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Sample records for telomere-centromere-driven genomic instability

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

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    Amanda Gonçalves dos Santos Silva

    2010-01-01

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

  2. Bacterial Genome Instability

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    Darmon, Elise

    2014-01-01

    SUMMARY Bacterial genomes are remarkably stable from one generation to the next but are plastic on an evolutionary time scale, substantially shaped by horizontal gene transfer, genome rearrangement, and the activities of mobile DNA elements. This implies the existence of a delicate balance between the maintenance of genome stability and the tolerance of genome instability. In this review, we describe the specialized genetic elements and the endogenous processes that contribute to genome instability. We then discuss the consequences of genome instability at the physiological level, where cells have harnessed instability to mediate phase and antigenic variation, and at the evolutionary level, where horizontal gene transfer has played an important role. Indeed, this ability to share DNA sequences has played a major part in the evolution of life on Earth. The evolutionary plasticity of bacterial genomes, coupled with the vast numbers of bacteria on the planet, substantially limits our ability to control disease. PMID:24600039

  3. Causes of genome instability

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

    2015-01-01

    Genome instability is a prerequisite for the development of cancer. It occurs when genome maintenance systems fail to safeguard the genome's integrity, whether as a consequence of inherited defects or induced via exposure to environmental agents (chemicals, biological agents and radiation). Thus,...

  4. 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

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

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    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.

  6. Genome instabilities arising from ribonucleotides in DNA.

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    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.

  7. Mechanisms of cadmium induced genomic instability

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

    2012-05-01

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

  8. Genomic Instability and Breast Cancer

    Science.gov (United States)

    2011-01-01

    endogenous sources like free radicals, or from exogenous agents such as UV light and ionizing radiation . To ensure genome stability, cells have evolved...specific siRNAs. RPA and RAD51 foci formation were determined after ionizing radiation (IR) and quantified. (E) Cells with DR-GFP reporter were...Bishop, D.K. (2009). The Mei5-Sae3 protein complex mediates Dmc1 activity in Saccharomyces cerevisiae. J Biol Chem 284, 11766-11770. Haruta, N

  9. How Do Cytokines Trigger Genomic Instability?

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    Ioannis L. Aivaliotis

    2012-01-01

    Full Text Available Inflammation is a double-edged sword presenting a dual effect on cancer development, from one hand promoting tumor initiation and progression and from the other hand protecting against cancer through immunosurveillance mechanisms. Cytokines are crucial components of inflammation, participating in the interaction between the cells of tumor microenvironment. A comprehensive study of the role of cytokines in the context of the inflammation-tumorigenesis interplay helps us to shed light in the pathogenesis of cancer. In this paper we focus on the role of cytokines in the development of genomic instability, an evolving hallmark of cancer.

  10. One-hit wonders of genomic instability

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    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.

  11. SPOP mutation leads to genomic instability in prostate cancer

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    Boysen, Gunther; Barbieri, Christopher E; Prandi, Davide; Blattner, Mirjam; Chae, Sung-Suk; Dahija, Arun; Nataraj, Srilakshmi; Huang, Dennis; Marotz, Clarisse; Xu, Limei; Huang, Julie; Lecca, Paola; Chhangawala, Sagar; Liu, Deli; Zhou, Pengbo; Sboner, Andrea; de Bono, Johann S

    2015-01-01

    Genomic instability is a fundamental feature of human cancer often resulting from impaired genome maintenance. In prostate cancer, structural genomic rearrangements are a common mechanism driving tumorigenesis. However, somatic alterations predisposing to chromosomal rearrangements in prostate cancer remain largely undefined. Here, we show that SPOP, the most commonly mutated gene in primary prostate cancer modulates DNA double strand break (DSB) repair, and that SPOP mutation is associated with genomic instability. In vivo, SPOP mutation results in a transcriptional response consistent with BRCA1 inactivation resulting in impaired homology-directed repair (HDR) of DSB. Furthermore, we found that SPOP mutation sensitizes to DNA damaging therapeutic agents such as PARP inhibitors. These results implicate SPOP as a novel participant in DSB repair, suggest that SPOP mutation drives prostate tumorigenesis in part through genomic instability, and indicate that mutant SPOP may increase response to DNA-damaging therapeutics. DOI: http://dx.doi.org/10.7554/eLife.09207.001 PMID:26374986

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

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    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

  13. Genome instability in Lactobacillus rhamnosus GG

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    W. Sybesma (Wilbert); D. Molenaar (Douwe); W.F.J. van IJcken (Wilfred); K. Venema (Koen); R. Kort (Remco)

    2013-01-01

    textabstractWe 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

  14. 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

  15. Hydrophobic bile acids, genomic instability, Darwinian selection, and colon carcinogenesis

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    Claire M Payne

    2008-12-01

    Full Text Available Claire M Payne, Carol Bernstein, Katerina Dvorak, Harris BernsteinDepartment of Cell Biology and Anatomy, College of Medicine, University of Arizona, Tucson, Arizona, USAAbstract: Sporadic colon cancer is caused predominantly by dietary factors. We have selected bile acids as a focus of this review since high levels of hydrophobic bile acids accompany a Western-style diet, and play a key role in colon carcinogenesis. We describe how bile acid-induced stresses cause cell death in susceptible cells, contribute to genomic instability in surviving cells, impose Darwinian selection on survivors and enhance initiation and progression to colon cancer. The most likely major mechanisms by which hydrophobic bile acids induce stresses on cells (DNA damage, endoplasmic reticulum stress, mitochondrial damage are described. Persistent exposure of colon epithelial cells to hydrophobic bile acids can result in the activation of pro-survival stress-response pathways, and the modulation of numerous genes/proteins associated with chromosome maintenance and mitosis. The multiple mechanisms by which hydrophobic bile acids contribute to genomic instability are discussed, and include oxidative DNA damage, p53 and other mutations, micronuclei formation and aneuploidy. Since bile acids and oxidative stress decrease DNA repair proteins, an increase in DNA damage and increased genomic instability through this mechanism is also described. This review provides a mechanistic explanation for the important link between a Western-style diet and associated increased levels of colon cancer.Keywords: bile acids, genomic instability, colon cancer

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

    African Journals Online (AJOL)

    DIRECTOR

    2011-05-16

    May 16, 2011 ... based technique, was adopted using ten random primers in twelve cases and twelve controls. The primer detectability on .... control sample was used as a criterion of genomic instability. RESULTS AND DISCUSSION .... Fingerprinting and assessment of genetic variability of Varroa destructor in Egypt.

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

    African Journals Online (AJOL)

    STORAGESEVER

    2009-07-20

    Jul 20, 2009 ... RAPD-based detection of genomic instability in cucumber plants derived from somatic embryogenesis. Khaled M. Suliman Elmeer1*, Thomas F. Gallagher2 and Michael J. Hennerty2. 1Plant Tissue Culture Laboratory. Department of Water Research and Agriculture Doha-Qatar. 2School of biology and ...

  18. Genomic instability of micronucleated cells revealed by single-cell comparative genomic hybridization.

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    Imle, A.; Polzer, B.; Alexander, S.; Klein, C.A.; Friedl, P.H.A.

    2009-01-01

    Nuclear variation in size and shape and genomic instability are hallmarks of dedifferentiated cancer cells. Although micronuclei are a typical long-term consequence of DNA damage, their contribution to chromosomal instability and clonal diversity in cancer disease is unclear. We isolated cancer

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

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    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 ...... [discovery data: hazard ratio (HR), 4.70, 95% confidence interval (CI), 1.04–21.37; validation data: HR, 1.59, 95% CI, 1.05–2.42]. These data highlight an important role for the tolerance of genome doubling in driving cancer genome evolution.......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...

  20. Genome-wide analysis of HPV integration in human cancers reveals recurrent, focal genomic instability

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    Akagi, Keiko; Li, Jingfeng; Broutian, Tatevik R.; Padilla-Nash, Hesed; Xiao, Weihong; Jiang, Bo; Rocco, James W.; Teknos, Theodoros N.; Kumar, Bhavna; Wangsa, Danny; He, Dandan; Ried, Thomas; Symer, David E.; Gillison, Maura L.

    2014-01-01

    Genomic instability is a hallmark of human cancers, including the 5% caused by human papillomavirus (HPV). Here we report a striking association between HPV integration and adjacent host genomic structural variation in human cancer cell lines and primary tumors. Whole-genome sequencing revealed HPV integrants flanking and bridging extensive host genomic amplifications and rearrangements, including deletions, inversions, and chromosomal translocations. We present a model of “looping” by which HPV integrant-mediated DNA replication and recombination may result in viral–host DNA concatemers, frequently disrupting genes involved in oncogenesis and amplifying HPV oncogenes E6 and E7. Our high-resolution results shed new light on a catastrophic process, distinct from chromothripsis and other mutational processes, by which HPV directly promotes genomic instability. PMID:24201445

  1. Microsatellite instability in mitochondrial genome of common female cancers.

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    Wang, Y; Liu, V W S; Tsang, P C K; Chiu, P M; Cheung, A N Y; Khoo, U S; Nagley, P; Ngan, H Y S

    2006-01-01

    To investigate the occurrence of mitochondrial genome instability in primary cervical, endometrial, ovarian, and breast carcinomas, we analyzed 12 microsatellite regions in mitochondrial DNA (mtDNA) of tumor tissues and their matched normal controls. Four of the 12 microsatellite markers starting at nucleotide position (np) 303, 514, 956, and 16184, respectively, exhibited instability as indicated by the change in length of short base-repetitive sequences of mtDNA in cancer tissue relative to that in control normal tissue from the same patient. About 25.4% of cervical cancers, 48.4% of endometrial cancers, 21.9% of ovarian cancers, and 29.4% of breast cancers carried one or more mitochondrial microsatellite instability (mtMSI). mtMSI was frequently detected in the D-loop region but rarely occurred in the coding region. A relatively long C tract interrupted by a T residue is the mtMSI hot spot in all four types of cancer studied. Different tumors have different mtMSI profiles. In particular, the frequency of mtMSI in endometrial cancer was significantly higher than in the other three types of cancer. Furthermore, carriers of a germ-line T to C polymorphism at np 16189 could be more susceptible to breast cancer development in light of the higher frequency detected in cancer patients than in normal individuals.

