumococci that reach the meninges. Our analysis, however, supports the requirement of a range of previously described virulence factors and vaccine candidates for both meningitis- and bacteremia-causing pneumococci. This high-resolution view suggests that, despite considerable competency for genetic exchange, all pneumococci are under considerable pressure to retain key components advantageous for colonization and transmission and that these components are essential for access to and survival in sterile sites. Copyright © 2015 Kulohoma et al.

  16. Comparative Genomic Analysis of Meningitis- and Bacteremia-Causing Pneumococci Identifies a Common Core Genome

    Science.gov (United States)

    Cornick, Jennifer E.; Chaguza, Chrispin; Yalcin, Feyruz; Harris, Simon R.; Gray, Katherine J.; Kiran, Anmol M.; Molyneux, Elizabeth; French, Neil; Faragher, Brian E.; Everett, Dean B.; Bentley, Stephen D.

    2015-01-01

    Streptococcus pneumoniae is a nasopharyngeal commensal that occasionally invades normally sterile sites to cause bloodstream infection and meningitis. Although the pneumococcal population structure and evolutionary genetics are well defined, it is not clear whether pneumococci that cause meningitis are genetically distinct from those that do not. Here, we used whole-genome sequencing of 140 isolates of S. pneumoniae recovered from bloodstream infection (n = 70) and meningitis (n = 70) to compare their genetic contents. By fitting a double-exponential decaying-function model, we show that these isolates share a core of 1,427 genes (95% confidence interval [CI], 1,425 to 1,435 genes) and that there is no difference in the core genome or accessory gene content from these disease manifestations. Gene presence/absence alone therefore does not explain the virulence behavior of pneumococci that reach the meninges. Our analysis, however, supports the requirement of a range of previously described virulence factors and vaccine candidates for both meningitis- and bacteremia-causing pneumococci. This high-resolution view suggests that, despite considerable competency for genetic exchange, all pneumococci are under considerable pressure to retain key components advantageous for colonization and transmission and that these components are essential for access to and survival in sterile sites. PMID:26259813

  17. 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

  18. Comparative genomic analysis of human fungal pathogens causing paracoccidioidomycosis.

    Directory of Open Access Journals (Sweden)

    Christopher A Desjardins

    2011-10-01

    Full Text Available Paracoccidioides is a fungal pathogen and the cause of paracoccidioidomycosis, a health-threatening human systemic mycosis endemic to Latin America. Infection by Paracoccidioides, a dimorphic fungus in the order Onygenales, is coupled with a thermally regulated transition from a soil-dwelling filamentous form to a yeast-like pathogenic form. To better understand the genetic basis of growth and pathogenicity in Paracoccidioides, we sequenced the genomes of two strains of Paracoccidioides brasiliensis (Pb03 and Pb18 and one strain of Paracoccidioides lutzii (Pb01. These genomes range in size from 29.1 Mb to 32.9 Mb and encode 7,610 to 8,130 genes. To enable genetic studies, we mapped 94% of the P. brasiliensis Pb18 assembly onto five chromosomes. We characterized gene family content across Onygenales and related fungi, and within Paracoccidioides we found expansions of the fungal-specific kinase family FunK1. Additionally, the Onygenales have lost many genes involved in carbohydrate metabolism and fewer genes involved in protein metabolism, resulting in a higher ratio of proteases to carbohydrate active enzymes in the Onygenales than their relatives. To determine if gene content correlated with growth on different substrates, we screened the non-pathogenic onygenale Uncinocarpus reesii, which has orthologs for 91% of Paracoccidioides metabolic genes, for growth on 190 carbon sources. U. reesii showed growth on a limited range of carbohydrates, primarily basic plant sugars and cell wall components; this suggests that Onygenales, including dimorphic fungi, can degrade cellulosic plant material in the soil. In addition, U. reesii grew on gelatin and a wide range of dipeptides and amino acids, indicating a preference for proteinaceous growth substrates over carbohydrates, which may enable these fungi to also degrade animal biomass. These capabilities for degrading plant and animal substrates suggest a duality in lifestyle that could enable pathogenic

  19. 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.

  20. 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.

  1. Misregulation of Scm3p/HJURP causes chromosome instability in Saccharomyces cerevisiae and human cells.

    Science.gov (United States)

    Mishra, Prashant K; Au, Wei-Chun; Choy, John S; Kuich, P Henning; Baker, Richard E; Foltz, Daniel R; Basrai, Munira A

    2011-09-01

    The kinetochore (centromeric DNA and associated proteins) is a key determinant for high fidelity chromosome transmission. Evolutionarily conserved Scm3p is an essential component of centromeric chromatin and is required for assembly and function of kinetochores in humans, fission yeast, and budding yeast. Overexpression of HJURP, the mammalian homolog of budding yeast Scm3p, has been observed in lung and breast cancers and is associated with poor prognosis; however, the physiological relevance of these observations is not well understood. We overexpressed SCM3 and HJURP in Saccharomyces cerevisiae and HJURP in human cells and defined domains within Scm3p that mediate its chromosome loss phenotype. Our results showed that the overexpression of SCM3 (GALSCM3) or HJURP (GALHJURP) caused chromosome loss in a wild-type yeast strain, and overexpression of HJURP led to mitotic defects in human cells. GALSCM3 resulted in reduced viability in kinetochore mutants, premature separation of sister chromatids, and reduction in Cse4p and histone H4 at centromeres. Overexpression of CSE4 or histone H4 suppressed chromosome loss and restored levels of Cse4p at centromeres in GALSCM3 strains. Using mutant alleles of scm3, we identified a domain in the N-terminus of Scm3p that mediates its interaction with CEN DNA and determined that the chromosome loss phenotype of GALSCM3 is due to centromeric association of Scm3p devoid of Cse4p/H4. Furthermore, we determined that similar to other systems the centromeric association of Scm3p is cell cycle regulated. Our results show that altered stoichiometry of Scm3p/HJURP, Cse4p, and histone H4 lead to defects in chromosome segregation. We conclude that stringent regulation of HJURP and SCM3 expression are critical for genome stability.

  2. Misregulation of Scm3p/HJURP causes chromosome instability in Saccharomyces cerevisiae and human cells.

    Directory of Open Access Journals (Sweden)

    Prashant K Mishra

    2011-09-01

    Full Text Available The kinetochore (centromeric DNA and associated proteins is a key determinant for high fidelity chromosome transmission. Evolutionarily conserved Scm3p is an essential component of centromeric chromatin and is required for assembly and function of kinetochores in humans, fission yeast, and budding yeast. Overexpression of HJURP, the mammalian homolog of budding yeast Scm3p, has been observed in lung and breast cancers and is associated with poor prognosis; however, the physiological relevance of these observations is not well understood. We overexpressed SCM3 and HJURP in Saccharomyces cerevisiae and HJURP in human cells and defined domains within Scm3p that mediate its chromosome loss phenotype. Our results showed that the overexpression of SCM3 (GALSCM3 or HJURP (GALHJURP caused chromosome loss in a wild-type yeast strain, and overexpression of HJURP led to mitotic defects in human cells. GALSCM3 resulted in reduced viability in kinetochore mutants, premature separation of sister chromatids, and reduction in Cse4p and histone H4 at centromeres. Overexpression of CSE4 or histone H4 suppressed chromosome loss and restored levels of Cse4p at centromeres in GALSCM3 strains. Using mutant alleles of scm3, we identified a domain in the N-terminus of Scm3p that mediates its interaction with CEN DNA and determined that the chromosome loss phenotype of GALSCM3 is due to centromeric association of Scm3p devoid of Cse4p/H4. Furthermore, we determined that similar to other systems the centromeric association of Scm3p is cell cycle regulated. Our results show that altered stoichiometry of Scm3p/HJURP, Cse4p, and histone H4 lead to defects in chromosome segregation. We conclude that stringent regulation of HJURP and SCM3 expression are critical for genome stability.

  3. 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.

  4. 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.

  5. 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

  6. Macroparticle model for longitudinal emittance growth caused by negative mass instability in a proton synchrotron

    CERN Document Server

    MacLachlan, J A

    2004-01-01

    Both theoretical models and beam observations of negative mass instability fall short of a full description of the dynamics and the dynamical effects. Clarification by numerical modeling is now practicable because of the recent proliferation of so-called computing farms. The results of modeling reported in this paper disagree with some predictions based on a long-standing linear perturbation calculation. Validity checks on the macroparticle model are described.

  7. Outbreeding causes developmental instability in Drosophila subobscura

    DEFF Research Database (Denmark)

    Kurbalija, Zorana; Stamenkovic-Radak, Marina; Pertoldi, C.

    2010-01-01

    A possible effect of interpopulation hybridization is either outbreeding depression, as a consequence of breakdown of coadapted gene complexes which can increase developmental instability (DI) of the traits, or increased heterozygosity, which can reduce DI. One of the principal methods commonly u......, compared to intrapopulation hybrids in same generations. These results suggest that the association between coadaptive genes with the same evolutionary history are the most probable mechanism that maintains the developmental homeostasis in Drosophila subobscura populations....

  8. Sausage mode instability of thin current sheets as a cause of magnetospheric substorms

    Directory of Open Access Journals (Sweden)

    J. Büchner

    Full Text Available Observations have shown that, prior to substorm explosions, thin current sheets are formed in the plasma sheet of the Earth's magnetotail. This provokes the question, to what extent current-sheet thinning and substorm onsets are physically, maybe even causally, related. To answer this question, one has to understand the plasma stability of thin current sheets. Kinetic effects must be taken into account since particle scales are reached in the course of tail current-sheet thinning. We present the results of theoretical investigations of the stability of thin current sheets and about the most unstable mode of their decay. Our conclusions are based upon a non-local linear dispersion analysis of a cross-magnetic field instability of Harris-type current sheets. We found that a sausage-mode bulk current instability starts after a sheet has thinned down to the ion inertial length. We also present the results of three-dimensional electromagnetic PIC-code simulations carried out for mass ratios up to Mi / me=64. They verify the linearly predicted properties of the sausage mode decay of thin current sheets in the parameter range of interest.

    Key words. Magnetospheric physics (plasma waves and instabilities; storms and substorms · Space plasma physics (magnetic reconnection

  9. 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.

  10. Detection of evaluation bias caused by genomic preselection.

    Science.gov (United States)

    Tyrisevä, A-M; Mäntysaari, E A; Jakobsen, J; Aamand, G P; Dürr, J; Fikse, W F; Lidauer, M H

    2018-04-01

    The aim of this simulation study was to investigate whether it is possible to detect the effect of genomic preselection on Mendelian sampling (MS) means or variances obtained by the MS validation test. Genomic preselection of bull calves is 1 additional potential source of bias in international evaluations unless adequately accounted for in national evaluations. Selection creates no bias in traditional breeding value evaluation if the data of all animals are included. However, this is not the case with genomic preselection, as it excludes culled bulls. Genomic breeding values become biased if calculated using a multistep procedure instead of, for example, a single-step method. Currently, about 60% of the countries participating in international bull evaluations have already adopted genomic selection in their breeding schemes. The data sent for multiple across-country evaluation can, therefore, be very heterogeneous, and a proper validation method is needed to ensure a fair comparison of the bulls included in international genetic evaluations. To study the effect of genomic preselection, we generated a total of 50 replicates under control and genomic preselection schemes using the structures of the real data and pedigree from a medium-size cow population. A genetic trend of 15% of the genetic standard deviation was created for both schemes. In carrying out the analyses, we used 2 different heritabilities: 0.25 and 0.10. From the start of genomic preselection, all bulls were genomically preselected. Their MS deviations were inflated with a value corresponding to selection of the best 10% of genomically tested bull calves. For cows, the MS deviations were unaltered. The results revealed a clear underestimation of bulls' breeding values (BV) after genomic preselection started, as well as a notable deviation from zero both in true and estimated MS means. The software developed recently for the MS validation test already produces yearly MS means, and they can be used to

  11. 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.

  12. 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

  13. Minor or occult ankle instability as a cause of anterolateral pain after ankle sprain.

    Science.gov (United States)

    Vega, Jordi; Peña, Fernando; Golanó, Pau

    2016-04-01

    The aim of this study was to determine which intra-articular injuries are associated with chronic anterolateral pain and functional instability after an ankle sprain. From 2008 to 2010, records of all patients who underwent ankle joint arthroscopy with anterolateral pain and functional instability after an ankle sprain were reviewed. A systematic arthroscopic examination of the intra-articular structures of the ankle joint was performed. Location and characteristics of the injuries were identified and recorded. A total of 36 ankle arthroscopic procedures were reviewed. A soft-tissue occupying mass over the lateral recess was present in 18 patients (50%). A partial injury of the anterior talofibular ligament (ATFL) was observed in 24 patients (66.6%). Cartilage abrasion due to the distal fascicle of the anteroinferior tibiofibular ligament coming into contact with the talus was seen in 21 patients (58.3%), but no thickening of the ligament was observed. Injury to the intra-articular posterior structures, including the transverse ligament in 19 patients (52.7%) and the posterior surface of the distal tibia in 21 patients (58.3%), was observed. Intra-articular pathological findings have been observed in patients affected by anterolateral pain after an ankle sprain. Despite no demonstrable abnormal lateral laxity, morphologic ATFL abnormality has been observed on arthroscopic evaluation. An injury of the ATFL is present in patients with chronic anterolateral pain and functional instability after an ankle sprain. A degree of microinstability due to a deficiency of the ATFL could explain the intra-articular pathological findings and the patients' complaints. IV.

  14. 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

  15. 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

  16. 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

  17. 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)

  18. Molecular Basis of Genomic Instability in Breast Cancer: Regulation of the Centrosome Duplication Cycle

    National Research Council Canada - National Science Library

    Du, Jian

    2003-01-01

    Alteration in the expression and activity of the centrosomal kinase in breast cancers, Aurora-A/STK15, affect genomic stability, disrupt the fidelity of centrsome duplication, and induce cellular transformation...

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

    Directory of Open Access Journals (Sweden)

    Jacqueline R. Kemp

    2015-12-01

    Full Text Available 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.

  20. 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

  1. Opposite roles for p38MAPK-driven responses and reactive oxygen species in the persistence and resolution of radiation-induced genomic instability.

    Directory of Open Access Journals (Sweden)

    Erica Werner

    Full Text Available We report the functional and temporal relationship between cellular phenotypes such as oxidative stress, p38MAPK-dependent responses and genomic instability persisting in the progeny of cells exposed to sparsely ionizing low-Linear Energy Transfer (LET radiation such as X-rays or high-charge and high-energy (HZE particle high-LET radiation such as (56Fe ions. We found that exposure to low and high-LET radiation increased reactive oxygen species (ROS levels as a threshold-like response induced independently of radiation quality and dose. This response was sustained for two weeks, which is the period of time when genomic instability is evidenced by increased micronucleus formation frequency and DNA damage associated foci. Indicators for another persisting response sharing phenotypes with stress-induced senescence, including beta galactosidase induction, increased nuclear size, p38MAPK activation and IL-8 production, were induced in the absence of cell proliferation arrest during the first, but not the second week following exposure to high-LET radiation. This response was driven by a p38MAPK-dependent mechanism and was affected by radiation quality and dose. This stress response and elevation of ROS affected genomic instability by distinct pathways. Through interference with p38MAPK activity, we show that radiation-induced stress phenotypes promote genomic instability. In contrast, exposure to physiologically relevant doses of hydrogen peroxide or increasing endogenous ROS levels with a catalase inhibitor reduced the level of genomic instability. Our results implicate persistently elevated ROS following exposure to radiation as a factor contributing to genome stabilization.

  2. Kelvin-Helmholtz instability in an ultrathin air film causes drop splashing on smooth surfaces.

    Science.gov (United States)

    Liu, Yuan; Tan, Peng; Xu, Lei

    2015-03-17

    When a fast-moving drop impacts onto a smooth substrate, splashing will be produced at the edge of the expanding liquid sheet. This ubiquitous phenomenon lacks a fundamental understanding. Combining experiment with model, we illustrate that the ultrathin air film trapped under the expanding liquid front triggers splashing. Because this film is thinner than the mean free path of air molecules, the interior airflow transfers momentum with an unusually high velocity comparable to the speed of sound and generates a stress 10 times stronger than the airflow in common situations. Such a large stress initiates Kelvin-Helmholtz instabilities at small length scales and effectively produces splashing. Our model agrees quantitatively with experimental verifications and brings a fundamental understanding to the ubiquitous phenomenon of drop splashing on smooth surfaces.

  3. Identifying the underlying causes of biological instability in a full-scale drinking water supply system.

    Science.gov (United States)

    Nescerecka, Alina; Juhna, Talis; Hammes, Frederik

    2018-05-15

    Changes in bacterial concentration and composition in drinking water during distribution are often attributed to biological (in)stability. Here we assessed temporal biological stability in a full-scale distribution network (DN) supplied with different types of source water: treated and chlorinated surface water and chlorinated groundwater produced at three water treatment plants (WTP). Monitoring was performed weekly during 12 months in two locations in the DN. Flow cytometric total and intact cell concentration (ICC) measurements showed considerable seasonal fluctuations, which were different for two locations. ICC varied between 0.1-3.75 × 10 5  cells mL -1 and 0.69-4.37 × 10 5  cells mL -1 at two locations respectively, with ICC increases attributed to temperature-dependent bacterial growth during distribution. Chlorinated water from the different WTP was further analysed with a modified growth potential method, identifying primary and secondary growth limiting compounds. It was observed that bacterial growth in the surface water sample after chlorination was primarily inhibited by phosphorus limitation and secondly by organic carbon limitation, while carbon was limiting in the chlorinated groundwater samples. However, the ratio of available nutrients changed during distribution, and together with disinfection residual decay, this resulted in higher bacterial growth potential detected in the DN than at the WTP. In this study, bacterial growth was found to be higher (i) at higher water temperatures, (ii) in samples with lower chlorine residuals and (iii) in samples with less nutrient (carbon, phosphorus, nitrogen, iron) limitation, while this was significantly different between the samples of different origin. Thus drinking water microbiological quality and biological stability could change during different seasons, and the extent of these changes depends on water temperature, the water source and treatment. Furthermore, differences in primary

  4. 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

  5. Increased calf and plantar muscle fibrotic contents in obese subjects may cause ankle instability.

    Science.gov (United States)

    Zhu, Junwei; Zhang, Lei; Chen, Yong; Zhao, Jianning

    2016-08-01

    Obesity is strongly associated with musculoskeletal disorders of the lower limb, including ankle instability and resulting gait problems. In the present study, we aimed to examine, using paired comparisons of subjects, whether moderate duration of obesity in patients with mild to moderate elevations of body mass index (BMI), changes the fibrous contents of muscles that support the ankle mortices, namely calf and plantar muscles. We attempted to examine these parameters because this shall provide direct evidence of whether obesity directly impacts myoarchitecture and support of the adjoining joints. MRI image segmentation and pixel correlations by grey level co-occurrence matrix (GLCM) and entropy were used to analyse the changes. The differences in the means between groups (both GLCM and entropy) were significant from control lean populations (Pcalf and the plantar muscles. Reduction in weight should thus be a first-line approach in preventing these changes that may significantly affect quality of life due to gait disturbances. © 2016 The Author(s).

  6. Plathelminth abundance in North Sea salt marshes: environmental instability causes high diversity

    Science.gov (United States)

    Armonies, Werner

    1986-09-01

    Although supralittoral salt marshes are habitats of high environmental instability, the meiofauna is rich in species and abundance is high. The community structure of free-living Plathelminthes (Turbellaria) in these salt marshes is described. On an average, 104 individuals are found below an area of 10 cm2. The average species density in ungrazed salt marshes is 11.3 below 10 cm2 and 45.2 below 100 cm2, indicating strong small-scale heterogenity. The faunal similarity between sediment and the corresponding above-ground vegetation is higher than between adjacent sample sites. Species prefer distinct ranges of salinity. In the lower part of the supralittoral salt marshes, the annual fluctuations of salinity are strongest and highly unpredictable. This region is richest in plathelminth species and abundance; diversity is highest, and the faunal composition of parallel samples is quite similar. In the upper part of the supralittoral salt marshes, the annual variability of salinity is lower, plathelminths are poor in species diversity and abundance. Parallel samples often have no species in common. Thus, those salt marsh regions with the most unstable environment are inhabited by the most diverse species assemblage. Compared to other littoral zones of the North Sea, however, plathelminth diversity in salt marshes is low. The observed plathelminth diversity pattern can apparently be explained by the “dynamic equilibrium model” (Huston, 1979).

  7. Chromosomal instability in Afrotheria: fragile sites, evolutionary breakpoints and phylogenetic inference from genome sequence assemblies

    Directory of Open Access Journals (Sweden)

    Ruiz-Herrera Aurora

    2007-10-01

    Full Text Available Abstract Background Extant placental mammals are divided into four major clades (Laurasiatheria, Supraprimates, Xenarthra and Afrotheria. Given that Afrotheria is generally thought to root the eutherian tree in phylogenetic analysis of large nuclear gene data sets, the study of the organization of the genomes of afrotherian species provides new insights into the dynamics of mammalian chromosomal evolution. Here we test if there are chromosomal bands with a high tendency to break and reorganize in Afrotheria, and by analyzing the expression of aphidicolin-induced common fragile sites in three afrotherian species, whether these are coincidental with recognized evolutionary breakpoints. Results We described 29 fragile sites in the aardvark (OAF genome, 27 in the golden mole (CAS, and 35 in the elephant-shrew (EED genome. We show that fragile sites are conserved among afrotherian species and these are correlated with evolutionary breakpoints when compared to the human (HSA genome. Inddition, by computationally scanning the newly released opossum (Monodelphis domestica and chicken sequence assemblies for use as outgroups to Placentalia, we validate the HSA 3/21/5 chromosomal synteny as a rare genomic change that defines the monophyly of this ancient African clade of mammals. On the other hand, support for HSA 1/19p, which is also thought to underpin Afrotheria, is currently ambiguous. Conclusion We provide evidence that (i the evolutionary breakpoints that characterise human syntenies detected in the basal Afrotheria correspond at the chromosomal band level with fragile sites, (ii that HSA 3p/21 was in the amniote ancestor (i.e., common to turtles, lepidosaurs, crocodilians, birds and mammals and was subsequently disrupted in the lineage leading to marsupials. Its expansion to include HSA 5 in Afrotheria is unique and (iii that its fragmentation to HSA 3p/21 + HSA 5/21 in elephant and manatee was due to a fission within HSA 21 that is probably shared

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

    Energy Technology Data Exchange (ETDEWEB)

    Josee, Lavoie [McMaster Univ., Hamilton, ON (Canada). Medical Physics and Applied Radiation Sciences; Dolling, Jo-Anna [Credit Valley Hospital, Missassauga, ON (Canada); Mitchel, Ron E.J. [Atomic Energy of Canada (AECL), Limited, Chalk River, ON (Canada); Boreham, Douglas R. [McMaster Univ., Hamilton, ON (Canada). Medical Physics and Applied Radiation Sciences

    2004-09-28

    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

  9. 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

  10. Genomic instability in liver cells caused by an LPS-induced bystander-like effect.

    Directory of Open Access Journals (Sweden)

    Igor Kovalchuk

    Full Text Available Bacterial infection has been linked to carcinogenesis, however, there is lack of knowledge of molecular mechanisms that associate infection with the development of cancer. We analyzed possible effects of the consumption of heat-killed E. coli O157:H7 cells or its cellular components, DNA, RNA, protein or lipopolysaccharides (LPS on gene expression in naïve liver cells. Four week old mice were provided water supplemented with whole heat-killed bacteria or bacterial components for a two week period. One group of animals was sacrificed immediately, whereas another group was allowed to consume uncontaminated tap water for an additional two weeks, and liver samples were collected, post mortem. Liver cells responded to exposure of whole heat-killed bacteria and LPS with alteration in γH2AX levels and levels of proteins involved in proliferation, DNA methylation (MeCP2, DNMT1, DNMT3A and 3B or DNA repair (APE1 and KU70 as well as with changes in the expression of genes involved in stress response, cell cycle control and bile acid biosynthesis. Other bacterial components analysed in this study did not lead to any significant changes in the tested molecular parameters. This study suggests that lipopolysaccharides are a major component of Gram-negative bacteria that induce molecular changes within naïve cells of the host.

  11. Mutations in SPRTN cause early onset hepatocellular carcinoma, genomic instability and progeroid features

    NARCIS (Netherlands)

    Lessel, Davor; Vaz, Bruno; Halder, Swagata; Lockhart, Paul J.; Marinovic-Terzic, Ivana; Lopez-Mosqueda, Jaime; Philipp, Melanie; Sim, Joe C. H.; Smith, Katherine R.; Oehler, Judith; Cabrera, Elisa; Freire, Raimundo; Pope, Kate; Nahid, Amsha; Norris, Fiona; Leventer, Richard J.; Delatycki, Martin B.; Barbi, Gotthold; von Ameln, Simon; Högel, Josef; Degoricija, Marina; Fertig, Regina; Burkhalter, Martin D.; Hofmann, Kay; Thiele, Holger; Altmüller, Janine; Nürnberg, Gudrun; Nürnberg, Peter; Bahlo, Melanie; Martin, George M.; Aalfs, Cora M.; Oshima, Junko; Terzic, Janos; Amor, David J.; Dikic, Ivan; Ramadan, Kristijan; Kubisch, Christian

    2014-01-01

    Age-related degenerative and malignant diseases represent major challenges for health care systems. Elucidation of the molecular mechanisms underlying carcinogenesis and age-associated pathologies is thus of growing biomedical relevance. We identified biallelic germline mutations in SPRTN (also

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

    Science.gov (United States)

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

    2013-01-01

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

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

    OpenAIRE

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

    2012-01-01

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

  14. Zinc sulfate supplementation of cultured peripheral blood Lymphocytes: genomic instability related to its deficiency and excess

    OpenAIRE

    Padula, Gisel; Ponzinibbio, Maria Virginia; Seoane, Analia Isabel

    2017-01-01

    Zinc (Zn) plays a vital role in children growth and is involved in DNA synthesis and maintenance processes. The current nutrient intake recommendations do not consider the levels required for maintaining genomic stability. The objective of this study is to analyze the cytotoxic and genotoxic effect of in vitro Zn supplementation to evaluate deficiency and excess, and the concentrations within the normal physiological range established for children (80-280 µg/dl). To achieve Zn deficiency, the...

  15. Two familial cases of Hb Tyne confirm instability as cause of low expression

    Directory of Open Access Journals (Sweden)

    Beverley M. Pullon

    2017-05-01

    Full Text Available We report a second occurrence of hemoglobin (Hb Tyne, [β5 (A2 Pro>Ser] HBB:c.16C>T(p.Pro6Ser, which like the first case was associated with normal hematology. We verified the variant was mildly unstable by showing it was greatly enriched in isopropanol precipitates. This minor instability accounts for the slightly decreased expression of the new β chain. The variant was picked up as an interfering component on HbA1c testing using cation exchange high performance liquid chromatography (HPLC. However, this may be an advantage in detecting electrophoretically silent variants. Furthermore, this report also highlights the importance of uneven or sloping baselines on HPLC, which could reflect the presence of a variant hemoglobin even in the presence of normal electrophoresis and full blood count.   我们报告了第二例血红蛋白(Hb Tyne [β5 (A2 Pro>Ser] HBB:c.16C>T(p.Pro6Ser的出现,其与第一例一样伴随血象正常。我们通过将该变体在异丙醇沉淀物中的显著富集证实了其有轻度不稳定性。这种微小的不稳定性可用来说明新β链表达的轻微下降。该变体在使用阳离子交换高效液相色谱(HPLC)的HbA1c检测中作为干扰成分检出。然而,在检测电泳沉默变体方面这可能使一个优势。此外,本报告还强调了不平或倾斜的基线对HPLC的重要性,这会反映出血红蛋白变异体的存在,即使电泳和全血计数正常。

  16. 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.

  17. Lingering Questions about Enhancer RNA and Enhancer Transcription-Coupled Genomic Instability.

    Science.gov (United States)

    Rothschild, Gerson; Basu, Uttiya

    2017-02-01

    Intergenic and intragenic enhancers found inside topologically associated regulatory domains (TADs) express noncoding RNAs, known as enhancer RNAs (eRNAs). Recent studies have indicated these eRNAs play a role in gene regulatory networks by controlling promoter and enhancer interactions and topology of higher-order chromatin structure. Misregulation of enhancer and promoter associated noncoding RNAs (ncRNAs) could stabilize deleterious secondary DNA structures, noncoding RNA associated DNA/RNA hybrid formation, and promote collisions of transcription complexes with replisomes. It is revealing that many chromosomal aberrations, some associated with malignancies, are present inside enhancer and/or promoter sequences. Here, we expand on current concepts to discuss enhancer RNAs and enhancer transcription, and how enhancer transcription influences genomic organization and integrity. Copyright © 2016 Elsevier Ltd. All rights reserved.

  18. 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....

  19. Genomic Instability of the Sex-Determining Locus in Atlantic Salmon (Salmo salar).

    Science.gov (United States)

    Lubieniecki, Krzysztof P; Lin, Song; Cabana, Emily I; Li, Jieying; Lai, Yvonne Y Y; Davidson, William S

    2015-09-22

    Atlantic salmon and rainbow trout, like other members of the subfamily Salmoninae, are gonochoristic with male heterogamety. The finding that sex-linked genetic markers varied between species suggested that the sex-determining gene differs among salmonid species, or that there is one sex-determining gene that has the capacity to move around the genome. The discovery of sdY, the sex-determining gene in rainbow trout, and its presence in many male salmonids gave support to the latter. Additional evidence for a salmonid-specific, sex-determining jumping gene came from the mapping of the sex-determining locus to three different chromosomes in Tasmanian male Atlantic salmon lineages. To characterize the sex-determining region, we isolated three sdY containing BACs from an Atlantic salmon male library. Sequencing of these BACs yielded two contigs, one of which contained the sdY gene. Sequence analysis of the borders of male-specific and female/male common regions revealed highly repetitive sequences associated with mobile elements, which may allow an sdY cassette to jump around the genome. FISH analysis using a BAC or a plasmid containing the sdY gene showed that the sdY gene did indeed localize to the chromosomes where SEX had been mapped in different Tasmanian Atlantic salmon families. Moreover, the plasmid sdY gene probe hybridized primarily to one of the sex chromosomes as would be expected of a male-specific gene. Our results suggest that a common salmonid sex-determining gene (sdY) can move between three specific loci on chromosomes 2, 3, and 6, giving the impression that there are multiple SEX loci both within and between salmonid species. Copyright © 2015 Lubieniecki et al.

  20. Phase instability of alloys caused by transmutation effects during neutron irradiation

    International Nuclear Information System (INIS)

    Platov, Yu.M.; Pletnev, M.N.

    1994-01-01

    A theory of the phase changes in a two-phase binary A-B alloy in the coarsening condition caused by burnout of solute B due to nuclear reactions is presented. It is shown that this burnout process introduces diffusion redistribution of solute between second phase precipitates and solid solution. The burnout induced solute flux away from second phase precipitates to solid solution maintaining the concentration of element B in the vicinity to its solubility limit and stimulates, thus, the second phase particle dissolution. This occurs in addition to a process decreasing their sizes as a result of direct burnout of atoms B in the precipitates. In the framework of the theory developed here, analytical expressions describing time evolution of the precipitate size distributions, changes of mean radius and number density of the precipitates, and second phase dissolution times are obtained. On the basis of these results and numerical calculations for aluminium-scandium alloy, it is shown that the burnout processes can induce essential phase changes, and thus cause significant changes of the properties of irradiated materials at high neutron fluences. ((orig.))

  1. Dynamic left ventricular outflow tract obstruction: underestimated cause of hypotension and hemodynamic instability

    Directory of Open Access Journals (Sweden)

    Dorota Sobczyk

    2014-12-01

    Full Text Available Left ventricular outflow tract obstruction, which is typically associated with hypertrophic cardiomyopathy, is the third most frequent cause of unexplained hypotension. This underestimated problem may temporarily accompany various diseases (it is found in even <1% of patients with no tangible cardiac disease and clinical situations (hypovolemia, general anesthesia. It is currently assumed that left ventricular outflow tract obstruction is a dynamic phenomenon, the occurrence of which requires the coexistence of predisposing anatomic factors and a physiological condition that induces it. The diagnosis of left ventricular outflow tract obstruction should entail immediate implementation of the therapy to eliminate the factors that can potentially intensify the obstruction. Echocardiography is the basic modality in the diagnosis and treatment of left ventricular outflow tract obstruction. This paper presents four patients in whom the immediate implementation of bedside echocardiography enabled a rapid diagnosis of left ventricular outflow tract obstruction and implementation of proper treatment.

  2. Effects of two organomodified clays intended to food contact materials on the genomic instability and gene expression of hepatoma cells.