  2. Bystander effects in radiation-induced genomic instability

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    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.

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

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    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.

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

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    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

  5. BLM protein mitigates formaldehyde-induced genomic instability.

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    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.

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

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    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...

  7. Modeling Genomic Instability and Selection Pressure in a Mouse Model of Melanoma

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    Lawrence N. Kwong

    2017-05-01

    Full Text Available Tumor evolution is an iterative process of selection for pro-oncogenic aberrations. This process can be accelerated by genomic instability, but how it interacts with different selection bottlenecks to shape the evolving genomic landscape remains understudied. Here, we assessed tumor initiation and therapy resistance bottlenecks in mouse models of melanoma, with or without genomic instability. At the initiation bottleneck, whole-exome sequencing revealed that drug-naive tumors were genomically silent, and this was surprisingly unaffected when genomic instability was introduced via telomerase inactivation. We hypothesize that the strong engineered alleles created low selection pressure. At the therapy resistance bottleneck, strong selective pressure was applied using a BRAF inhibitor. In the absence of genomic instability, tumors acquired a non-genomic drug resistance mechanism. By contrast, telomerase-deficient, drug-resistant melanomas acquired highly recurrent copy number gains. These proof-of-principle experiments demonstrate how different selection pressures can interact with genomic instability to impact tumor evolution.

  8. The X chromosome: does it have a role in Bloom syndrome, a genomic instability disorder?

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    Aslan, Deniz

    2014-01-01

    The Bloom syndrome, caused by mutations in a single gene [BLM (15q26.1)], is a rare genomic instability syndrome. Despite its autosomal recessive transmission, it shows a male dominance, suggesting the possibility of a subgroup with X-linked recessive inheritance. In view of the latest molecular developments achieved in the other genomic instability syndromes, the potential functions of the X chromosome in maintaining genomic stability, and particularly, the first clues of Bloom syndrome development by mechanisms other than the BLM, we suggest herein that the X chromosome should be investigated in Bloom syndrome.

  9. Fhit and Wwox loss-associated genome instability: A genome caretaker one-two punch.

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    Schrock, Morgan S; Karras, Jenna R; Guggenbiller, Matthew J; Druck, Teresa; Batar, Bahadir; Huebner, Kay

    2017-01-01

    Expression of Fhit and Wwox protein is frequently lost or reduced in many human cancers. In this report, we provide data that further characterizes the molecular consequences of Fhit loss in the initiation of DNA double-strand breaks (DSBs), and of Wwox loss in altered repair of DSBs. We show that loss of Fhit initiates mild genome instability in early passage mouse kidney cells, confirming that DNA damage associated with Fhit-deficiency is not limited to cancer cells. We also demonstrate that the cause of Fhit-deficient DSBs: thymidine deficiency-induced replication stress, can be resolved with thymidine supplementation in early passage mouse kidney cells before extensive genome instability occurs. As for consequences of Wwox loss in cancer, we show in a small panel of breast cancer cells and mouse embryonic fibroblasts that Wwox expression predicts response to radiation and mitomycin C, all agents that cause DSBs. In addition, loss of Wwox significantly reduced progression free survival in a cohort of ovarian cancer patients treated with platin-based chemotherapies. Finally, stratification of a cohort of squamous lung cancers by Fhit expression reveals that Wwox expression is significantly reduced in the low Fhit-expressing group, suggesting that loss of Fhit is quickly succeeded by loss of Wwox. We propose that Fhit and Wwox loss work synergistically in cancer progression and that DNA damage caused by Fhit could be targeted early in cancer initiation for prevention, while DNA damage caused by Wwox loss could be targeted later in cancer progression, particularly in cancers that develop resistance to genotoxic therapies. Copyright © 2017. Published by Elsevier Ltd.

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

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    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.

  11. 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.

  12. 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

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

    Science.gov (United States)

    Hudson, Damien F; Amor, David J; Boys, Amber; Butler, Kathy; Williams, Lorna; Zhang, Tao; Kalitsis, Paul

    2016-12-01

    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.

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

    Directory of Open Access Journals (Sweden)

    Damien F Hudson

    2016-12-01

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

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

    African Journals Online (AJOL)

    Hypospadias is a urogenital malformation, and it is a common inborn disorder in male individuals. The etiology of hypospadias is still unsolved. The present study is aimed to identify the genetic instability in hypospadias patients. Random amplified polymorphic DNA (RAPD), a polymerase chain reaction (PCR) based ...

  16. Genomic instability and bystander effects: a paradigm shift in radiation biology?

    Science.gov (United States)

    Morgan, William F.

    2002-01-01

    A basic paradigm in radiobiology is that, following exposure to ionizing radiation, the deposition of energy in the cell nucleus and the resulting damage to DNA, the principal target, are responsible for the radiation's deleterious biological effects. Findings in two rapidly expanding fields of research--radiation-induced genomic instability and bystander effects--have caused us to reevaluate these central tenets. In this article, the potential influence of induced genomic instability and bystander effects on cellular injury after exposure to low-level radiation will be reviewed.

  17. Development of cancer-initiating cells and immortalized cells with genomic instability

    Science.gov (United States)

    Yoshioka, Ken-ichi; Atsumi, Yuko; Nakagama, Hitoshi; Teraoka, Hirobumi

    2015-01-01

    Cancers that develop after middle age usually exhibit genomic instability and multiple mutations. This is in direct contrast to pediatric tumors that usually develop as a result of specific chromosomal translocations and epigenetic aberrations. The development of genomic instability is associated with mutations that contribute to cellular immortalization and transformation. Cancer occurs when cancer-initiating cells (CICs), also called cancer stem cells, develop as a result of these mutations. In this paper, we explore how CICs develop as a result of genomic instability, including looking at which cancer suppression mechanisms are abrogated. A recent in vitro study revealed the existence of a CIC induction pathway in differentiating stem cells. Under aberrant differentiation conditions, cells become senescent and develop genomic instabilities that lead to the development of CICs. The resulting CICs contain a mutation in the alternative reading frame of CDKN2A (ARF)/p53 module, i.e., in either ARF or p53. We summarize recently established knowledge of CIC development and cellular immortality, explore the role of the ARF/p53 module in protecting cells from transformation, and describe a risk factor for genomic destabilization that increases during the process of normal cell growth and differentiation and is associated with the downregulation of histone H2AX to levels representative of growth arrest in normal cells. PMID:25815132

  18. Role of DNA Polymerases in Repeat-Mediated Genome Instability

    Directory of Open Access Journals (Sweden)

    Kartik A. Shah

    2012-11-01

    Full Text Available Expansions of simple DNA repeats cause numerous hereditary diseases in humans. We analyzed the role of DNA polymerases in the instability of Friedreich’s ataxia (GAAn repeats in a yeast experimental system. The elementary step of expansion corresponded to ∼160 bp in the wild-type strain, matching the size of Okazaki fragments in yeast. This step increased when DNA polymerase α was mutated, suggesting a link between the scale of expansions and Okazaki fragment size. Expandable repeats strongly elevated the rate of mutations at substantial distances around them, a phenomenon we call repeat-induced mutagenesis (RIM. Notably, defects in the replicative DNA polymerases δ and ∊ strongly increased rates for both repeat expansions and RIM. The increases in repeat-mediated instability observed in DNA polymerase δ mutants depended on translesion DNA polymerases. We conclude that repeat expansions and RIM are two sides of the same replicative mechanism.

  19. A novel mechanism inducing genome instability in Kaposi's sarcoma-associated herpesvirus infected cells.

    Directory of Open Access Journals (Sweden)

    Brian R Jackson

    2014-05-01

    Full Text Available Kaposi's sarcoma-associated herpesvirus (KSHV is an oncogenic herpesvirus associated with multiple AIDS-related malignancies. Like other herpesviruses, KSHV has a biphasic life cycle and both the lytic and latent phases are required for tumorigenesis. Evidence suggests that KSHV lytic replication can cause genome instability in KSHV-infected cells, although no mechanism has thus far been described. A surprising link has recently been suggested between mRNA export, genome instability and cancer development. Notably, aberrations in the cellular transcription and export complex (hTREX proteins have been identified in high-grade tumours and these defects contribute to genome instability. We have previously shown that the lytically expressed KSHV ORF57 protein interacts with the complete hTREX complex; therefore, we investigated the possible intriguing link between ORF57, hTREX and KSHV-induced genome instability. Herein, we show that lytically active KSHV infected cells induce a DNA damage response and, importantly, we demonstrate directly that this is due to DNA strand breaks. Furthermore, we show that sequestration of the hTREX complex by the KSHV ORF57 protein leads to this double strand break response and significant DNA damage. Moreover, we describe a novel mechanism showing that the genetic instability observed is a consequence of R-loop formation. Importantly, the link between hTREX sequestration and DNA damage may be a common feature in herpesvirus infection, as a similar phenotype was observed with the herpes simplex virus 1 (HSV-1 ICP27 protein. Our data provide a model of R-loop induced DNA damage in KSHV infected cells and describes a novel system for studying genome instability caused by aberrant hTREX.