    Science.gov (United States)

    Maisanaba, Sara; Jordá-Beneyto, María; Cameán, Ana M; Jos, Ángeles

    2016-02-01

    Globally, food industries have made significant progress in order to increase the shelf-life of food products and have fewer economic losses. In this sense, the use of organomodified clays destined to be incorporated in polymer matrices play a novel role, leading to improved materials named nanocomposites with enhanced technological profiles. Due to the presence of these clays into the package, the safety of the consumers is a main concern. Cloisite(®)30B and Clay1 are two organomodified clays containing quaternary ammonium salts as modifiers, that can be potentially used to reinforce packaging polymers. Available toxicity data about these clays, specifically genotoxicity, is still limited and inconclusive in some aspects. Thus, the purpose of this work was to evaluate both clays ability to induce genomic instability through the cytokinesis block micronucleus cytome assay (CBMN) and for the first time, their influence in the modulation of several genes involved in genotoxicity and cell death mechanisms. Overall, no genotoxicity response was obtained in any case at the conditions tested. On the other hand, significant expression changes were observed on the genes selected. Nevertheless, further studies are highly needed to elucidate and increase the knowledge about the molecular mechanisms of clays toxicity. Copyright © 2015 Elsevier Ltd. All rights reserved.

  3. 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

  4. 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.

  5. Genome microevolution of chikungunya viruses causing the Indian Ocean outbreak.

    Directory of Open Access Journals (Sweden)

    Isabelle Schuffenecker

    2006-07-01

    Full Text Available BACKGROUND: A chikungunya virus outbreak of unprecedented magnitude is currently ongoing in Indian Ocean territories. In Réunion Island, this alphavirus has already infected about one-third of the human population. The main clinical symptom of the disease is a painful and invalidating poly-arthralgia. Besides the arthralgic form, 123 patients with a confirmed chikungunya infection have developed severe clinical signs, i.e., neurological signs or fulminant hepatitis. METHODS AND FINDINGS: We report the nearly complete genome sequence of six selected viral isolates (isolated from five sera and one cerebrospinal fluid, along with partial sequences of glycoprotein E1 from a total of 127 patients from Réunion, Seychelles, Mauritius, Madagascar, and Mayotte islands. Our results indicate that the outbreak was initiated by a strain related to East-African isolates, from which viral variants have evolved following a traceable microevolution history. Unique molecular features of the outbreak isolates were identified. Notably, in the region coding for the non-structural proteins, ten amino acid changes were found, four of which were located in alphavirus-conserved positions of nsP2 (which contains helicase, protease, and RNA triphosphatase activities and of the polymerase nsP4. The sole isolate obtained from the cerebrospinal fluid showed unique changes in nsP1 (T301I, nsP2 (Y642N, and nsP3 (E460 deletion, not obtained from isolates from sera. In the structural proteins region, two noteworthy changes (A226V and D284E were observed in the membrane fusion glycoprotein E1. Homology 3D modelling allowed mapping of these two changes to regions that are important for membrane fusion and virion assembly. Change E1-A226V was absent in the initial strains but was observed in >90% of subsequent viral sequences from Réunion, denoting evolutionary success possibly due to adaptation to the mosquito vector. CONCLUSIONS: The unique molecular features of the analyzed

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

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    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.

  7. Genomic analysis of a Streptococcus pyogenes strain causing endocarditis in a child

    Directory of Open Access Journals (Sweden)

    M. Beye

    2017-05-01

    Full Text Available We sequenced the genome of Streptococcus pyogenes strain G773 that caused an infective endocarditis in a 4-year-old boy suffering from acute endocarditis. The 1.9-Mb genome exhibited a specific combination of virulence factors including a complete integrative and conjugative element, sp2905, previously described as incomplete in S. pyogenes, and five bacteriocin-coding genes. However, strain G773 lacked a CRISPR-Cas system.

  8. 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.)

  9. The unstable painful shoulder (UPS) as a cause of pain from unrecognized anteroinferior instability in the young athlete.

    Science.gov (United States)

    Boileau, Pascal; Zumstein, Matthias; Balg, Frederic; Penington, Scott; Bicknell, Ryan T

    2011-01-01

    The etiology of shoulder pain in the overhead athlete is often difficult to determine. This study hypothesized that (1) instability can present in a purely painful form, without any apparent history of instability, but with anatomic lesions indicative of instability, termed unstable painful shoulder (UPS), and that (2) arthroscopic shoulder stabilization is effective. The study evaluated 20 patients (mean age, 22 ± 8 years) at a mean of 38 months postoperatively (range, 24-69 months). Inclusion criteria were painful shoulder with lesions indicative of instability on imaging or at surgery, minimum 2-year follow-up. Exclusion criteria were recognized instability, other associated pathologies, and previous shoulder surgery. Patients were young, hyperlax athletes who complained of deep, anterior shoulder pain and denied any instability. Pain was reproduced with the arm in an anterior apprehension position and relieved by a relocation test; however, no actual apprehension was experienced. Patients often had glenohumeral laxity and hyperlaxity. Lesions indicative of instability confirmed that at least 1 unapparent shoulder subluxation occurred. The Rowe, Walch-Duplay, and University of California, Los Angeles scores improved significantly (P Shoulder and Elbow Surgery Board of Trustees. Published by Mosby, Inc. All rights reserved.

  10. Features of 5'-splice-site efficiency derived from disease-causing mutations and comparative genomics

    DEFF Research Database (Denmark)

    Roca, Xavier; Olson, Andrew J; Rao, Atmakuri R

    2008-01-01

    Many human diseases, including Fanconi anemia, hemophilia B, neurofibromatosis, and phenylketonuria, can be caused by 5'-splice-site (5'ss) mutations that are not predicted to disrupt splicing, according to position weight matrices. By using comparative genomics, we identify pairwise dependencies...

  11. Draft Genome Sequence of a Virulent Pectobacterium carotovorum subsp. brasiliense Isolate Causing Soft Rot of Cucumber.

    Science.gov (United States)

    Onkendi, Edward M; Ramesh, Aadi Moolam; Kwenda, Stanford; Naidoo, Sanushka; Moleleki, Lucy

    2016-01-07

    Pectobacterium carotovorum subsp. brasiliense causes soft rot and blackleg diseases on potatoes, ornamentals, and other crops of economic importance. Here, we report a draft genome sequence of a highly virulent P. carotovorum subsp. brasiliense strain, PcbHPI01, isolated from a cucumber in South Africa. Copyright © 2016 Onkendi et al.

  12. 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

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

    Directory of Open Access Journals (Sweden)

    Ulises Urzúa

    2016-10-01

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

  14. 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.

  15. IR-inducible clusterin gene expression: a protein with potential roles in ionizing radiation-induced adaptive responses, genomic instability, and bystander effects

    Energy Technology Data Exchange (ETDEWEB)

    Klokov, Dmitry [Laboratory of Molecular Stress Responses, Department of Radiation Oncology, Case Western Reserve University, 2103 Cornell Road, Wolstein Research Building 3-531, Cleveland, OH 44106-4942 (United States); Criswell, Tracy [Laboratory of Molecular Stress Responses, Department of Radiation Oncology, Case Western Reserve University, 2103 Cornell Road, Wolstein Research Building 3-531, Cleveland, OH 44106-4942 (United States); Program in Molecular and Cellular Basis of Disease, Case Western Reserve University School of Medicine, Cleveland, OH 44106-4942 (United States); Leskov, Konstantin S. [Laboratory of Molecular Stress Responses, Department of Radiation Oncology, Case Western Reserve University, 2103 Cornell Road, Wolstein Research Building 3-531, Cleveland, OH 44106-4942 (United States); Araki, Shinako [Laboratory of Molecular Stress Responses, Department of Radiation Oncology, Case Western Reserve University, 2103 Cornell Road, Wolstein Research Building 3-531, Cleveland, OH 44106-4942 (United States); Mayo, Lindsey [Laboratory of Molecular Stress Responses, Department of Radiation Oncology, Case Western Reserve University, 2103 Cornell Road, Wolstein Research Building 3-531, Cleveland, OH 44106-4942 (United States); Boothman, David A. [Laboratory of Molecular Stress Responses, Department of Radiation Oncology, Case Western Reserve University, 2103 Cornell Road, Wolstein Research Building 3-531, Cleveland, OH 44106-4942 (United States) and Program in Molecular and Cellular Basis of Disease, Case Western Reserve University School of Medicine, Cleveland, OH 44106-4942 (United States)]. E-mail: dab30@po.cwru.edu

    2004-12-02

    Clusterin (CLU) plays numerous roles in mammalian cells after stress. A review of the recent literature strongly suggests potential roles for CLU proteins in low dose ionizing radiation (IR)-inducible adaptive responses, bystander effects, and delayed death and genomic instability. Its most striking and evident feature is the inducibility of the CLU promoter after low, as well as high, doses of IR. Two major forms of CLU, secreted (sCLU) and nuclear (nCLU), possess opposite functions in cellular responses to IR: sCLU is cytoprotective, whereas nCLU (a byproduct of alternative splicing) is a pro-death factor. Recent studies from our laboratory and others demonstrated that down-regulation of sCLU by specific siRNA increased cytotoxic responses to chemotherapy and IR. sCLU was induced after low non-toxic doses of IR (0.02-0.5 Gy) in human cultured cells and in mice in vivo. The low dose inducibility of this survival protein suggests a possible role for sCLU in radiation adaptive responses, characterized by increased cell radioresistance after exposure to low adapting IR doses. Although it is still unclear whether the adaptive response is beneficial or not to cells, survival of damaged cells after IR may lead to genomic instability in the descendants of surviving cells. Recent studies indicate a link between sCLU accumulation and cancer incidence, as well as aging, supporting involvement of the protein in the development of genomic instability. Secreted after IR, sCLU may also alter intracellular communication due to its ability to bind cell surface receptors, such as the TGF-{beta} receptors (types I and II). This interference with signaling pathways may contribute to IR-induced bystander effects. We hypothesize that activation of the TGF-{beta} signaling pathway, which often occurs after IR exposure, can in turn activate the CLU promoter. TGF-{beta} and IR-inducible de novo synthesized sCLU may then bind the TGF-{beta} receptors and suppress downstream growth arrest

  16. The genome sequence of the fungal pathogen Fusarium virguliforme that causes sudden death syndrome in soybean.

    Directory of Open Access Journals (Sweden)

    Subodh K Srivastava

    Full Text Available Fusarium virguliforme causes sudden death syndrome (SDS of soybean, a disease of serious concern throughout most of the soybean producing regions of the world. Despite the global importance, little is known about the pathogenesis mechanisms of F. virguliforme. Thus, we applied Next-Generation DNA Sequencing to reveal the draft F. virguliforme genome sequence and identified putative pathogenicity genes to facilitate discovering the mechanisms used by the pathogen to cause this disease.We have generated the draft genome sequence of F. virguliforme by conducting whole-genome shotgun sequencing on a 454 GS-FLX Titanium sequencer. Initially, single-end reads of a 400-bp shotgun library were assembled using the PCAP program. Paired end sequences from 3 and 20 Kb DNA fragments and approximately 100 Kb inserts of 1,400 BAC clones were used to generate the assembled genome. The assembled genome sequence was 51 Mb. The N50 scaffold number was 11 with an N50 Scaffold length of 1,263 Kb. The AUGUSTUS gene prediction program predicted 14,845 putative genes, which were annotated with Pfam and GO databases. Gene distributions were uniform in all but one of the major scaffolds. Phylogenic analyses revealed that F. virguliforme was closely related to the pea pathogen, Nectria haematococca. Of the 14,845 F. virguliforme genes, 11,043 were conserved among five Fusarium species: F. virguliforme, F. graminearum, F. verticillioides, F. oxysporum and N. haematococca; and 1,332 F. virguliforme-specific genes, which may include pathogenicity genes. Additionally, searches for candidate F. virguliforme pathogenicity genes using gene sequences of the pathogen-host interaction database identified 358 genes.The F. virguliforme genome sequence and putative pathogenicity genes presented here will facilitate identification of pathogenicity mechanisms involved in SDS development. Together, these resources will expedite our efforts towards discovering pathogenicity mechanisms in

  17. Diet and genomic stability.

    Science.gov (United States)

    Young, Graeme P

    2007-01-01

    Cancer results from a disordered and unstable genome - the degree of abnormality progresses as the process of oncogenesis proceeds. Such genomic instability appears to be subject to control by environmental factors as evidenced by the number of cancers that are either caused by specific environmental agents (lung, skin, cervix) or else regulated by a broader range of agents such as effect of diet on gastric and colorectal cancers. Dietary factors might interact in several ways with the genome to protect against cancer. An agent might interact directly with the genome and regulate expression (as a genetic or epigenetic regulator) or indirectly by influencing DNA 'repair' responses and so improve genomic stability. Research now shows that diet-genomic interactions in cancer go beyond interactions with the normal genome and involve enhancement of normal cellular responses to DNA damage such that genome stability is more effectively maintained. Activation of apoptosis may be a key to protection.

  18. Analysis of the Legionella longbeachae genome and transcriptome uncovers unique strategies to cause Legionnaires' disease.

    Directory of Open Access Journals (Sweden)

    Christel Cazalet

    2010-02-01

    Full Text Available Legionella pneumophila and L. longbeachae are two species of a large genus of bacteria that are ubiquitous in nature. L. pneumophila is mainly found in natural and artificial water circuits while L. longbeachae is mainly present in soil. Under the appropriate conditions both species are human pathogens, capable of causing a severe form of pneumonia termed Legionnaires' disease. Here we report the sequencing and analysis of four L. longbeachae genomes, one complete genome sequence of L. longbeachae strain NSW150 serogroup (Sg 1, and three draft genome sequences another belonging to Sg1 and two to Sg2. The genome organization and gene content of the four L. longbeachae genomes are highly conserved, indicating strong pressure for niche adaptation. Analysis and comparison of L. longbeachae strain NSW150 with L. pneumophila revealed common but also unexpected features specific to this pathogen. The interaction with host cells shows distinct features from L. pneumophila, as L. longbeachae possesses a unique repertoire of putative Dot/Icm type IV secretion system substrates, eukaryotic-like and eukaryotic domain proteins, and encodes additional secretion systems. However, analysis of the ability of a dotA mutant of L. longbeachae NSW150 to replicate in the Acanthamoeba castellanii and in a mouse lung infection model showed that the Dot/Icm type IV secretion system is also essential for the virulence of L. longbeachae. In contrast to L. pneumophila, L. longbeachae does not encode flagella, thereby providing a possible explanation for differences in mouse susceptibility to infection between the two pathogens. Furthermore, transcriptome analysis revealed that L. longbeachae has a less pronounced biphasic life cycle as compared to L. pneumophila, and genome analysis and electron microscopy suggested that L. longbeachae is encapsulated. These species-specific differences may account for the different environmental niches and disease epidemiology of these

  19. Can Kelvin-Helmholtz Instabilities of Jet-Like Structures and Plumes Cause Solar Wind Fluctuations at 1 AU?

    Science.gov (United States)

    Shyamsundar, Parhi; Suess, Steven T.; Sulkanen, Martin E.

    1998-01-01

    The long high latitude sampling of Ulysses provides the opportunity to study fine structures. At latitudes poleward of approx. -60 deg, the solar wind had fluctuations in velocity gradients which were attributed to "microstreams". The data also suggested fluctuations characterized by magnetic plus thermal pressure balance structures ("PBS"). At higher frequencies, MHD turbulence was observed and found to be less evolved than in the ecliptic, but essentially independent of heliographic latitude. It is argued here that microstreams, PBS, and MHD turbulence could all be the remnants of mixing due to shear instabilities associated with plumes and other filamentarystructures ("jets") in coronal holes. To show this we simulate a plume-like jet in the presence of an ambient magnetic field. We find the presence of the ambient field reduces the growth rate of the instability, but the shear between a jet and its ambient still becomes unstable to the MHD Kelvin-Helmholtz ("KH") instability when the shear speed is larger than the largest local magnetosonic speed - a condition probably satisfied for plumes.

  20. Genome Reduction for Niche Association in Campylobacter Hepaticus, A Cause of Spotty Liver Disease in Poultry

    Directory of Open Access Journals (Sweden)

    Liljana Petrovska

    2017-08-01

    Full Text Available The term “spotty liver disease” (SLD has been used since the late 1990s for a condition seen in the UK and Australia that primarily affects free range laying hens around peak lay, causing acute mortality and a fall in egg production. A novel thermophilic SLD-associated Campylobacter was reported in the United Kingdom (UK in 2015. Subsequently, similar isolates occurring in Australia were formally described as a new species, Campylobacter hepaticus. We describe the comparative genomics of 10 C. hepaticus isolates recovered from 5 geographically distinct poultry holdings in the UK between 2010 and 2012. Hierarchical gene-by-gene analyses of the study isolates and representatives of 24 known Campylobacter species indicated that C. hepaticus is most closely related to the major pathogens Campylobacter jejuni and Campylobacter coli. We observed low levels of within-farm variation, even between isolates collected over almost 3 years. With respect to C. hepaticus genome features, we noted that the study isolates had a ~140 Kb reduction in genome size, ~144 fewer genes, and a lower GC content compared to C. jejuni. The most notable reduction was in the subsystem containing genes for iron acquisition and metabolism, supported by reduced growth of C. hepaticus in an iron depletion assay. Genome reduction is common among many pathogens and in C. hepaticus has likely been driven at least in part by specialization following the occupation of a new niche, the chicken liver.

  1. Draft genome sequence of Cercospora sojina isolate S9, a fungus causing frogeye leaf spot (FLS disease of soybean

    Directory of Open Access Journals (Sweden)

    Fanchang Zeng

    2017-06-01

    Full Text Available Fungi are the causal agents of many of the world's most serious plant diseases causing disastrous consequences for large-scale agricultural production. Pathogenicity genomic basis is complex in fungi as multicellular eukaryotic pathogens. The fungus Cercospora sojina is a plant pathogen that threatens global soybean supplies. Here, we report the genome sequence of C. sojina strain S9 and detect genome features and predicted genomic elements. The genome sequence of C. sojina is a valuable resource with potential in studying the fungal pathogenicity and soybean host resistance to frogeye leaf spot (FLS, which is caused by C. sojina. The C. sojina genome sequence has been deposited and available at DDBJ/EMBL/GenBank under the project accession number AHPQ00000000.

  2. Targets for, and consequences of, radiation-induced chromosomal instability

    Science.gov (United States)

    Kaplan, Mark Isaac

    Chromosomal instability has been demonstrated in a human- hamster hybrid cell line, GM10115, after exposure to x- rays. Chromosomal instability in these cells is characterized by the appearance of novel chromosomal rearrangements multiple generations after exposure to ionizing radiation. To identify the cellular target(s) for radiation-induced chromosomal instability, cells were treated with 125I-labeled compounds. Labeling cells with 125I-iododeoxyuridine, which caused radiation damage to the DNA and associated nuclear structures, did induce chromosomal instability. While cell killing and first-division chromosomal rearrangements increased with increasing numbers of 125I decays, the frequency of chromosomal instability was independent of dose. Incorporation of an 125I-labeled protein, 125I-succinyl- concanavalin A, into either the plasma membrane or the cytoplasm, failed to elicit chromosomal instability. These results show that radiation damage to the nucleus, and not to extranuclear regions, contributes to the induction of chromosomal instability. To determine the role of DNA strand breaks as a molecular lesion responsible for initiating chromosomal instability, cells were treated with a variety of DNA strand breaking agents. Agents capable of producing complex DNA double strand breaks, including X-rays, Neocarzinostatin and bleomycin, were able to induce chromosomal instability. In contrast, double strand breaks produced by restriction endonucleases as well as DNA strand breaks produced by hydrogen peroxide failed to induce chromosomal instability. This demonstrates that the type of DNA breakage is important in the eventual manifestation of chromosomal instability. In order to understand the relationship between chromosomal instability and other end points of genomic instability, chromosomally stable and unstable clones were analyzed for sister chromatid exchange, delayed reproductive cell death, delayed mutation, mismatch repair and delayed gene amplification

  3. Comparative and population genomic landscape of Phellinus noxius: A hypervariable fungus causing root rot in trees.

    Science.gov (United States)

    Chung, Chia-Lin; Lee, Tracy J; Akiba, Mitsuteru; Lee, Hsin-Han; Kuo, Tzu-Hao; Liu, Dang; Ke, Huei-Mien; Yokoi, Toshiro; Roa, Marylette B; Lu, Mei-Yeh J; Chang, Ya-Yun; Ann, Pao-Jen; Tsai, Jyh-Nong; Chen, Chien-Yu; Tzean, Shean-Shong; Ota, Yuko; Hattori, Tsutomu; Sahashi, Norio; Liou, Ruey-Fen; Kikuchi, Taisei; Tsai, Isheng J

    2017-11-01

    The order Hymenochaetales of white rot fungi contain some of the most aggressive wood decayers causing tree deaths around the world. Despite their ecological importance and the impact of diseases they cause, little is known about the evolution and transmission patterns of these pathogens. Here, we sequenced and undertook comparative genomic analyses of Hymenochaetales genomes using brown root rot fungus Phellinus noxius, wood-decomposing fungus Phellinus lamaensis, laminated root rot fungus Phellinus sulphurascens and trunk pathogen Porodaedalea pini. Many gene families of lignin-degrading enzymes were identified from these fungi, reflecting their ability as white rot fungi. Comparing against distant fungi highlighted the expansion of 1,3-beta-glucan synthases in P. noxius, which may account for its fast-growing attribute. We identified 13 linkage groups conserved within Agaricomycetes, suggesting the evolution of stable karyotypes. We determined that P. noxius has a bipolar heterothallic mating system, with unusual highly expanded ~60 kb A locus as a result of accumulating gene transposition. We investigated the population genomics of 60 P. noxius isolates across multiple islands of the Asia Pacific region. Whole-genome sequencing showed this multinucleate species contains abundant poly-allelic single nucleotide polymorphisms with atypical allele frequencies. Different patterns of intra-isolate polymorphism reflect mono-/heterokaryotic states which are both prevalent in nature. We have shown two genetically separated lineages with one spanning across many islands despite the geographical barriers. Both populations possess extraordinary genetic diversity and show contrasting evolutionary scenarios. These results provide a framework to further investigate the genetic basis underlying the fitness and virulence of white rot fungi. © 2017 John Wiley & Sons Ltd.

  4. Flutter instability of cantilevered carbon nanotubes caused by magnetic fluid flow subjected to a longitudinal magnetic field

    Science.gov (United States)

    Sadeghi-Goughari, Moslem; Jeon, Soo; Kwon, Hyock-Ju

    2018-04-01

    CNT (Carbon nanotube)-based fluidic systems hold a great potential for emerging medical applications such as drug delivery for cancer therapy. CNTs can be used to deliver anticancer drugs into a target site under a magnetic field guidance. One of the critical issues in designing such systems is how to avoid the vibration induced by the fluid flow, which is undesirable and may even promote the structural instability. The main objective of the present research is to develop a fluid structure interaction (FSI) model to investigate the flutter instability of a cantilevered CNT induced by a magnetic fluid flow under a longitudinal magnetic field. The CNT is assumed to be embedded in a viscoelastic matrix to consider the effect of biological medium around it. To obtain a dynamical model for the system, the Navier-Stokes theory of magnetic-fluid flow is coupled to the Euler-Bernoulli beam model for CNT. The small size effects of the magnetic fluid and CNT are considered through the small scale parameters including Knudsen number (Kn) and the nonlocal parameter. Then, the extended Galerkin's method is applied to solve the FSI governing equations, and to derive the stability diagrams of the system. Results show how the magnetic properties of the fluid flow have an effect on improving the stability of the cantilevered CNT by increasing the flutter velocity.

  5. Genome sequence analysis of emm89 Streptococcus pyogenes strains causing infections in Scotland, 2010-2016.

    Science.gov (United States)

    Beres, Stephen B; Olsen, Randall J; Ojeda Saavedra, Matthew; Ure, Roisin; Reynolds, Arlene; Lindsay, Diane S J; Smith, Andrew J; Musser, James M

    2017-12-01

    Strains of type emm89 Streptococcus pyogenes have recently increased in frequency as a cause of human infections in several countries in Europe and North America. This increase has been molecular epidemiologically linked with the emergence of a new genetically distinct clone, designated clade 3. We sought to extend our understanding of this epidemic behavior by the genetic characterization of type emm89 strains responsible in recent years for an increased frequency of infections in Scotland. We sequenced the genomes of a retrospective cohort of 122 emm89 strains recovered from patients with invasive and noninvasive infections throughout Scotland during 2010 to 2016. All but one of the 122 emm89 infection isolates are of the recently emerged epidemic clade 3 clonal lineage. The Scotland isolates are closely related to and not genetically distinct from recent emm89 strains from England, they constitute a single genetic population. The clade 3 clone causes virtually all-contemporary emm89 infections in Scotland. These findings add Scotland to a growing list of countries of Europe and North America where, by whole genome sequencing, emm89 clade 3 strains have been demonstrated to be the cause of an ongoing epidemic of invasive infections and to be genetically related due to descent from a recent common progenitor.

  6. Overexpression of eIF-5A2 in mice causes accelerated organismal aging by increasing chromosome instability

    Directory of Open Access Journals (Sweden)

    Chen Leilei

    2011-05-01

    Full Text Available Abstract Background Amplification of 3q26 is one of the most frequent genetic alterations in many human malignancies. Recently, we isolated a novel oncogene eIF-5A2 within the 3q26 region. Functional study has demonstrated the oncogenic role of eIF-5A2 in the initiation and progression of human cancers. In the present study, we aim to investigate the physiological and pathological effect of eIF-5A2 in an eIF-5A2 transgenic mouse model. Methods An eIF-5A2 transgenic mouse model was generated using human eIF-5A2 cDNA. The eIF-5A2 transgenic mice were characterized by histological and immunohistochemistry analyses. The aging phenotypes were further characterized by wound healing, bone X-ray imaging and calcification analysis. Mouse embryo fibroblasts (MEF were isolated to further investigate molecular mechanism of eIF-5A2 in aging. Results Instead of resulting in spontaneous tumor formation, overexpression of eIF-5A2 accelerated the aging process in adult transgenic mice. This included decreased growth rate and body weight, shortened life span, kyphosis, osteoporosis, delay of wound healing and ossification. Investigation of the correlation between cellular senescence and aging showed that cellular senescence is not required for the aging phenotypes in eIF-5A2 mice. Interestingly, we found that activation of eIF-5A2 repressed p19 level and therefore destabilized p53 in transgenic mouse embryo fibroblast (MEF cells. This subsequently allowed for the accumulation of chromosomal instability, such as errors in cell dividing during metaphase and anaphase. Additionally, a significantly increase in number of aneuploidy cells (p Conclusion These observations suggest that eIF-5A2 mouse models could accelerate organismal aging by increasing chromosome instability.

  7. 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

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

    Science.gov (United States)

    Guo, Xihan; Wang, Xu

    2016-09-03

    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 genomic damages partially by enhancing the function of SAC.

  9. 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.

  10. Global patterns in human mitochondrial DNA and Y-chromosome variation caused by spatial instability of the local cultural processes.

    Directory of Open Access Journals (Sweden)

    Vikrant Kumar

    2006-04-01

    Full Text Available Because of the widespread phenomenon of patrilocality, it is hypothesized that Y-chromosome variants tend to be more localized geographically than those of mitochondrial DNA (mtDNA. Empirical evidence confirmatory to this hypothesis was subsequently provided among certain patrilocal and matrilocal groups of Thailand, which conforms to the isolation by distance mode of gene diffusion. However, we expect intuitively that the patterns of genetic variability may not be consistent with the above hypothesis among populations with different social norms governing the institution of marriage, particularly among those that adhere to strict endogamy rules. We test the universality of this hypothesis by analyzing Y-chromosome and mtDNA data in three different sets of Indian populations that follow endogamy rules to varying degrees. Our analysis of the Indian patrilocal and the matrilocal groups is not confirmatory to the sex-specific variation observed among the tribes of Thailand. Our results indicate spatial instability of the impact of different cultural processes on the genetic variability, resulting in the lack of universality of the hypothesized pattern of greater Y-chromosome variation when compared to that of mtDNA among the patrilocal populations.

  11. Sparsely Ionizing Diagnostic and Natural Background Radiations are Likely Preventing Cancer and Other Genomic-Instability-Associated Diseases

    OpenAIRE

    Scott, Bobby R.; Di Palma, Jennifer

    2006-01-01

    Routine diagnostic X-rays (e.g., chest X-rays, mammograms, computed tomography scans) and routine diagnostic nuclear medicine procedures using sparsely ionizing radiation forms (e.g., beta and gamma radiations) stimulate the removal of precancerous neo-plastically transformed and other genomically unstable cells from the body (medical radiation hormesis). The indicated radiation hormesis arises because radiation doses above an individual-specific stochastic threshold activate a system of coop...

  12. Germ-line CAG repeat instability causes extreme CAG repeat expansion with infantile-onset spinocerebellar ataxia type 2

    DEFF Research Database (Denmark)

    Vinther-Jensen, Tua; Ek, Jakob; Duno, Morten

    2013-01-01

    The spinocerebellar ataxias (SCA) are a genetically and clinically heterogeneous group of diseases, characterized by dominant inheritance, progressive cerebellar ataxia and diverse extracerebellar symptoms. A subgroup of the ataxias is caused by unstable CAG-repeat expansions in their respective...

  13. Opening of the TAR hairpin in the HIV-1 genome causes aberrant RNA dimerization and packaging

    Directory of Open Access Journals (Sweden)

    Das Atze T

    2012-07-01

    Full Text Available Abstract Background The TAR hairpin is present at both the 5′ and 3′ end of the HIV-1 RNA genome. The 5′ element binds the viral Tat protein and is essential for Tat-mediated activation of transcription. We recently observed that complete TAR deletion is allowed in the context of an HIV-1 variant that does not depend on this Tat-TAR axis for transcription. Mutations that open the 5′ stem-loop structure did however affect the leader RNA conformation and resulted in a severe replication defect. In this study, we set out to analyze which step of the HIV-1 replication cycle is affected by this conformational change of the leader RNA. Results We demonstrate that opening the 5′ TAR structure through a deletion in either side of the stem region caused aberrant dimerization and reduced packaging of the unspliced viral RNA genome. In contrast, truncation of the TAR hairpin through deletions in both sides of the stem did not affect RNA dimer formation and packaging. Conclusions These results demonstrate that, although the TAR hairpin is not essential for RNA dimerization and packaging, mutations in TAR can significantly affect these processes through misfolding of the relevant RNA signals.

  14. A Complex Genomic Rearrangement Involving the Endothelin 3 Locus Causes Dermal Hyperpigmentation in the Chicken

    Science.gov (United States)

    Dorshorst, Ben; Molin, Anna-Maja; Rubin, Carl-Johan; Johansson, Anna M.; Strömstedt, Lina; Pham, Manh-Hung; Chen, Chih-Feng; Hallböök, Finn; Ashwell, Chris; Andersson, Leif

    2011-01-01

    Dermal hyperpigmentation or Fibromelanosis (FM) is one of the few examples of skin pigmentation phenotypes in the chicken, where most other pigmentation variants influence feather color and patterning. The Silkie chicken is the most widespread and well-studied breed displaying this phenotype. The presence of the dominant FM allele results in extensive pigmentation of the dermal layer of skin and the majority of internal connective tissue. Here we identify the causal mutation of FM as an inverted duplication and junction of two genomic regions separated by more than 400 kb in wild-type individuals. One of these duplicated regions contains endothelin 3 (EDN3), a gene with a known role in promoting melanoblast proliferation. We show that EDN3 expression is increased in the developing Silkie embryo during the time in which melanoblasts are migrating, and elevated levels of expression are maintained in the adult skin tissue. We have examined four different chicken breeds from both Asia and Europe displaying dermal hyperpigmentation and conclude that the same structural variant underlies this phenotype in all chicken breeds. This complex genomic rearrangement causing a specific monogenic trait in the chicken illustrates how novel mutations with major phenotypic effects have been reused during breed formation in domestic animals. PMID:22216010

  15. 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.

  16. Correlation of MLH1 and MGMT expression and promoter methylation with genomic instability in patients with thyroid carcinoma

    Directory of Open Access Journals (Sweden)

    Santos Juliana Carvalho

    2013-02-01

    Full Text Available Abstract Background 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. Methods 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. Results 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. Conclusions 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.

  17. MTHFR Functional Polymorphism C677T and Genomic Instability in the Etiology of Idiopathic Autism in Simplex Families

    Science.gov (United States)

    2014-12-01

    INTRODUCTION: Autism Spectrum Disorder (ASD) are a group of neurodevelopmental disorders that are caused by a range of factors, including: genetic, epigenetic...DISTRIBUTION / AVAILABILITY STATEMENT Approved for Public Release; Distribution Unlimited 13. SUPPLEMENTARY NOTES 14. ABSTRACT Autism Spectrum Disorder (ASD...are a group of neurodevelopmental disorders that are caused by a range of factors, including: genetic, epigenetic and environmental, with a genetic

  18. 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.

  19. 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

  20. Genome Sequence of the Banana Pathogen Dickeya zeae Strain MS1, Which Causes Bacterial Soft Rot.

    Science.gov (United States)

    Zhang, Jing-Xin; Lin, Bi-Run; Shen, Hui-Fang; Pu, Xiao-Ming

    2013-06-13

    We report a draft genome sequence of Dickeya zeae strain MS1, which is the causative agent of banana soft rot in China, and we show several of its specific properties compared with those of other D. zeae strains. Genome sequencing provides a tool for understanding the genomic determination of the pathogenicity and phylogeny placement of this pathogen.

  1. Genome Sequence of the Banana Pathogen Dickeya zeae Strain MS1, Which Causes Bacterial Soft Rot

    OpenAIRE

    Zhang, Jing-Xin; Lin, Bi-Run; Shen, Hui-Fang; Pu, Xiao-Ming

    2013-01-01

    We report a draft genome sequence of Dickeya zeae strain MS1, which is the causative agent of banana soft rot in China, and we show several of its specific properties compared with those of other D.?zeae strains. Genome sequencing provides a tool for understanding the genomic determination of the pathogenicity and phylogeny placement of this pathogen.

  2. Comparative genomics of Tunisian Leishmania major isolates causing human cutaneous leishmaniasis with contrasting clinical severity.

    Science.gov (United States)

    Ghouila, Amel; Guerfali, Fatma Z; Atri, Chiraz; Bali, Aymen; Attia, Hanene; Sghaier, Rabiaa M; Mkannez, Ghada; Dickens, Nicholas J; Laouini, Dhafer

    2017-06-01

    Zoonotic cutaneous leishmaniasis caused by Leishmania (L.) major parasites affects urban and suburban areas in the center and south of Tunisia where the disease is endemo-epidemic. Several cases were reported in human patients for which infection due to L. major induced lesions with a broad range of severity. However, very little is known about the mechanisms underlying this diversity. Our hypothesis is that parasite genomic variability could, in addition to the host immunological background, contribute to the intra-species clinical variability observed in patients and explain the lesion size differences observed in the experimental model. Based on several epidemiological, in vivo and in vitro experiments, we focused on two clinical isolates showing contrasted severity in patients and BALB/c experimental mice model. We used DNA-seq as a high-throughput technology to facilitate the identification of genetic variants with discriminating potential between both isolates. Our results demonstrate that various levels of heterogeneity could be found between both L. major isolates in terms of chromosome or gene copy number variation (CNV), and that the intra-species divergence could surprisingly be related to single nucleotide polymorphisms (SNPs) and Insertion/Deletion (InDels) events. Interestingly, we particularly focused here on genes affected by both types of variants and correlated them with the observed gene CNV. Whether these differences are sufficient to explain the severity in patients is obviously still open to debate, but we do believe that additional layers of -omic information is needed to complement the genomic screen in order to draw a more complete map of severity determinants. Copyright © 2016 Elsevier B.V. All rights reserved.

  3. Genetic instability in human tumors.

    Science.gov (United States)

    Raptis, Stavroula; Bapat, Bharati

    2006-01-01

    Genetic, or genomic, instability refers to a series of observed spontaneous genetic changes occurring at an accelerated rate in cell populations derived from the same ancestral precursor. This is far from a new finding, but is one that has increasingly gained more attention in the last decade due to its plausible role(s) in tumorigenesis. The majority of genetic alterations contributing to the malignant transformation are seen in growth regulatory genes, and in genes involved in cell cycle progression and arrest. Genomic instability may present itself through alterations in the length of short repeat stretches of coding and non-coding DNA, resulting in microsatellite instability. Tumors with such profiles are referred to as exhibiting a mutator phenotype, which is largely a consequence of inactivating mutations in DNA damage repair genes. Genomic instability may also, and most commonly, results from gross chromosomal changes, such as translocations or amplifications, which lead to chromosomal instability. Telomere length and telomerase activity, important in maintaining chromosomal structure and in regulating a normal cell's lifespan, have been shown to have a function in both suppressing and facilitating malignant transformation. In addition to such direct sequence and structural changes, gene silencing through the hypermethylation of promoter regions, or increased gene expression through the hypomethylation of such regions, together, form an alternative, epigenetic mechanism leading to instability. Emerging evidence also suggests that dietary and environmental agents can further modulate the contribution of genetic instability to tumorigenesis. Currently, there is still much debate over the distinct classes of genomic instability and their specific roles in the initiation of tumor formation, as well as in the progressive transition to a cancerous state. This review examines the various molecular mechanisms that result in this genomic instability and the potential

  4. Imbalanced lipid homeostasis in the conditional Dicer1 knockout mouse epididymis causes instability of the sperm membrane.

    Science.gov (United States)

    Björkgren, Ida; Gylling, Helena; Turunen, Heikki; Huhtaniemi, Ilpo; Strauss, Leena; Poutanen, Matti; Sipilä, Petra

    2015-02-01

    During epididymal sperm maturation, the lipid content of the sperm membrane is modified, which facilitates sperm motility and fertility. However, little is known about the mechanisms regulating the maturation process. By generating a conditional knockout (cKO) of Dicer1 in the proximal part of the mouse epididymis, we studied the role of RNA interference in epididymal functions. The Dicer1 cKO epididymis displayed an altered lipid homeostasis associated with a 0.6-fold reduction in the expression of the gene elongation of very long chain fatty acids-like 2, an enzyme needed for production of long-chain polyunsaturated fatty acids (PUFAs). Furthermore, the expression of several factors involved in cholesterol synthesis was up-regulated. Accordingly, the Dicer1 cKO sperm membrane showed a 0.7-fold decrease in long-chain PUFAs, whereas the amount of cholesterol in acrosome-reacted sperm displayed a 1.7-fold increase. The increased cholesterol:PUFA ratio of the sperm membrane caused breakage of the neck and acrosome region and immotility of sperm. Dicer1 cKO mice sperm also displayed reduced ability to bind to and fertilize the oocyte in vitro. This study thus shows that Dicer1 is critical for lipid synthesis in the epididymis, which directly affects sperm membrane integrity and male fertility. © FASEB.

  5. 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.

  6. Genome-wide association analysis of ear rot resistance caused by Fusarium verticillioides in maize.

    Science.gov (United States)

    de Jong, Guilherme; Pamplona, Andrezza Kellen Alves; Von Pinho, Renzo Garcia; Balestre, Marcio

    2017-12-06

    The identification of causal regions associated with resistance to Fusarium verticillioides can be useful to understand resistance mechanisms and further be used in breeding programs. In this study, a genome-wide association study (GWAS) was conducted to identify candidate markers associated with resistance to the ear rot caused by the fungus F. verticillioides. A total of 242 maize inbred lines were genotyped with 23,153 DArT-seq markers. A total of 12 DArTs were associated with ear rot resistance. Some DArTs were localized close to genes with functions directly related to ear rot resistance, such as a gene responsible for the innate immune response that belongs to the class of NBS-LRR receptors. Some markers were also found to be closely associated with genes that synthesize transcription factors (nactf11 and nactf61), genes responsible for the oxidation-reduction process and peroxidase activity. These results are encouraging since some candidate markers can present functional relationship with ear rot resistance in maize. Copyright © 2017 Elsevier Inc. All rights reserved.

  7. 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.)

  8. Architecture of Burkholderia cepacia complex σ70 gene family: evidence of alternative primary and clade-specific factors, and genomic instability

    Directory of Open Access Journals (Sweden)

    Menard Aymeric

    2007-09-01

    Full Text Available Abstract Background The Burkholderia cepacia complex (Bcc groups bacterial species with beneficial properties that can improve crop yields or remediate polluted sites but can also lead to dramatic human clinical outcomes among cystic fibrosis (CF or immuno-compromised individuals. Genome-wide regulatory processes of gene expression could explain parts of this bacterial duality. Transcriptional σ70 factors are components of these processes. They allow the reversible binding of the DNA-dependent RNA polymerase to form the holoenzyme that will lead to mRNA synthesis from a DNA promoter region. Bcc genome-wide analyses were performed to investigate the major evolutionary trends taking place in the σ70 family of these bacteria. Results Twenty σ70 paralogous genes were detected in the Burkholderia cenocepacia strain J2315 (Bcen-J2315 genome, of which 14 were of the ECF (extracytoplasmic function group. Non-ECF paralogs were related to primary (rpoD, alternative primary, stationary phase (rpoS, flagellin biosynthesis (fliA, and heat shock (rpoH factors. The number of σ70 genetic determinants among this genome was of 2,86 per Mb. This number is lower than the one of Pseudomonas aeruginosa, a species found in similar habitats including CF lungs. These two bacterial groups showed strikingly different σ70 family architectures, with only three ECF paralogs in common (fecI-like, pvdS and algU. Bcen-J2315 σ70 paralogs showed clade-specific distributions. Some paralogs appeared limited to the ET12 epidemic clone (ecfA2, particular Bcc species (sigI, the Burkholderia genus (ecfJ, ecfF, and sigJ, certain proteobacterial groups (ecfA1, ecfC, ecfD, ecfE, ecfG, ecfL, ecfM and rpoS, or were broadly distributed in the eubacteria (ecfI, ecfK, ecfH, ecfB, and rpoD-, rpoH-, fliA-like genes. Genomic instability of this gene family was driven by chromosomal inversion (ecfA2, recent duplication events (ecfA and RpoD, localized (ecfG and large scale deletions (sig

  9. Genome Sequence of Aspergillus flavus NRRL 3357, a Strain That Causes Aflatoxin Contamination of Food and Feed

    OpenAIRE

    Nierman, William C.; Yu, Jiujiang; Fedorova-Abrams, Natalie D.; Losada, Liliana; Cleveland, Thomas E.; Bhatnagar, Deepak; Bennett, Joan W.; Dean, Ralph; Payne, Gary A.

    2015-01-01

    Aflatoxin contamination of food and livestock feed results in significant annual crop losses internationally. Aspergillus flavus is the major fungus responsible for this loss. Additionally, A.?flavus is the second leading cause of aspergillosis in immunocompromised human patients. Here, we report the genome sequence of strain NRRL 3357.

  10. In silico analysis of virulence associated genes in genomes of Escherichia coli strains causing colibacillosis in poultry

    Directory of Open Access Journals (Sweden)

    Kołsut Joanna

    2017-12-01

    Full Text Available Introduction: Colibacillosis – the most common disease of poultry, is caused mainly by avian pathogenic Escherichia coli (APEC. However, thus far, no pattern to the molecular basis of the pathogenicity of these bacteria has been established beyond dispute. In this study, genomes of APEC were investigated to ascribe importance and explore the distribution of 16 genes recognised as their virulence factors.

  11. 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

  12. Genome sequence of a Lancefield group C Streptococcus zooepidemicus strain causing epidemic nephritis: new information about an old disease.

    Directory of Open Access Journals (Sweden)

    Stephen B Beres

    Full Text Available Outbreaks of disease attributable to human error or natural causes can provide unique opportunities to gain new information about host-pathogen interactions and new leads for pathogenesis research. Poststreptococcal glomerulonephritis (PSGN, a sequela of infection with pathogenic streptococci, is a common cause of preventable kidney disease worldwide. Although PSGN usually occurs after infection with group A streptococci, organisms of Lancefield group C and G also can be responsible. Despite decades of study, the molecular pathogenesis of PSGN is poorly understood. As a first step toward gaining new information about PSGN pathogenesis, we sequenced the genome of Streptococcus equi subsp. zooepidemicus strain MGCS10565, a group C organism that caused a very large and unusually severe epidemic of nephritis in Brazil. The genome is a circular chromosome of 2,024,171 bp. The genome shares extensive gene content, including many virulence factors, with genetically related group A streptococci, but unexpectedly lacks prophages. The genome contains many apparently foreign genes interspersed around the chromosome, consistent with the presence of a full array of genes required for natural competence. An inordinately large family of genes encodes secreted extracellular collagen-like proteins with multiple integrin-binding motifs. The absence of a gene related to speB rules out the long-held belief that streptococcal pyrogenic exotoxin B or antibodies reacting with it singularly cause PSGN. Many proteins previously implicated in GAS PSGN, such as streptokinase, are either highly divergent in strain MGCS10565 or are not more closely related between these species than to orthologs present in other streptococci that do not commonly cause PSGN. Our analysis provides a comparative genomics framework for renewed appraisal of molecular events underlying APSGN pathogenesis.

  13. Genome sequence of a Lancefield group C Streptococcus zooepidemicus strain causing epidemic nephritis: new information about an old disease.

    Science.gov (United States)

    Beres, Stephen B; Sesso, Ricardo; Pinto, Sergio Wyton L; Hoe, Nancy P; Porcella, Stephen F; Deleo, Frank R; Musser, James M

    2008-08-21

    Outbreaks of disease attributable to human error or natural causes can provide unique opportunities to gain new information about host-pathogen interactions and new leads for pathogenesis research. Poststreptococcal glomerulonephritis (PSGN), a sequela of infection with pathogenic streptococci, is a common cause of preventable kidney disease worldwide. Although PSGN usually occurs after infection with group A streptococci, organisms of Lancefield group C and G also can be responsible. Despite decades of study, the molecular pathogenesis of PSGN is poorly understood. As a first step toward gaining new information about PSGN pathogenesis, we sequenced the genome of Streptococcus equi subsp. zooepidemicus strain MGCS10565, a group C organism that caused a very large and unusually severe epidemic of nephritis in Brazil. The genome is a circular chromosome of 2,024,171 bp. The genome shares extensive gene content, including many virulence factors, with genetically related group A streptococci, but unexpectedly lacks prophages. The genome contains many apparently foreign genes interspersed around the chromosome, consistent with the presence of a full array of genes required for natural competence. An inordinately large family of genes encodes secreted extracellular collagen-like proteins with multiple integrin-binding motifs. The absence of a gene related to speB rules out the long-held belief that streptococcal pyrogenic exotoxin B or antibodies reacting with it singularly cause PSGN. Many proteins previously implicated in GAS PSGN, such as streptokinase, are either highly divergent in strain MGCS10565 or are not more closely related between these species than to orthologs present in other streptococci that do not commonly cause PSGN. Our analysis provides a comparative genomics framework for renewed appraisal of molecular events underlying APSGN pathogenesis.

  14. 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.

  15. Large Genomic Deletions in CACNA1A Cause Episodic Ataxia Type 2

    Directory of Open Access Journals (Sweden)

    Jijun eWan

    2011-09-01

    Full Text Available Episodic ataxia (EA syndromes are heritable diseases characterized by dramatic episodes of imbalance and incoordination. Episodic ataxia type 2 (EA2, the most common and the best characterized subtype, is caused by mostly nonsense, splice site, small indel and sometimes missense mutations in CACNA1A. Direct sequencing of CACNA1A fails to identify mutations in some patients with EA2-like features, possibly due to incomplete interrogation of CACNA1A or defects in other EA genes not yet defined. Previous reports described genomic deletions between 4-40kb in EA2. In 47 subjects with EA (26 with EA2-like features who tested negative for mutations in the known EA genes, we used Multiplex Ligation-dependent Probe Amplification (MLPA to analyze CACNA1A for exonic copy number variations. Breakpoints were further defined by long-range PCR. We identified distinct multi-exonic deletions in three probands with classic EA2-like features: episodes of prolonged vertigo and ataxia triggered by stress and fatigue, interictal nystagmus, with onset during infancy or early childhood. The breakpoints in all three probands are located in Alu sequences, indicating errors in homologous recombination of Alu sequences as the underlying mechanism. The smallest deletion spanned exons 39 and 40, while the largest deletion spanned 200kb, missing all but the first three exons. One deletion involving exons 39 through 47 arose spontaneously. The search for mutations in CACNA1A appears most fruitful in EA patients with interictal nystagmus and onset early in life. The finding of large heterozygous deletions suggests haploinsufficiency as a possible pathomechanism of EA2.

  16. 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.)

  17. 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.)

  18. Characteristics and complete genome analysis of a novel jumbo phage infecting pathogenic Bacillus pumilus causing ginger rhizome rot disease.

    Science.gov (United States)

    Yuan, Yihui; Gao, Meiying

    2016-12-01

    Tailed phages with genomes larger than 200 kbp are classified as jumbo phage and exhibit extremely high diversity. In this study, a novel jumbo phage, vB_BpuM_BpSp, infecting pathogenic Bacillus pumilus, the cause of ginger rhizome rot disease, was isolated. Notable features of phage vB_BpuM_BpSp are the large phage capsid of 137 nm and baseplate-attached curly tail fibers. The genome of the phage is 255,569 bp in size with G+C content of 25.9 %, and it shows low similarity to known biological entities. The phage genome contains 318 predicted coding sequences. Among these predicted coding sequences, 26 genes responsible for nucleotide metabolism were found, and seven structural genes could be identified. The findings of this study provide new understanding of the genetic diversity of phages.

  19. Relaxation of selective constraints causes independent selenoprotein extinction in insect genomes.

    Directory of Open Access Journals (Sweden)

    Charles E Chapple

    Full Text Available BACKGROUND: Selenoproteins are a diverse family of proteins notable for the presence of the 21st amino acid, selenocysteine. Until very recently, all metazoan genomes investigated encoded selenoproteins, and these proteins had therefore been believed to be essential for animal life. Challenging this assumption, recent comparative analyses of insect genomes have revealed that some insect genomes appear to have lost selenoprotein genes. METHODOLOGY/PRINCIPAL FINDINGS: In this paper we investigate in detail the fate of selenoproteins, and that of selenoprotein factors, in all available arthropod genomes. We use a variety of in silico comparative genomics approaches to look for known selenoprotein genes and factors involved in selenoprotein biosynthesis. We have found that five insect species have completely lost the ability to encode selenoproteins and that selenoprotein loss in these species, although so far confined to the Endopterygota infraclass, cannot be attributed to a single evolutionary event, but rather to multiple, independent events. Loss of selenoproteins and selenoprotein factors is usually coupled to the deletion of the entire no-longer functional genomic region, rather than to sequence degradation and consequent pseudogenisation. Such dynamics of gene extinction are consistent with the high rate of genome rearrangements observed in Drosophila. We have also found that, while many selenoprotein factors are concomitantly lost with the selenoproteins, others are present and conserved in all investigated genomes, irrespective of whether they code for selenoproteins or not, suggesting that they are involved in additional, non-selenoprotein related functions. CONCLUSIONS/SIGNIFICANCE: Selenoproteins have been independently lost in several insect species, possibly as a consequence of the relaxation in insects of the selective constraints acting across metazoans to maintain selenoproteins. The dispensability of selenoproteins in insects may

  20. On Kelvin-Helmholtz instability in superfluids

    International Nuclear Information System (INIS)

    Volovik, G.E.

    2002-01-01

    The problem of the Kelvin-Helmholtz (KH) instability in superfluids is discussed. The classical KH instability and the KH instability in superfluids at low temperature are considered. The results of experimental observations of such instabilities at the interface between superfluid 3 He-A and superfluid 3 He-B are analyzed. The causes of the disagreement of values for the instability threshold obtained by means of the Kelvin Helmholtz criterion and the modified Landau criterion are discussed [ru

  1. Draft genome sequencing of giardia intestinalis assemblage B isolate GS: is human giardiasis caused by two different species?

    Directory of Open Access Journals (Sweden)

    Oscar Franzén

    2009-08-01

    Full Text Available Giardia intestinalis is a major cause of diarrheal disease worldwide and two major Giardia genotypes, assemblages A and B, infect humans. The genome of assemblage A parasite WB was recently sequenced, and the structurally compact 11.7 Mbp genome contains simplified basic cellular machineries and metabolism. We here performed 454 sequencing to 16x coverage of the assemblage B isolate GS, the only Giardia isolate successfully used to experimentally infect animals and humans. The two genomes show 77% nucleotide and 78% amino-acid identity in protein coding regions. Comparative analysis identified 28 unique GS and 3 unique WB protein coding genes, and the variable surface protein (VSP repertoires of the two isolates are completely different. The promoters of several enzymes involved in the synthesis of the cyst-wall lack binding sites for encystation-specific transcription factors in GS. Several synteny-breaks were detected and verified. The tetraploid GS genome shows higher levels of overall allelic sequence polymorphism (0.5 versus <0.01% in WB. The genomic differences between WB and GS may explain some of the observed biological and clinical differences between the two isolates, and it suggests that assemblage A and B Giardia can be two different species.

  2. Microsatellite instability in hematological malignancies

    OpenAIRE

    Maletzki, Claudia; Stier, Saskia; Linnebacher, Michael

    2013-01-01

    The genome of colorectal carcinomas displaying pronounced microsatellite instability codes for an extraordinarily high number of mutated proteins that elicit tumor-specific cellular immune responses. We have recently demonstrated that leukemic cells are also vulnerable to T cells specific for tumor-associated antigens produced in the context of microsatellite instability. This finding extends our understanding of secondary and therapy-related leukemogenesis, linking it to the mutual interacti...

  3. Genomic deletion of CNGB3 is identical by descent in multiple canine breeds and causes achromatopsia.

    Science.gov (United States)

    Yeh, Connie Y; Goldstein, Orly; Kukekova, Anna V; Holley, Debbie; Knollinger, Amy M; Huson, Heather J; Pearce-Kelling, Susan E; Acland, Gregory M; Komáromy, András M

    2013-04-20

    Achromatopsia is an autosomal recessive disease characterized by the loss of cone photoreceptor function that results in day-blindness, total colorblindness, and decreased central visual acuity. The most common causes for the disease are mutations in the CNGB3 gene, coding for the beta subunit of the cyclic nucleotide-gated channels in cones. CNGB3-achromatopsia, or cone degeneration (cd), is also known to occur in two canine breeds, the Alaskan malamute (AM) and the German shorthaired pointer. Here we report an in-depth characterization of the achromatopsia phenotype in a new canine breed, the miniature Australian shepherd (MAS). Genotyping revealed that the dog was homozygous for a complete genomic deletion of the CNGB3 gene, as has been previously observed in the AM. Identical breakpoints on chromosome 29 were identified in both the affected AM and MAS with a resulting deletion of 404,820 bp. Pooled DNA samples of unrelated purebred Australian shepherd, MAS, Siberian husky, Samoyed and Alaskan sled dogs were screened for the presence of the affected allele; one Siberian husky and three Alaskan sled dogs were identified as carriers. The affected chromosomes from the AM, MAS, and Siberian husky were genotyped for 147 SNPs in a 3.93 Mb interval within the cd locus. An identical shared affected haplotype, 0.5 Mb long, was observed in all three breeds and defined the minimal linkage disequilibrium (LD) across breeds. This supports the idea that the mutated allele was identical by descent (IBD). We report the occurrence of CNGB3-achromatopsia in a new canine breed, the MAS. The CNGB3-deletion allele previously described in the AM was also observed in a homozygous state in the affected MAS, as well as in a heterozygous carrier state in a Siberian husky and Alaskan sled dogs. All affected alleles were shown to be IBD, strongly suggesting an affected founder effect. Since the MAS is not known to be genetically related to the AM, other breeds may potentially carry the

  4. Suggested mechanisms for Zika virus causing microcephaly: what do the genomes tell us?

    Science.gov (United States)

    Jun, Se-Ran; Wassenaar, Trudy M; Wanchai, Visanu; Patumcharoenpol, Preecha; Nookaew, Intawat; Ussery, David W

    2017-12-28

    Zika virus (ZIKV) is an emerging human pathogen. Since its arrival in the Western hemisphere, from Africa via Asia, it has become a serious threat to pregnant women, causing microcephaly and other neuropathies in developing fetuses. The mechanisms behind these teratogenic effects are unknown, although epidemiological evidence suggests that microcephaly is not associated with the original, African lineage of ZIKV. The sequences of 196 published ZIKV genomes were used to assess whether recently proposed mechanistic explanations for microcephaly are supported by molecular level changes that may have increased its virulence since the virus left Africa. For this we performed phylogenetic, recombination, adaptive evolution and tetramer frequency analyses, and compared protein sequences for the presence of protease cleavage sites, Pfam domains, glycosylation sites, signal peptides, trans-membrane protein domains, and phosphorylation sites. Recombination events within or between Asian and Brazilian lineages were not observed, and likewise there were no differences in protease cleavage, glycosylation sites, signal peptides or trans-membrane domains between African and Brazilian strains. The frequency of Retinoic Acid Response Element (RARE) sequences was increased in Brazilian strains. Genetic adaptation was also apparent by tetramer signatures that had undergone major changes in the past but has stabilized in the Brazilian lineage despite subsequent geographic spread, suggesting the viral population presently propagates in the same host species in various regions. Evidence for selection pressure was recognized for several amino acid sites in the Brazilian lineage compared to the African lineage, mainly in nonstructural proteins, especially protein NS4B. A number of these positively selected mutations resulted in an increased potential to be phosphorylated in the Brazilian lineage compared to the African linage, which may have increased their potential to interfere with

  5. Genomic Instability and Breast Cancer

    Science.gov (United States)

    2011-01-01

    chromatin. J Cell Biol 181, 227-240. Sung, P., Krejci, L., Van Komen, S., and Sehorn, M.G. (2003). Rad51 recombinase and recombination mediators. J Biol...8. Nijman, S. M., Luna-Vargas, M. P., Velds , A., Brummelkamp, T. R., Dirac, BRCC36 Is Regulated by Two Scaffold Proteins OCTOBER 1, 2010 • VOLUME 285...and Research (Y.W.). E.S. is the incumbent of the Soretta and Henry Shapiro career development chair. Y.S. is co-founder and on the scientific

  6. Genomic Instability and Breast Cancer

    Science.gov (United States)

    2011-06-01

    indicated. (B) Schematic diagrams of wild-type and mutant FIGN1 used in this study. (C) GST pull down experiments confirmed a direct interaction...States, Korea, Hong Kong, India and China. Many of them are continuing breast cancer research, with topics ranging from DNA damage response, mitotic...N-terminal-tagged fusion protein. SFB (triple-epitope of S-protein, FLAG, and streptavi- din binding peptide), Myc, MBP, and GST -tagged proteins were

  7. Genomic Instability and Breast Cancer

    Science.gov (United States)

    2009-10-01

    EDVP complex and katanin p60. (b) Bacterially expressed recombinant MBP-tagged EDD, DDB1 or VPRBP bound to amylase -Sepharose beads was incubated with...or MBP–VPRBP bound to amylase -Sepharose beads were incubated with bacterially purified GST–katanin for 1 h at 4 °C; the washed complexes were eluted...2 heterogeneous nuclear ribonucleoprotein u (hnrnp u) 1 dna-binding protein a 1 tubulin alpha -6 chain 1 60s acidic

  8. Cause-Effect relationship of the Laguna Verde BWR power instability by empirical mode decomposition; Relacion efecto-causa de la inestabilidad de potencia del BWR de Laguna Verde por descomposicion modal empirica

    Energy Technology Data Exchange (ETDEWEB)

    Blazquez, J.; Ruiz, J.; Castillo, R. [ININ, 52750 La Marquesa, Estado de Mexico (Mexico)

    2008-07-01

    The signals coming from natural phenomena are in essence non lineal and not stationary. A recent development, well-known as Empirical Mode Decomposition (EMD) it presents a novel focus that allows to represent in adaptative form non stationary signals as a sum of components of half zero. These components denominated Intrinsic Mode Functions (IMF) they help to the analysis of the frequency composition of unidimensional signals. The use of the EMD followed by the Hilbert transform of the IMFs it allows to carry out an analysis in time-frequency of the non lineal and not stationary data. This technique is known as the Hilbert Huang Transform (HHT). In this work a power instability event occurred in January 24, 1995 in the unit I of the nuclear power station of Laguna Verde (Mexico), corresponding to a BWR/5 is analyzed. When a Nuclear Plant suffers a power instability event, it is required obligatorily to explain to the Regulator Organism the effects and the causes of the event. The effects are described simply; not in vain there is a registration of signals in the Process Computer of where the required information is extracted. But the causes are not always immediate and easy for to identify. The power instability can happen during the start, when the refrigeration flow is relatively low in front to the power. By reason of that the reactivity coefficient by holes is negative, the power oscillates with a very defined frequency, generally of the order of 0.5 Hz. If the oscillations increase progressively of amplitude, we are in an instability event. It is interesting to include in the report the instant in that the began instability and the actions of the operator before and after the same one. As the actions are registered, the investigation is focused toward the instant of the beginning to be able to identify them. In this work the power signal in five empiric ways of Hilbert-Huang and a residual breaks down. The instability is only reflected in the way of smaller

  9. Comparative Genomics of Pathogens Causing Brown Spot Disease of Tobacco: Alternaria longipes and Alternaria alternata.

    Science.gov (United States)

    Hou, Yujie; Ma, Xiao; Wan, Wenting; Long, Ni; Zhang, Jing; Tan, Yuntao; Duan, Shengchang; Zeng, Yan; Dong, Yang

    2016-01-01

    The genus Alternaria is a group of infectious/contagious pathogenic fungi that not only invade a wide range of crops but also induce severe allergic reactions in a part of the human population. In this study, two strains Alternaria longipes cx1 and Alternaria alternata cx2 were isolated from different brown spot lesions on infected tobacco leaves. Their complete genomes were sequenced, de novo assembled, and comparatively analyzed. Phylogenetic analysis revealed that A. longipes cx1 and A. alternata cx2 diverged 3.3 million years ago, indicating a recent event of speciation. Seventeen non-ribosomal peptide synthetase (NRPS) genes and 13 polyketide synthase (PKS) genes in A. longipes cx1 and 13 NRPS genes and 12 PKS genes in A. alternata cx2 were identified in these two strains. Some of these genes were predicted to participate in the synthesis of non-host specific toxins (non-HSTs), such as tenuazonic acid (TeA), alternariol (AOH) and alternariol monomethyl ether (AME). By comparative genome analysis, we uncovered that A. longipes cx1 had more genes putatively involved in pathogen-plant interaction, more carbohydrate-degrading enzymes and more secreted proteins than A. alternata cx2. In summary, our results demonstrate the genomic distinction between A. longipes cx1 and A. altenata cx2. They will not only improve the understanding of the phylogenetic relationship among genus Alternaria, but more importantly provide valuable genomic resources for the investigation of plant-pathogen interaction.

  10. Comparative Genomics of Pathogens Causing Brown Spot Disease of Tobacco: Alternaria longipes and Alternaria alternata.

    Directory of Open Access Journals (Sweden)

    Yujie Hou

    Full Text Available The genus Alternaria is a group of infectious/contagious pathogenic fungi that not only invade a wide range of crops but also induce severe allergic reactions in a part of the human population. In this study, two strains Alternaria longipes cx1 and Alternaria alternata cx2 were isolated from different brown spot lesions on infected tobacco leaves. Their complete genomes were sequenced, de novo assembled, and comparatively analyzed. Phylogenetic analysis revealed that A. longipes cx1 and A. alternata cx2 diverged 3.3 million years ago, indicating a recent event of speciation. Seventeen non-ribosomal peptide synthetase (NRPS genes and 13 polyketide synthase (PKS genes in A. longipes cx1 and 13 NRPS genes and 12 PKS genes in A. alternata cx2 were identified in these two strains. Some of these genes were predicted to participate in the synthesis of non-host specific toxins (non-HSTs, such as tenuazonic acid (TeA, alternariol (AOH and alternariol monomethyl ether (AME. By comparative genome analysis, we uncovered that A. longipes cx1 had more genes putatively involved in pathogen-plant interaction, more carbohydrate-degrading enzymes and more secreted proteins than A. alternata cx2. In summary, our results demonstrate the genomic distinction between A. longipes cx1 and A. altenata cx2. They will not only improve the understanding of the phylogenetic relationship among genus Alternaria, but more importantly provide valuable genomic resources for the investigation of plant-pathogen interaction.

  11. 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...

  12. Rice-Infecting Pseudomonas Genomes Are Highly Accessorized and Harbor Multiple Putative Virulence Mechanisms to Cause Sheath Brown Rot

    Science.gov (United States)

    Quibod, Ian Lorenzo; Grande, Genelou; Oreiro, Eula Gems; Borja, Frances Nikki; Dossa, Gerbert Sylvestre; Mauleon, Ramil; Cruz, Casiana Vera; Oliva, Ricardo

    2015-01-01

    Sheath rot complex and seed discoloration in rice involve a number of pathogenic bacteria that cannot be associated with distinctive symptoms. These pathogens can easily travel on asymptomatic seeds and therefore represent a threat to rice cropping systems. Among the rice-infecting Pseudomonas, P. fuscovaginae has been associated with sheath brown rot disease in several rice growing areas around the world. The appearance of a similar Pseudomonas population, which here we named P. fuscovaginae-like, represents a perfect opportunity to understand common genomic features that can explain the infection mechanism in rice. We showed that the novel population is indeed closely related to P. fuscovaginae. A comparative genomics approach on eight rice-infecting Pseudomonas revealed heterogeneous genomes and a high number of strain-specific genes. The genomes of P. fuscovaginae-like harbor four secretion systems (Type I, II, III, and VI) and other important pathogenicity machinery that could probably facilitate rice colonization. We identified 123 core secreted proteins, most of which have strong signatures of positive selection suggesting functional adaptation. Transcript accumulation of putative pathogenicity-related genes during rice colonization revealed a concerted virulence mechanism. The study suggests that rice-infecting Pseudomonas causing sheath brown rot are intrinsically diverse and maintain a variable set of metabolic capabilities as a potential strategy to occupy a range of environments. PMID:26422147

  13. Rice-Infecting Pseudomonas Genomes Are Highly Accessorized and Harbor Multiple Putative Virulence Mechanisms to Cause Sheath Brown Rot.