  20. Fhit deficiency-induced global genome instability promotes mutation and clonal expansion.

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    Satoshi Miuma

    Full Text Available Loss of Fhit expression, encoded at chromosome fragile site FRA3B, leads to increased replication stress, genome instability and accumulation of genetic alterations. We have proposed that Fhit is a genome 'caretaker' whose loss initiates genome instability in preneoplastic lesions. We have characterized allele copy number alterations and expression changes observed in Fhit-deficient cells in conjunction with alterations in cellular proliferation and exome mutations, using cells from mouse embryo fibroblasts (MEFs, mouse kidney, early and late after establishment in culture, and in response to carcinogen treatment. Fhit (-/- MEFs escape senescence to become immortal more rapidly than Fhit (+/+ MEFs; -/- MEFs and kidney cultures show allele losses and gains, while +/+ derived cells show few genomic alterations. Striking alterations in expression of p53, p21, Mcl1 and active caspase 3 occurred in mouse kidney -/- cells during progressive tissue culture passage. To define genomic changes associated with preneoplastic changes in vivo, exome DNAs were sequenced for +/+ and -/- liver tissue after treatment of mice with the carcinogen, 7,12-dimethylbenz[a]anthracene, and for +/+ and -/- kidney cells treated in vitro with this carcinogen. The -/- exome DNAs, in comparison with +/+ DNA, showed small insertions, deletions and point mutations in more genes, some likely related to preneoplastic changes. Thus, Fhit loss provides a 'mutator' phenotype, a cellular environment in which mild genome instability permits clonal expansion, through proliferative advantage and escape from apoptosis, in response to pressures to survive.

  1. Fhit deficiency-induced global genome instability promotes mutation and clonal expansion.

    Science.gov (United States)

    Miuma, Satoshi; Saldivar, Joshua C; Karras, Jenna R; Waters, Catherine E; Paisie, Carolyn A; Wang, Yao; Jin, Victor; Sun, Jin; Druck, Teresa; Zhang, Jie; Huebner, Kay

    2013-01-01

    Loss of Fhit expression, encoded at chromosome fragile site FRA3B, leads to increased replication stress, genome instability and accumulation of genetic alterations. We have proposed that Fhit is a genome 'caretaker' whose loss initiates genome instability in preneoplastic lesions. We have characterized allele copy number alterations and expression changes observed in Fhit-deficient cells in conjunction with alterations in cellular proliferation and exome mutations, using cells from mouse embryo fibroblasts (MEFs), mouse kidney, early and late after establishment in culture, and in response to carcinogen treatment. Fhit (-/-) MEFs escape senescence to become immortal more rapidly than Fhit (+/+) MEFs; -/- MEFs and kidney cultures show allele losses and gains, while +/+ derived cells show few genomic alterations. Striking alterations in expression of p53, p21, Mcl1 and active caspase 3 occurred in mouse kidney -/- cells during progressive tissue culture passage. To define genomic changes associated with preneoplastic changes in vivo, exome DNAs were sequenced for +/+ and -/- liver tissue after treatment of mice with the carcinogen, 7,12-dimethylbenz[a]anthracene, and for +/+ and -/- kidney cells treated in vitro with this carcinogen. The -/- exome DNAs, in comparison with +/+ DNA, showed small insertions, deletions and point mutations in more genes, some likely related to preneoplastic changes. Thus, Fhit loss provides a 'mutator' phenotype, a cellular environment in which mild genome instability permits clonal expansion, through proliferative advantage and escape from apoptosis, in response to pressures to survive.

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

    Directory of Open Access Journals (Sweden)

    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.

  3. 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

  4. 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...

  5. 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

    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...

  6. 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

  7. Genomic instability measured by inter-(simple sequence repeat) PCR and high-resolution microsatellite instability are prognostic of colorectal carcinoma survival after surgical resection.

    Science.gov (United States)

    Brenner, Bruce M; Swede, Helen; Jones, Beth A; Anderson, Garth R; Stoler, Daniel L

    2012-01-01

    During the multiyear progression to colorectal cancer, numerous genomic alterations arise in events ranging from single base mutations to gains or losses of entire chromosomes. A single genetic change might not stand out as an independent predictor of outcome. The goal of this study was to determine if more comprehensive measurements of genomic instability provide clinically relevant prognostic information. Our study included 65 sporadic colorectal cancer patients diagnosed from 1987 to 1991 with last follow-up ascertained in 2006. We estimated an overall tally of alterations using the genome-wide sampling technique of inter-(simple sequence repeat [SSR]) polymerase chain reaction (PCR), and evaluated its relationship with all-cause survival. We also extended and sensitized the Bethesda criteria for microsatellite instability (MSI), by analyzing 348 microsatellite markers instead of the normal five. We expanded the MSI categories into four levels: MSI stable (MSS), very low-level MSI, moderately low-level MSI, and classical high-level MSI. Tumors with genomic instability above the median value of 2.6% as measured by inter-SSR PCR, were associated with far greater risk of death compared to tumors with lower levels of genomic instability. Adverse outcome was most pronounced for patients presenting with stage 3 disease. A gradient of increased survival was observed across increasing MSI levels but did not reach statistical significance. Our findings suggest genomic instabilities quantified by inter-SSR PCR and increased precision in MSI values may be clinically useful tools for estimating prognosis in colorectal cancer.

  8. 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).

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

    Science.gov (United States)

    2014-03-01

    Copenhagen, Copenhagen, Denmark 6Program in Cellular and Molecular Medicine, Immune Disease Institute and Howard Hughes Medical Institute, Children’s...Blegdamsvej 3b, 2200 Copenhagen N, Denmark 2Laboratory of Genome Integrity, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892, USA...14, 1293–1301 (1994). 46. Wang, H. et al. Biochemical evidence for Ku-independent backup pathways of NHEJ. Nucleic Acids Res. 31, 5377–5388 (2003

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

    Science.gov (United States)

    2014-11-01

    02115; hRodent Histology Core, Dana-Farber/Harvard Cancer Center, Harvard Medical School, Boston, MA 02115; and iLaboratory of Genome Integrity...before the BRCA2-interacting, seven- bladed WD40-type β-pro- peller domain (Fig. 1A, Fig. S1A). Due to premature truncation Author contributions: C.B.-C...Bryant for assistance with histology . The work was supported by the Intramural Research Program of the NIH, the National Cancer Institute, and the Center

  11. 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.

  12. The WRN and MUS81 proteins limit cell death and genome instability following oncogene activation.

    Science.gov (United States)

    Murfuni, I; Nicolai, S; Baldari, S; Crescenzi, M; Bignami, M; Franchitto, A; Pichierri, P

    2013-01-31

    Oncogene-induced replication stress is recognized as the primary cause of accumulation of DNA damage and genome instability in precancerous cells. Although the molecular mechanisms responding to such type of replication perturbation are not fully characterized, it has been speculated that their dysfunction may enhance genome instability and accelerate tumor progression. Here, we show that the WRN protein, a member of the human RecQ helicases, is necessary to sustain replication fork progression in response to oncogene-induced replication stress. Loss of WRN affects cell cycle progression and results in enhanced accumulation of double-strand breaks and instability at common fragile sites in cells experiencing oncogene-induced replication stress. Moreover, we demonstrate that double-strand breaks, observed upon oncogene over-expression, depend on the MUS81 endonuclease, which represents a parallel pathway collaborating with WRN to prevent cell death. Overall, our findings give insights into the mechanisms protecting replication forks in cells experiencing oncogene-induced replication stress, and identify factors that, when mutated or dysfunctional, may enhance genome instability in precancerous cells. In addition, because concomitant depletion of WRN and MUS81 causes synthetic sickness in cells growing under oncogene-induced replication stress, our results support the possibility of targeting cancer cells with an impaired replication fork recovery pathway by a specific inactivation of the other parallel pathway.

  13. 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

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

    Science.gov (United States)

    Saldivar, Joshua C; Miuma, Satoshi; Bene, Jessica; Hosseini, Seyed Ali; Shibata, Hidetaka; Sun, Jin; Wheeler, Linda J; Mathews, Christopher K; Huebner, Kay

    2012-01-01

    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 initiation of

  15. Genomic instability in human cancer: Molecular insights and opportunities for therapeutic attack and prevention through diet and nutrition.

    Science.gov (United States)

    Ferguson, Lynnette R; Chen, Helen; Collins, Andrew R; Connell, Marisa; Damia, Giovanna; Dasgupta, Santanu; Malhotra, Meenakshi; Meeker, Alan K; Amedei, Amedeo; Amin, Amr; Ashraf, S Salman; Aquilano, Katia; Azmi, Asfar S; Bhakta, Dipita; Bilsland, Alan; Boosani, Chandra S; Chen, Sophie; Ciriolo, Maria Rosa; Fujii, Hiromasa; Guha, Gunjan; Halicka, Dorota; Helferich, William G; Keith, W Nicol; Mohammed, Sulma I; Niccolai, Elena; Yang, Xujuan; Honoki, Kanya; Parslow, Virginia R; Prakash, Satya; Rezazadeh, Sarallah; Shackelford, Rodney E; Sidransky, David; Tran, Phuoc T; Yang, Eddy S; Maxwell, Christopher A

    2015-12-01

    Genomic instability can initiate cancer, augment progression, and influence the overall prognosis of the affected patient. Genomic instability arises from many different pathways, such as telomere damage, centrosome amplification, epigenetic modifications, and DNA damage from endogenous and exogenous sources, and can be perpetuating, or limiting, through the induction of mutations or aneuploidy, both enabling and catastrophic. Many cancer treatments induce DNA damage to impair cell division on a global scale but it is accepted that personalized treatments, those that are tailored to the particular patient and type of cancer, must also be developed. In this review, we detail the mechanisms from which genomic instability arises and can lead to cancer, as well as treatments and measures that prevent genomic instability or take advantage of the cellular defects caused by genomic instability. In particular, we identify and discuss five priority targets against genomic instability: (1) prevention of DNA damage; (2) enhancement of DNA repair; (3) targeting deficient DNA repair; (4) impairing centrosome clustering; and, (5) inhibition of telomerase activity. Moreover, we highlight vitamin D and B, selenium, carotenoids, PARP inhibitors, resveratrol, and isothiocyanates as priority approaches against genomic instability. The prioritized target sites and approaches were cross validated to identify potential synergistic effects on a number of important areas of cancer biology. Copyright © 2015 The Authors. Published by Elsevier Ltd.. All rights reserved.