    Directory of Open Access Journals (Sweden)

    Ian Lorenzo Quibod

    Full Text Available Sheath rot complex and seed discoloration in rice involve a number of pathogenic bacteria that cannot be associated with distinctive symptoms. These pathogens can easily travel on asymptomatic seeds and therefore represent a threat to rice cropping systems. Among the rice-infecting Pseudomonas, P. fuscovaginae has been associated with sheath brown rot disease in several rice growing areas around the world. The appearance of a similar Pseudomonas population, which here we named P. fuscovaginae-like, represents a perfect opportunity to understand common genomic features that can explain the infection mechanism in rice. We showed that the novel population is indeed closely related to P. fuscovaginae. A comparative genomics approach on eight rice-infecting Pseudomonas revealed heterogeneous genomes and a high number of strain-specific genes. The genomes of P. fuscovaginae-like harbor four secretion systems (Type I, II, III, and VI and other important pathogenicity machinery that could probably facilitate rice colonization. We identified 123 core secreted proteins, most of which have strong signatures of positive selection suggesting functional adaptation. Transcript accumulation of putative pathogenicity-related genes during rice colonization revealed a concerted virulence mechanism. The study suggests that rice-infecting Pseudomonas causing sheath brown rot are intrinsically diverse and maintain a variable set of metabolic capabilities as a potential strategy to occupy a range of environments.

  14. APC/C Dysfunction Limits Excessive Cancer Chromosomal Instability

    Science.gov (United States)

    Sansregret, Laurent; 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

    2017-01-01

    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. Significance 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. PMID:28069571

  15. Draft Genome Sequences of Three Pectobacterium Strains Causing Blackleg of Potato: P. carotovorum subsp. brasiliensis ICMP 19477, P. atrosepticum ICMP 1526, and P. carotovorum subsp. carotovorum UGC32.

    Science.gov (United States)

    Panda, Preetinanda; Fiers, Mark W E J; Lu, Ashley; Armstrong, Karen F; Pitman, Andrew R

    2015-08-06

    Blackleg is a disease caused by several species of Pectobacterium that results in losses to potato crops worldwide. Here, we report the draft genomes of three taxonomically and geographically distinct blackleg-causing strains of Pectobacterium: P. carotovorum subsp. brasiliensis ICMP 19477, P. atrosepticum ICMP 1526, and P. carotovorum subsp. carotovorum UGC32. Comparison of these genomes will support the identification of common traits associated with their capacity to cause blackleg. Copyright © 2015 Panda et al.

  16. 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

  17. Sequence-Based Mapping and Genome Editing Reveal Mutations in Stickleback Hps5 Cause Oculocutaneous Albinism and the casper Phenotype

    Directory of Open Access Journals (Sweden)

    James C. Hart

    2017-09-01

    Full Text Available Here, we present and characterize the spontaneous X-linked recessive mutation casper, which causes oculocutaneous albinism in threespine sticklebacks (Gasterosteus aculeatus. In humans, Hermansky-Pudlak syndrome results in pigmentation defects due to disrupted formation of the melanin-containing lysosomal-related organelle (LRO, the melanosome. casper mutants display not only reduced pigmentation of melanosomes in melanophores, but also reductions in the iridescent silver color from iridophores, while the yellow pigmentation from xanthophores appears unaffected. We mapped casper using high-throughput sequencing of genomic DNA from bulked casper mutants to a region of the stickleback X chromosome (chromosome 19 near the stickleback ortholog of Hermansky-Pudlak syndrome 5 (Hps5. casper mutants have an insertion of a single nucleotide in the sixth exon of Hps5, predicted to generate an early frameshift. Genome editing using CRISPR/Cas9 induced lesions in Hps5 and phenocopied the casper mutation. Injecting single or paired Hps5 guide RNAs revealed higher incidences of genomic deletions from paired guide RNAs compared to single gRNAs. Stickleback Hps5 provides a genetic system where a hemizygous locus in XY males and a diploid locus in XX females can be used to generate an easily scored visible phenotype, facilitating quantitative studies of different genome editing approaches. Lastly, we show the ability to better visualize patterns of fluorescent transgenic reporters in Hps5 mutant fish. Thus, Hps5 mutations present an opportunity to study pigmented LROs in the emerging stickleback model system, as well as a tool to aid in assaying genome editing and visualizing enhancer activity in transgenic fish.

  18. Whole-Genome Characterization and Strain Comparison of VT2f-Producing Escherichia coli Causing Hemolytic Uremic Syndrome

    Science.gov (United States)

    Michelacci, Valeria; Bondì, Roslen; Gigliucci, Federica; Franz, Eelco; Badouei, Mahdi Askari; Schlager, Sabine; Minelli, Fabio; Tozzoli, Rosangela; Caprioli, Alfredo; Morabito, Stefano

    2016-01-01

    Verotoxigenic Escherichia coli infections in humans cause disease ranging from uncomplicated intestinal illnesses to bloody diarrhea and systemic sequelae, such as hemolytic uremic syndrome (HUS). Previous research indicated that pigeons may be a reservoir for a population of verotoxigenic E. coli producing the VT2f variant. We used whole-genome sequencing to characterize a set of VT2f-producing E. coli strains from human patients with diarrhea or HUS and from healthy pigeons. We describe a phage conveying the vtx2f genes and provide evidence that the strains causing milder diarrheal disease may be transmitted to humans from pigeons. The strains causing HUS could derive from VT2f phage acquisition by E. coli strains with a virulence genes asset resembling that of typical HUS-associated verotoxigenic E. coli. PMID:27584691

  19. Do Non-Genomically Encoded Fusion Transcripts Cause Recurrent Chromosomal Translocations?

    Directory of Open Access Journals (Sweden)

    Theo Dingermann

    2012-10-01

    Full Text Available We among others have recently demonstrated that normal cells produce “fusion mRNAs”. These fusion mRNAs do not derive from rearranged genomic loci, but rather they are derived from “early-terminated transcripts” (ETTs. Premature transcriptional termination takes place in intronic sequences that belong to “breakpoint cluster regions”. One important property of ETTs is that they exhibit an unsaturated splice donor site. This results in: (1 splicing to “cryptic exons” present in the final intron; (2 Splicing to another transcript of the same gene (intragenic trans-splicing, resulting in “exon repetitions”; (3 splicing to a transcript of another gene (intergenic trans-splicing, leading to “non-genomically encoded fusion transcripts” (NGEFTs. These NGEFTs bear the potential risk to influence DNA repair processes, since they share identical nucleotides with their DNA of origin, and thus, could be used as “guidance RNA” for DNA repair processes. Here, we present experimental data about four other genes. Three of them are associated with hemato-malignancies (ETV6, NUP98 and RUNX1, while one is associated with solid tumors (EWSR1. Our results demonstrate that all genes investigated so far (MLL, AF4, AF9, ENL, ELL, ETV6, NUP98, RUNX1 and EWSR1 display ETTs and produce transpliced mRNA species, indicating that this is a genuine property of translocating genes.

  20. Do Non-Genomically Encoded Fusion Transcripts Cause Recurrent Chromosomal Translocations?

    Energy Technology Data Exchange (ETDEWEB)

    Kowarz, Eric; Dingermann, Theo; Marschalek, Rolf, E-mail: Rolf.Marschalek@em.uni-frankfurt.de [Institute of Pharmaceutical Biology/ZAFES/DCAL, Goethe-University of Frankfurt, Biocenter, Max-von-Laue-Str. 9, D-60438 Frankfurt/Main (Germany)

    2012-10-18

    We among others have recently demonstrated that normal cells produce “fusion mRNAs”. These fusion mRNAs do not derive from rearranged genomic loci, but rather they are derived from “early-terminated transcripts” (ETTs). Premature transcriptional termination takes place in intronic sequences that belong to “breakpoint cluster regions”. One important property of ETTs is that they exhibit an unsaturated splice donor site. This results in: (1) splicing to “cryptic exons” present in the final intron; (2) Splicing to another transcript of the same gene (intragenic trans-splicing), resulting in “exon repetitions”; (3) splicing to a transcript of another gene (intergenic trans-splicing), leading to “non-genomically encoded fusion transcripts” (NGEFTs). These NGEFTs bear the potential risk to influence DNA repair processes, since they share identical nucleotides with their DNA of origin, and thus, could be used as “guidance RNA” for DNA repair processes. Here, we present experimental data about four other genes. Three of them are associated with hemato-malignancies (ETV6, NUP98 and RUNX1), while one is associated with solid tumors (EWSR1). Our results demonstrate that all genes investigated so far (MLL, AF4, AF9, ENL, ELL, ETV6, NUP98, RUNX1 and EWSR1) display ETTs and produce transpliced mRNA species, indicating that this is a genuine property of translocating genes.

  1. 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

  2. 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)

  3. Multifragmentation: surface instabilities or statistical decay

    Energy Technology Data Exchange (ETDEWEB)

    Moretto, L.G.; Tso, K.; Delis, D.; Colonna, N.; Wozniak, G.J. (Lawrence Berkeley Lab., Berkeley, CA (United States). Nuclear Science Div.)

    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. Multifragmentation: Surface instabilities or statistical decay?

    Science.gov (United States)

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

    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.

  5. Multifragmentation: Surface instabilities or statistical decay

    Energy Technology Data Exchange (ETDEWEB)

    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.

  6. Genome-wide molecular dissection of serotype M3 group A Streptococcus strains causing two epidemics of invasive infections.

    Science.gov (United States)

    Beres, Stephen B; Sylva, Gail L; Sturdevant, Daniel E; Granville, Chanel N; Liu, Mengyao; Ricklefs, Stacy M; Whitney, Adeline R; Parkins, Larye D; Hoe, Nancy P; Adams, Gerald J; Low, Donald E; DeLeo, Frank R; McGeer, Allison; Musser, James M

    2004-08-10

    Molecular factors that contribute to the emergence of new virulent bacterial subclones and epidemics are poorly understood. We hypothesized that analysis of a population-based strain sample of serotype M3 group A Streptococcus (GAS) recovered from patients with invasive infection by using genome-wide investigative methods would provide new insight into this fundamental infectious disease problem. Serotype M3 GAS strains (n = 255) cultured from patients in Ontario, Canada, over 11 years and representing two distinct infection peaks were studied. Genetic diversity was indexed by pulsed-field gel electrophoresis, DNA-DNA microarray, whole-genome PCR scanning, prophage genotyping, targeted gene sequencing, and single-nucleotide polymorphism genotyping. All variation in gene content was attributable to acquisition or loss of prophages, a molecular process that generated unique combinations of proven or putative virulence genes. Distinct serotype M3 genotypes experienced rapid population expansion and caused infections that differed significantly in character and severity. Molecular genetic analysis, combined with immunologic studies, implicated a 4-aa duplication in the extreme N terminus of M protein as a factor contributing to an epidemic wave of serotype M3 invasive infections. This finding has implications for GAS vaccine research. Genome-wide analysis of population-based strain samples cultured from clinically well defined patients is crucial for understanding the molecular events underlying bacterial epidemics.

  7. SCREEN FOR DOMINANT BEHAVIORAL MUTATIONS CAUSED BY GENOMIC INSERTION OF P-ELEMENT TRANSPOSONS IN DROSOPHILA: AN EXAMINATION OF THE INTEGRATION OF VIRAL VECTOR SEQUENCES

    OpenAIRE

    FOX, LYLE E.; GREEN, DAVID; YAN, ZIYING; ENGELHARDT, JOHN F.; WU, CHUN-FANG

    2007-01-01

    Here we report the development of a high-throughput screen to assess dominant mutation rates caused by P-element transposition within the Drosophila genome that is suitable for assessing the undesirable effects of integrating foreign regulatory sequences (viral cargo) into a host genome. Three different behavioral paradigms were used: sensitivity to mechanical stress, response to heat stress, and ability to fly. The results, from our screen of 35,000 flies, indicate that mutations caused by t...

  8. Full-genome analysis of a canine pneumovirus causing acute respiratory disease in dogs, Italy.

    Directory of Open Access Journals (Sweden)

    Nicola Decaro

    Full Text Available An outbreak of canine infectious respiratory disease (CIRD associated to canine pneumovirus (CnPnV infection is reported. The outbreak occurred in a shelter of the Apulia region and involved 37 out of 350 dogs that displayed cough and/or nasal discharge with no evidence of fever. The full-genomic characterisation showed that the causative agent (strain Bari/100-12 was closely related to CnPnVs that have been recently isolated in the USA, as well as to murine pneumovirus, which is responsible for respiratory disease in mice. The present study represents a useful contribution to the knowledge of the pathogenic potential of CnPnV and its association with CIRD in dogs. Further studies will elucidate the pathogenicity and epidemiology of this novel pneumovirus, thus addressing the eventual need for specific vaccines.

  9. Detecting Microsatellites in Genome Data: Variance in Definitions and Bioinformatic Approaches Cause Systematic Bias

    Directory of Open Access Journals (Sweden)

    Angelika Merkel

    2008-01-01

    Full Text Available Microsatellites are currently one of the most commonly used genetic markers. The application of bioinformatic tools has become common practice in the study of these short tandem repeats (STR. However, in silico studies can suffer from study bias. Using a meta-analysis on microsatellite distribution in yeast we show that estimates of numbers of repeats reported by different studies can differ in the order of several magnitudes, even within a single genome. These differences arise because varying definitions of microsatellites, spanning repeat size, array length and array composition, are used in different search paradigms, with minimum array length being the main influencing factor. Structural differences in the implemented search algorithm additionally contribute to variation in the number of repeats detected. We suggest that for future studies a consistent approach to STR searches is adopted in order to improve the power of intra- and interspecific comparisons

  10. Genome stability in Caenorhabditis elegans

    NARCIS (Netherlands)

    Haaften, G.W. van

    2006-01-01

    Genome stability is closely linked to cancer. Most, if not all tumor cells show some form of genome instability, mutations can range from single point mutations to gross chromosomal rearrangements and aneuploidy. Genome instability is believed to be the driving force behind tumorigenesis. In order

  11. Radiation-induced chromosomal instability

    Energy Technology Data Exchange (ETDEWEB)

    Ritter, S. [GSI, Biophysics, Darmstadt (Germany)

    1999-03-01

    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/{mu}m) 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. Simulation, measurement, and mitigation of beam instability caused by the kicker impedance in the 3-GeV rapid cycling synchrotron at the Japan Proton Accelerator Research Complex

    Science.gov (United States)

    Saha, P. K.; Shobuda, Y.; Hotchi, H.; Harada, H.; Hayashi, N.; Kinsho, M.; Tamura, F.; Tani, N.; Yamamoto, M.; Watanabe, Y.; Chin, Yong Ho; Holmes, J. A.

    2018-02-01

    The transverse impedance of eight extraction pulsed kicker magnets is a strong beam instability source in the 3-GeV rapid cycling synchrotron (RCS) at the Japan Proton Accelerator Research Complex. Significant beam instability occurs even at half of the designed 1 MW beam power when the chromaticity (ξ ) is fully corrected for the entire acceleration cycle by using ac sextupole (SX) fields. However, if ξ is fully corrected only at the injection energy by using dc SX fields, the beam is stable. In order to study realistic beam instability scenarios, including the effect of space charge and to determine practical measures to accomplish 1 MW beam power, we enhance the orbit particle tracking code to incorporate all realistic time-dependent machine parameters, including the time dependence of the impedance itself. The beam stability properties beyond 0.5 MW beam power are found to be very sensitive to a number of parameters in both simulations and measurements. In order to stabilize a beam at 1 MW beam power, two practical measures based on detailed and systematic simulation studies are determined, namely, (i) proper manipulation of the betatron tunes during acceleration and (ii) reduction of the dc SX field to reduce the ξ correction even at injection. The simulation results are well reproduced by measurements, and, as a consequence, an acceleration to 1 MW beam power is successfully demonstrated. In this paper, details of the orbit simulation and the corresponding experimental results up to 1 MW of beam power are presented. To further increase the RCS beam power, beam stability issues and possible measures beyond 1 MW beam power are also considered.

  13. FINANCIAL INSTABILITY AND POLITICAL INSTABILITY

    Directory of Open Access Journals (Sweden)

    Ionescu Cristian

    2012-12-01

    Full Text Available There is an important link between the following two variables: financial instability and political instability. Often, the link is bidirectional, so both may influence each other. This is way the lately crisis are becoming larger and increasingly complex. Therefore, the academic environment is simultaneously talking about economic crises, financial crises, political crises, social crises, highlighting the correlation and causality between variables belonging to the economic, financial, political and social areas, with repercussions and spillover effects that extend from one area to another. Given the importance, relevance and the actuality of the ones described above, I consider that at least a theoretical analysis between economic, financial and political factors is needed in order to understand the reality. Thus, this paper aims to find links and connections to complete the picture of the economic reality.

  14. Tiny cause with huge impact: polar instability through strong magneto-electric-elastic coupling in bulk EuTiO3.

    Science.gov (United States)

    Reuvekamp, Patrick; Caslin, Kevin; Guguchia, Zurab; Keller, Hugo; Kremer, Reinhard K; Simon, Arndt; Köhler, Jürgen; Bussmann-Holder, Annette

    2015-07-08

    EuTiO3 exhibits strong magneto-electric coupling at the onset of antiferromagnetic order below TN = 5.7 K. The dielectric permittivity drops at TN by 7% and recovers to normal values with increasing magnetic field. This effect is shown to stem from tiny lattice effects as seen in magnetostriction data which directly affect the soft optic mode and its polarizability coordinate. By combining experimental results with theory we show that marginal changes in the lattice parameter of the order of 0.01% have a more than 1000% effect on the transverse optic soft mode of ETO and thus easily induce a ferroelectric instability.

  15. Hemodynamic Instability after Low-Energy Thigh Contusion Caused by Injury to the Femoral Artery: A Case Report and Literature Review

    Directory of Open Access Journals (Sweden)

    Juan Miguel Rodríguez-Roiz

    2016-01-01

    Full Text Available Acute vascular injuries have been described in relation to high-energy trauma accidents or in patients undergoing surgery in the femoral area. We describe a healthy patient who sustained a direct, low-energy contusion in the thigh and presented haemodynamic instability. Arteriography was used to locate the point of bleeding, and embolisation and vessel occlusion were carried out to stop the haemorrhage. The genetic study identified the COL3A1 gene mutation; accordingly, the patient was diagnosed with the Ehlers-Danlos syndrome type IV (vascular type.

  16. Direct observation of electrically active interfacial layer defects which may cause threshold voltage instabilities in HfO2 based metal-oxide-silicon field-effect transistors

    Science.gov (United States)

    Ryan, J. T.; Lenahan, P. M.; Robertson, J.; Bersuker, G.

    2008-03-01

    We show that a Si /HfO2 interfacial layer defect with an electron spin resonance spectrum similar to that of some E' center variants responds to oxide bias consistent with an amphoteric defect. The spectrum is weakly orientation dependent indicating that the defect does not reside in a completely amorphous matrix. The defect's spin lattice relaxation time is much shorter than that of conventional E' centers suggesting that the defect involves some coupling of a Hf atom to a nearby oxygen deficient silicon dangling bond defect. This defect very likely plays an important role in widely reported instabilities in HfO2 based transistors.

  17. Imatinib Mesylate Causes Genome-wide Transcriptional Changes in Systemic Sclerosis Fibroblasts in vitro

    Science.gov (United States)

    Hinchcliff, Monique; Huang, Chiang-Ching; Ishida, Wataru; Fang, Feng; Lee, Jungwha; Jafari, Nadereh; Wilkes, Mark; Bhattacharyya, Swati; Leof, Edward; Varga, John

    2013-01-01

    Objective Systemic sclerosis (SSc) is a heterogeneous multifactorial disease dominated by progressive skin and internal organ fibrosis that is driven in part by Transforming Growth Factor-beta (TGF-β). An important downstream target of TGF-β is the Abelson (c-Abl) tyrosine kinase, and its inhibition by imatinib mesylate (Gleevec)attenuates fibrosis in mice. Here we examined the effect of c-Abl activation and blockade in explanted healthy control and SSc fibroblasts. Methods Skin biopsies and explanted fibroblasts from healthy subjects and patients with SSc were studied. Changes in genome-wide expression patterns in imatinib-treated control and SSc fibroblasts were analyzed by DNA microarray. Results Treatment of control fibroblasts with TGF-β resulted in activation of c-Abl and stimulation of fibrotic gene expression that was prevented by imatinib. Moreover, imatinib reduced basal collagen gene expression in SSc but not control fibroblasts. No significant differences in tissue levels of c-Abl and phospho-c-Abl were detected between SSc and control skin biopsies. In vitroimatinib induced dramatic changes in the expression of genes involved in fibrosis, cardiovascular disease, inflammation, and lipid and cholesterol metabolism. Remarkably, of the 587-imatinib-responsive genes, 91% showed significant change in SSc fibroblasts, but only 12% in control fibroblasts. Conclusion c-Abl plays a key role in fibrotic responses. Imatinib treatment results in dramatic changes in gene expression in SSc fibroblasts but has only modest effects in control fibroblasts. These data provide novel insights into the mechanisms underlying the antifibrotic effect of imatinib in SSc. PMID:22691216

  18. Characterization of Streptococcus tigurinus small-colony variants causing prosthetic joint infection by comparative whole-genome analyses.

    Science.gov (United States)

    Zbinden, Andrea; Quiblier, Chantal; Hernandez, David; Herzog, Kathrin; Bodler, Paul; Senn, Maria M; Gizard, Yann; Schrenzel, Jacques; François, Patrice

    2014-02-01

    Small-colony variants (SCVs) of bacteria are associated with recurrent and persistent infections. We describe for the first time SCVs of Streptococcus tigurinus in a patient with a prosthetic joint infection. S. tigurinus is a novel pathogen of the Streptococcus mitis group and causes invasive infections. We sought to characterize S. tigurinus SCVs using experimental methods and find possible genetic explanations for their phenotypes. The S. tigurinus SCVs were compared with the wild-type (WT) isolate using phenotypic methods, including growth under different conditions, autolysis, and visualization of the cell ultrastructure by use of transmission electron microscopy (TEM). Furthermore, comparative genome analyses were performed. The S. tigurinus SCVs displayed reduced growth compared to the WT and showed either a very stable or a fluctuating SCV phenotype. TEM analyses revealed major alterations in cell separation and morphological abnormalities, which were partially explained by impaired autolytic behavior. Intriguingly, the SCVs were more resistant to induced autolysis. Whole-genome sequencing revealed mutations in the genes involved in general cell metabolism, cell division, stringent response, and virulence. Clinically, the patient recovered after a 2-stage exchange of the prosthesis. Comparative whole-genome sequencing in clinical strains is a useful tool for identifying novel genetic signatures leading to the most persistent bacterial forms. The detection of viridans streptococcal SCVs is challenging in a clinical laboratory due to the small colony size. Thus, it is of major clinical importance for microbiologists and clinicians to be aware of viridans streptococcal SCVs, such as those of S. tigurinus, which lead to difficult-to-treat infections.

  19. Fifteen novel FBN1 mutations causing Marfan syndrome detected by heteroduplex analysis of genomic amplicons

    Energy Technology Data Exchange (ETDEWEB)

    Nijbroek, G.; Sood, S.; McIntosh, I. [John Hopkins Univ. School of Medicine, Baltimore, MD (United States)] [and others

    1995-07-01

    Mutations in the gene encoding fibrillin-1 (FBN1), a component of the extracellular microfibril, cause the Marfan syndrome (MFS). This statement is supported by the observations that the classic Marfan phenotype cosegregates with intragenic and/or flanking marker alleles in all families tested and that a significant number of FBN1 mutations have been identified in affected individuals. We have now devised a method to screen the entire coding sequence and flanking splice junctions of FBN1. On completion for a panel of nine probands with classic MFS, six new mutations were identified that accounted for disease in seven (78%) of nine patients. Nine additional new mutations have been characterized in the early stages of a larger screening project. These 15 mutations were equally distributed throughout the gene and, with one exception, were specific to single families. One-third of mutations created premature termination codons, and 6 of 15 substituted residues with putative significance for calcium finding to epidermal growth factor (EGF)-like domains. Mutations causing severe and rapidly progressive disease that presents in the neonatal period can occur in a larger region of the gene than previously demonstrated, and the nature of the mutation is as important a determinant as its location, in predisposing to this phenotype. 56 refs., 5 figs., 3 tabs.

  20. Is cell aging caused by respiration-dependent injury to the mitochondrial genome

    Science.gov (United States)

    Fleming, J. E.; Yengoyan, L. S.; Miquel, J.; Cottrell, S. F.; Economos, A. C.

    1982-01-01

    Though intrinsic mitochondrial aging has been considered before as a possible cause of cellular senescence, the mechanisms of such mitochondrial aging have remained obscure. In this article, the hypothesis of free-radical-induced inhibition of mitochondrial replenishment in fixed postmitotic cells is expanded. It is maintained that the respiration-dependent production of superoxide and hydroxyl radicals may not be fully counteracted, leading to a continuous production of lipoperoxides and malonaldehyde in actively respiring mitochondria. These compounds, in turn, can easily react with the mitochondrial DNA which is in close spatial relationship with the inner mitochondrial membrane, producing an injury that the mitochondria may be unable to counteract because of their apparent lack of adequate repair mechanisms. Mitochondrial division may thus be inhibited leading to age-related reduction of mitochondrial numbers, a deficit in energy production with a concomitant decrease in protein synthesis, deterioration of physiological performance, and, therefore, of organismic performance.

  1. Draft Genome Sequence for ICMP 5702, the Type Strain of Pectobacterium carotovorum subsp. carotovorum That Causes Soft Rot Disease on Potato.

    Science.gov (United States)

    Panda, Preetinanda; Lu, Ashley; Armstrong, Karen F; Pitman, Andrew R

    2015-08-06

    Pectobacterium species are economically important bacteria that cause soft rotting of potato tubers in the field and in storage. Here, we report the draft genome sequence of the type strain for P. carotovorum subsp. carotovorum, ICMP 5702 (ATCC 15713). The genome sequence of ICMP 5702 will provide an important reference for future phylogenomic and taxonomic studies of the phytopathogenic Enterobacteriaceae. Copyright © 2015 Panda et al.

  2. Catastrophic failure of hip arthroscopy due to iatrogenic instability: can partial division of the ligamentum teres and iliofemoral ligament cause subluxation?

    Science.gov (United States)

    Mei-Dan, Omer; McConkey, Mark O; Brick, Matthew

    2012-03-01

    Hip arthroscopy is an evolving surgical tool, and with any new procedure, it is important to learn from the complications encountered. A patient with mild hip dysplasia and a symptomatic labral tear underwent uneventful hip arthroscopy and labral repair including partial debridement of a hypertrophied ligamentum teres. Despite preservation of the labrum, no pincer resection, and a modest capsulotomy, 3 months, subluxation and joint space narrowing were noted. One year, end-stage arthritis was present, requiring total hip replacement. Instability after hip arthroscopy is due to a number of factors, including excessive rim trimming, capsulotomy, overzealous labral resection, or inadequate labral repair. This report emphasizes the importance of the ligamentum teres and small disruptions of the capsule in patients with mild dysplasia. Copyright © 2012 Arthroscopy Association of North America. Published by Elsevier Inc. All rights reserved.

  3. 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

  4. 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

  5. Genomic Characterization of Urethritis-Associated Neisseria meningitidis Shows that a Wide Range of N. meningitidis Strains Can Cause Urethritis.

    Science.gov (United States)

    Ma, Kevin C; Unemo, Magnus; Jeverica, Samo; Kirkcaldy, Robert D; Takahashi, Hideyuki; Ohnishi, Makoto; Grad, Yonatan H

    2017-12-01

    Neisseria meningitidis , typically a resident of the oro- or nasopharynx and the causative agent of meningococcal meningitis and meningococcemia, is capable of invading and colonizing the urogenital tract. This can result in urethritis, akin to the syndrome caused by its sister species, N. gonorrhoeae , the etiologic agent of gonorrhea. Recently, meningococcal strains associated with outbreaks of urethritis were reported to share genetic characteristics with the gonococcus, raising the question of the extent to which these strains contain features that promote adaptation to the genitourinary niche, making them gonococcus-like and distinguishing them from other N. meningitidis strains. Here, we analyzed the genomes of 39 diverse N. meningitidis isolates associated with urethritis, collected independently over a decade and across three continents. In particular, we characterized the diversity of the nitrite reductase gene ( aniA ), the factor H-binding protein gene ( fHbp ), and the capsule biosynthetic locus, all of which are loci previously suggested to be associated with urogenital colonization. We observed notable diversity, including frameshift variants, in aniA and fHbp and the presence of intact, disrupted, and absent capsule biosynthetic genes, indicating that urogenital colonization and urethritis caused by N. meningitidis are possible across a range of meningococcal genotypes. Previously identified allelic patterns in urethritis-associated N. meningitidis strains may reflect genetic diversity in the underlying meningococcal population rather than novel adaptation to the urogenital tract. Copyright © 2017 American Society for Microbiology.

  6. Lennox-Gastaut syndrome of unknown cause: phenotypic characteristics of patients in the Epilepsy Phenome/Genome Project.

    Science.gov (United States)

    Widdess-Walsh, Peter; Dlugos, Dennis; Fahlstrom, Robyn; Joshi, Sucheta; Shellhaas, Renée; Boro, Alex; Sullivan, Joseph; Geller, Eric

    2013-11-01

    Lennox-Gastaut syndrome (LGS) is a devastating childhood-onset epilepsy syndrome. The cause is unknown in 25% of cases. Little has been described about the specific clinical or electroencephalography (EEG) features of LGS of unknown or genetic cause (LGS(u)). The Epilepsy Phenome/Genome Project (EPGP) aims to characterize LGS(u) by phenotypic analysis of patients with LGS(u) and their parents. One hundred thirty-five patients with LGS with no known etiology and their parents were enrolled from 19 EPGP centers in the United States and Australia. Clinical data from medical records, standardized questionnaires, imaging, and EEG were collected with use of online informatics systems developed for EPGP. LGS(u) in the EPGP cohort had a broad range of onset of epilepsy from 1 to 13 years, was male predominant (p syndrome. LGS(u) has distinctive characteristics including a broad age range of onset, male predominance, and often normal development prior to the onset of seizures. Cognitive achievements such as completion of secondary school were possible in half of adult patients. Our phenotypic description of LGS(u) coupled with future genetic studies will advance our understanding of this epilepsy syndrome. Wiley Periodicals, Inc. © 2013 International League Against Epilepsy.

  7. 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.

  8. Analysis of microsatellite instability in CRISPR/Cas9 editing mice.

    Science.gov (United States)

    Huo, Xueyun; Du, Yating; Lu, Jing; Guo, Meng; Li, Zhenkun; Zhang, Shuangyue; Li, Xiaohong; Chen, Zhenwen; Du, Xiaoyan

    2017-03-01

    Clustered regularly interspaced short palindromic repeats (CRISPR)/CRISPR- associated (Cas) protein 9 system is a novel and powerful tool which is widely used for genome editing. CRISPR/Cas9 is RNA-guided and can lead to desired genomic modifications. However, whether the CRISPR/Cas9-mediated genome editing causes genomic alterations and genomic instability, such as microsatellite instability (MSI), is still unknown. Here we detected MSI in 21 CRISPR/Cas9 mouse strains using a panel of 42 microsatellite loci which were selected from our previous studies. Surprisingly, MSI occurrence was common in CRISPR/Cas9 modified genome, and most of the strains (19/21, 90.5%) examined showed MSI. Of 42 loci examined, 8 loci (8/42, 19.05%) exhibited MSI in the Cas9 editing mice. The Ttll9 (4/42, 9.5%) were the most unstable strains, and D10Mit3 and D10Mit198 (9/21, 42.9%) were considered to be the most "hot" loci in the Cas9 strains we tested. Through analyzing the mutation of microsatellite loci, we provide new insights into the genomic alterations of CRISPR/Cas9 models and it will help us for a better understanding of this powerful technology. Copyright © 2017 Elsevier B.V. All rights reserved.

  9. Genome rhetoric and the emergence of compositional bias

    Science.gov (United States)

    Vetsigian, Kalin; Goldenfeld, Nigel

    2009-01-01

    Genomes exhibit diverse patterns of species-specific GC content, GC and AT skews, codon bias, and mutation bias. Despite intensive investigations and the rapid accumulation of sequence data, the causes of these a priori different genome biases have not been agreed on and seem multifactorial and idiosyncratic. We show that these biases can arise generically from an instability of the coevolutionary dynamics between genome composition and resource allocation for translation, transcription, and replication. Thus, we offer a unifying framework for understanding and analyzing different genome biases. We develop a test of multistability of nucleotide composition of completely sequenced genomes and reveal a bistability for Borrelia burgdorferi, a genome with pronounced replication-related biases. These results indicate that evolution generates rhetoric, it improves the efficiency of the genome's communication with the cell without modifying the message, and this leads to bias. PMID:19116280

  10. Hidden spondylolisthesis: unrecognized cause of low back pain? Prospective study about the use of dynamic projections in standing and recumbent position for the individuation of lumbar instability

    Energy Technology Data Exchange (ETDEWEB)

    Landi, Alessandro; Gregori, Fabrizio; Marotta, Nicola; Donnarumma, Pasquale; Delfini, Roberto [University of Rome - Policlinico Umberto I, Department of Neurology and Psychiatry, Division of Neurosurgery, Rome (Italy)

    2015-03-26

    Dynamic X-rays (DXR) are widely recognized as an effective method to detect lumbar instability (LI). They are usually performed with the patient in standing position (SDXR). In our opinion, standing position inhibits micromovements of the lumbar segment interested by the listhesis, thanks to paravertebral muscles antalgic contraction and augmented tone. We aim to demonstrate that DXR in recumbent position (RDXR), reducing the action of paravertebral muscles, can discover hypermovements not evidenced in SDXR. Between January 2011 and January 2013, we studied 200 consecutive patients with lumbar degenerative disease with MRI, SDXR, and RDXR. We aimed to find a correlation between low back or radicular pain and the presence of a spondylolisthesis not showed by the SDXR, but showed by the RDXR. We analysed 200 patients: of the 133 not pathologic in SDXR, 43 patients (32.3 %) showed an hypermovement in RDXR (p = 0.0001) without any significant correlation between hidden listhesis and age, sex, or level involved. The aim of our study is to determine whether in patients with lumbalgy without evidence of listhesis in SDXR, pain can be attributed to a faccettal syndrome or to a spondylolisthesis. Consequence of pain is augmented muscular tone of the paravertebral musculature, particularly in standing position. Augmented muscular tone tries to inhibit the pain generator, attempting to limit the slippage of the involved segment. In patients examined in RDXR, the tone of paravertebral musculature is reduced, showing the hidden spondylolisthesis. (orig.)

  11. Comparative analysis of pepper and tomato reveals euchromatin expansion of pepper genome caused by differential accumulation of Ty3/Gypsy-like elements

    Directory of Open Access Journals (Sweden)

    Ahn Jong Hwa

    2011-01-01

    Full Text Available Abstract Background Among the Solanaceae plants, the pepper genome is three times larger than that of tomato. Although the gene repertoire and gene order of both species are well conserved, the cause of the genome-size difference is not known. To determine the causes for the expansion of pepper euchromatic regions, we compared the pepper genome to that of tomato. Results For sequence-level analysis, we generated 35.6 Mb of pepper genomic sequences from euchromatin enriched 1,245 pepper BAC clones. The comparative analysis of orthologous gene-rich regions between both species revealed insertion of transposons exclusively in the pepper sequences, maintaining the gene order and content. The most common type of the transposon found was the LTR retrotransposon. Phylogenetic comparison of the LTR retrotransposons revealed that two groups of Ty3/Gypsy-like elements (Tat and Athila were overly accumulated in the pepper genome. The FISH analysis of the pepper Tat elements showed a random distribution in heterochromatic and euchromatic regions, whereas the tomato Tat elements showed heterochromatin-preferential accumulation. Conclusions Compared to tomato pepper euchromatin doubled its size by differential accumulation of a specific group of Ty3/Gypsy-like elements. Our results could provide an insight on the mechanism of genome evolution in the Solanaceae family.

  12. Draft genome sequence of Bacillus velezensis 2A-2B strain: a rhizospheric inhabitant of Sporobolus airoides (Torr.) Torr., with antifungal activity against root rot causing phytopathogens.

    Science.gov (United States)

    Martínez-Raudales, Inés; De La Cruz-Rodríguez, Yumiko; Alvarado-Gutiérrez, Alejandro; Vega-Arreguín, Julio; Fraire-Mayorga, Ahuitz; Alvarado-Rodríguez, Miguel; Balderas-Hernández, Victor; Fraire-Velázquez, Saúl

    2017-01-01

    A Bacillus velezensis strain from the rhizosphere of Sporobolus airoides (Torr.) Torr . , a grass in central-north México, was isolated during a biocontrol of phytopathogens scrutiny study. The 2A-2B strain exhibited at least 60% of growth inhibition of virulent isolates of phytopathogens causing root rot. These phytopathogens include Phytophthora capsici , Fusarium solani , Fusarium oxysporum and Rhizoctonia solani . Furthermore, the 2A-2B strain is an indolacetic acid producer, and a plant inducer of PR1, which is an induced systemic resistance related gene in chili pepper plantlets. Whole genome sequencing was performed to generate a draft genome assembly of 3.953 MB with 46.36% of GC content, and a N50 of 294,737. The genome contains 3713 protein coding genes and 89 RNA genes. Moreover, comparative genome analysis revealed that the 2A-2B strain had the greatest identity (98.4%) with Bacillus velezensis.

  13. Polygonal instabilities

    Science.gov (United States)

    Labousse, Matthieu

    2015-11-01

    The interaction of a vortex with a free surface is encountered in a series of experiments, the hydraulic jump, the hydraulic bump, the toroidal Leidenfrost experiment. All these experiments share in common an unstable configuration in which azimuthal perturbations give rise to polygonal patterns. We propose a unified theoretical framework to model the emergence of this instability by investigating the stability of a liquid torus with a poloidal motion. As simple as it is, we show that the model retains the necessary ingredients to account for the experimental observations. In this talk, I will first describe the model and compare it to the existing data. However this model is purely inviscid and reaches its limits when being applied to relatively moderate Reynolds flows. So in a second part, I will present a recent experimental and theoretical investigation in which polygonal patterns are now driven by Marangoni flows. To our great surprise, it extends the range of validity of the initial proposed framework, much more than initially expected.

  14. Expression of Cyclins A, E and Topoisomerase II α correlates with centrosome amplification and genomic instability and influences the reliability of cytometric S-phase determination

    Directory of Open Access Journals (Sweden)

    Laytragoon-Lewin Nongnit

    2003-07-01

    Full Text Available Abstract Background The progression of normal cells through the cell cycle is meticulously regulated by checkpoints guaranteeing the exact replication of the genome during S-phase and its equal division at mitosis. A prerequisite for this achievement is synchronized DNA-replication and centrosome duplication. In this context the expression of cyclins A and E has been shown to play a principal role. Results Our results demonstrated a correlation between centrosome amplification, cell cycle fidelity and the level of mRNA and protein expression of cyclins A and E during the part of the cell cycle defined as G1-phase by means of DNA content based histogram analysis. It is shown that the normal diploid breast cell line HTB-125, the genomically relatively stable aneuploid breast cancer cell line MCF-7, and the genomically unstable aneuploid breast cancer cell line MDA-231 differ remarkably concerning both mRNA and protein expression of the two cyclins during G1-phase. In MDA-231 cells the expression of e.g. cyclin A mRNA was found to be ten times higher than in MCF-7 cells and about 500 times higher than in HTB-125 cells. Topoisomerase II α showed high mRNA expression in MDA compared to MCF-7 cells, but the difference in protein expression was small. Furthermore, we measured centrosome aberrations in 8.4% of the MDA-231 cells, and in only 1.3% of the more stable aneuploid cell line MCF-7. MDA cells showed 27% more incorporation of BrdU than reflected by S-phase determination with flow cytometric DNA content analysis, whereas these values were found to be of the same size in both HTB-125 and MCF-7 cells. Conclusions Our data indicate that the breast cancer cell lines MCF-7 and MDA-231, although both DNA-aneuploid, differ significantly regarding the degree of cell cycle disturbance and centrosome aberrations, which partly could explain the different genomic stability of the two cell lines. The results also question the reliability of cytometric DNA

  15. A Novel Mutation in a Critical Region for the Methyl Donor Binding in DNMT3B Causes Immunodeficiency, Centromeric Instability, and Facial Anomalies Syndrome (ICF).

    Science.gov (United States)

    Rechavi, Erez; Lev, Atar; Eyal, Eran; Barel, Ortal; Kol, Nitzan; Barhom, Sarit Farage; Pode-Shakked, Ben; Anikster, Yair; Somech, Raz; Simon, Amos J

    2016-11-01

    Immunodeficiency, centromeric instability, and facial anomalies (ICF) syndrome is an extremely rare autosomal recessive disease. The immune phenotype is characterized by hypogammaglobulinemia in the presence of B cells. T cell lymphopenia also develops in some patients. We sought to further investigate the immune defect in an ICF patient with a novel missense mutation in DNMT3B and a severe phenotype. Patient lymphocytes were examined for subset counts, immunoglobulin levels, T and B cell de novo production (via excision circles) and receptor repertoire diversity. Mutated DNMT3B protein structure was modeled to assess the effect of a mutation located outside of the catalytic region on protein function. A novel homozygous missense mutation, Ala585Thr, was found in DNMT3B. The patient had decreased B cell counts with hypogammaglobulinemia, and normal T cell counts. CD4 + T cells decreased over time, leading to an inversion of the CD4 + to CD8 + ratio. Excision circle copy numbers were normal, signifying normal de novo lymphocyte production, but the ratio between naïve and total B cells was low, indicating decreased in vivo B cell replication. T and B cell receptor repertoires displayed normal diversity. Computerized modeling of the mutated Ala585 residue suggested reduced thermostability, possibly affecting the enzyme kinetics. Our results highlight the existence of a T cell defect that develops over time in ICF patient, in addition to the known B cell dysfunction. With intravenous immunoglobulin (IVIG) treatment ameliorating the B cell defect, the extent of CD4 + lymphopenia may determine the severity of ICF immunodeficiency.

  16. USH1G with unique retinal findings caused by a novel truncating mutation identified by genome-wide linkage analysis

    Science.gov (United States)

    Taibah, Khalid; Bin-Khamis, Ghada; Kennedy, Shelley; Hemidan, Amal; Al-Qahtani, Faisal; Tabbara, Khalid; Mubarak, Bashayer Al; Ramzan, Khushnooda; Meyer, Brian F.; Al-Owain, Mohammed

    2012-01-01

    Purpose Usher syndrome (USH) is an autosomal recessive disorder divided into three distinct clinical subtypes based on the severity of the hearing loss, manifestation of vestibular dysfunction, and the age of onset of retinitis pigmentosa and visual symptoms. To date, mutations in seven different genes have been reported to cause USH type 1 (USH1), the most severe form. Patients diagnosed with USH1 are known to be ideal candidates to benefit from cochlear implantation. Methods Genome-wide linkage analysis using Affymetrix GeneChip Human Mapping 10K arrays were performed in three cochlear implanted Saudi siblings born from a consanguineous marriage, clinically diagnosed with USH1 by comprehensive clinical, audiological, and ophthalmological examinations. From the linkage results, the USH1G gene was screened for mutations by direct sequencing of the coding exons. Results We report the identification of a novel p.S243X truncating mutation in USH1G that segregated with the disease phenotype and was not present in 300 ethnically matched normal controls. We also report on the novel retinal findings and the outcome of cochlear implantation in the affected individuals. Conclusions In addition to reporting a novel truncating mutation, this report expands the retinal phenotype in USH1G and presents the first report of successful cochlear implants in this disease. PMID:22876113

  17. Multiplex CRISPR/Cas9-based genome editing for correction of dystrophin mutations that cause Duchenne muscular dystrophy.

    Science.gov (United States)

    Ousterout, David G; Kabadi, Ami M; Thakore, Pratiksha I; Majoros, William H; Reddy, Timothy E; Gersbach, Charles A

    2015-02-18

    The CRISPR/Cas9 genome-editing platform is a promising technology to correct the genetic basis of hereditary diseases. The versatility, efficiency and multiplexing capabilities of the CRISPR/Cas9 system enable a variety of otherwise challenging gene correction strategies. Here, we use the CRISPR/Cas9 system to restore the expression of the dystrophin gene in cells carrying dystrophin mutations that cause Duchenne muscular dystrophy (DMD). We design single or multiplexed sgRNAs to restore the dystrophin reading frame by targeting the mutational hotspot at exons 45-55 and introducing shifts within exons or deleting one or more exons. Following gene editing in DMD patient myoblasts, dystrophin expression is restored in vitro. Human dystrophin is also detected in vivo after transplantation of genetically corrected patient cells into immunodeficient mice. Importantly, the unique multiplex gene-editing capabilities of the CRISPR/Cas9 system facilitate the generation of a single large deletion that can correct up to 62% of DMD mutations.

  18. 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

  19. 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

  20. Results of medial patellofemoral ligament reconstruction compared with trochleoplasty plus individual extensor apparatus balancing in patellar instability caused by severe trochlear dysplasia: a systematic review and meta-analysis.

    Science.gov (United States)

    Balcarek, Peter; Rehn, Stephan; Howells, Nick R; Eldridge, Jonathan D; Kita, Keisuke; Dejour, David; Nelitz, Manfred; Banke, Ingo J; Lambrecht, Delphine; Harden, Markus; Friede, Tim

    2017-12-01

    Many studies have reported satisfactory clinical outcomes and low redislocation rates after reconstruction of the medial patellofemoral ligament (MPFL) for the treatment of lateral patellar instability. Despite uncorrected severe trochlear dysplasia (Dejour type B to D) being acknowledged as a major reason for less favourable clinical outcomes and a higher incidence of patellar redislocations after an isolated MPFL reconstruction, the evidence for a deepening trochleoplasty procedure remains scarce in the current literature. The hypothesis of this systematic review and meta-analysis was that a deepening trochleoplasty in combination with an a la carte extensor apparatus balancing procedure provides lower redislocation rates and superior clinical outcomes than isolated MPFL reconstruction in patients with lateral patellar instability caused by severe trochlear dysplasia. A systematic review of the literature was conducted using specific inclusion and exclusion criteria for clinical studies reporting index operations (trochleoplasty and MPFL reconstruction) for the treatment of patellar instability caused by severe trochlear dysplasia. The Kujala score was analysed as the primary clinical outcome parameter in a random effects meta-analysis. Ten uncontrolled studies with a total of 407 knees (374 patients) were included in this analysis. The MPFL group comprised 4 studies with a total of 221 knees (210 patients), and the trochleoplasty group comprised 6 studies with a total of 186 knees (164 patients). The mean preoperative Kujala score ranged between 50.4 and 70.5 in the MPFL group and between 44.8 and 75.1 in the trochleoplasty group. The pooled Kujala score increased significantly by 26.4 (95% CI 21.4, 31.3; P subluxation rate was 7% in the MPFL group and 2.1% in the trochleoplasty group. This analysis found significant post-operative improvements in patient-reported outcomes for patients undergoing both an MPFL reconstruction and in those undergoing a

  1. In a shake of a lamb's tail: using genomics to unravel a cause of chondrodysplasia in Texel sheep.

    Science.gov (United States)

    Zhao, X; Onteru, S K; Piripi, S; Thompson, K G; Blair, H T; Garrick, D J; Rothschild, M F

    2012-07-01

    Chondrodysplasia in Texel sheep is a recessively inherited disorder characterized by dwarfism and angular deformities of the forelimbs. A genome-wide association study using the Illumina OvineSNP50 BeadChip on 15 sheep diagnosed as affected and eight carriers descended from three affected rams was conducted to uncover the genetic cause. A homozygous region of 25 consecutive single nucleotide polymorphism (SNP) loci was identified in all affected sheep, covering a region of 1 Mbp on ovine chromosome 4. Seven positional candidate genes - including the solute carrier family 13 (sodium/sulphate symporters), member 1 (SLC13A1) - were identified and used to search for new SNPs for fine mapping of the causal locus. The SLC13A1 gene, encoding a sodium/sulphate transporter, was the primary candidate gene attributable to similar phenotypes observed in the Slc13a1 knockout mouse model. We discovered a 1-bp deletion of T (g.25513delT) at the 107 bp position of exon 3 in the SLC13A1 gene. Genotyping by direct sequencing and restriction fragment length polymorphism analysis for this mutation showed that all 15 affected sheep were g.25513delT/g.25513delT; the eight carriers were g.25513delT/T and 54 normal controls were T/T. The mutation g.25513delT shifts the open reading frame of SLC13A1 to introduce a stop codon and truncate C-terminal amino acids. It was concluded that the g.25513delT mutation in the SLC13A1 gene was responsible for the chondrodysplasia seen in these Texel sheep. This knowledge can be used to identify carriers with the defective g.[25513delT] allele to avoid at-risk matings to improve animal welfare and decrease economic losses. © 2011 The Authors, Animal Genetics © 2011 Stichting International Foundation for Animal Genetics.

  2. 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

  3. DNA damage-induced alterations in chromatin contribute to genomic integrity and age-related changes in gene expression

    Science.gov (United States)

    Oberdoerffer, Philipp; Michan, Shaday; McVay, Michael; Mostoslavsky, Raul; Vann, James; Park, Sang-Kyu; Hartlerode, Andrea; Stegmuller, Judith; Hafner, Angela; Loerch, Patrick; Wright, Sarah M.; Mills, Kevin D.; Bonni, Azad; Yankner, Bruce A.; Scully, Ralph; Prolla, Tomas A.; Alt, Frederick W.; Sinclair, David A.

    2008-01-01

    Genomic instability and alterations in gene expression are hallmarks of eukaryotic aging. The yeast histone deacetylase Sir2 silences transcription and stabilizes repetitive DNA, but during aging or in response to a DNA break, the Sir complex relocalizes to sites of genomic instability, resulting in the desilencing of genes that cause sterility, a characteristic of yeast aging. Using embryonic stem cells, we show that mammalian Sir2, SIRT1, represses repetitive DNA and a functionally diverse set of genes across the mouse genome. In response to DNA damage, SIRT1 dissociates from these loci and relocalizes to DNA breaks to promote repair, resulting in transcriptional changes that parallel those in the aging mouse brain. Increased SIRT1 expression promotes survival in a mouse model of genomic instability and suppresses age-dependent transcriptional changes. Thus, DNA damage-induced redistribution of SIRT1 and other chromatin modifying proteins may be a conserved mechanism of aging in eukaryotes. PMID:19041753

  4. Genome Sequence of Pectobacterium carotovorum subsp. carotovorum Strain PCC21, a Pathogen Causing Soft Rot in Chinese Cabbage

    OpenAIRE

    Park, Tae-Ho; Choi, Beom-Soon; Choi, Ah-Young; Choi, Ik-Young; Heu, Sunggi; Park, Beom-Seok

    2012-01-01

    Pectobacterium carotovorum is a plant-pathogenic enterobacterium responsible for soft rot in various commercially important plants. Here we report the complete genome sequence and automatic annotation of strain PCC21.

  5. Genome sequence of Pectobacterium carotovorum subsp. carotovorum strain PCC21, a pathogen causing soft rot in Chinese cabbage.

    Science.gov (United States)

    Park, Tae-Ho; Choi, Beom-Soon; Choi, Ah-Young; Choi, Ik-Young; Heu, Sunggi; Park, Beom-Seok

    2012-11-01

    Pectobacterium carotovorum is a plant-pathogenic enterobacterium responsible for soft rot in various commercially important plants. Here we report the complete genome sequence and automatic annotation of strain PCC21.

  6. Identification and Whole Genome Sequencing of the First Case of Kosakonia radicincitans Causing a Human Bloodstream Infection

    OpenAIRE

    Bhatti, Micah D.; Kalia, Awdhesh; Sahasrabhojane, Pranoti; Kim, Jiwoong; Greenberg, David E.; Shelburne, Samuel A.

    2017-01-01

    The taxonomy of Enterobacter species is rapidly changing. Herein we report a bloodstream infection isolate originally identified as Enterobacter cloacae by Vitek2 methodology that we found to be Kosakonia radicincitans using genetic means. Comparative whole genome sequencing of our isolate and other published Kosakonia genomes revealed these organisms lack the AmpC β-lactamase present on the chromosome of Enterobacter sp. A fimbriae operon primarily found in Escherichia coli O157:H7 isolates ...

  7. Low power lasers on genomic stability.

    Science.gov (United States)

    Trajano, Larissa Alexsandra da Silva Neto; Sergio, Luiz Philippe da Silva; Stumbo, Ana Carolina; Mencalha, Andre Luiz; Fonseca, Adenilson de Souza da

    2018-03-01

    Exposure of cells to genotoxic agents causes modifications in DNA, resulting to alterations in the genome. To reduce genomic instability, cells have DNA damage responses in which DNA repair proteins remove these lesions. Excessive free radicals cause DNA damages, repaired by base excision repair and nucleotide excision repair pathways. When non-oxidative lesions occur, genomic stability is maintained through checkpoints in which the cell cycle stops and DNA repair occurs. Telomere shortening is related to the development of various diseases, such as cancer. Low power lasers are used for treatment of a number of diseases, but they are also suggested to cause DNA damages at sub-lethal levels and alter transcript levels from DNA repair genes. This review focuses on genomic and telomere stabilization modulation as possible targets to improve therapeutic protocols based on low power lasers. Several studies have been carried out to evaluate the laser-induced effects on genome and telomere stabilization suggesting that exposure to these lasers modulates DNA repair mechanisms, telomere maintenance and genomic stabilization. Although the mechanisms are not well understood yet, low power lasers could be effective against DNA harmful agents by induction of DNA repair mechanisms and modulation of telomere maintenance and genomic stability. Copyright © 2018 Elsevier B.V. All rights reserved.

  8. 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...

  9. 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

    (CGH) for copy number changes and single-copy number polymorphism (SNP) microarrays for allelic loss (LOH). Many array-based CGH changes were not found by LOH because they did not cause true reduction-to-homozygosity. Conversely, many regions of SNP-LOH occurred in the absence of copy number change...

  10. Full-genome dissection of an epidemic of severe invasive disease caused by a hypervirulent, recently emerged clone of group A Streptococcus.

    Science.gov (United States)

    Fittipaldi, Nahuel; Beres, Stephen B; Olsen, Randall J; Kapur, Vivek; Shea, Patrick R; Watkins, M Ebru; Cantu, Concepcion C; Laucirica, Daniel R; Jenkins, Leslie; Flores, Anthony R; Lovgren, Marguerite; Ardanuy, Carmen; Liñares, Josefina; Low, Donald E; Tyrrell, Gregory J; Musser, James M

    2012-04-01

    Group A Streptococcus (GAS) causes an exceptionally broad range of infections in humans, from relatively mild pharyngitis and skin infections to life-threatening necrotizing fasciitis and toxic shock syndrome. An epidemic of severe invasive human infections caused by type emm59 GAS, heretofore an exceedingly rare cause of disease, spread west to east across Canada over a 3-year period (2006 to 2008). By sequencing the genomes of 601 epidemic, historic, and other emm59 organisms, we discovered that a recently emerged, genetically distinct emm59 clone is responsible for the Canadian epidemic. Using near-real-time genome sequencing, we were able to show spread of the Canadian epidemic clone into the United States. The extensive genome data permitted us to identify patterns of geographic dissemination as well as links between emm59 subclonal lineages that cause infections. Mouse and nonhuman primate models of infection demonstrated that the emerged clone is unusually virulent. Transmission of epidemic emm59 strains may have occurred primarily by skin contact, as suggested by an experimental model of skin transmission. In addition, the emm59 strains had a significantly impaired ability to persist in human saliva and to colonize the oropharynx of mice, and seldom caused human pharyngitis. Our study contributes new information to the rapidly emerging field of molecular pathogenomics of bacterial epidemics and illustrates how full-genome data can be used to precisely illuminate the landscape of strain dissemination during a bacterial epidemic. Copyright © 2012 American Society for Investigative Pathology. Published by Elsevier Inc. All rights reserved.

  11. Genome-wide mapping of histone H3K9me2 in acute myeloid leukemia reveals large chromosomal domains associated with massive gene silencing and sites of genome instability.

    Directory of Open Access Journals (Sweden)

    Anna C Salzberg

    Full Text Available A facultative heterochromatin mark, histone H3 lysine 9 dimethylation (H3K9me2, which is mediated by histone methyltransferases G9a/GLP (EHMT2/1, undergoes dramatic rearrangements during myeloid cell differentiation as observed by chromatin imaging. To determine whether these structural transitions also involve genomic repositioning of H3K9me2, we used ChIP-sequencing to map genome-wide topography of H3K9me2 in normal human granulocytes, normal CD34+ hematopoietic progenitors, primary myeloblasts from acute myeloid leukemia (AML patients, and a model leukemia cell line K562. We observe that H3K9me2 naturally repositions from the previously designated "repressed" chromatin state in hematopoietic progenitors to predominant association with heterochromatin regions in granulocytes. In contrast, AML cells accumulate H3K9me2 on previously undefined large (> 100 Kb genomic blocks that are enriched with AML-specific single nucleotide variants, sites of chromosomal translocations, and genes downregulated in AML. Specifically, the AML-specific H3K9me2 blocks are enriched with genes regulated by the proto-oncogene ERG that promotes stem cell characteristics. The AML-enriched H3K9me2 blocks (in contrast to the heterochromatin-associated H3K9me2 blocks enriched in granulocytes are reduced by pharmacological inhibition of the histone methyltransferase G9a/GLP in K562 cells concomitantly with transcriptional activation of ERG and ETS1 oncogenes. Our data suggest that G9a/GLP mediate formation of transient H3K9me2 blocks that are preserved in AML myeloblasts and may lead to an increased rate of AML-specific mutagenesis and chromosomal translocations.

  12. Genome-wide mapping of histone H3K9me2 in acute myeloid leukemia reveals large chromosomal domains associated with massive gene silencing and sites of genome instability.

    Science.gov (United States)

    Salzberg, Anna C; Harris-Becker, Abigail; Popova, Evgenya Y; Keasey, Nikki; Loughran, Thomas P; Claxton, David F; Grigoryev, Sergei A

    2017-01-01

    A facultative heterochromatin mark, histone H3 lysine 9 dimethylation (H3K9me2), which is mediated by histone methyltransferases G9a/GLP (EHMT2/1), undergoes dramatic rearrangements during myeloid cell differentiation as observed by chromatin imaging. To determine whether these structural transitions also involve genomic repositioning of H3K9me2, we used ChIP-sequencing to map genome-wide topography of H3K9me2 in normal human granulocytes, normal CD34+ hematopoietic progenitors, primary myeloblasts from acute myeloid leukemia (AML) patients, and a model leukemia cell line K562. We observe that H3K9me2 naturally repositions from the previously designated "repressed" chromatin state in hematopoietic progenitors to predominant association with heterochromatin regions in granulocytes. In contrast, AML cells accumulate H3K9me2 on previously undefined large (> 100 Kb) genomic blocks that are enriched with AML-specific single nucleotide variants, sites of chromosomal translocations, and genes downregulated in AML. Specifically, the AML-specific H3K9me2 blocks are enriched with genes regulated by the proto-oncogene ERG that promotes stem cell characteristics. The AML-enriched H3K9me2 blocks (in contrast to the heterochromatin-associated H3K9me2 blocks enriched in granulocytes) are reduced by pharmacological inhibition of the histone methyltransferase G9a/GLP in K562 cells concomitantly with transcriptional activation of ERG and ETS1 oncogenes. Our data suggest that G9a/GLP mediate formation of transient H3K9me2 blocks that are preserved in AML myeloblasts and may lead to an increased rate of AML-specific mutagenesis and chromosomal translocations.

  13. Whole-Genome DNA Methylation Analyses Revealed Epigenetic Instability in Tumorigenic Human iPS Cell-Derived Neural Stem/Progenitor Cells.

    Science.gov (United States)

    Iida, Tsuyoshi; Iwanami, Akio; Sanosaka, Tsukasa; Kohyama, Jun; Miyoshi, Hiroyuki; Nagoshi, Narihito; Kashiwagi, Rei; Toyama, Yoshiaki; Matsumoto, Morio; Nakamura, Masaya; Okano, Hideyuki

    2017-05-01

    Although human induced pluripotent stem cell (hiPSC) derivatives are considered promising cellular resources for regenerative medicine, their tumorigenicity potentially limits their clinical application in hiPSC technologies. We previously demonstrated that oncogenic hiPSC-derived neural stem/progenitor cells (hiPSC-NS/PCs) produced tumor-like tissues that were distinct from teratomas. To gain insight into the mechanisms underlying the regulation of tumorigenicity in hiPSC-NS/PCs, we performed an integrated analysis using the Infinium HumanMethylation450 BeadChip array and the HumanHT-12 v4.0 Expression BeadChip array to compare the comprehensive DNA methylation and gene expression profiles of tumorigenic hiPSC-NS/PCs (253G1-NS/PCs) and non-tumorigenic cells (201B7-NS/PCs). Although the DNA methylation profiles of 253G1-hiPSCs and 201B7-hiPSCs were similar regardless of passage number, the methylation status of the global DNA methylation profiles of 253G1-NS/PCs and 201B7-NS/PCs differed; the genomic regions surrounding the transcriptional start site of the CAT and PSMD5 genes were hypermethylated in 253G1-NS/PCs but not in 201B7-NS/PCs. Interestingly, the aberrant DNA methylation profile was more pronounced in 253G1-NS/PCs that had been passaged more than 15 times. In addition, we identified aberrations in DNA methylation at the RBP1 gene locus; the DNA methylation frequency in RBP1 changed as 253G1-NS/PCs were sequentially passaged. These results indicate that different NS/PC clones have different DNA methylomes and that DNA methylation patterns are unstable as cells are passaged. Therefore, DNA methylation profiles should be included in the criteria used to evaluate the tumorigenicity of hiPSC-NS/PCs in the clinical setting. Stem Cells 2017;35:1316-1327. © 2017 AlphaMed Press.

  14. 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

  15. Analysis of genomic instability in primary spermatocytes of interspecific hybrids of the red fox (Vulpes vulpes) and the Arctic fox (Alopex lagopus).

    Science.gov (United States)

    Bugno-Poniewierska, Monika; Pawlina, Klaudia; Jakubczak, Andrzej; Jeżewska-Witkowska, Grażyna

    2014-01-01

    The aim of this study was to analyse meiotic cells of male interspecific hybrids of the red fox (Vulpes vulpes) and the arctic fox (Alopex lagopus). To this end we determined stages of meiotic cells as well as carried out FISH analyses with probes specific to heterosomes and a TUNEL assay on synaptonemal complex preparations. The meiotic cell analysis revealed only the presence of stages of the first meiotic division from leptotene to pachytene. Moreover, we observed an increased level of early dissociation of the X-Y bivalent as well as a high percentage of apoptotic cells. These results indicate the disruption of meiotic division in male hybrids manifested through meiotic arrest of the cells. Faulty pairing of the heterosomes can be considered as one of the causes leading to the initiation of the apoptotic process.

  16. Microsatellite instability in human mammary epithelial cells transformed by heavy ions

    Science.gov (United States)

    Yanada, S.; Yang, T. C.; George, K.; Okayasu, R.; Ando, K.; Tsujii, H.

    1998-11-01

    We analyzed DNA and proteins obtained from normal and transformed human mammary epithelial cells for studying the neoplastic transformation by high-LET irradiation in vitro. We also examined microsatellite instability in human mammary cells transformed to various stages of carcinogenesis, such as normal, growth variant and tumorigenic, using microsatellite marker D5S177 on the chromosome 5 and CY17 on the Chromosome 10. Microsatellite instabilities were detected in the tumorigenic stage. These results suggest that microsatellite instability may play a role in the progression of tumorigenecity. The cause of the genomic instability has been suggested as abnormalities of DNA-repair systems which may be due to one of the three reasons: 1) alterations of cell cycle regulating genes. 2) mutations in any of the DNA mismatch repair genes, 3) mutation in any of the DNA strand breaks repair genes. No abnormality of these genes and encoded proteins, however was found in the present studies. These studies thus suggest that the microsatellite instability is induced by an alternative mechanism.

  17. Draft Genome Sequence of Blood Disease Bacterium A2 HR-MARDI, a Pathogen Causing Banana Bacterial Wilt.

    Science.gov (United States)

    Badrun, Rafidah; Abu Bakar, Norliza; Laboh, Rozeita; Redzuan, Rohaiza; Bala Jaganath, Indu

    2017-06-01

    Blood disease bacterium A2 HR-MARDI was isolated from banana plants infected with banana blood disease and which were planted in Kuala Kangsar, Malaysia. Here, we report a draft genome sequence of blood disease bacterium A2 HR-MARDI, which could provide important information on the virulence mechanism of this pathogen. Copyright © 2017 Badrun et al.