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

    Directory of Open Access Journals (Sweden)

    Streffer C

    2015-12-01

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

  17. Genomic and epigenetic instability in chordoma: current insights

    Directory of Open Access Journals (Sweden)

    Feng Y

    2014-05-01

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

  18. 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.

  19. ZSCAN10 expression corrects the genomic instability of iPSCs from aged donors.

    Science.gov (United States)

    Skamagki, Maria; Correia, Cristina; Yeung, Percy; Baslan, Timour; Beck, Samuel; Zhang, Cheng; Ross, Christian A; Dang, Lam; Liu, Zhong; Giunta, Simona; Chang, Tzu-Pei; Wang, Joye; Ananthanarayanan, Aparna; Bohndorf, Martina; Bosbach, Benedikt; Adjaye, James; Funabiki, Hironori; Kim, Jonghwan; Lowe, Scott; Collins, James J; Lu, Chi-Wei; Li, Hu; Zhao, Rui; Kim, Kitai

    2017-09-01

    Induced pluripotent stem cells (iPSCs), which are used to produce transplantable tissues, may particularly benefit older patients, who are more likely to suffer from degenerative diseases. However, iPSCs generated from aged donors (A-iPSCs) exhibit higher genomic instability, defects in apoptosis and a blunted DNA damage response compared with iPSCs generated from younger donors. We demonstrated that A-iPSCs exhibit excessive glutathione-mediated reactive oxygen species (ROS) scavenging activity, which blocks the DNA damage response and apoptosis and permits survival of cells with genomic instability. We found that the pluripotency factor ZSCAN10 is poorly expressed in A-iPSCs and addition of ZSCAN10 to the four Yamanaka factors (OCT4, SOX2, KLF4 and c-MYC) during A-iPSC reprogramming normalizes ROS-glutathione homeostasis and the DNA damage response, and recovers genomic stability. Correcting the genomic instability of A-iPSCs will ultimately enhance our ability to produce histocompatible functional tissues from older patients' own cells that are safe for transplantation.

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

    Science.gov (United States)

    Jacobs, Kurt; Zambelli, Filippo; Mertzanidou, Afroditi; Smolders, Ilse; Geens, Mieke; Nguyen, Ha Thi; Barbé, Lise; Sermon, Karen; Spits, Claudia

    2016-01-01

    Summary Human embryonic stem cells (hESC) show great promise for clinical and research applications, but their well-known proneness to genomic instability hampers the development to their full potential. Here, we demonstrate that medium acidification linked to culture density is the main cause of DNA damage and genomic alterations in hESC grown on feeder layers, and this even in the short time span of a single passage. In line with this, we show that increasing the frequency of the medium refreshments minimizes the levels of DNA damage and genetic instability. Also, we show that cells cultured on laminin-521 do not present this increase in DNA damage when grown at high density, although the (long-term) impact on their genomic stability remains to be elucidated. Our results explain the high levels of genome instability observed over the years by many laboratories worldwide, and show that the development of optimal culture conditions is key to solving this problem. PMID:26923824

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

    Science.gov (United States)

    Aghajanyan, Anna; Suskov, Igor

    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, paccident (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 ((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.

  2. 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.

  3. 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.

  4. 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.

  5. 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.

  6. Ectopic expression of cancer/testis antigen SSX2 induces DNA damage and promotes genomic instability

    DEFF Research Database (Denmark)

    Greve, Katrine Buch Vidén; Lindgreen, Jonas; Terp, Mikkel Green

    2015-01-01

    of senescence (i.e. an irregular and enlarged cell shape, enhanced β-galactosidase activity and DNA double-strand breaks). Since replication defects, DNA damage and senescence are interconnected and well-documented effects of oncogene expression, we tested the oncogenic potential of SSX2. Importantly, knockdown...... in an increased DNA content and enlargement of cell nuclei, suggestive of replication aberrations. The cells further displayed signs of DNA damage and genomic instability, associated with p53-mediated G1 cell cycle arrest and a late apoptotic response. These results suggest a model wherein SSX2-mediated...... replication stress translates into mitotic defects and genomic instability. Arrest of cell growth and induction of DNA double-strand breaks was also observed in MCF7 breast cancer cells in response to SSX2 expression. Additionally, MCF7 cells with ectopic SSX2 expression demonstrated typical signs...

  7. A mutation in separase causes genome instability and increased susceptibility to epithelial cancer

    OpenAIRE

    Shepard, Jennifer L.; Amatruda, James F.; Finkelstein, David; Ziai, James; Finley, K. Rose; Stern, Howard M.; Chiang, Ken; Hersey, Candace; Barut, Bruce; Freeman, Jennifer L.; Lee, Charles; Glickman, Jonathan N.; Kutok, Jeffery L; Aster, Jon C; Zon, Leonard I.

    2007-01-01

    Proper chromosome segregation is essential for maintenance of genomic integrity and instability resulting from failure of this process may contribute to cancer. Here, we demonstrate that a mutation in the mitotic regulator separase is responsible for the cell cycle defects seen in the zebrafish mutant, cease&desist (cds). Analysis of cds homozygous mutant embryos reveals high levels of polyploidy and aneuploidy, spindle defects, and a mitotic exit delay. Carcinogenesis studies demonstrated th...

  8. Global analysis of genomic instability caused by DNA replication stress in Saccharomyces cerevisiae.

    Science.gov (United States)

    Zheng, Dao-Qiong; Zhang, Ke; Wu, Xue-Chang; Mieczkowski, Piotr A; Petes, Thomas D

    2016-12-13

    DNA replication stress (DRS)-induced genomic instability is an important factor driving cancer development. To understand the mechanisms of DRS-associated genomic instability, we measured the rates of genomic alterations throughout the genome in a yeast strain with lowered expression of the replicative DNA polymerase δ. By a genetic test, we showed that most recombinogenic DNA lesions were introduced during S or G 2 phase, presumably as a consequence of broken replication forks. We observed a high rate of chromosome loss, likely reflecting a reduced capacity of the low-polymerase strains to repair double-stranded DNA breaks (DSBs). We also observed a high frequency of deletion events within tandemly repeated genes such as the ribosomal RNA genes. By whole-genome sequencing, we found that low levels of DNA polymerase δ elevated mutation rates, both single-base mutations and small insertions/deletions. Finally, we showed that cells with low levels of DNA polymerase δ tended to accumulate small promoter mutations that increased the expression of this polymerase. These deletions conferred a selective growth advantage to cells, demonstrating that DRS can be one factor driving phenotypic evolution.

  9. Genome instability and transcription elongation impairment in human cells depleted of THO/TREX.

    Science.gov (United States)

    Domínguez-Sánchez, María S; Barroso, Sonia; Gómez-González, Belén; Luna, Rosa; Aguilera, Andrés

    2011-12-01

    THO/TREX connects transcription with genome integrity in yeast, but a role of mammalian THO in these processes is uncertain, which suggests a differential implication of mRNP biogenesis factors in genome integrity in yeast and humans. We show that human THO depletion impairs transcription elongation and mRNA export and increases instability associated with DNA breaks, leading to hyper-recombination and γH2AX and 53BP1 foci accumulation. This is accompanied by replication alteration as determined by DNA combing. Genome instability is R-loop-dependent, as deduced from the ability of the AID enzyme to increase DNA damage and of RNaseH to reduce it, or from the enhancement of R-loop-dependent class-switching caused by THOC1-depletion in CH12 murine cells. Therefore, mammalian THO prevents R-loop formation and has a role in genome dynamics and function consistent with an evolutionary conservation of the functional connection between these mRNP biogenesis factors and genome integrity that had not been anticipated.

  10. Genome instability and transcription elongation impairment in human cells depleted of THO/TREX.

    Directory of Open Access Journals (Sweden)

    María S Domínguez-Sánchez

    2011-12-01

    Full Text Available THO/TREX connects transcription with genome integrity in yeast, but a role of mammalian THO in these processes is uncertain, which suggests a differential implication of mRNP biogenesis factors in genome integrity in yeast and humans. We show that human THO depletion impairs transcription elongation and mRNA export and increases instability associated with DNA breaks, leading to hyper-recombination and γH2AX and 53BP1 foci accumulation. This is accompanied by replication alteration as determined by DNA combing. Genome instability is R-loop-dependent, as deduced from the ability of the AID enzyme to increase DNA damage and of RNaseH to reduce it, or from the enhancement of R-loop-dependent class-switching caused by THOC1-depletion in CH12 murine cells. Therefore, mammalian THO prevents R-loop formation and has a role in genome dynamics and function consistent with an evolutionary conservation of the functional connection between these mRNP biogenesis factors and genome integrity that had not been anticipated.

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

    Science.gov (United States)

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

    2016-08-01

    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. Copyright © 2016 Elsevier B.V. All rights reserved.