  18. Uncovering genomic causes of co-morbidity in epilepsy: gene-driven phenotypic characterization of rare microdeletions

    NARCIS (Netherlands)

    Kasperavičiūtė, Dalia; Catarino, Claudia B.; Chinthapalli, Krishna; Clayton, Lisa M. S.; Thom, Maria; Martinian, Lillian; Cohen, Hannah; Adalat, Shazia; Bockenhauer, Detlef; Pope, Simon A.; Lench, Nicholas; Koltzenburg, Martin; Duncan, John S.; Hammond, Peter; Hennekam, Raoul C. M.; Land, John M.; Sisodiya, Sanjay M.

    2011-01-01

    Patients with epilepsy often suffer from other important conditions. The existence of such co-morbidities is frequently not recognized and their relationship with epilepsy usually remains unexplained. We describe three patients with common, sporadic, non-syndromic epilepsies in whom large genomic

  19. 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.

  20. CRISPR/Cas9-Induced (CTG⋅CAG)nRepeat Instability in the Myotonic Dystrophy Type 1 Locus: Implications for Therapeutic Genome Editing.

    Science.gov (United States)

    van Agtmaal, Ellen L; André, Laurène M; Willemse, Marieke; Cumming, Sarah A; van Kessel, Ingeborg D G; van den Broek, Walther J A A; Gourdon, Geneviève; Furling, Denis; Mouly, Vincent; Monckton, Darren G; Wansink, Derick G; Wieringa, Bé

    2017-01-04

    Myotonic dystrophy type 1 (DM1) is caused by (CTG⋅CAG) n -repeat expansion within the DMPK gene and thought to be mediated by a toxic RNA gain of function. Current attempts to develop therapy for this disease mainly aim at destroying or blocking abnormal properties of mutant DMPK (CUG)n RNA. Here, we explored a DNA-directed strategy and demonstrate that single clustered regularly interspaced short palindromic repeats (CRISPR)/Cas9-cleavage in either its 5' or 3' unique flank promotes uncontrollable deletion of large segments from the expanded trinucleotide repeat, rather than formation of short indels usually seen after double-strand break repair. Complete and precise excision of the repeat tract from normal and large expanded DMPK alleles in myoblasts from unaffected individuals, DM1 patients, and a DM1 mouse model could be achieved at high frequency by dual CRISPR/Cas9-cleavage at either side of the (CTG⋅CAG)n sequence. Importantly, removal of the repeat appeared to have no detrimental effects on the expression of genes in the DM1 locus. Moreover, myogenic capacity, nucleocytoplasmic distribution, and abnormal RNP-binding behavior of transcripts from the edited DMPK gene were normalized. Dual sgRNA-guided excision of the (CTG⋅CAG)n tract by CRISPR/Cas9 technology is applicable for developing isogenic cell lines for research and may provide new therapeutic opportunities for patients with DM1. Copyright © 2017 The Author(s). Published by Elsevier Inc. All rights reserved.

  1. The genome of the nucleopolyhedrosis-causing virus from Tipula oleracea sheds new light on the Nudiviridae family.

    Science.gov (United States)

    Bézier, Annie; Thézé, Julien; Gavory, Frederick; Gaillard, Julien; Poulain, Julie; Drezen, Jean-Michel; Herniou, Elisabeth A

    2015-03-01

    A large double-stranded DNA (dsDNA) virus that produces occlusion bodies, typical of baculoviruses, has been described to infect crane fly larvae of the genus Tipula (Diptera, Tipulidae). Because of a lack of genomic data, this virus has remained unclassified. Electron microscopy of an archival virus isolated from Tipula oleracea, T. oleracea nudivirus (ToNV), showed irregularly shaped occlusion bodies measuring from 2 to 5 μm in length and 2 μm in middiameter, filled with rod-shape virions containing single nucleocapsids within a bilayer envelope. Whole-genome amplification and Roche 454 sequencing revealed a complete circular genome sequence of 145.7 kb, containing five direct repeat regions. We predicted 131 open reading frames, including a homolog of the polyhedrin gene encoding the major occlusion body protein of T. paludosa nucleopolyhedrovirus (NPV). BLAST searches demonstrated that ToNV had 21 of the 37 baculovirus core genes but shared 52 genes with nudiviruses (NVs). Phylogenomic analyses indicated that ToNV clearly belongs to the Nudiviridae family but should probably be assigned to a new genus. Among nudiviruses, ToNV was most closely related to the Penaeus monodon NV and Heliothis zea NV clade but distantly related to Drosophila innubia NV, the other nudivirus infecting a Diptera. Lastly, ToNV was found to be most closely related to the nuvidirus ancestor of bracoviruses. This was also reflected in terms of gene content, as ToNV was the only known exogenous virus harboring homologs of the Cc50C22.6 and 27b (Cc50C22.7) genes found in the nudiviral genomic cluster involved in bracovirus particle production. The Nudiviridae is a family of arthropod dsDNA viruses from which striking cases of endogenization have been reported (i.e., symbiotic bracoviruses deriving from a nudivirus and the endogenous nudivirus of the brown planthopper). Although related to baculoviruses, relatively little is known about the genomic diversity of exogenous nudiviruses. Here

  2. 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.

  3. Uncovering genomic causes of co-morbidity in epilepsy: gene-driven phenotypic characterization of rare microdeletions.

    Directory of Open Access Journals (Sweden)

    Dalia Kasperavičiūtė

    Full Text Available Patients with epilepsy often suffer from other important conditions. The existence of such co-morbidities is frequently not recognized and their relationship with epilepsy usually remains unexplained.We describe three patients with common, sporadic, non-syndromic epilepsies in whom large genomic microdeletions were found during a study of genetic susceptibility to epilepsy. We performed detailed gene-driven clinical investigations in each patient. Disruption of the function of genes in the deleted regions can explain co-morbidities in these patients.Co-morbidities in patients with epilepsy can be part of a genomic abnormality even in the absence of (known congenital malformations or intellectual disabilities. Gene-driven phenotype examination can also reveal clinically significant unsuspected condition.

  4. Sequence-Based Mapping and Genome Editing Reveal Mutations in SticklebackHps5Cause Oculocutaneous Albinism and thecasperPhenotype.

    Science.gov (United States)

    Hart, James C; Miller, Craig T

    2017-09-07

    Here, we present and characterize the spontaneous X-linked recessive mutation casper , which causes oculocutaneous albinism in threespine sticklebacks ( Gasterosteus aculeatus ). In humans, Hermansky-Pudlak syndrome results in pigmentation defects due to disrupted formation of the melanin-containing lysosomal-related organelle (LRO), the melanosome. casper mutants display not only reduced pigmentation of melanosomes in melanophores, but also reductions in the iridescent silver color from iridophores, while the yellow pigmentation from xanthophores appears unaffected. We mapped casper using high-throughput sequencing of genomic DNA from bulked casper mutants to a region of the stickleback X chromosome (chromosome 19) near the stickleback ortholog of Hermansky-Pudlak syndrome 5 ( Hps5 ). casper mutants have an insertion of a single nucleotide in the sixth exon of Hps5 , predicted to generate an early frameshift. Genome editing using CRISPR/Cas9 induced lesions in Hps5 and phenocopied the casper mutation. Injecting single or paired Hps5 guide RNAs revealed higher incidences of genomic deletions from paired guide RNAs compared to single gRNAs. Stickleback Hps5 provides a genetic system where a hemizygous locus in XY males and a diploid locus in XX females can be used to generate an easily scored visible phenotype, facilitating quantitative studies of different genome editing approaches. Lastly, we show the ability to better visualize patterns of fluorescent transgenic reporters in Hps5 mutant fish. Thus, Hps5 mutations present an opportunity to study pigmented LROs in the emerging stickleback model system, as well as a tool to aid in assaying genome editing and visualizing enhancer activity in transgenic fish. Copyright © 2017 Hart and Milller.

  5. 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.

  6. Interaction of a common painkiller piroxicam and copper-piroxicam with chromatin causes structural alterations accompanied by modulation at the epigenomic/genomic level.

    Science.gov (United States)

    Goswami, Sathi; Sanyal, Sulagna; Chakraborty, Payal; Das, Chandrima; Sarkar, Munna

    2017-08-01

    NSAIDs are the most common class of painkillers and anti-inflammatory agents. They also show other functions like chemoprevention and chemosuppression for which they act at the protein but not at the genome level since they are mostly anions at physiological pH, which prohibit their approach to the poly-anionic DNA. Complexing the drugs with bioactive metal obliterate their negative charge and allow them to bind to the DNA, thereby, opening the possibility of genome level interaction. To test this hypothesis, we present the interaction of a traditional NSAID, Piroxicam and its copper complex with core histone and chromatin. Spectroscopy, DLS, and SEM studies were applied to see the effect of the interaction on the structure of histone/chromatin. This was coupled with MTT assay, immunoblot analysis, confocal microscopy, micro array analysis and qRT-PCR. The interaction of Piroxicam and its copper complex with histone/chromatin results in structural alterations. Such structural alterations can have different biological manifestations, but to test our hypothesis, we have focused only on the accompanied modulations at the epigenomic/genomic level. The complex, showed alteration of key epigenetic signatures implicated in transcription in the global context, although Piroxicam caused no significant changes. We have correlated such alterations caused by the complex with the changes in global gene expression and validated the candidate gene expression alterations. Our results provide the proof of concept that DNA binding ability of the copper complexes of a traditional NSAID, opens up the possibility of modulations at the epigenomic/genomic level. Copyright © 2017 Elsevier B.V. All rights reserved.

  7. Decondensation of chromosomal 45S rDNA sites in Lolium and Festuca genotypes does not result in karyotype instability.

    Science.gov (United States)

    Rocha, Laiane Corsini; Jankowska, Maja; Fuchs, Joerg; Mittelmann, Andréa; Techio, Vânia Helena; Houben, Andreas

    2017-01-01

    Fragile sites (FSs) in plants have been described for species like Lolium and other grasses. Whereas in humans FSs were shown to be involved in genome instabilities; the consequences of FSs expression in plants are not known yet. To evaluate whether FSs cause karyotype instabilities, we assessed the frequency of micronuclei and lagging chromosomes in meristematic cells, the stability of the DNA content, and the occurrence of neocentromeres in the presumed chromosomal fragments of Lolium perenne, Lolium multiflorum, Festuca arrundinacea, and two Festulolium hybrids. The cell cycle analysis along with flow cytometric genome size measurements showed high stability in all genomes evaluated. Neocentromeric activity was neither observed in the presumed fragments nor in any other chromosomal region, then this is not the mechanism responsible by the stability. However, Fluorescence in situ hybridization (FISH) with a 45S ribosomal DNA (rDNA) probe in combination with YOYO staining of metaphasic chromosomes showed that many extended nucleolus organizing region (NOR) form very thin YOYO-positive chromatin fibers connecting the acentric 'fragment' with the centromere-containing chromosome region. The obtained data indicate that the expression of FSs does not result in genome instabilities or neocentromere formation. The FS-containing 45S rDNA carrying chromatin fibers undergo a cell cycle and gene activity-dependent dynamic decondensation process.

  8. Corona-induced electrohydrodynamic instabilities in low conducting liquids

    Energy Technology Data Exchange (ETDEWEB)

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

    2003-06-01

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

  9. Genome duplication and mutations in ACE2 cause multicellular, fast-sedimenting phenotypes in evolved Saccharomyces cerevisiae.

    Science.gov (United States)

    Oud, Bart; Guadalupe-Medina, Victor; Nijkamp, Jurgen F; de Ridder, Dick; Pronk, Jack T; van Maris, Antonius J A; Daran, Jean-Marc

    2013-11-05

    Laboratory evolution of the yeast Saccharomyces cerevisiae in bioreactor batch cultures yielded variants that grow as multicellular, fast-sedimenting clusters. Knowledge of the molecular basis of this phenomenon may contribute to the understanding of natural evolution of multicellularity and to manipulating cell sedimentation in laboratory and industrial applications of S. cerevisiae. Multicellular, fast-sedimenting lineages obtained from a haploid S. cerevisiae strain in two independent evolution experiments were analyzed by whole genome resequencing. The two evolved cell lines showed different frameshift mutations in a stretch of eight adenosines in ACE2, which encodes a transcriptional regulator involved in cell cycle control and mother-daughter cell separation. Introduction of the two ace2 mutant alleles into the haploid parental strain led to slow-sedimenting cell clusters that consisted of just a few cells, thus representing only a partial reconstruction of the evolved phenotype. In addition to single-nucleotide mutations, a whole-genome duplication event had occurred in both evolved multicellular strains. Construction of a diploid reference strain with two mutant ace2 alleles led to complete reconstruction of the multicellular-fast sedimenting phenotype. This study shows that whole-genome duplication and a frameshift mutation in ACE2 are sufficient to generate a fast-sedimenting, multicellular phenotype in S. cerevisiae. The nature of the ace2 mutations and their occurrence in two independent evolution experiments encompassing fewer than 500 generations of selective growth suggest that switching between unicellular and multicellular phenotypes may be relevant for competitiveness of S. cerevisiae in natural environments.

  10. Integrating multiple genomic data to predict disease-causing nonsynonymous single nucleotide variants in exome sequencing studies.

    Directory of Open Access Journals (Sweden)

    Jiaxin Wu

    2014-03-01

    Full Text Available Exome sequencing has been widely used in detecting pathogenic nonsynonymous single nucleotide variants (SNVs for human inherited diseases. However, traditional statistical genetics methods are ineffective in analyzing exome sequencing data, due to such facts as the large number of sequenced variants, the presence of non-negligible fraction of pathogenic rare variants or de novo mutations, and the limited size of affected and normal populations. Indeed, prevalent applications of exome sequencing have been appealing for an effective computational method for identifying causative nonsynonymous SNVs from a large number of sequenced variants. Here, we propose a bioinformatics approach called SPRING (Snv PRioritization via the INtegration of Genomic data for identifying pathogenic nonsynonymous SNVs for a given query disease. Based on six functional effect scores calculated by existing methods (SIFT, PolyPhen2, LRT, MutationTaster, GERP and PhyloP and five association scores derived from a variety of genomic data sources (gene ontology, protein-protein interactions, protein sequences, protein domain annotations and gene pathway annotations, SPRING calculates the statistical significance that an SNV is causative for a query disease and hence provides a means of prioritizing candidate SNVs. With a series of comprehensive validation experiments, we demonstrate that SPRING is valid for diseases whose genetic bases are either partly known or completely unknown and effective for diseases with a variety of inheritance styles. In applications of our method to real exome sequencing data sets, we show the capability of SPRING in detecting causative de novo mutations for autism, epileptic encephalopathies and intellectual disability. We further provide an online service, the standalone software and genome-wide predictions of causative SNVs for 5,080 diseases at http://bioinfo.au.tsinghua.edu.cn/spring.

  11. Genetic instability in inherited and sporadic leukemias.

    Science.gov (United States)

    Popp, Henning D; Bohlander, Stefan K

    2010-12-01

    Genetic instability due to increased DNA damage and altered DNA repair is of central significance in the initiation and progression of inherited and sporadic human leukemias. Although very rare, some inherited DNA repair insufficiency syndromes (e.g., Fanconi anemia, Bloom's syndrome) have added substantially to our understanding of crucial mechanisms of leukemogenesis in recent years. Conversely, sporadic leukemias account for the main proportion of leukemias and here DNA damaging reactive oxygen species (ROS) play a central role. Although the exact mechanisms of increased ROS production remain largely unknown and no single pathway has been detected thus far, some oncogenic proteins (e.g., the activated tyrosine kinases BCR-ABL1 and FLT3-ITD) seem to play a key role in driving genetic instability by increased ROS generation which influences the disease course (e.g., blast crisis in chronic myeloid leukemia or relapse in FLT3-ITD positive acute myeloid leukemia). Of course other mechanisms, which promote genetic instability in leukemia also exist. A newly emerging mechanism is the genome-wide alteration of epigenetic marks (e.g., hypomethylation of histone H3K79), which promotes chromosomal instability. Taken together genetic instability plays a critical role both in inherited and sporadic leukemias and emerges as a common theme in both inherited and sporadic leukemias. Beyond its theoretical impact, the analysis of genetic instability may lead the way to the development of innovative therapy strategies. © 2010 Wiley-Liss, Inc.

  12. 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.

  13. Whole-genome reconstruction and mutational signatures in gastric cancer.

    Science.gov (United States)

    Nagarajan, Niranjan; Bertrand, Denis; Hillmer, Axel M; Zang, Zhi Jiang; Yao, Fei; Jacques, Pierre-Étienne; Teo, Audrey S M; Cutcutache, Ioana; Zhang, Zhenshui; Lee, Wah Heng; Sia, Yee Yen; Gao, Song; Ariyaratne, Pramila N; Ho, Andrea; Woo, Xing Yi; Veeravali, Lavanya; Ong, Choon Kiat; Deng, Niantao; Desai, Kartiki V; Khor, Chiea Chuen; Hibberd, Martin L; Shahab, Atif; Rao, Jaideepraj; Wu, Mengchu; Teh, Ming; Zhu, Feng; Chin, Sze Yung; Pang, Brendan; So, Jimmy B Y; Bourque, Guillaume; Soong, Richie; Sung, Wing-Kin; Tean Teh, Bin; Rozen, Steven; Ruan, Xiaoan; Yeoh, Khay Guan; Tan, Patrick B O; Ruan, Yijun

    2012-12-13

    Gastric cancer is the second highest cause of global cancer mortality. To explore the complete repertoire of somatic alterations in gastric cancer, we combined massively parallel short read and DNA paired-end tag sequencing to present the first whole-genome analysis of two gastric adenocarcinomas, one with chromosomal instability and the other with microsatellite instability. Integrative analysis and de novo assemblies revealed the architecture of a wild-type KRAS amplification, a common driver event in gastric cancer. We discovered three distinct mutational signatures in gastric cancer--against a genome-wide backdrop of oxidative and microsatellite instability-related mutational signatures, we identified the first exome-specific mutational signature. Further characterization of the impact of these signatures by combining sequencing data from 40 complete gastric cancer exomes and targeted screening of an additional 94 independent gastric tumors uncovered ACVR2A, RPL22 and LMAN1 as recurrently mutated genes in microsatellite instability-positive gastric cancer and PAPPA as a recurrently mutated gene in TP53 wild-type gastric cancer. These results highlight how whole-genome cancer sequencing can uncover information relevant to tissue-specific carcinogenesis that would otherwise be missed from exome-sequencing data.

  14. Comparative genomics of Streptococcus pyogenes M1 isolates differing in virulence and propensity to cause systemic infection in mice

    NARCIS (Netherlands)

    Fiebig, A.; Loof, T.G.; Babbar, A.; Itzeg, A.; Koehorst, J.J.; Schaap, P.J.; Nitsche-Schmitz, D.P.

    2015-01-01

    Streptococcus pyogenes serotype M1 is a frequent cause of severe infections in humans. Some M1 isolates are pathogenic in mice and used in studies on infection pathogenesis. We observed marked differences in murine infections caused by M1 strain SF370, 5448, 5448AP or AP1 which prompted us to

  15. Understanding the causes and implications of endothelial metabolic variation in cardiovascular disease through genome scale metabolic modeling

    Directory of Open Access Journals (Sweden)

    Sarah eMcGarrity

    2016-04-01

    Full Text Available High-throughput biochemical profiling has led to a requirement for advanced data interpretation techniques capable of integrating the analysis of gene, protein, and metabolic profiles to shed light on genotype-phenotype relationships. Herein, we consider the current state of knowledge of endothelial cell (EC metabolism and its connections to cardiovascular disease, and explore the use of genome scale metabolic models (GEMs for integrating metabolic and genomic data. GEMs combine gene expression and metabolic data acting as frameworks for their analysis and, ultimately, afford mechanistic understanding of how genetic variation impacts metabolism. We demonstrate how GEMs can be used to investigate cardiovascular disease-related genetic variation, drug resistance mechanisms, and novel metabolic pathways, in ECs. The application of GEMs in personalized medicine is also highlighted. Particularly, we focus on the potential of GEMs to identify metabolic biomarkers of endothelial dysfunction and to discover methods of stratifying treatments for cardiovascular diseases based on individual genetic markers. Recent advances in systems biology methodology, and how these methodologies can be applied to understand EC metabolism in both health and disease, are thus highlighted.

  16. Sex Differences in Aging: Genomic Instability.

    Science.gov (United States)

    Fischer, Kathleen E; Riddle, Nicole C

    2018-01-16

    Aging is characterized by decreasing physiological integration, reduced function, loss of resilience, and increased risk of death. Paradoxically, although women live longer, they suffer greater morbidity particularly late in life. These sex differences in human lifespan and healthspan are consistently observed in all countries and during every era for which reliable data exist. While these differences are ubiquitous in humans, evidence of sex differences in longevity and health for other species is more equivocal. Among fruit flies, nematodes, and mice, sex differences in lifespan vary depending on strain and treatment. In this review, we focus on sex differences in age-related alterations in DNA damage and mutation rates, telomere attrition, epigenetics, and nuclear architecture. We find that robust sex differences exist, eg, the higher incidence of DNA damage in men compared to women, but sex differences are not often conserved between species. For most mechanisms reviewed here, there are insufficient data to make a clear determination regarding the impact of sex, largely because sex differences have not been analyzed. Overall, our findings reveal an urgent need for well-designed studies that explicitly examine sex differences in molecular drivers of aging. © The Author(s) 2017. Published by Oxford University Press on behalf of The Gerontological Society of America. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.

  17. Application of Detailed Chemical Kinetics to Combustion Instability Modeling

    Science.gov (United States)

    2016-01-04

    sustained by combustion . Irreparable damage can occur in less than 1 second. CI caused a four year delay in the development of the F-1 engine used...Distribution A: approved for public release; distribution unlimited. 2 Challenges of Combustion Instability Damaged engine injector faceplate...caused by combustion instability “ Combustion instabilities have been observed in almost every engine development effort, including even the most recent

  18. A framework to quantify karyotype variation associated with CHO cell line instability at a single-cell level.

    Science.gov (United States)

    Baik, Jong Youn; Lee, Kelvin H

    2017-05-01

    Chinese hamster ovary (CHO) cells, the major mammalian host cells for biomanufacturing of therapeutic proteins, have been extensively investigated to enhance productivity and product quality. However, cell line instability resulting in unexpected changes in productivity or product quality continues to be a challenge. Based on previous reports about causes and characteristics of production instability, we hypothesized that chromosomal rearrangements due to genomic instability are associated with production instability and that these events can be characterized. We developed a production instability model using secreted alkaline phosphatase (SEAP)-expressing CHO cells (CHO-SEAP) as well as a framework to quantify chromosomal rearrangements by karyotyping. In the absence of methotrexate (MTX), CHO-SEAP cells exhibited a slightly increased growth rate, a significantly decreased specific productivity, and changes in the chromosomal rearrangement ratio of seven chromosomes. In contrast, when MTX was re-introduced, the growth rate and SEAP productivity reversed to the initial values, demonstrating the reversibility of production instability in CHO-SEAP cells. Fluorescence in situ hybridization analysis identified that the SEAP genes were incorporated in the chromosomal rearrangement (insertion) part of the der(Z9) chromosome. Karyotype analysis indicated that the insertion ratio of the der(Z9) chromosome decreased in the CHO-SEAP cells grown without MTX, demonstrating a correlation between chromosomal rearrangement and production instability. Our results support a mechanism for production instability, wherein a randomly generated chromosomal rearrangement (or genotype) results in cells with a growth advantage that is also associated with non (or low)-producing traits. As a result, the non-producing cells grow faster and thereby outgrow the producing population. Biotechnol. Bioeng. 2017;114: 1045-1053. © 2016 Wiley Periodicals, Inc. © 2016 Wiley Periodicals, Inc.

  19. Pattern formation - Instabilities in sand ripples

    DEFF Research Database (Denmark)

    Hansen, J. L.; v. Hecke, M.; Haaning, A.

    2001-01-01

    Sand ripples are seen below shallow wavy water and are formed whenever water oscillates over a bed of sand. Here we analyse the instabilities that can upset this perfect patterning when the ripples are subjected to large changes in driving amplitude or frequency, causing them to deform both...... parallel and transverse to their crests. Our results reveal new pattern-forming instabilities in granular matter exposed to fluid flow with strong vorticity....

  20. Electron cloud instability in high intensity proton rings

    Directory of Open Access Journals (Sweden)

    K. Ohmi

    2002-11-01

    Full Text Available An e^{-}p instability has been observed in some proton rings. The instability, which causes beam loss, limits the performance of the ring. The instability may be serious for 3 and 50 GeV proton storage rings in the Japan Proton Accelerator Research Complex (J-PARC. We study the e^{-}p instability in several high intensity proton storage rings operated in the world. This work informs J-PARC of the necessity to cure the instability, for example, by applying a TiN coating on the chamber surface.

  1. 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

  2. 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

  3. The genome of a Bacillus isolate causing anthrax in chimpanzees combines chromosomal properties of B. cereus with B. anthracis virulence plasmids.

    Directory of Open Access Journals (Sweden)

    Silke R Klee

    Full Text Available Anthrax is a fatal disease caused by strains of Bacillus anthracis. Members of this monophyletic species are non motile and are all characterized by the presence of four prophages and a nonsense mutation in the plcR regulator gene. Here we report the complete genome sequence of a Bacillus strain isolated from a chimpanzee that had died with clinical symptoms of anthrax. Unlike classic B. anthracis, this strain was motile and lacked the four prohages and the nonsense mutation. Four replicons were identified, a chromosome and three plasmids. Comparative genome analysis revealed that the chromosome resembles those of non-B. anthracis members of the Bacillus cereus group, whereas two plasmids were identical to the anthrax virulence plasmids pXO1 and pXO2. The function of the newly discovered third plasmid with a length of 14 kbp is unknown. A detailed comparison of genomic loci encoding key features confirmed a higher similarity to B. thuringiensis serovar konkukian strain 97-27 and B. cereus E33L than to B. anthracis strains. For the first time we describe the sequence of an anthrax causing bacterium possessing both anthrax plasmids that apparently does not belong to the monophyletic group of all so far known B. anthracis strains and that differs in important diagnostic features. The data suggest that this bacterium has evolved from a B. cereus strain independently from the classic B. anthracis strains and established a B. anthracis lifestyle. Therefore we suggest to designate this isolate as "B. cereus variety (var. anthracis".

  4. Neutrino beam plasma instability

    Indian Academy of Sciences (India)

    We derive relativistic fluid set of equations for neutrinos and electrons from relativistic Vlasov equations with Fermi weak interaction force. Using these fluid equations, we obtain a dispersion relation describing neutrino beam plasma instability, which is little different from normal dispersion relation of streaming instability.

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

    DEFF Research Database (Denmark)

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

    2009-01-01

    PURPOSE: Helicobacter pylori is a major cause of gastric carcinoma. To investigate a possible link between bacterial infection and genetic instability of the host genome, we examined the effect of H. pylori infection on known cellular repair pathways in vitro and in vivo. Moreover, various types...... of genetic instabilities in the nuclear and mitochondrial DNA (mtDNA) were examined. EXPERIMENTAL DESIGN: We observed the effects of H. pylori infection on a gastric cell line (AGS), on C57BL/6 mice, and on individuals with chronic gastritis. In AGS cells, the effect of H. pylori infection on base excision...... cells and chronic gastritis tissue were determined by PCR, single-stranded conformation polymorphism, and sequencing. H. pylori vacA and cagA genotyping was determined by multiplex PCR and reverse hybridization. RESULTS: Following H. pylori infection, the activity and expression of base excision repair...

  6. Nonlinear evolution of drift instabilities

    International Nuclear Information System (INIS)

    Lee, W.W.; Krommes, J.A.; Oberman, C.R.; Smith, R.A.

    1984-01-01

    The nonlinear evolution of collisionless drift instabilities in a shear-free magnetic field has been studied by means of gyrokinetic particle simulation as well as numerical integration of model mode-coupling equations. The purpose of the investigation is to identify relevant nonlinear mechanisms responsible for the steady-state drift wave fluctuations. It is found that the saturation of the instability is mainly caused by the nonlinear E x B convection of the resonant electrons and their associated velocity space nonlinearity. The latter also induces energy exchange between the competing modes, which, in turn, gives rise to enhanced diffusion. The nonlinear E x B convection of the ions, which contributes to the nonlinear frequency shift, is also an important ingredient for the saturation

  7. Whole genome sequencing analyses of Listeria monocytogenes that persisted in a milkshake machine for a year and caused illnesses in Washington State.

    Science.gov (United States)

    Li, Zhen; Pérez-Osorio, Ailyn; Wang, Yu; Eckmann, Kaye; Glover, William A; Allard, Marc W; Brown, Eric W; Chen, Yi

    2017-06-15

    In 2015, in addition to a United States multistate outbreak linked to contaminated ice cream, another outbreak linked to ice cream was reported in the Pacific Northwest of the United States. It was a hospital-acquired outbreak linked to milkshakes, made from contaminated ice cream mixes and milkshake maker, served to patients. Here we performed multiple analyses on isolates associated with this outbreak: pulsed-field gel electrophoresis (PFGE), whole genome single nucleotide polymorphism (SNP) analysis, species-specific core genome multilocus sequence typing (cgMLST), lineage-specific cgMLST and whole genome-specific MLST (wgsMLST)/outbreak-specific cgMLST. We also analyzed the prophages and virulence genes. The outbreak isolates belonged to sequence type 1038, clonal complex 101, genetic lineage II. There were no pre-mature stop codons in inlA. Isolates contained Listeria Pathogenicity Island 1 and multiple internalins. PFGE and multiple whole genome sequencing (WGS) analyses all clustered together food, environmental and clinical isolates when compared to outgroup from the same clonal complex, which supported the finding that L. monocytogenes likely persisted in the soft serve ice cream/milkshake maker from November 2014 to November 2015 and caused 3 illnesses, and that the outbreak strain was transmitted between two ice cream production facilities. The whole genome SNP analysis, one of the two species-specific cgMLST, the lineage II-specific cgMLST and the wgsMLST/outbreak-specific cgMLST showed that L. monocytogenes cells persistent in the milkshake maker for a year formed a unique clade inside the outbreak cluster. This clustering was consistent with the cleaning practice after the outbreak was initially recognized in late 2014 and early 2015. Putative prophages were conserved among prophage-containing isolates. The loss of a putative prophage in two isolates resulted in the loss of the AscI restriction site in the prophage, which contributed to their Asc

  8. Whole-Genome Characterization and Strain Comparison of VT2f-Producing Escherichia coli Causing Hemolytic Uremic Syndrome.

    NARCIS (Netherlands)

    Grande, Laura; Michelacci, Valeria; Bondì, Roslen; Gigliucci, Federica; Franz, Eelco; Badouei, Mahdi Askari; Schlager, Sabine; Minelli, Fabio; Tozzoli, Rosangela; Caprioli, Alfredo; Morabito, Stefano

    2016-01-01

    Verotoxigenic Escherichia coli infections in humans cause disease ranging from uncomplicated intestinal illnesses to bloody diarrhea and systemic sequelae, such as hemolytic uremic syndrome (HUS). Previous research indicated that pigeons may be a reservoir for a population of verotoxigenic E. coli

  9. A Rare Complication of Tuberculous Meningitis Pediatric Anterior Glenohumeral Instability

    Directory of Open Access Journals (Sweden)

    Kerem Bilsel

    2012-01-01

    Full Text Available Dislocation and instability of the shoulder joint are rare occurrences in childhood. Traumatic, infectious, congenital, and neuromuscular causes of pediatric recurrent shoulder dislocations are reported before. Central nervous system infection in infancy may be a reason for shoulder instability during childhood. This situation, which causes a disability for children, can be treated successfully with arthroscopic stabilization of the shoulder and postoperative effective rehabilitation protocols. Tuberculous meningitis may be a reason for neuromuscular shoulder instability. We describe a 12-year-old child with a recurrent anterior instability of the shoulder, which developed after tuberculous meningitis at 18 months of age. We applied arthroscopic treatment and stabilized the joint.

  10. 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

  11. Fiber amplifiers under thermal loads leading to transverse mode instability

    DEFF Research Database (Denmark)

    Johansen, Mette Marie; Hansen, Kristian Rymann; Alkeskjold, Thomas Tanggaard

    2014-01-01

    Transverse mode instability (TMI) in rare-earth doped fiber amplifiers operating above an average power threshold is caused by intermodal stimulated thermal Rayleigh scattering due to quantum defect heating. We investigate thermally induced longitudinal waveguide perturbations causing power trans...

  12. MRI of shoulder instability

    Energy Technology Data Exchange (ETDEWEB)

    Steinbach, Lynne S. [University of California San Francisco, 505 Parnassus, Suite M392, San Francisco, CA 94143-0628 (United States)], E-mail: lynne.steinbach@radiology.ucsf.edu

    2008-10-15

    The most unstable joint in the body, the glenohumeral joint is subject to many insults including microinstability, subluxation and dislocation. During the last two decades, MRI has allowed for direct visualization of many of the lesions related to instability, aiding in diagnosis as well as therapeutic planning and follow-up. This article reviews the use of MRI for shoulder instability and describes the different types of lesions associated with this disorder. Topics include technical considerations, the use of MR arthrography, normal anatomy and variants, labral and glenohumeral ligament pathology, and osseous lesions related to instability.