  12. Genomic instability of murine hepatocellular carcinomas with low and high metastatic capacities

    Science.gov (United States)

    Zhang, Shu-Hui; Cong, Wen-Ming; Shi, Jing-Quan; Wei, Hong

    2004-01-01

    AIM: To investigate the frequency of genomic instability in murine hepatocellular carcinoma (HCC) cell lines Hca/A2-P(P) and Hca/163-F(F) with low and high metastatic capacity, and to explore its association with the occurrence and metastasis of hepatocellular carcinomas. METHODS: Forty microsatellite markers were randomly selected to examine P and F cells for genomic instability using PCR-simple sequence length polymorphism (PCR-SSLP) analysis. RESULTS: Allelic genes on the chromosomes of P cell line with thirty informative microsatellite loci were paralleled to those of inbred strain C3H mouse, while those of F cell line with 28 loci were paralleled to those of inbred strain C3H mice. The frequency of microsatellite alterations was 37.5% and 42.5% in P cell line and F cell line, respectively. There were different alterations of allelic band 9 at loci between P and F cells, among which, the frequency of microsatellite alterations was most commonly seen on chromosomes 3, 7, 11 and 16. CONCLUSION: Genomic instability in mouse chromosomes 3, 7, 11 and 16 may play a more important role in the development and progression of HCC in mice. It is suggested that these two sub-clones derived from a same hepatic tumor in homozygous mouse present different genetic features. PMID:14966909

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

    OpenAIRE

    Streffer C

    2015-01-01

    Christian Streffer Institute for Medical Radiobiology, University Clinics Essen, Essen, Germany Abstract: The genome of eukaryotic cells is generally instable. DNA damage occurs by endogenous processes and exogenous toxic agents. The efficient DNA repair pathways conserve the genetic information to a large extent throughout the life. However, exposure to genotoxic agents can increase the genomic instability. This phenomenon develops in a delayed manner after approximately 20 and more cell ge...

  14. 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.

  15. 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

  16. The landscape of microsatellite instability in colorectal and endometrial cancer genomes.

    Science.gov (United States)

    Kim, Tae-Min; Laird, Peter W; Park, Peter J

    2013-11-07

    Microsatellites-simple tandem repeats present at millions of sites in the human genome-can shorten or lengthen due to a defect in DNA mismatch repair. We present here a comprehensive genome-wide analysis of the prevalence, mutational spectrum, and functional consequences of microsatellite instability (MSI) in cancer genomes. We analyzed MSI in 277 colorectal and endometrial cancer genomes (including 57 microsatellite-unstable ones) using exome and whole-genome sequencing data. Recurrent MSI events in coding sequences showed tumor type specificity, elevated frameshift-to-inframe ratios, and lower transcript levels than wild-type alleles. Moreover, genome-wide analysis revealed differences in the distribution of MSI versus point mutations, including overrepresentation of MSI in euchromatic and intronic regions compared to heterochromatic and intergenic regions, respectively, and depletion of MSI at nucleosome-occupied sequences. Our results provide a panoramic view of MSI in cancer genomes, highlighting their tumor type specificity, impact on gene expression, and the role of chromatin organization. Copyright © 2013 Elsevier Inc. All rights reserved.

  17. Frequently mutated genes/pathways and genomic instability as prevention targets in liver cancer.

    Science.gov (United States)

    Rao, Chinthalapally V; Asch, Adam S; Yamada, Hiroshi Y

    2017-01-01

    The incidence of liver cancer has increased in recent years. Worldwide, liver cancer is common: more than 600000 related deaths are estimated each year. In the USA, about 27170 deaths due to liver cancer are estimated for 2016. Liver cancer is highly resistant to conventional chemotherapy and radiotherapy. For all stages combined, the 5-year survival rate is 15-17%, leaving much to be desired for liver cancer prevention and therapy. Heterogeneity, which can originate from genomic instability, is one reason for poor outcome. About 80-90% of liver cancers are hepatocellular carcinoma (HCC), and recent cancer genome sequencing studies have revealed frequently mutated genes in HCC. In this review, we discuss the cause of the tumor heterogeneity based on the functions of genes that are frequently mutated in HCC. We overview the functions of the genes that are most frequently mutated (e.g. TP53, CTNNB1, AXIN1, ARID1A and WWP1) that portray major pathways leading to HCC and identify the roles of these genes in preventing genomic instability. Notably, the pathway analysis suggested that oxidative stress management may be critical to prevent accumulation of DNA damage and further mutations. We propose that both chromosome instability (CIN) and microsatellite instability (MIN) are integral to the hepatic carcinogenesis process leading to heterogeneity in HCC and that the pathways leading to heterogeneity may be targeted for prognosis, prevention and treatment. © The Author 2016. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oup.com.

  18. Urinary tract infection drives genome instability in uropathogenic Escherichia coli and necessitates translesion synthesis DNA polymerase IV for virulence.

    Science.gov (United States)

    Gawel, Damian; Seed, Patrick C

    2011-01-01

    Uropathogenic Escherichia coli (UPEC) produces ~80% of community-acquired UTI, the second most common infection in humans. During UTI, UPEC has a complex life cycle, replicating and persisting in intracellular and extracellular niches. Host and environmental stresses may affect the integrity of the UPEC genome and threaten its viability. We determined how the host inflammatory response during UTI drives UPEC genome instability and evaluated the role of multiple factors of genome replication and repair for their roles in the maintenance of genome integrity and thus virulence during UTI. The urinary tract environment enhanced the mutation frequency of UPEC ~100-fold relative to in vitro levels. Abrogation of inflammation through a host TLR4-signaling defect significantly reduced the mutation frequency, demonstrating in the importance of the host response as a driver of UPEC genome instability. Inflammation induces the bacterial SOS response, leading to the hypothesis that the UPEC SOS-inducible translesion synthesis (TLS) DNA polymerases would be key factors in UPEC genome instability during UTI. However, while the TLS DNA polymerases enhanced in vitro, they did not increase in vivo mutagenesis. Although it is not a source of enhanced mutagenesis in vivo, the TLS DNA polymerase IV was critical for the survival of UPEC during UTI during an active inflammatory assault. Overall, this study provides the first evidence of a TLS DNA polymerase being critical for UPEC survival during urinary tract infection and points to independent mechanisms for genome instability and the maintenance of genome replication of UPEC under host inflammatory stress.

  19. Genomic instability and cellular stress in organ biopsies and peripheral blood lymphocytes from patients with colorectal cancer and predisposing pathologies

    Science.gov (United States)

    Lombardi, Sara; Fuoco, Ilenia; di Fluri, Giorgia; Costa, Francesco; Ricchiuti, Angelo; Biondi, Graziano; Nardini, Vincenzo; Scarpato, Roberto

    2015-01-01

    Inflammatory bowel disease (IBD) and polyps, are common colorectal pathologies in western society and are risk factors for development of colorectal cancer (CRC). Genomic instability is a cancer hallmark and is connected to changes in chromosomal structure, often caused by double strand break formation (DSB), and aneuploidy. Cellular stress, may contribute to genomic instability. In colorectal biopsies and peripheral blood lymphocytes of patients with IBD, polyps and CRC, we evaluated 1) genomic instability using the γH2AX assay as marker of DSB and micronuclei in mononuclear lymphocytes kept under cytodieresis inhibition, and 2) cellular stress through expression and cellular localization of glutathione-S-transferase omega 1 (GSTO1). Colon biopsies showed γH2AX increase starting from polyps, while lymphocytes already from IBD. Micronuclei frequency began to rise in lymphocytes of subjects with polyps, suggesting a systemic genomic instability condition. Colorectal tissues lost GSTO1 expression but increased nuclear localization with pathology progression. Lymphocytes did not change GSTO1 expression and localization until CRC formation, where enzyme expression was increased. We propose that the growing genomic instability found in our patients is connected with the alteration of cellular environment. Evaluation of genomic damage and cellular stress in colorectal pathologies may facilitate prevention and management of CRC. PMID:26046795

  20. 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.

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

    Energy Technology Data Exchange (ETDEWEB)

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

    2006-03-20

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

  2. Dysregulation of DNA methylation induced by past arsenic treatment causes persistent genomic instability in mammalian cells.

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    Mauro, Maurizio; Caradonna, Fabio; Klein, Catherine B

    2016-03-01

    The mechanisms by which arsenic-induced genomic instability is initiated and maintained are poorly understood. To investigate potential epigenetic mechanisms, in this study we evaluated global DNA methylation levels in V79 cells and human HaCaT keratinocytes at several time points during expanded growth of cell cultures following removal of arsenite exposures. We have found altered genomic methylation patterns that persisted up to 40 cell generations in HaCaT cells after the treatments were withdrawn. Moreover, mRNA expression levels were evaluated by RT-PCR for DNMT1, DNMT3A, DNMT3B, HMLH1, and HMSH2 genes, demonstrating that the down regulation of DNMT3A and DNMT3B genes, but not DNMT1, occurred in an arsenic dose-dependent manner, and persisted for many cell generations following removal of the arsenite, offering a plausible mechanism of persistently genotoxic arsenic action. Analyses of promoter methylation status of the DNA mismatch repair genes HMLH1 and HMSH2 show that HMSH2, but not HMLH1, was epigenetically regulated by promoter hypermethylation changes following arsenic treatment. The results reported here demonstrate that arsenic exposure promptly induces genome-wide global DNA hypomethylation, and some specific gene promoter methylation changes, that persist for many cell generations following withdrawal of arsenite, supporting the hypothesis that the cells undergo epigenetic reprogramming at both the gene and genome level that is durable over many cell generations in the absence of further arsenic treatment. These DNA methylation changes, in concert with other known epigenome alterations, are likely contributing to long-lasting arsenic-induced genomic instability that manifests in several ways, including aberrant chromosomal effects. © 2015 Wiley Periodicals, Inc.

  3. 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.

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

    DEFF Research Database (Denmark)

    Galanos, Panagiotis; Vougas, Konstantinos; Walter, David

    2016-01-01

    The cyclin-dependent kinase inhibitor p21(WAF1/CIP1) (p21) is a cell-cycle checkpoint effector and inducer of senescence, regulated by p53. Yet, evidence suggests that p21 could also be oncogenic, through a mechanism that has so far remained obscure. We report that a subset of atypical cancerous......-normal cellular models showed that after an initial senescence-like phase, a subpopulation of p21-expressing proliferating cells emerged, featuring increased genomic instability, aggressiveness and chemoresistance. Mechanistically, sustained p21 accumulation inhibited mainly the CRL4-CDT2 ubiquitin ligase...... 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...

  5. Genomic Instability in Human Pluripotent Stem Cells Arises from Replicative Stress and Chromosome Condensation Defects.

    Science.gov (United States)

    Lamm, Noa; Ben-David, Uri; Golan-Lev, Tamar; Storchová, Zuzana; Benvenisty, Nissim; Kerem, Batsheva

    2016-02-04

    Human pluripotent stem cells (hPSCs) frequently acquire chromosomal aberrations such as aneuploidy in culture. These aberrations progressively increase over time and may compromise the properties and clinical utility of the cells. The underlying mechanisms that drive initial genomic instability and its continued progression are largely unknown. Here, we show that aneuploid hPSCs undergo DNA replication stress, resulting in defective chromosome condensation and segregation. Aneuploid hPSCs show altered levels of actin cytoskeletal genes controlled by the transcription factor SRF, and overexpression of SRF rescues impaired chromosome condensation and segregation defects in aneuploid hPSCs. Furthermore, SRF downregulation in diploid hPSCs induces replication stress and perturbed condensation similar to that seen in aneuploid cells. Together, these results suggest that decreased SRF expression induces replicative stress and chromosomal condensation defects that underlie the ongoing chromosomal instability seen in aneuploid hPSCs. A similar mechanism may also operate during initiation of instability in diploid cells. Copyright © 2016 Elsevier Inc. All rights reserved.

  6. Replication independent DNA double-strand break retention may prevent genomic instability

    Directory of Open Access Journals (Sweden)

    Pornthanakasem Wichai

    2010-03-01

    Full Text Available Abstract Background Global hypomethylation and genomic instability are cardinal features of cancers. Recently, we established a method for the detection of DNA methylation levels at sites close to endogenous DNA double strand breaks (EDSBs, and found that those sites have a higher level of methylation than the rest of the genome. Interestingly, the most significant differences between EDSBs and genomes were observed when cells were cultured in the absence of serum. DNA methylation levels on each genomic location are different. Therefore, there are more replication-independent EDSBs (RIND-EDSBs located in methylated genomic regions. Moreover, methylated and unmethylated RIND-EDSBs are differentially processed. Euchromatins respond rapidly to DSBs induced by irradiation with the phosphorylation of H2AX, γ-H2AX, and these initiate the DSB repair process. During G0, most DSBs are repaired by non-homologous end-joining repair (NHEJ, mediated by at least two distinct pathways; the Ku-mediated and the ataxia telangiectasia-mutated (ATM-mediated. The ATM-mediated pathway is more precise. Here we explored how cells process methylated RIND-EDSBs and if RIND-EDSBs play a role in global hypomethylation-induced genomic instability. Results We observed a significant number of methylated RIND-EDSBs that are retained within deacetylated chromatin and free from an immediate cellular response to DSBs, the γ-H2AX. When cells were treated with tricostatin A (TSA and the histones became hyperacetylated, the amount of γ-H2AX-bound DNA increased and the retained RIND-EDSBs were rapidly repaired. When NHEJ was simultaneously inhibited in TSA-treated cells, more EDSBs were detected. Without TSA, a sporadic increase in unmethylated RIND-EDSBs could be observed when Ku-mediated NHEJ was inhibited. Finally, a remarkable increase in RIND-EDSB methylation levels was observed when cells were depleted of ATM, but not of Ku86 and RAD51. Conclusions Methylated RIND-EDSBs are

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

    Science.gov (United States)

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

    2016-03-01

    Carotenoids are a class of nutrients with antioxidant properties that have been purported to protect against cancer. However, the reported associations between carotenoids and prostate cancer have been heterogeneous and lacking data on interactions with nucleotide sequence variations and genomic biomarkers. To examine the associations between carotenoid levels and the risk of high-grade prostate cancer, also considering antioxidant-related genes and tumor instability. We measured plasma levels of carotenoids and genotyped 20 single nucleotide polymorphisms (SNP) in SOD1, SOD2, SOD3, XRCC1, and OGG1 among 559 men with non-metastatic prostate cancer undergoing radical prostatectomy. We performed copy number analysis in a subset of these men (n = 67) to study tumor instability assessed as Fraction of the Genome Altered (FGA). We examined associations between carotenoids, genotypes, tumor instability and risk of high-grade prostate cancer (Gleason grade ≥ 4 + 3) using logistic and linear regression. Circulating carotenoid levels were inversely associated with the risk of high-grade prostate cancer; odds ratios (OR) and 95% confidence intervals (CI) comparing highest versus lowest quartiles were: 0.34 (95% CI: 0.18-0.66) for α-carotene, 0.31 (95% CI: 0.15-0.63) for β-carotene, 0.55 (0.28-1.08) for lycopene and 0.37 (0.18-0.75) for total carotenoids. SNPs rs25489 in XRCC1, rs699473 in SOD3 and rs1052133 in OGG1 modified these associations for α-carotene, β-carotene and lycopene, respectively (P ≤ 0.05). The proportion of men with a high degree of FGA increased with Gleason Score (P levels were associated with lower FGA (P = 0.04). Circulating 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

  8. Genome Instability in Development and Aging: Insights from Nucleotide Excision Repair in Humans, Mice, and Worms

    Directory of Open Access Journals (Sweden)

    Diletta Edifizi

    2015-08-01

    Full Text Available DNA damage causally contributes to aging and cancer. Congenital defects in nucleotide excision repair (NER lead to distinct cancer-prone and premature aging syndromes. The genetics of NER mutations have provided important insights into the distinct consequences of genome instability. Recent work in mice and C. elegans has shed new light on the mechanisms through which developing and aging animals respond to persistent DNA damage. The various NER mouse mutants have served as important disease models for Xeroderma pigmentosum (XP, Cockayne syndrome (CS, and trichothiodystrophy (TTD, while the traceable genetics of C. elegans have allowed the mechanistic delineation of the distinct outcomes of genome instability in metazoan development and aging. Intriguingly, highly conserved longevity assurance mechanisms respond to transcription-blocking DNA lesions in mammals as well as in worms and counteract the detrimental consequences of persistent DNA damage. The insulin-like growth factor signaling (IIS effector transcription factor DAF-16 could indeed overcome DNA damage-driven developmental growth delay and functional deterioration even when DNA damage persists. Longevity assurance mechanisms might thus delay DNA damage-driven aging by raising the threshold when accumulating DNA damage becomes detrimental for physiological tissue functioning.

  9. Genome Instability in Development and Aging: Insights from Nucleotide Excision Repair in Humans, Mice, and Worms.

    Science.gov (United States)

    Edifizi, Diletta; Schumacher, Björn

    2015-08-13

    DNA damage causally contributes to aging and cancer. Congenital defects in nucleotide excision repair (NER) lead to distinct cancer-prone and premature aging syndromes. The genetics of NER mutations have provided important insights into the distinct consequences of genome instability. Recent work in mice and C. elegans has shed new light on the mechanisms through which developing and aging animals respond to persistent DNA damage. The various NER mouse mutants have served as important disease models for Xeroderma pigmentosum (XP), Cockayne syndrome (CS), and trichothiodystrophy (TTD), while the traceable genetics of C. elegans have allowed the mechanistic delineation of the distinct outcomes of genome instability in metazoan development and aging. Intriguingly, highly conserved longevity assurance mechanisms respond to transcription-blocking DNA lesions in mammals as well as in worms and counteract the detrimental consequences of persistent DNA damage. The insulin-like growth factor signaling (IIS) effector transcription factor DAF-16 could indeed overcome DNA damage-driven developmental growth delay and functional deterioration even when DNA damage persists. Longevity assurance mechanisms might thus delay DNA damage-driven aging by raising the threshold when accumulating DNA damage becomes detrimental for physiological tissue functioning.

  10. Bloom syndrome, genomic instability and cancer: the SOS-like hypothesis.

    Science.gov (United States)

    Amor-Guéret, Mounira

    2006-05-08

    Bloom syndrome (BS) displays one of the strongest known correlations between chromosomal instability and an increased risk of malignancy at an early age. The prevention of genomic instability and cancer depends on a complex network of pathways induced in response to DNA damage and stalled replication forks, including cell-cycle checkpoints, DNA repair, and apoptosis. Several studies have demonstrated that BLM is involved in the cellular response to DNA damage and stalled replication forks. BLM interacts physically and functionally with several proteins involved in the maintenance of genome integrity and BLM is redistributed and/or phosphorylated in response to several genotoxic stresses. The data concerning the relationship between BLM and these cellular pathways are summarized and the role of BLM in the rescue of arrested replication forks is discussed. Moreover, I speculate that BLM deficiency is lethal, and that BLM-deficient cells escaping apoptotic death do so by constitutively inducing a bacterial SOS-like response including the induction of alternative replication pathway(s) dependent on recombination, contributing to the mutator and hyper-Rec phenotypes characteristic of BS cells. This mechanism may be dependent on the RAD51 gene family, and involved in carcinogenesis in the general population.