  13. 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

  14. 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.

  15. Two listeria outbreaks caused by smoked fish consumption-using whole-genome sequencing for outbreak investigations

    DEFF Research Database (Denmark)

    Gillesberg Lassen, S.; Ethelberg, S.; Björkman, J. T.

    2016-01-01

    low-intensity, extended time-period outbreaks and link them to food products from two different contaminated production facilities with sufficient strength for food authorities to intervene on. Cold smoked and gravad fish constitute risk products and may be responsible for more listeriosis cases than......Listeria monocytogenes may contaminate and persist in food production facilities and cause repeated, seemingly sporadic, illnesses over extended periods of time. We report on the investigation of two such concurrent outbreaks. We compared patient isolates and available isolates from foods and food...... polymorphism differences. We performed routine food consumption interviews of L. monocytogenes patients and compared outbreak cases with sporadic cases. Two outbreaks were defined, each consisting of ten outbreak cases in the period 2013-15. Seven outbreak cases and a fetus in gestational week 38 died...

  16. Genomic analysis reveals multi-drug resistance clusters in Group B Streptococcus CC17 hypervirulent isolates causing neonatal invasive disease in southern mainland China

    Directory of Open Access Journals (Sweden)

    Edmondo Campisi

    2016-08-01

    Full Text Available Neonatal invasive disease caused by group B Streptococcus (GBS represents a significant public health care concern globally. However, data related to disease burden, serotype distribution and molecular epidemiology in China and other Asian countries are very few and specifically relative to confined regions. The aim of this study was to investigate the genetic characteristics of GBS isolates recovered from neonates with invasive disease during 2013-2014 at Guangzhou and Changsha hospitals in southern mainland China. We assessed the capsular polysaccharide (CPS type, pilus islands (PIs distribution and hvgA gene presence in a panel of 26 neonatal clinical isolates, of which 8 were recovered from Early Onset Disease (EOD and 18 from Late Onset Disease (LOD. Among 26 isolates examined, five serotypes were identified. Type III was the most represented (15 cases, particularly among LOD strains (n=11, followed by types Ib (n=5, V (n=3, Ia (n=2 and II (n=1. We performed whole-genome sequencing (WGS analysis and antimicrobial susceptibility testing on the 14 serotype III isolates belonging to the hypervirulent Clonal Complex 17 (serotype III-CC17.The presence of PI-2b alone was associated with 13 out of 14 serotype III-CC17 strains. Genome analysis led us to identify two multi-drug resistance gene clusters harbored in two new versions of integrative and conjugative elements (ICEs, carrying five or eight antibiotic resistance genes, respectively. These ICEs replaced the 16 kb-locus that normally contains the PI-1 operon. All isolates harboring the identified ICEs showed multiple resistances to aminoglycoside, macrolide and tetracycline antibiotic classes. In conclusion, we report the first whole-genome sequence analysis of 14 GBS serotype III-CC17 strains isolated in China, representing the most prevalent lineage causing neonatal invasive disease. The acquisition of newly identified ICEs conferring multiple antibiotic resistances could in part explain

  17. Dynamic Instability of Barlike Modes

    Science.gov (United States)

    Durisen, Richard H.; Pickett, Brian K.; Bate, Matthew R.; Imamura, James N.; Brandl, Andreas; Sterzik, Michael F.

    Numerical simulations during the 1980's established that prompt binary formation (or ``fission'') through dynamic growth of barlike modes is aborted by gravitational torques. Because these instabilities may occur during star formation and because their outcome over long times is still uncertain, we have combined various linear analyses with simulations by hydrodynamics codes to refine our understanding. We show that it is in fact the torques which cause nonlinear saturation of the mode amplitude. Excellent agreement for the early nonlinear phase is obtained using radically different hydrodynamics codes. However, the ultimate outcome is sensitive to assumptions about dissipative heating and is also somewhat code-dependent.

  18. Methylene Blue Is Effective to Reverse Refractory Hemodynamic Instability due to Dimethoate Poisoning

    Directory of Open Access Journals (Sweden)

    Nick Youssefi

    2015-09-01

    Conclusion:MB treatment was effective to reverse hypotension and restore hemodynamic instability caused by dimethoate poisoning. This index case may pave way to further investigation of MB therapy for OP-induced hemodynamic instabilities.

  19. Comparative Genomic Analyses of the Human NPHP1 Locus Reveal Complex Genomic Architecture and Its Regional Evolution in Primates.

    Directory of Open Access Journals (Sweden)

    Bo Yuan

    2015-12-01

    Full Text Available Many loci in the human genome harbor complex genomic structures that can result in susceptibility to genomic rearrangements leading to various genomic disorders. Nephronophthisis 1 (NPHP1, MIM# 256100 is an autosomal recessive disorder that can be caused by defects of NPHP1; the gene maps within the human 2q13 region where low copy repeats (LCRs are abundant. Loss of function of NPHP1 is responsible for approximately 85% of the NPHP1 cases-about 80% of such individuals carry a large recurrent homozygous NPHP1 deletion that occurs via nonallelic homologous recombination (NAHR between two flanking directly oriented ~45 kb LCRs. Published data revealed a non-pathogenic inversion polymorphism involving the NPHP1 gene flanked by two inverted ~358 kb LCRs. Using optical mapping and array-comparative genomic hybridization, we identified three potential novel structural variant (SV haplotypes at the NPHP1 locus that may protect a haploid genome from the NPHP1 deletion. Inter-species comparative genomic analyses among primate genomes revealed massive genomic changes during evolution. The aggregated data suggest that dynamic genomic rearrangements occurred historically within the NPHP1 locus and generated SV haplotypes observed in the human population today, which may confer differential susceptibility to genomic instability and the NPHP1 deletion within a personal genome. Our study documents diverse SV haplotypes at a complex LCR-laden human genomic region. Comparative analyses provide a model for how this complex region arose during primate evolution, and studies among humans suggest that intra-species polymorphism may potentially modulate an individual's susceptibility to acquiring disease-associated alleles.

  20. [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.

  1. Disorder induced gap states as a cause of threshold voltage instabilities in Al2O3/AlGaN/GaN metal-oxide-semiconductor high-electron-mobility transistors

    Science.gov (United States)

    Matys, M.; Kaneki, S.; Nishiguchi, K.; Adamowicz, B.; Hashizume, T.

    2017-12-01

    We proposed that the disorder induced gap states (DIGS) can be responsible for the threshold voltage (Vth) instability in Al2O3/AlGaN/GaN metal-oxide-semiconductor high-electron-mobility transistors. In order to verify this hypothesis, we performed the theoretical calculations of the capacitance voltage (C-V) curves for the Al2O3/AlGaN/GaN structures using the DIGS model and compared them with measured ones. We found that the experimental C-V curves with a complex hysteresis behavior varied with the maximum forward bias and the sweeping rate can be well reproduced theoretically by assuming a particular distribution in energy and space of the DIGS continuum near the Al2O3/AlGaN interface, i.e., a U-shaped energy density distribution and exponential depth decay from the interface into Al2O3 layer (up to 4 nm), as well as suitable DIGS capture cross sections (the order of magnitude of 10-15 cm2). Finally, we showed that the DIGS model can also explain the negative bias induced threshold voltage instability. We believe that these results should be critical for the successful development of the passivation techniques, which allows to minimize the Vth instability related effects.

  2. Manipulation of interfacial instabilities by using a soft, deformable ...

    Indian Academy of Sciences (India)

    Multilayer flows are oftensusceptible to interfacial instabilities caused due to jump in viscosity/elasticity across thefluid–fluid interface. It is frequently required to manipulate and control these interfacial instabilities in various applications such as coating processes or polymer coextrusion. We demonstrate here the possibility ...

  3. Isotope separation of uranium by laser: tuning and frequency instability

    International Nuclear Information System (INIS)

    Broglia, M.; Massimi, M.; Spoglia, U.; Zampetti, P.

    1983-01-01

    Intensity measurements of laser induced fluorescence in an uranium atomic beam are affected by the axial mode structure of the commercial pulsed dye laser used and by its strong frequency instability. Qualitative and quantitative evaluations on the possible causes of frequency instability are reported

  4. 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.

  5. A genome-wide association study identifies a potential novel gene locus for keratoconus, one of the commonest causes for corneal transplantation in developed countries

    Science.gov (United States)

    Li, Xiaohui; Bykhovskaya, Yelena; Haritunians, Talin; Siscovick, David; Aldave, Anthony; Szczotka-Flynn, Loretta; Iyengar, Sudha K.; Rotter, Jerome I.; Taylor, Kent D.; Rabinowitz, Yaron S.

    2012-01-01

    Keratoconus is a condition in which the cornea progressively thins over time, and is a major cause for cornea transplantation. To identify keratoconus susceptibility regions, we performed a comprehensive genome-wide association study (GWAS) using a discovery and replication design. A discovery panel of 222 keratoconus Caucasian patients and 3324 Caucasian controls was genotyped using Illumina 370K beadchips. Further associated and fine-mapping single nucleotide polymorphisms (SNPs) (n= 4905) were genotyped in an independent replication case–control panel of 304 cases and 518 controls and a family panel of 307 subjects in 70 families. Logistic regression models implemented in PLINK were performed to test associations in case–control samples with and without principal component (PC) adjustments. Generalized estimation equation models accounting for familial correlations implemented in GWAF were used for association testing in families. No genome-wide associations were identified in the discovery GWAS panel. From the initial testing without adjustments for PCs, the top three SNPs located at 3p26 (rs6442925), 2q21.3 (rs4954218) and 19q13.3 (rs1428642) were identified with unadjusted P-values of 6.5 × 10−8, 2.4 × 10−7 and 3.1 × 10−7, respectively. After adjustments for PCs, rs1428642 became the most significant through the genome with a P-value of 1.4 × 10−6, while rs6442925 and rs4954218 were less significant (P= 1.9 × 10−5 and 2.6 × 10−4). SNP rs4954218 was confirmed in two independent replication panels with P-values of 0.004 and 0.009, respectively. Meta-analysis revealed a highest association at rs4954218 with adjusted P= 1.6 × 10−7 (unadjusted P= 1.2 × 10−9). These findings suggest SNP rs4954218, located near the RAB3GAP1 gene, previously reported to be associated with corneal malformation, is a potential susceptibility locus for keratoconus. PMID:21979947

  6. MODEL OF ELECTRON CLOUD INSTABILITY IN FERMILAB RECYCLER

    Energy Technology Data Exchange (ETDEWEB)

    Antipov, Sergey A. [Chicago U.; Burov, A. [Fermilab; Nagaitsev, S. [Fermilab

    2016-10-04

    An electron cloud instability might limit the intensity in the Fermilab Recycler after the PIP-II upgrade. A multibunch instability typically develops in the horizontal plane within a hundred turns and, in certain conditions, leads to beam loss. Recent studies have indicated that the instability is caused by an electron cloud, trapped in the Recycler index dipole magnets. We developed an analytical model of an electron cloud driven instability with the electrons trapped in combined function dipoles. The resulting instability growth rate of about 30 revolutions is consistent with experimental observations and qualitatively agrees with the simulation in the PEI code. The model allows an estimation of the instability rate for the future intensity upgrades.

  7. Caudal regression in adrenocortical dysplasia (acd) mice is caused by telomere dysfunction with subsequent p53-dependent apoptosis.

    Science.gov (United States)

    Vlangos, Christopher N; O'Connor, Bridget C; Morley, Madeleine J; Krause, Andrea S; Osawa, Gail A; Keegan, Catherine E

    2009-10-15

    Adrenocortical dysplasia (acd) is a spontaneous autosomal recessive mouse mutation that exhibits a pleiotropic phenotype with perinatal lethality. Mutant acd embryos have caudal truncation, vertebral segmentation defects, hydronephrosis, and limb hypoplasia, resembling humans with Caudal Regression syndrome. Acd encodes Tpp1, a component of the shelterin complex that maintains telomere integrity, and consequently acd mutant mice have telomere dysfunction and genomic instability. While the association between genomic instability and cancer is well documented, the association between genomic instability and birth defects is unexplored. To determine the relationship between telomere dysfunction and embryonic malformations, we investigated mechanisms leading to the caudal dysgenesis phenotype of acd mutant embryos. We report that the caudal truncation is caused primarily by apoptosis, not altered cell proliferation. We show that the apoptosis and consequent skeletal malformations in acd mutants are dependent upon the p53 pathway by genetic rescue of the limb hypoplasia and vertebral anomalies with p53 null mice. Furthermore, rescue of the acd phenotype by p53 deficiency is a dosage-sensitive process, as acd/acd, p53(-/-) double mutants exhibit preaxial polydactyly. These findings demonstrate that caudal dysgenesis in acd embryos is secondary to p53-dependent apoptosis. Importantly, this study reinforces a significant link between genomic instability and birth defects.

  8. Nonlinear parametric instability of wind turbine wings

    DEFF Research Database (Denmark)

    Larsen, Jesper Winther; Nielsen, Søren R.K.

    2006-01-01

    Nonlinear rotor dynamic is characterized by parametric excitation of both linear and nonlinear terms caused by centrifugal and Coriolis forces when formulated in a moving frame of reference. Assuming harmonically varying support point motions from the tower, the nonlinear parametric instability...

  9. 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

  10. 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

  11. Mono-allelic retrotransposon insertion addresses epigenetic transcriptional repression in human genome.

    Science.gov (United States)

    Byun, Hyang-Min; Heo, Kyu; Mitchell, Kasey J; Yang, Allen S

    2012-02-02

    Retrotransposons have been extensively studied in plants and animals and have been shown to have an impact on human genome dynamics and evolution. Their ability to move within genomes gives retrotransposons to affect genome instability. we examined the polymorphic inserted AluYa5, evolutionary young Alu, in the progesterone receptor gene to determine the effects of Alu insertion on molecular environment. We used mono-allelic inserted cell lines which carry both Alu-present and Alu-absent alleles. To determine the epigenetic change and gene expression, we performed restriction enzyme digestion, Pyrosequencing, and Chromatin Immunoprecipitation. We observed that the polymorphic insertion of evolutionally young Alu causes increasing levels of DNA methylation in the surrounding genomic area and generates inactive histone tail modifications. Consequently the Alu insertion deleteriously inactivates the neighboring gene expression. The mono-allelic Alu insertion cell line clearly showed that polymorphic inserted repetitive elements cause the inactivation of neighboring gene expression, bringing aberrant epigenetic changes.

  12. Chromosomal instability determines taxane response

    DEFF Research Database (Denmark)

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

    2009-01-01

    Microtubule-stabilizing (MTS) agents, such as taxanes, are important chemotherapeutics with a poorly understood mechanism of action. We identified a set of genes repressed in multiple cell lines in response to MTS agents and observed that these genes are overexpressed in tumors exhibiting...... 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...

  13. Alu pair exclusions in the human genome

    Directory of Open Access Journals (Sweden)

    Cook George W

    2011-09-01

    Full Text Available Abstract Background The human genome contains approximately one million Alu elements which comprise more than 10% of human DNA by mass. Alu elements possess direction, and are distributed almost equally in positive and negative strand orientations throughout the genome. Previously, it has been shown that closely spaced Alu pairs in opposing orientation (inverted pairs are found less frequently than Alu pairs having the same orientation (direct pairs. However, this imbalance has only been investigated for Alu pairs separated by 650 or fewer base pairs (bp in a study conducted prior to the completion of the draft human genome sequence. Results We performed a comprehensive analysis of all (> 800,000 full-length Alu elements in the human genome. This large sample size permits detection of small differences in the ratio between inverted and direct Alu pairs (I:D. We have discovered a significant depression in the full-length Alu pair I:D ratio that extends to repeat pairs separated by ≤ 350,000 bp. Within this imbalance bubble (those Alu pairs separated by ≤ 350,000 bp, direct pairs outnumber inverted pairs. Using PCR, we experimentally verified several examples of inverted Alu pair exclusions that were caused by deletions. Conclusions Over 50 million full-length Alu pairs reside within the I:D imbalance bubble. Their collective impact may represent one source of Alu element-related human genomic instability that has not been previously characterized.

  14. STRUCTURAL STRESS RELAXATION IN STAINLESS INSTABILITY STEEL

    Directory of Open Access Journals (Sweden)

    S. Lyabuk

    2017-06-01

    Full Text Available The approach to the description of conditions of martensitic transformation in austenitic steel is advanced. Transformation induced hardening is the result of Le Chatelier principle in instability alloys. The phase transformation in austenitic instability stainless steel is the cause of reduction of grain refining and increase of strength. It was experimentally shown that physical-mechanical characteristics of the prepared materials were defined by the structure and inhomogeneous distribution of the hardening phase within a grain. The reasons for high thermal stability of inverse austenitic were established. The factors determining the inverse austenitic relaxation resistibility and resources for its increasing were revealed.

  15. 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)

  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. 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)

  18. Fluid Instabilities of Magnetar-Powered Supernovae

    Science.gov (United States)

    Chen, Ke-Jung

    2017-05-01

    Magnetar-powered supernova explosions are competitive models for explaining very luminous optical transits. Until recently, these explosion models were mainly calculated in 1D. Radiation emitted from the magnetar snowplows into the previous supernovae ejecta and causes a nonphysical dense shell (spike) found in previous 1D studies. This suggests that strong fluid instabilities may have developed within the magnetar-powered supernovae. Such fluid instabilities emerge at the region where luminous transits later occur, so they can affect the consequent observational signatures. We examine the magnetar-powered supernovae with 2D hydrodynamics simulations and find that the 1D dense shell transforms into the development of Rayleigh-Taylor and thin shell instabilities in 2D. The resulting mixing is able to fragment the entire shell and break the spherical symmetry of supernovae ejecta.

  19. Prediction of flow instability during natural convection

    International Nuclear Information System (INIS)

    Farhadi, Kazem

    2005-01-01

    The occurrence of flow excursion instability during passive heat removal for Tehran Research Reactor (TRR) has been analyzed at low-pressure and low-mass rate of flow conditions without boiling taking place. Pressure drop-flow rate characteristics in the general case are determined upon a developed code for this purpose. The code takes into account variations of different pressure drop components caused by different powers as well as different core inlet temperatures. The analysis revealed the fact that the instability can actually occur in the natural convection mode for a range of powers per fuel plates at a predetermined inlet temperature with fixed geometry of the core. Low mass rate of flow and high sub-cooling are the two important conditions for the occurrence of static instability in the TRR. The calculated results are compared with the existing data in the literature. (author)

  20. Neutrino beam plasma instability

    Indian Academy of Sciences (India)

    Abstract. We derive relativistic fluid set of equations for neutrinos and electrons from relativistic. Vlasov equations with Fermi weak interaction force. Using these fluid equations, we obtain a dis- persion relation describing neutrino beam plasma instability, which is little different from normal dispersion relation of streaming ...

  1. 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...

  2. 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...

  3. Atlantooccipital instability. Case report.

    Science.gov (United States)

    Finney, H L; Roberts, T S

    1978-04-01

    A patient is presented who had neck pain and transient episodes of visual-field defect followed by unconsciousness when he hyperextended his neck. Radiographic examination revealed atlantooccipital instability on flexion and extension views. Treatment by fusion of the occiput to C-2 resulted in relief of symptoms.

  4. Parametric instability of shaft with discs

    Science.gov (United States)

    Wahab, A. M. Abdul; Rasid, Z. A.; Abu, A.; Rudin, N. F. Mohd Noor

    2017-12-01

    The occurrence of resonance is a major criterion to be considered in the design of shaft. While force resonance occurs merely when the natural frequency of the rotor system equals speed of the shaft, parametric resonance or parametric instability can occur at excitation speed that is integral or sub-multiple of the frequency of the rotor. This makes the study on parametric resonance crucial. Parametric instability of a shaft system consisting of a shaft and disks has been investigated in this study. The finite element formulation of the Mathieu-Hill equation that represents the parametric instability problem of the shaft is developed based on Timoshenko’s beam theory and Nelson’s finite element method (FEM) model that considers the effect of torsional motion on such problem. The Bolotin’s method is used to determine the regions of instability and the Strut-Ince diagram. The validation works show that the results of this study are in close agreement to past results. It is found that a larger radius of disk will cause the shaft to become more unstable compared to smaller radius although both weights are similar. Furthermore, the effect of torsional motion on the parametric instability of the shaft is significant at higher rotating speed.

  5. 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.

  6. Computational and Experimental Investigation of Liquid Propellant Rocket Combustion Instability

    Data.gov (United States)

    National Aeronautics and Space Administration — Combustion instability has been a problem faced by rocket engine developers since the 1940s. The complicated phenomena has been highly unpredictable, causing engine...

  7. 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

  8. 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

  9. Maintenance of Genome Integrity: How Mammalian Cells Orchestrate Genome Duplication by Coordinating Replicative and Specialized DNA Polymerases

    Directory of Open Access Journals (Sweden)

    Ryan Barnes

    2017-01-01

    Full Text Available Precise duplication of the human genome is challenging due to both its size and sequence complexity. DNA polymerase errors made during replication, repair or recombination are central to creating mutations that drive cancer and aging. Here, we address the regulation of human DNA polymerases, specifically how human cells orchestrate DNA polymerases in the face of stress to complete replication and maintain genome stability. DNA polymerases of the B-family are uniquely adept at accurate genome replication, but there are numerous situations in which one or more additional DNA polymerases are required to complete genome replication. Polymerases of the Y-family have been extensively studied in the bypass of DNA lesions; however, recent research has revealed that these polymerases play important roles in normal human physiology. Replication stress is widely cited as contributing to genome instability, and is caused by conditions leading to slowed or stalled DNA replication. Common Fragile Sites epitomize “difficult to replicate” genome regions that are particularly vulnerable to replication stress, and are associated with DNA breakage and structural variation. In this review, we summarize the roles of both the replicative and Y-family polymerases in human cells, and focus on how these activities are regulated during normal and perturbed genome replication.

  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. Whole-genome Sequencing Used to Investigate a Nationwide Outbreak of Listeriosis Caused by Ready-to-eat Delicatessen Meat, Denmark, 2014.

    Science.gov (United States)

    Kvistholm Jensen, Anne; Nielsen, Eva Møller; Björkman, Jonas Torgny; Jensen, Tenna; Müller, Luise; Persson, Søren; Bjerager, Gitte; Perge, Annette; Krause, Tyra Grove; Kiil, Kristoffer; Sørensen, Gitte; Andersen, Jens Kirk; Mølbak, Kåre; Ethelberg, Steen

    2016-07-01

    Listeriosis is a serious foodborne infection. Outbreaks of listeriosis occur rarely, but have often proved difficult to solve. In June 2014, we detected and investigated a listeriosis outbreak in Denmark using patient interviews and whole-genome sequencing (WGS). We performed WGS on Listeria monocytogenes isolates from patients and available isolates from ready-to-eat foods and compared them using single-nucleotide polymorphism (SNP) analysis. Case patients had L. monocytogenes with ≤3 SNPs (the outbreak strain) isolated in September 2013-December 2014. Through interviews, we established case patients' food and clinical histories. Food production facilities were inspected and sampled, and we performed trace-back/trace-forward of food delivery chains. In total, 41 cases were identified; 17 deaths occurred (41%). An isolate from a delicatessen meat (spiced meat roll) from company A was identical to the outbreak strain. Half of the patients were infected while hospitalized/institutionalized; institutions were supplied food by company A. The outbreak strain was repeatedly isolated from further samples taken within this company and within companies in its distribution chain. Products from company A were traced and recalled from >6000 food establishments, after which the outbreak ended. Ready-to-eat spiced meat roll from a single production facility caused this outbreak. The product, served sliced and cold, is popular among the elderly; serving it at hospitals probably contributed to the high case-fatality rate. WGS used for patient isolates and isolates from food control inspections, coupled with routine epidemiological follow-up, was instrumental in swiftly locating the source of infections, preventing further illnesses and deaths. © The Author 2016. Published by Oxford University Press for the Infectious Diseases Society of America. All rights reserved. For permissions, e-mail journals.permissions@oup.com.

  12. State Instability and Terrorism

    Science.gov (United States)

    2010-01-01

    security, heterosexual relationships and goods and services. Although prisons constitute a very controlled social structure to begin with, it is...closely although the NBRM model fits slightly better. The Vuong test preferred the ZINB model over the NBRM (p<.0000). This suggests that I ought to...then, it is preferred because it allows me to examine the effects of instability within-country only. This is the purest test of the 109 concept

  13. Instability of gravitating sphalerons

    International Nuclear Information System (INIS)

    Boschung, P.; Brodbeck, O.; Moser, F.; Straumann, N.; Volkov, M.

    1994-01-01

    We prove the instability of the gravitating regular sphaleron solutions of the SU(2) Einstein-Yang-Mills-Higgs system with a Higgs doublet, by studying the frequency spectrum of a class of radial perturbations. With the help of a variational principle we show that there exist always unstable modes. Our method has the advantage that no detailed knowledge of the equilibrium solution is required. It does, however, not directly apply to black holes

  14. 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.

  15. Instability of warped discs

    Science.gov (United States)

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

    2018-01-01

    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 which would generally encapsulate the classical Lightman-Eardley instability in planar discs (given by ∂(νΣ)/∂Σ 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.

  16. Thresholds of a bunched beam longitudinal instability in proton synchrotrons

    International Nuclear Information System (INIS)

    Balbekov, V.I.; Ivanov, S.V.

    1986-01-01

    The formulas and graphs for calculating instability thresholds arising during the interaction of a bunched proton beam with narrow-band resonator are given. The instabilities of three types with oscillations of a definite multipolarity, oscillations of some bound multipoles and with microwave oscillations arising as a result of addition of a great number of multipoles. The analysis of the above data shows that the increase of oscillations nonlinearity is accompanied by the growth of instability threshold only in the zone of separated and weakly bound multipoles. The increase of spread of synchrotron frequencies reduces the zone separated multipoles owing to which the microwave bunch instability can be caused by more and more low-frequency resonators. In the microwave zone practically there is no stabilizing effect of synchrotron frequencies spread. The instability threshold of the bunched beam now - where exceeds the microwave level

  17. 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

  18. Study of microwave instability

    International Nuclear Information System (INIS)

    Heifets, S.; Chao, A.

    1996-12-01

    The microwave instability is usually described by linearizing Vlasov equation in the angle-action variables I, φ and assuming that the interaction of azimuthal harmonics ρ n (I) of the distribution function ρ is weak. The argument implied here is that the Hamiltonian flow smears out particles over invariant tori characterized by the action variables, and the remaining azimuthal dependence of the distribution function is small. Indeed, such an approach successfully describes bunch spectrum and the threshold of the microwave instability. However, recently there have been interesting observations of bunch centroid and bunch shape oscillations above instability threshold at LEP and the damping ring at SLAC. There are also indicates that the oscillations sometimes occur in localized region in the longitudinal coordinate instead of affecting the entire longitudinal distribution as one expects by an action-angle analysis. In this paper the authors describe an alternative approach to the problem of bunch stability using decomposition of the Fokker-Plank equation in the system of nonlinear equations for the moments of the distribution function. In particular, this approach allows them to avoid the conventional action-angle decomposition. The physical quantities they are interested in, the moments, are expressed in the Cartesian z - δ phase space. To close the infinite hierarchy of moments equations, the authors assume that higher order correlations are small. Although both the action-angle and the Cartesian languages must be equivalent before truncation, they may have different speed of convergence depending on the problem being studied. It is hoped that Cartesian expansion approach would converge faster for the cases corresponding to those observed recently above threshold. The recent experimental observations made them interested in it again. This note is a progress report of their work

  19. 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.

  20. High beta tokamak instabilities

    International Nuclear Information System (INIS)

    Bateman, G.

    1977-01-01

    Theoretical predictions using the ideal MHD model indicable that large-scale ballooning modes should appear when the average beta is raised about 1 to 2% in present-day tokamak geometries or 5 to 10% in more optimized geometries. The onset of instability is predicted to be sudden and the behavior of ballooning modes to be strikingly different from the saw-tooth and Mirnov oscillations experimentally observed at low beta. Conditions close to the predicted onset were achieved in ORMAK with no noticeable change in plasma behavior. Experiments are planned for the ISX tokamak to test the beta limit. 15 references, 3 figures

  1. 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.

  2. 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.

  3. Atlantooccipital instability in Down syndrome.

    Science.gov (United States)

    Rosenbaum, D M; Blumhagen, J D; King, H A

    1986-06-01

    Atlantooccipital instability is an uncommon and usually lethal result of major trauma. Nontraumatic cases of instability at this site are rare. We report the findings in two children with Down syndrome who have striking atlantooccipital subluxation demonstrated on flexion and extension radiographs. Since there is increasing radiologic evaluation of cervical spine stability in patients with Down syndrome who wish to participate in athletic activities, the status of the atlantooccipital joint needs careful assessment, especially after cervical fusion for C1-C2 instability.

  4. Iron and genome stability: An update

    International Nuclear Information System (INIS)

    Prá, Daniel; Franke, Silvia Isabel Rech; Henriques, João Antonio Pêgas; Fenech, Michael

    2012-01-01

    Iron is an essential micronutrient which is required in a relatively narrow range for maintaining metabolic homeostasis and genome stability. Iron participates in oxygen transport and mitochondrial respiration as well as in antioxidant and nucleic acid metabolism. Iron deficiency impairs these biological pathways, leading to oxidative stress and possibly carcinogenesis. Iron overload has been linked to genome instability as well as to cancer risk increase, as seen in hereditary hemochromatosis. Iron is an extremely reactive transition metal that can interact with hydrogen peroxide to generate hydroxyl radicals that form the 8-hydroxy-guanine adduct, cause point mutations as well as DNA single and double strand breaks. Iron overload also induces DNA hypermethylation and can reduce telomere length. The current Recommended Dietary Allowances (RDA) for iron, according with Institute of Medicine Dietary Reference Intake (DRI), is based in the concept of preventing anemia, and ranges from 7 mg/day to 18 mg/day depending on life stage and gender. Pregnant women need 27 mg/day. The maximum safety level for iron intake, the Upper Level (UL), is 40–45 mg/day, based on the prevention of gastrointestinal distress associated to high iron intakes. Preliminary evidence indicates that 20 mg/day iron, an intake slightly higher than the RDA, may reduce the risk of gastrointestinal cancer in the elderly as well as increasing genome stability in lymphocytes of children and adolescents. Current dietary recommendations do not consider the concept of genome stability which is of concern because damage to the genome has been linked to the origin and progression of many diseases and is the most fundamental pathology. Given the importance of iron for homeostasis and its potential influence over genome stability and cancer it is recommended to conduct further studies that conclusively define these relationships.

  5. Iron and genome stability: An update

    Energy Technology Data Exchange (ETDEWEB)

    Pra, Daniel, E-mail: daniel_pra@yahoo.com [PPG em Promocao da Saude, Universidade de Santa Cruz do Sul (UNISC), Santa Cruz do Sul, RS (Brazil); PPG em Saude e Comportamento, Universidade Catolica de Pelotas, Pelotas, RS (Brazil); Franke, Silvia Isabel Rech [PPG em Promocao da Saude, Universidade de Santa Cruz do Sul (UNISC), Santa Cruz do Sul, RS (Brazil); Henriques, Joao Antonio Pegas [Instituto de Biotecnologia, Universidade de Caxias do Sul, Caxias do Sul, RS (Brazil); Fenech, Michael [CSIRO Food and Nutritional Sciences, Adelaide, SA (Australia)

    2012-05-01

    Iron is an essential micronutrient which is required in a relatively narrow range for maintaining metabolic homeostasis and genome stability. Iron participates in oxygen transport and mitochondrial respiration as well as in antioxidant and nucleic acid metabolism. Iron deficiency impairs these biological pathways, leading to oxidative stress and possibly carcinogenesis. Iron overload has been linked to genome instability as well as to cancer risk increase, as seen in hereditary hemochromatosis. Iron is an extremely reactive transition metal that can interact with hydrogen peroxide to generate hydroxyl radicals that form the 8-hydroxy-guanine adduct, cause point mutations as well as DNA single and double strand breaks. Iron overload also induces DNA hypermethylation and can reduce telomere length. The current Recommended Dietary Allowances (RDA) for iron, according with Institute of Medicine Dietary Reference Intake (DRI), is based in the concept of preventing anemia, and ranges from 7 mg/day to 18 mg/day depending on life stage and gender. Pregnant women need 27 mg/day. The maximum safety level for iron intake, the Upper Level (UL), is 40-45 mg/day, based on the prevention of gastrointestinal distress associated to high iron intakes. Preliminary evidence indicates that 20 mg/day iron, an intake slightly higher than the RDA, may reduce the risk of gastrointestinal cancer in the elderly as well as increasing genome stability in lymphocytes of children and adolescents. Current dietary recommendations do not consider the concept of genome stability which is of concern because damage to the genome has been linked to the origin and progression of many diseases and is the most fundamental pathology. Given the importance of iron for homeostasis and its potential influence over genome stability and cancer it is recommended to conduct further studies that conclusively define these relationships.