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

    Directory of Open Access Journals (Sweden)

    Jan Christian Kaiser

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

  12. Mutagenic capacity of endogenous G4 DNA underlies genome instability in FANCJ-defective C. elegans.

    Science.gov (United States)

    Kruisselbrink, Evelien; Guryev, Victor; Brouwer, Karin; Pontier, Daphne B; Cuppen, Edwin; Tijsterman, Marcel

    2008-06-24

    To safeguard genetic integrity, cells have evolved an accurate but not failsafe mechanism of DNA replication. Not all DNA sequences tolerate DNA replication equally well [1]. Also, genomic regions that impose structural barriers to the DNA replication fork are a potential source of genetic instability [2, 3]. Here, we demonstrate that G4 DNA-a sequence motif that folds into quadruplex structures in vitro [4, 5]-is highly mutagenic in vivo and is removed from genomes that lack dog-1, the C. elegans ortholog of mammalian FANCJ [6, 7], which is mutated in Fanconi anemia patients [8-11]. We show that sequences that match the G4 DNA signature G3-5N1-3G3-5N1-3G3-5N1-3G3-5 are deleted in germ and somatic tissues of dog-1 animals. Unbiased aCGH analyses of dog-1 genomes that were allowed to accumulate mutations in >100 replication cycles indicate that deletions are found exclusively at G4 DNA; deletion frequencies can reach 4% per site per animal generation. We found that deletion sizes fall short of Okazaki fragment lengths [12], and no significant microhomology was observed at deletion junctions. The existence of 376,000 potentially mutagenic G4 DNA sites in the human genome could have major implications for the etiology of hereditary FancJ and nonhereditary cancers.

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

    LENUS (Irish Health Repository)

    Gorman, Sheeona

    2012-02-01

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

  14. Radiation 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

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

    Directory of Open Access Journals (Sweden)

    Sara Stigliani

    2012-09-01

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

  16. 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.

  17. Spatial and temporal diversity in genomic instability processes defines lung cancer evolution.

    Science.gov (United States)

    de Bruin, Elza C; McGranahan, Nicholas; Mitter, Richard; Salm, Max; Wedge, David C; Yates, Lucy; Jamal-Hanjani, Mariam; Shafi, Seema; Murugaesu, Nirupa; Rowan, Andrew J; Grönroos, Eva; Muhammad, Madiha A; Horswell, Stuart; Gerlinger, Marco; Varela, Ignacio; Jones, David; Marshall, John; Voet, Thierry; Van Loo, Peter; Rassl, Doris M; Rintoul, Robert C; Janes, Sam M; Lee, Siow-Ming; Forster, Martin; Ahmad, Tanya; Lawrence, David; Falzon, Mary; Capitanio, Arrigo; Harkins, Timothy T; Lee, Clarence C; Tom, Warren; Teefe, Enock; Chen, Shann-Ching; Begum, Sharmin; Rabinowitz, Adam; Phillimore, Benjamin; Spencer-Dene, Bradley; Stamp, Gordon; Szallasi, Zoltan; Matthews, Nik; Stewart, Aengus; Campbell, Peter; Swanton, Charles

    2014-10-10

    Spatial and temporal dissection of the genomic changes occurring during the evolution of human non-small cell lung cancer (NSCLC) may help elucidate the basis for its dismal prognosis. We sequenced 25 spatially distinct regions from seven operable NSCLCs and found evidence of branched evolution, with driver mutations arising before and after subclonal diversification. There was pronounced intratumor heterogeneity in copy number alterations, translocations, and mutations associated with APOBEC cytidine deaminase activity. Despite maintained carcinogen exposure, tumors from smokers showed a relative decrease in smoking-related mutations over time, accompanied by an increase in APOBEC-associated mutations. In tumors from former smokers, genome-doubling occurred within a smoking-signature context before subclonal diversification, which suggested that a long period of tumor latency had preceded clinical detection. The regionally separated driver mutations, coupled with the relentless and heterogeneous nature of the genome instability processes, are likely to confound treatment success in NSCLC. Copyright © 2014, American Association for the Advancement of Science.

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

    Science.gov (United States)

    Hamperl, Stephan; Cimprich, Karlene A.

    2014-01-01

    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. PMID:24746923

  19. 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.

  20. 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.

  1. Molecular mechanisms of radiation-induced genomic instability in human cells

    Energy Technology Data Exchange (ETDEWEB)

    Liber, Howard L.

    2003-02-13

    The overall strategy was to create a series of isogenic human cell lines that differ in key elements of cell cycle checkpoint, apoptosis, or DNA repair in response to radiation-induced damage. The goal then was to quantify the fractions of cells within a population that exhibit reduced telomere lengths and relate this to the genetic background of the cell, as well as to the response to ionizing radiation. Association between telomere length and degree of genomic instability in the population is being examined for seven closely related cell lines, that vary in p53 status, bcl-2 status, or ability to repair double strand breaks. Experiments utilize gamma rays at doses of 0, 10, and 200 cGy. During this time period the effort concentrated on generating data with two cell lines. Approximately one-third of the required clones were isolated, and analyses for mutagenesis and chromosome aberrations were undertaken.

  2. Increased chemosensitivity of paclitaxel by telomeric fusion-induced genomic instability

    Energy Technology Data Exchange (ETDEWEB)

    Woo, Seon Rang; Juhn, Kyoung Mi; Park, Jeong Eun; Ju, Yeun Jin; Yun, Mi Yong; Lee, Kee Ho [Korea Institute of Radiological and Medical Sciences, Seoul (Korea, Republic of); Park, Gil Hong; Kim, Joon [College of Medicine, Korea University, Seoul (Korea, Republic of)

    2009-05-15

    A telomere is a region of repetitive DNA at the end of chromosomes. They protect a cell's chromosomes from fusing with each other or rearranging and so cells are normally destroyed when their telomeres are consumed. Most normal somatic cells lose telomeric repeats after each cell division. Telomeric shortening in humans can induce replicative senescence which blocks cell division. This mechanism appears to prevent genomic instability by limiting the number of cell divisions. Telomerase is an attractive molecular target, since its activity has been found in more than 85% of human cancers. Combination therapy with chemotherapeutic agent is superior to single in overall response rate and progression free survival. In this study, we showed that telomerase null cells are more hypersensitive by paclitaxel treatment than at wild type cells.

  3. Transgenerational genomic instability as revealed by a somatic mutation assay using the medaka fish

    Energy Technology Data Exchange (ETDEWEB)

    Shimada, Atsuko; Shima, Akihiro

    2004-08-18

    We previously established a somatic mutation assay of the medaka wl (white leucophores) locus based on visual inspection, and showed that somatic mutations at paternally derived alleles frequently arise during the development of F{sub 1} embryos fertilized by sperm/late spermatids that had been exposed to {gamma}-rays. To further study such delayed mutations, we determined the frequency of mutant embryos obtained from three different crosses between irradiated males and non-irradiated females. When sperm and late spermatids were irradiated, the mutant frequency within non-irradiated maternally derived alleles was {approx}3 times higher than in the control group. In the F{sub 2} generation, however, no increase in mutant frequency was observed. Similarly, there was no significant increase in the F{sub 1}mutant frequency when stem spermatogonia were irradiated. These data suggest that irradiation of sperm and late spermatids can induce indirect mutations in F{sub 1} somatic cells, supporting the idea that genomic instability arises during F{sub 1} embryonic development. Moreover, such instability apparently arises most frequently when eggs are fertilized just after the sperm are irradiated.

  4. 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.

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

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    Valentina eTosato

    2013-01-01

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

  6. The tammar wallaby major histocompatibility complex shows evidence of past genomic instability

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    Harrow Jennifer

    2011-08-01

    Full Text Available Abstract Background The major histocompatibility complex (MHC is a group of genes with a variety of roles in the innate and adaptive immune responses. MHC genes form a genetically linked cluster in eutherian mammals, an organization that is thought to confer functional and evolutionary advantages to the immune system. The tammar wallaby (Macropus eugenii, an Australian marsupial, provides a unique model for understanding MHC gene evolution, as many of its antigen presenting genes are not linked to the MHC, but are scattered around the genome. Results Here we describe the 'core' tammar wallaby MHC region on chromosome 2q by ordering and sequencing 33 BAC clones, covering over 4.5 MB and containing 129 genes. When compared to the MHC region of the South American opossum, eutherian mammals and non-mammals, the wallaby MHC has a novel gene organization. The wallaby has undergone an expansion of MHC class II genes, which are separated into two clusters by the class III genes. The antigen processing genes have undergone duplication, resulting in two copies of TAP1 and three copies of TAP2. Notably, Kangaroo Endogenous Retroviral Elements are present within the region and may have contributed to the genomic instability. Conclusions The wallaby MHC has been extensively remodeled since the American and Australian marsupials last shared a common ancestor. The instability is characterized by the movement of antigen presenting genes away from the core MHC, most likely via the presence and activity of retroviral elements. We propose that the movement of class II genes away from the ancestral class II region has allowed this gene family to expand and diversify in the wallaby. The duplication of TAP genes in the wallaby MHC makes this species a unique model organism for studying the relationship between MHC gene organization and function.