  6. Significance of genetic predisposition and genomic instability for individual sensitivity to radiation. Implications for radiation protection; Bedeutung der genetischen Praedisposition und der genomischen Instabilitaet fuer die individuelle Strahlenempfindlichkeit. Konsequenzen fuer den Strahlenschutz

    Energy Technology Data Exchange (ETDEWEB)

    Heller, H. (ed.)

    2001-07-01

    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. [German] Der Strahlenschutzkommission war es ein besonderes Anliegen, sich im Rahmen ihrer Klausurtagung am 20./21. Januar 2000 mit der Bedeutung der genetischen Praedisposition und der genetischen Instabilitaet fuer die individuelle Strahlenempfindlichkeit sowie mit den damit moeglicherweise verbundenen Auswirkungen auf den Strahlenschutz intensiv auseinanderzusetzen. Die vielfaeltigen ethischen, persoenlichkeitsrechtlichen, arbeitsmedizinischen und versicherungsrelevanten Aspekte dieser Thematik, die weit ueber rein fachliche Fragen des Strahlenschutzes hinausgehen, kamen waehrend des abschliessenden Podiumsgespraeches in Stellungnahmen und Diskussionsbeitraegen zur Sprache. Der vorliegende Band beinhaltet die Vortragsmanuskripte dieser Veranstaltung sowie eine zusammenfassende Bewertung durch die Strahlenschutzkommission. (orig.)

  7. Two phase flow instabilities in horizontal straight tube evaporator

    OpenAIRE

    2010-01-01

    Abstract It is essential to ensure the stability of a refrigeration system if the oscillation in evaporation process is the primary cause for the whole system instability. This paper is concerned with an experimental investigation of two phase flow instabilities in a horizontal straight tube evaporator of a refrigeration system. The relationship between pressure drop and mass flow with constant heat flux and evaporation pressure is measured and determined. It is found that there is...

  8. Analysis of Kelvin Helmholtz Instabilities of Plasma Jets

    Science.gov (United States)

    Friedman, Mark J.; Hollingsworth, Blane J.

    1999-01-01

    Ulysses data indicates density fluctuations which are theorized to be the result of shear between a solar jet and its ambient. The MHD Kelvin-Helmholtz ("KH") instability causes such fluctuations as observed by Ulysses. A new dispersion relationship which accounts for this KH instability is derived via the linearization of the MHD equations. This generalizes an earlier result by Hardee. This dispersion relationship has the form of eight non-linear equations with nine unknowns.

  9. Width of electromagnetic wave instability spectrum in tungsten plate

    International Nuclear Information System (INIS)

    Rinkevich, A.B.

    1995-01-01

    Based on the study of high-frequency signal modulation and spectrum analysis of the envelope a measurement of spectrum width for electromagnetic wave instability was carried out under conditions of current pulse action on tungsten plate in magnetic field. The existence of amplitude-frequency wave modulation was revealed. The width of current disturbance spectrum in a specimen was evaluated. Current disturbances are shown to cause the instability of electromagnetic wave. 11 refs.; 6 figs

  10. An Experimental Investigation of Incompressible Richtmyer-Meshkov Instability

    Science.gov (United States)

    Jacobs, J. W.; Niederhaus, C. E.

    2002-11-01

    Richtmyer-Meshkov (RM) instability occurs when two different density fluids are impulsively accelerated in the direction normal to their nearly planar interface. The instability causes small perturbations on the interface to grow and eventually become a turbulent flow. It is closely related to Rayleigh-Taylor instability, which is the instability of a planar interface undergoing constant acceleration, such as caused by the suspension of a heavy fluid over a lighter one in the earth's gravitational field. Like the well-known Kelvin-Helmholtz instability, RM instability is a fundamental hydrodynamic instability which exhibits many of the nonlinear complexities that transform simple initial conditions into a complex turbulent flow. Furthermore, the simplicity of RM instability (in that it requires very few defining parameters), and the fact that it can be generated in a closed container, makes it an excellent test bed to study nonlinear stability theory as well as turbulent transport in a heterogeneous system. However, the fact that RM instability involves fluids of unequal densities which experience negligible gravitational force, except during the impulsive acceleration, requires RM instability experiments to be carried out under conditions of microgravity. This experimental study investigates the instability of an interface between incompressible, miscible liquids with an initial sinusoidal perturbation. The impulsive acceleration is generated by bouncing a rectangular tank containing two different density liquids off a retractable vertical spring. The initial perturbation is produced prior to release by oscillating the tank in the horizontal direction to produce a standing wave. The instability evolves in microgravity as the tank travels up and then down the vertical rails of a drop tower until hitting a shock absorber at the bottom. Planar Laser Induced Fluorescence (PLIF) is employed to visualize the flow. PLIF images are captured by a video camera that travels

  11. Double Arc Instability in the Solar Corona

    Energy Technology Data Exchange (ETDEWEB)

    Ishiguro, N.; Kusano, K., E-mail: n-ishiguro@isee.nagoya-u.ac.jp [Institute for Space-Earth Environmental Research, Nagoya University, Furo-cho, Chikusa-ku, Nagoya, Aichi 464-8601 Japan (Japan)

    2017-07-10

    The stability of the magnetic field in the solar corona is important for understanding the causes of solar eruptions. Although various scenarios have been suggested to date, the tether-cutting reconnection scenario proposed by Moore et al. is one of the widely accepted models to explain the onset process of solar eruptions. Although the tether-cutting reconnection scenario proposes that the sigmoidal field formed by internal reconnection is the magnetic field in the pre-eruptive state, the stability of the sigmoidal field has not yet been investigated quantitatively. In this paper, in order to elucidate the stability problem of the pre-eruptive state, we developed a simple numerical analysis in which the sigmoidal field is modeled by a double arc electric current loop and its stability is analyzed. As a result, we found that the double arc loop is more easily destabilized than the axisymmetric torus, and it becomes unstable even if the external field does not decay with altitude, which is in contrast to the axisymmetric torus instability. This suggests that tether-cutting reconnection may well work as the onset mechanism of solar eruptions, and if so, the critical condition for eruption under a certain geometry may be determined by a new type of instability rather than by the torus instability. Based on them, we propose a new type of instability called double arc instability (DAI). We discuss the critical conditions for DAI and derive a new parameter κ , defined as the product of the magnetic twist and the normalized flux of the tether-cutting reconnection.

  12. Exome sequencing and CRISPR/Cas genome editing identify mutations of ZAK as a cause of limb defects in humans and mice

    NARCIS (Netherlands)

    Spielmann, M.; Kakar, N.; Tayebi, N.; Leettola, C.; Nurnberg, G.; Sowada, N.; Lupianez, D.G.; Harabula, I.; Flottmann, R.; Horn, D.; Chan, W.L.; Wittler, L.; Yilmaz, R.; Altmuller, J.; Thiele, H.; Bokhoven, H. van; Schwartz, C.E.; Nurnberg, P.; Bowie, J.U.; Ahmad, J.; Kubisch, C.; Mundlos, S.; Borck, G.

    2016-01-01

    The CRISPR/Cas technology enables targeted genome editing and the rapid generation of transgenic animal models for the study of human genetic disorders. Here we describe an autosomal recessive human disease in two unrelated families characterized by a split-foot defect, nail abnormalities of the

  13. Draft genome sequences of six neonatal meningitis-causing escherichia coli isolates (SP-4, SP-5, SP-13, SP-16, SP-46, and SP-65)

    Science.gov (United States)

    Neonatal meningitis Escherichia coli isolates (SP-4, SP-5, SP-13, SP-16, SP-46, and SP-65) were recovered from infants in the Netherlands from 1989 to 1997. Here, we report the draft genome sequences for these six E. coli isolates, which are currently being used to validate food safety processing te...

  14. Impact of inorganic nutrients on maintenance of genomic stability.

    Science.gov (United States)

    Cheng, Wen-Hsing

    2009-06-01

    Maintenance of genome stability is of fundamental importance for counteracting carcinogenesis. Many human genome instability syndromes exhibit a predisposition to cancer. An increasing body of epidemiological evidence has suggested a link between nutrient status and risk of cancer. Like other chemicals, nutrients can be toxic when consumed in excess. It has become clear that both nutritional deficiency and toxicity can compromise the integrity of the genome. This article focuses on roles of inorganic trace nutrients, including selenium, copper, zinc, and iron, in the redox regulation of genome stability and how they relate to the pathologies of genomic instability syndromes and cancer.

  15. 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.

  16. Cinerama sickness and postural instability

    NARCIS (Netherlands)

    Bos, J.E.; Ledegang, W.D.; Lubeck, A.J.A.; Stins, J.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

  17. Cohabitation and Children's Family Instability

    Science.gov (United States)

    Kelly Raley, R.; Wildsmith, Elizabeth

    2004-01-01

    This study estimates how much children's family instability is missed when we do not count transitions into and out of cohabitation, and examines early life course trajectories of children to see whether children who experience maternal cohabitation face more family instability than children who do not. Using data from the 1995 National Survey of…

  18. Nonlinear theory of drift instability

    International Nuclear Information System (INIS)

    Hatori, T.

    1981-01-01

    In this chapter, we review recent works on the analytical and numerical analysis for the nonlinear evolution of drift instabilities. Only the case of a coherent wave is considered. Contributions to the turbulence theory for drift instabilities are already presented in Chapter 4. (author)

  19. Early embryonic chromosome instability results in stable mosaic pattern in human tissues.

    Directory of Open Access Journals (Sweden)

    Hasmik Mkrtchyan

    Full Text Available The discovery of copy number variations (CNV in the human genome opened new perspectives on the study of the genetic causes of inherited disorders and the aetiology of common diseases. Here, a single-cell-level investigation of CNV in different human tissues led us to uncover the phenomenon of mitotically derived genomic mosaicism, which is stable in different cell types of one individual. The CNV mosaic ratios were different between the 10 individuals studied. However, they were stable in the T lymphocytes, immortalized B lymphoblastoid cells, and skin fibroblasts analyzed in each individual. Because these cell types have a common origin in the connective tissues, we suggest that mitotic changes in CNV regions may happen early during embryonic development and occur only once, after which the stable mosaic ratio is maintained throughout the differentiated tissues. This concept is further supported by a unique study of immortalized B lymphoblastoid cell lines obtained with 20 year difference from two subjects. We provide the first evidence of somatic mosaicism for CNV, with stable variation ratios in different cell types of one individual leading to the hypothesis of early embryonic chromosome instability resulting in stable mosaic pattern in human tissues. This concept has the potential to open new perspectives in personalized genetic diagnostics and can explain genetic phenomena like diminished penetrance in autosomal dominant diseases. We propose that further genomic studies should focus on the single-cell level, to better understand the aetiology of aging and diseases mediated by somatic mutations.

  20. 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.

  1. Dissipative drift instability in dusty plasma

    Directory of Open Access Journals (Sweden)

    Nilakshi Das

    2012-03-01

    Full Text Available An investigation has been done on the very low-frequency electrostatic drift waves in a collisional dusty plasma. The dust density gradient is taken perpendicular to the magnetic field B0⃗, which causes the drift wave. In this case, low-frequency drift instabilities can be driven by E1⃗×B0⃗ and diamagnetic drifts, where E1⃗ is the perturbed electric field. Dust charge fluctuation is also taken into consideration for our study. The dust- neutral and ion-neutral collision terms have been included in equations of motion. It is seen that the low-frequency drift instability gets damped in such a system. Both dust charging and collision of plasma particles with the neutrals may be responsible for the damping of the wave. Both analytical and numerical techniques have been used while developing the theory.

  2. Longwave instabilities and patterns in fluids

    CERN Document Server

    Shklyaev, Sergey

    2017-01-01

    This book summarizes the main advances in the field of nonlinear evolution and pattern formation caused by longwave instabilities in fluids. It will allow readers to master the multiscale asymptotic methods and become familiar with applications of these methods in a variety of physical problems.  Longwave instabilities are inherent to a variety of systems in fluid dynamics, geophysics, electrodynamics, biophysics, and many others. The techniques of the derivation of longwave amplitude equations, as well as the analysis of numerous nonlinear equations, are discussed throughout. This book will be of value to researchers and graduate students in applied mathematics, physics, and engineering, in particular within the fields of fluid mechanics, heat and mass transfer theory, and nonlinear dynamics. .

  3. Final report of the group research. Genome analysis on the biological effects of radiation. Second research group of NIRS

    International Nuclear Information System (INIS)

    2001-10-01

    This report concerns investigations on the title conducted by 5 subgroups of National Institute of Radiological Sciences (NIRS) during the period of 1993-2001. The report involves the organization of research teams and summary reports from the subgroups for Genome sequencing and informatics, Genome analysis on model organisms, The genome analysis on the specific chromosomal region related to radiation-sensitivity, Molecular analysis on the structure and function of particular regions of human genome, and Generation and characterization of DNA repair-deficient model mice. Significant results are as follows: Sequencing of the radiation sensitivity gene ATM, finding of a novel cell cycle regulator gene NPAT and regulation of gene expression of ATM/NPAT; Findings that the cause of the variability related to instability of human genome is derived from particular repeat structures of 5 and 35 bases and of the instability mutation, from the mutation of EPILS (mRNA synthase gene); Program development for novel human genome finding in the DNA sequences and making novel human gene as a resource by polymerase chain reaction (PCR) technique; and generation of the highly UV-sensitive mouse model for human xeroderma pigmentosum G. Conclusion is that findings will contribute for better understanding of the genes functioning radiation sensitivity and also biodefense mechanism against radiation and other environmental stress. (N.I.)

  4. Spatial-Temporal Instability of an Inviscid Shear Layer

    Directory of Open Access Journals (Sweden)

    Qing-fei Fu

    2017-01-01

    Full Text Available In this work, we explore the transition of absolute instability and convective instability in a compressible inviscid shear layer, through a linear spatial-temporal instability analysis. From linearized governing equations of the shear layer and the ideal-gas equation of state, the dispersion relation for the pressure perturbation was obtained. The eigenvalue problem for the evolution of two-dimensional perturbation was solved by means of shooting method. The zero group velocity is obtained by a saddle point method. The absolute/convective instability characteristics of the flow are determined by the temporal growth rate at the saddle point. The absolute/convective nature of the flow instability has strong dependence on the values of the temperature ratio, the velocity ratio, the oblique angle, and M number. A parametric study indicates that, for a great value of velocity ratio, the inviscid shear layer can transit to absolute instability. The increase of temperature ratio decreases the absolute growth rate when the temperature ratio is large; the effect of temperature ratio is opposite when the temperature ratio is relatively small. The obliquity of the perturbations would cause the increase of the absolute growth rate. The effect of M number is different when the oblique angle is great and small. Besides, the absolute instability boundary is found in the velocity ratio, temperature ratio, and M number space.

  5. 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

  6. Instability of ties in compression

    DEFF Research Database (Denmark)

    Buch-Hansen, Thomas Cornelius

    2013-01-01

    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...... 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......-connectors in cavity walls was developed. The method takes into account constraint conditions limiting the free length of the wall tie, and the instability in case of pure compression which gives an optimal load bearing capacity. The model is illustrated with examples from praxis....

  7. 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

  8. 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

  9. Limited influence of germline genetic variation on all-cause mortality in women with early onset breast cancer: evidence from gene-based tests, single-marker regression, and whole-genome prediction.

    Science.gov (United States)

    Scannell Bryan, Molly; Argos, Maria; Andrulis, Irene L; Hopper, John L; Chang-Claude, Jenny; Malone, Kathleen; John, Esther M; Gammon, Marilie D; Daly, Mary; Terry, Mary Beth; Buys, Saundra S; Huo, Dezheng; Olopade, Olofunmilayo; Genkinger, Jeanine M; Jasmine, Farzana; Kibriya, Muhammad G; Chen, Lin; Ahsan, Habibul

    2017-08-01

    Women diagnosed with breast cancer have heterogeneous survival outcomes that cannot be fully explained by known prognostic factors, and germline variation is a plausible but unconfirmed risk factor. We used three approaches to test the hypothesis that germline variation drives some differences in survival: mortality loci identification, tumor aggressiveness loci identification, and whole-genome prediction. The 2954 study participants were women diagnosed with breast cancer before age 50, with a median follow-up of 15 years who were genotyped on an exome array. We first searched for loci in gene regions that were associated with all-cause mortality. We next searched for loci in gene regions associated with five histopathological characteristics related to tumor aggressiveness. Last, we also predicted 10-year all-cause mortality on a subset of 1903 participants (3,245,343 variants after imputation) using whole-genome prediction methods. No risk loci for mortality or tumor aggressiveness were identified. This null result persisted when restricting to women with estrogen receptor-positive tumors, when examining suggestive loci in an independent study, and when restricting to previously published risk loci. Additionally, the whole-genome prediction model also found no evidence to support an association. Despite multiple complementary approaches, our study found no evidence that mortality in women with early onset breast cancer is influenced by germline variation.

  10. 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.

  11. Whole genome sequencing analyses of Listeria monocytogenes that persisted in a milkshake machine for a year and caused illnesses in Washington State

    OpenAIRE

    Li, Zhen; P?rez-Osorio, Ailyn; Wang, Yu; Eckmann, Kaye; Glover, William A.; Allard, Marc W.; Brown, Eric W.; Chen, Yi

    2017-01-01

    Background In 2015, in addition to a United States multistate outbreak linked to contaminated ice cream, another outbreak linked to ice cream was reported in the Pacific Northwest of the United States. It was a hospital-acquired outbreak linked to milkshakes, made from contaminated ice cream mixes and milkshake maker, served to patients. Here we performed multiple analyses on isolates associated with this outbreak: pulsed-field gel electrophoresis (PFGE), whole genome single nucleotide polymo...

  12. Evolutionary genomics of Entamoeba

    Science.gov (United States)

    Weedall, Gareth D.; Hall, Neil

    2011-01-01

    Entamoeba histolytica is a human pathogen that causes amoebic dysentery and leads to significant morbidity and mortality worldwide. Understanding the genome and evolution of the parasite will help explain how, when and why it causes disease. Here we review current knowledge about the evolutionary genomics of Entamoeba: how differences between the genomes of different species may help explain different phenotypes, and how variation among E. histolytica parasites reveals patterns of population structure. The imminent expansion of the amount genome data will greatly improve our knowledge of the genus and of pathogenic species within it. PMID:21288488

  13. Magnetically-Driven Convergent Instability Growth platform on Z.

    Energy Technology Data Exchange (ETDEWEB)

    Knapp, Patrick [Sandia National Lab. (SNL-NM), Albuquerque, NM (United States); Mattsson, Thomas [Sandia National Lab. (SNL-NM), Albuquerque, NM (United States); Martin, Matthew [Sandia National Lab. (SNL-NM), Albuquerque, NM (United States); Benage, John F. [Sandia National Lab. (SNL-NM), Albuquerque, NM (United States); Jenkins, James [Los Alamos National Lab. (LANL), Los Alamos, NM (United States); Albright, Brian James [Los Alamos National Lab. (LANL), Los Alamos, NM (United States)

    2017-09-01

    Hydrodynamic instability growth is a fundamentally limiting process in many applications. In High Energy Density Physics (HEDP) systems such as inertial confinement fusion implosions and stellar explosions, hydro instabilities can dominate the evolution of the object and largely determine the final state achievable. Of particular interest is the process by which instabilities cause perturbations at a density or material interface to grow nonlinearly, introducing vorticity and eventually causing the two species to mix across the interface. Although quantifying instabilities has been the subject of many investigations in planar geometry, few have been done in converging geometry. During FY17, the team executed six convergent geometry instability experiments. Based on earlier results, the platform was redesigned and improved with respect to load centering at installation making the installation reproducible and development of a new 7.2 keV, Co He-a backlighter system to better penetrate the liner. Together, the improvements yielded significantly improved experimental results. The results in FY17 demonstrate the viability of using experiments on Z to quantify instability growth in cylindrically convergent geometry. Going forward, we will continue the partnership with staff and management at LANL to analyze the past experiments, compare to hydrodynamics growth models, and design future experiments.

  14. A Tool for Multiple Targeted Genome Deletions that Is Precise, Scar-Free, and Suitable for Automation.

    Science.gov (United States)

    Aubrey, Wayne; Riley, Michael C; Young, Michael; King, Ross D; Oliver, Stephen G; Clare, Amanda

    2015-01-01

    Many advances in synthetic biology require the removal of a large number of genomic elements from a genome. Most existing deletion methods leave behind markers, and as there are a limited number of markers, such methods can only be applied a fixed number of times. Deletion methods that recycle markers generally are either imprecise (remove untargeted sequences), or leave scar sequences which can cause genome instability and rearrangements. No existing marker recycling method is automation-friendly. We have developed a novel openly available deletion tool that consists of: 1) a method for deleting genomic elements that can be repeatedly used without limit, is precise, scar-free, and suitable for automation; and 2) software to design the method's primers. Our tool is sequence agnostic and could be used to delete large numbers of coding sequences, promoter regions, transcription factor binding sites, terminators, etc in a single genome. We have validated our tool on the deletion of non-essential open reading frames (ORFs) from S. cerevisiae. The tool is applicable to arbitrary genomes, and we provide primer sequences for the deletion of: 90% of the ORFs from the S. cerevisiae genome, 88% of the ORFs from S. pombe genome, and 85% of the ORFs from the L. lactis genome.

  15. Canonical momenta and numerical instabilities in particle codes

    International Nuclear Information System (INIS)

    Godfrey, B.B.

    1975-01-01

    A set of warm plasma dispersion relations appropriate to a large class of electromagnetic plasma simulation codes is derived. The numerical Cherenkov instability is shown by analytic and numerical analysis of these dispersion relations to be the most significant nonphysical effect involving transverse electromagnetic waves. The instability arises due to a spurious phase shift between resonant particles and light waves, caused by a basic incompatibility between the Lagrangian treatment of particle positions and the Eulerian treatment of particle velocities characteristic of most PIC--CIC algorithms. It is demonstrated that, through the use of canonical momentum, this mismatch is alleviated sufficiently to completely eliminate the Cherenkov instability. Collateral effects on simulation accuracy and on other numerical instabilities appear to be minor

  16. Genome Stability Pathways in Head and Neck Cancers

    Directory of Open Access Journals (Sweden)

    Glenn Jenkins

    2013-01-01

    Full Text Available Genomic instability underlies the transformation of host cells toward malignancy, promotes development of invasion and metastasis and shapes the response of established cancer to treatment. In this review, we discuss recent advances in our understanding of genomic stability in squamous cell carcinoma of the head and neck (HNSCC, with an emphasis on DNA repair pathways. HNSCC is characterized by distinct profiles in genome stability between similarly staged cancers that are reflected in risk, treatment response and outcomes. Defective DNA repair generates chromosomal derangement that can cause subsequent alterations in gene expression, and is a hallmark of progression toward carcinoma. Variable functionality of an increasing spectrum of repair gene polymorphisms is associated with increased cancer risk, while aetiological factors such as human papillomavirus, tobacco and alcohol induce significantly different behaviour in induced malignancy, underpinned by differences in genomic stability. Targeted inhibition of signalling receptors has proven to be a clinically-validated therapy, and protein expression of other DNA repair and signalling molecules associated with cancer behaviour could potentially provide a more refined clinical model for prognosis and treatment prediction. Development and expansion of current genomic stability models is furthering our understanding of HNSCC pathophysiology and uncovering new, promising treatment strategies.

  17. Urethral morphology and bladder instability.

    Science.gov (United States)

    Hausegger, K A; Fotter, R; Sorantin, E; Schmidt, P

    1991-01-01

    In order to calculate the relationship between Spinning top urethra (STU) and bladder instability 160 voiding cystourethrogramms (VCU), performed in 102 girls, have been analysed retrospectively. 28 girls had STU, 16 of those had bladder instability as well (57%). We could not find the highly positive correlation between unstable bladder and STU as reported by other authors, although there was a statistically positive correlation between STU and bladder instability. However the confidence interval was very broad (38%-75%). We conclude that bladder instability may contribute to STU but cannot render the etiological explanation for all cases. STU seems to be a polyetiological sign. In our opinion only the combination of STU and bladder instability has a diagnostic impact, since several therapeutical concepts are available in cases of bladder instability. The finding of STU in the VCU should alert the examiner's attention to functional disorders of the lower urinary tract. If no instability can be found, STU should be considered to be a normal variant.

  18. Urethral morphology and bladder instability

    Energy Technology Data Exchange (ETDEWEB)

    Hausegger, K.A.; Fotter, R.; Sorantin, E. (Graz Univ. (Austria). Radiologische Klinik); Schmidt, P. (Rehabilitationszentrum, Schallerbach (Austria))

    1991-05-01

    In order to calculate the relationship between Spinning top urethra (STU) and bladder instability 160 voiding cystourethrogramms (VCU), performed in 102 girls, have been analysed retrospectively. 28 girls had STU, 16 of those had bladder instability as well (57%). We could not find the highly positive correlation between unstable bladder and STU as reported by other authors, although there was a statistically positive correlation between STU and bladder instability. However the confidence interval was very broad (38%-75%). We conclude that bladder instability may contribute to STU but cannot render the etiological explanation for all cases. STU seems to be a polyetiological sign. In our opinion only the combination of STU and bladder instability has a diagnostic impact, since several therapeutical concepts are available in cases of bladder instability. The finding of STU in the VCU should alert the examiner's attention to functional disorders of the lower urinary tract. If no instability can be found, STU should be considered to be a normal variant. (orig.).

  19. Genomic Testing

    Science.gov (United States)

    ... Events and Multimedia Implementation Genetics 101 Family Health History Genomics and Diseases Genetic Counseling Genomic Testing Epidemiology Pathogen Genomics Resources Genomic Testing Recommend on Facebook Tweet Share Compartir Fact Sheet: Identifying Opportunities to ...

  20. 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.

  1. 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

  2. Genome Maps, a new generation genome browser

    Science.gov (United States)

    Medina, Ignacio; Salavert, Francisco; Sanchez, Rubén; de Maria, Alejandro; Alonso, Roberto; Escobar, Pablo; Bleda, Marta; Dopazo, Joaquín

    2013-01-01

    Genome browsers have gained importance as more genomes and related genomic information become available. However, the increase of information brought about by new generation sequencing technologies is, at the same time, causing a subtle but continuous decrease in the efficiency of conventional genome browsers. Here, we present Genome Maps, a genome browser that implements an innovative model of data transfer and management. The program uses highly efficient technologies from the new HTML5 standard, such as scalable vector graphics, that optimize workloads at both server and client sides and ensure future scalability. Thus, data management and representation are entirely carried out by the browser, without the need of any Java Applet, Flash or other plug-in technology installation. Relevant biological data on genes, transcripts, exons, regulatory features, single-nucleotide polymorphisms, karyotype and so forth, are imported from web services and are available as tracks. In addition, several DAS servers are already included in Genome Maps. As a novelty, this web-based genome browser allows the local upload of huge genomic data files (e.g. VCF or BAM) that can be dynamically visualized in real time at the client side, thus facilitating the management of medical data affected by privacy restrictions. Finally, Genome Maps can easily be integrated in any web application by including only a few lines of code. Genome Maps is an open source collaborative initiative available in the GitHub repository (https://github.com/compbio-bigdata-viz/genome-maps). Genome Maps is available at: http://www.genomemaps.org. PMID:23748955

  3. Genome Maps, a new generation genome browser.

    Science.gov (United States)

    Medina, Ignacio; Salavert, Francisco; Sanchez, Rubén; de Maria, Alejandro; Alonso, Roberto; Escobar, Pablo; Bleda, Marta; Dopazo, Joaquín

    2013-07-01

    Genome browsers have gained importance as more genomes and related genomic information become available. However, the increase of information brought about by new generation sequencing technologies is, at the same time, causing a subtle but continuous decrease in the efficiency of conventional genome browsers. Here, we present Genome Maps, a genome browser that implements an innovative model of data transfer and management. The program uses highly efficient technologies from the new HTML5 standard, such as scalable vector graphics, that optimize workloads at both server and client sides and ensure future scalability. Thus, data management and representation are entirely carried out by the browser, without the need of any Java Applet, Flash or other plug-in technology installation. Relevant biological data on genes, transcripts, exons, regulatory features, single-nucleotide polymorphisms, karyotype and so forth, are imported from web services and are available as tracks. In addition, several DAS servers are already included in Genome Maps. As a novelty, this web-based genome browser allows the local upload of huge genomic data files (e.g. VCF or BAM) that can be dynamically visualized in real time at the client side, thus facilitating the management of medical data affected by privacy restrictions. Finally, Genome Maps can easily be integrated in any web application by including only a few lines of code. Genome Maps is an open source collaborative initiative available in the GitHub repository (https://github.com/compbio-bigdata-viz/genome-maps). Genome Maps is available at: http://www.genomemaps.org.

  4. Genome and secretome analysis of the hemibiotrophic fungal pathogen, Moniliophthora roreri, which causes frosty pod rot disease of cacao: mechanisms of the biotrophic and necrotrophic phases.

    Science.gov (United States)

    Meinhardt, Lyndel W; Costa, Gustavo Gilson Lacerda; Thomazella, Daniela P T; Teixeira, Paulo José P L; Carazzolle, Marcelo Falsarella; Schuster, Stephan C; Carlson, John E; Guiltinan, Mark J; Mieczkowski, Piotr; Farmer, Andrew; Ramaraj, Thiruvarangan; Crozier, Jayne; Davis, Robert E; Shao, Jonathan; Melnick, Rachel L; Pereira, Gonçalo A G; Bailey, Bryan A

    2014-02-27

    The basidiomycete Moniliophthora roreri is the causal agent of Frosty pod rot (FPR) disease of cacao (Theobroma cacao), the source of chocolate, and FPR is one of the most destructive diseases of this important perennial crop in the Americas. This hemibiotroph infects only cacao pods and has an extended biotrophic phase lasting up to sixty days, culminating in plant necrosis and sporulation of the fungus without the formation of a basidiocarp. We sequenced and assembled 52.3 Mb into 3,298 contigs that represent the M. roreri genome. Of the 17,920 predicted open reading frames (OFRs), 13,760 were validated by RNA-Seq. Using read count data from RNA sequencing of cacao pods at 30 and 60 days post infection, differential gene expression was estimated for the biotrophic and necrotrophic phases of this plant-pathogen interaction. The sequencing data were used to develop a genome based secretome for the infected pods. Of the 1,535 genes encoding putative secreted proteins, 1,355 were expressed in the biotrophic and necrotrophic phases. Analysis of the data revealed secretome gene expression that correlated with infection and intercellular growth in the biotrophic phase and invasive growth and plant cellular death in the necrotrophic phase. Genome sequencing and RNA-Seq was used to determine and validate the Moniliophthora roreri genome and secretome. High sequence identity between Moniliophthora roreri genes and Moniliophthora perniciosa genes supports the taxonomic relationship with Moniliophthora perniciosa and the relatedness of this fungus to other basidiomycetes. Analysis of RNA-Seq data from infected plant tissues revealed differentially expressed genes in the biotrophic and necrotrophic phases. The secreted protein genes that were upregulated in the biotrophic phase are primarily associated with breakdown of the intercellular matrix and modification of the fungal mycelia, possibly to mask the fungus from plant defenses. Based on the transcriptome data, the

  5. Exome sequencing and CRISPR/Cas genome editing identify mutations of ZAK as a cause of limb defects in humans and mice.

    Science.gov (United States)

    Spielmann, Malte; Kakar, Naseebullah; Tayebi, Naeimeh; Leettola, Catherine; Nürnberg, Gudrun; Sowada, Nadine; Lupiáñez, Darío G; Harabula, Izabela; Flöttmann, Ricarda; Horn, Denise; Chan, Wing Lee; Wittler, Lars; Yilmaz, Rüstem; Altmüller, Janine; Thiele, Holger; van Bokhoven, Hans; Schwartz, Charles E; Nürnberg, Peter; Bowie, James U; Ahmad, Jamil; Kubisch, Christian; Mundlos, Stefan; Borck, Guntram

    2016-02-01

    The CRISPR/Cas technology enables targeted genome editing and the rapid generation of transgenic animal models for the study of human genetic disorders. Here we describe an autosomal recessive human disease in two unrelated families characterized by a split-foot defect, nail abnormalities of the hands, and hearing loss, due to mutations disrupting the SAM domain of the protein kinase ZAK. ZAK is a member of the MAPKKK family with no known role in limb development. We show that Zak is expressed in the developing limbs and that a CRISPR/Cas-mediated knockout of the two Zak isoforms is embryonically lethal in mice. In contrast, a deletion of the SAM domain induces a complex hindlimb defect associated with down-regulation of Trp63, a known split-hand/split-foot malformation disease gene. Our results identify ZAK as a key player in mammalian limb patterning and demonstrate the rapid utility of CRISPR/Cas genome editing to assign causality to human mutations in the mouse in <10 wk. © 2016 Spielmann et al.; Published by Cold Spring Harbor Laboratory Press.

  6. Analyzing Growth and Instability in Subsistence Agriculture of Odisha: Evidence from Major Crops

    OpenAIRE