  7. Mutations in XRCC4 cause primary microcephaly, short stature and increased genomic instability.

    Science.gov (United States)

    Rosin, Nadine; Elcioglu, Nursel H; Beleggia, Filippo; Isgüven, Pinar; Altmüller, Janine; Thiele, Holger; Steindl, Katharina; Joset, Pascal; Rauch, Anita; Nürnberg, Peter; Wollnik, Bernd; Yigit, Gökhan

    2015-07-01

    DNA double-strand breaks (DSBs) are highly toxic lesions, which, if not properly repaired, can give rise to genomic instability. Non-homologous end-joining (NHEJ), a well-orchestrated, multistep process involving numerous proteins essential for cell viability, represents one major pathway to repair DSBs in mammalian cells, and mutations in different NHEJ components have been described in microcephalic syndromes associated, e.g. with short stature, facial dysmorphism and immune dysfunction. By using whole-exome sequencing, we now identified in three affected brothers of a consanguineous Turkish family a homozygous mutation, c.482G>A, in the XRCC4 gene encoding a crucial component of the NHEJ pathway. Moreover, we found one additional patient of Swiss origin carrying the compound heterozygous mutations c.25delG (p.His9Thrfs*8) and c.823C>T (p.Arg275*) in XRCC4. The clinical phenotype presented in these patients was characterized by severe microcephaly, facial dysmorphism and short stature, but they did not show a recognizable immunological phenotype. We showed that the XRCC4 c.482G>A mutation, which affects the last nucleotide of exon 4, induces defective splicing of XRCC4 pre-mRNA mainly resulting in premature protein truncation and most likely loss of XRCC4 function. Moreover, we observed on cellular level that XRCC4 deficiency leads to hypersensitivity to DSB-inducing agents and defective DSB repair, which results in increased cell death after exposure to genotoxic agents. Taken together, our data provide evidence that autosomal recessive mutations in XRCC4 induce increased genomic instability and cause a NHEJ-related syndrome defined by facial dysmorphism, primary microcephaly and short stature. © The Author 2015. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oup.com.

  8. Myc oncogene-induced genomic instability: DNA palindromes in bursal lymphomagenesis.

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    Paul E Neiman

    2008-07-01

    Full Text Available Genetic instability plays a key role in the formation of naturally occurring cancer. The formation of long DNA palindromes is a rate-limiting step in gene amplification, a common form of tumor-associated genetic instability. Genome-wide analysis of palindrome formation (GAPF has detected both extensive palindrome formation and gene amplification, beginning early in tumorigenesis, in an experimental Myc-induced model tumor system in the chicken bursa of Fabricius. We determined that GAPF-detected palindromes are abundant and distributed nonrandomly throughout the genome of bursal lymphoma cells, frequently at preexisting short inverted repeats. By combining GAPF with chromatin immunoprecipitation (ChIP, we found a significant association between occupancy of gene-proximal Myc binding sites and the formation of palindromes. Numbers of palindromic loci correlate with increases in both levels of Myc over-expression and ChIP-detected occupancy of Myc binding sites in bursal cells. However, clonal analysis of chick DF-1 fibroblasts suggests that palindrome formation is a stochastic process occurring in individual cells at a small number of loci relative to much larger numbers of susceptible loci in the cell population and that the induction of palindromes is not involved in Myc-induced acute fibroblast transformation. GAPF-detected palindromes at the highly oncogenic bic/miR-155 locus in all of our preneoplastic and neoplastic bursal samples, but not in DNA from normal and other transformed cell types. This finding indicates very strong selection during bursal lymphomagenesis. Therefore, in addition to providing a platform for gene copy number change, palindromes may alter microRNA genes in a fashion that can contribute to cancer development.

  9. Myc oncogene-induced genomic instability: DNA palindromes in bursal lymphomagenesis.

    Science.gov (United States)

    Neiman, Paul E; Elsaesser, Katrina; Loring, Gilbert; Kimmel, Robert

    2008-07-18

    Genetic instability plays a key role in the formation of naturally occurring cancer. The formation of long DNA palindromes is a rate-limiting step in gene amplification, a common form of tumor-associated genetic instability. Genome-wide analysis of palindrome formation (GAPF) has detected both extensive palindrome formation and gene amplification, beginning early in tumorigenesis, in an experimental Myc-induced model tumor system in the chicken bursa of Fabricius. We determined that GAPF-detected palindromes are abundant and distributed nonrandomly throughout the genome of bursal lymphoma cells, frequently at preexisting short inverted repeats. By combining GAPF with chromatin immunoprecipitation (ChIP), we found a significant association between occupancy of gene-proximal Myc binding sites and the formation of palindromes. Numbers of palindromic loci correlate with increases in both levels of Myc over-expression and ChIP-detected occupancy of Myc binding sites in bursal cells. However, clonal analysis of chick DF-1 fibroblasts suggests that palindrome formation is a stochastic process occurring in individual cells at a small number of loci relative to much larger numbers of susceptible loci in the cell population and that the induction of palindromes is not involved in Myc-induced acute fibroblast transformation. GAPF-detected palindromes at the highly oncogenic bic/miR-155 locus in all of our preneoplastic and neoplastic bursal samples, but not in DNA from normal and other transformed cell types. This finding indicates very strong selection during bursal lymphomagenesis. Therefore, in addition to providing a platform for gene copy number change, palindromes may alter microRNA genes in a fashion that can contribute to cancer development.

  10. R-loops and nicks initiate DNA breakage and genome instability in non-growing Escherichia coli.

    Science.gov (United States)

    Wimberly, Hallie; Shee, Chandan; Thornton, P C; Sivaramakrishnan, Priya; Rosenberg, Susan M; Hastings, P J

    2013-01-01

    Double-stranded DNA ends, often from replication, drive genomic instability, yet their origin in non-replicating cells is unknown. Here we show that transcriptional RNA/DNA hybrids (R-loops) generate DNA ends that underlie stress-induced mutation and amplification. Depleting RNA/DNA hybrids with overproduced RNase HI reduces both genomic changes, indicating RNA/DNA hybrids as intermediates in both. An Mfd requirement and inhibition by translation implicate transcriptional R-loops. R-loops promote instability by generating DNA ends, shown by their dispensability when ends are provided by I-SceI endonuclease. Both R-loops and single-stranded endonuclease TraI are required for end formation, visualized as foci of a fluorescent end-binding protein. The data suggest that R-loops prime replication forks that collapse at single-stranded nicks, producing ends that instigate genomic instability. The results illuminate how DNA ends form in non-replicating cells, identify R-loops as the earliest known mutation/amplification intermediate, and suggest that genomic instability during stress could be targeted to transcribed regions, accelerating adaptation.

  11. Lack of Genomic Instability in Bone Marrow Cells of SCID Mice Exposed Whole-Body to Low-Dose Radiation

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    Elbert Whorton

    2013-04-01

    Full Text Available It is clear that high-dose radiation is harmful. However, despite extensive research, assessment of potential health-risks associated with exposure to low-dose radiation (at doses below or equal to 0.1 Gy is still challenging. Recently, we reported that 0.05 Gy of 137Cs gamma rays (the existing limit for radiation-exposure in the workplace was incapable of inducing significant in vivo genomic instability (measured by the presence of late-occurring chromosomal damage at 6 months post-irradiation in bone marrow (BM cells of two mouse strains, one with constitutively high and one with intermediate levels of the repair enzyme DNA-dependent protein-kinase catalytic-subunit (DNA-PKcs. In this study, we present evidence for a lack of genomic instability in BM cells of the severely combined-immunodeficiency (SCID/J mouse (which has an extremely low-level of DNA-PKcs activity exposed whole-body to low-dose radiation (0.05 Gy. Together with our previous report, the data indicate that low-dose radiation (0.05 Gy is incapable of inducing genomic instability in vivo (regardless of the levels of DNA-PKcs activity of the exposed mice, yet higher doses of radiation (0.1 and 1 Gy do induce genomic instability in mice with intermediate and extremely low-levels of DNA-PKcs activity (indicating an important role of DNA-PKcs in DNA repair.

  12. Polyubiquitination of proliferating cell nuclear antigen by HLTF and SHPRH prevents genomic instability from stalled replication forks

    NARCIS (Netherlands)

    A. Motegi (Akira); H.J. Liaw; K.Y. Lee; H.P. Roest (Henk); A. Maas (Alex); X. Wu; H. Moinova (Helen); S.D. Markowitz (Sanford); H. Ding (Hao); J.H.J. Hoeijmakers (Jan); K. Myung (Kyungjae)

    2008-01-01

    textabstractChronic stalling of DNA replication forks caused by DNA damage can lead to genomic instability. Cells have evolved lesion bypass pathways such as postreplication repair (PRR) to resolve these arrested forks. In yeast, one branch of PRR involves proliferating cell nuclear antigen (PCNA)

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

    Science.gov (United States)

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

    2016-05-01

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

  14. Constitutive aneuploidy and genomic instability in the single-celled eukaryote Giardia intestinalis.

    Science.gov (United States)

    Tůmová, Pavla; Uzlíková, Magdalena; Jurczyk, Tomáš; Nohýnková, Eva

    2016-08-01

    Giardia intestinalis is an important single-celled human pathogen. Interestingly, this organism has two equal-sized transcriptionally active nuclei, each considered diploid. By evaluating condensed chromosome numbers and visualizing homologous chromosomes by fluorescent in situ hybridization, we determined that the Giardia cells are constitutively aneuploid. We observed karyotype inter-and intra-population heterogeneity in eight cell lines from two clinical isolates, suggesting constant karyotype evolution during in vitro cultivation. High levels of chromosomal instability and frequent mitotic missegregations observed in four cell lines correlated with a proliferative disadvantage and growth retardation. Other cell lines, although derived from the same clinical isolate, revealed a stable yet aneuploid karyotype. We suggest that both chromatid missegregations and structural rearrangements contribute to shaping the Giardia genome, leading to whole-chromosome aneuploidy, unequal gene distribution, and a genomic divergence of the two nuclei within one cell. Aneuploidy in Giardia is further propagated without p53-mediated cell cycle arrest and might have been a key mechanism in generating the genetic diversity of this human pathogen. © 2016 The Authors. MicrobiologyOpen published by John Wiley & Sons Ltd.

  15. 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.

  16. 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.

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

    Energy Technology Data Exchange (ETDEWEB)

    Knecht, Hans, E-mail: hans.knecht@usherbrooke.ca [Division d‘Hématologie, Département de Médecine, CHUS, Université de Sherbrooke, Québec, J1H 5N4 (Canada); Manitoba Institute of Cell Biology, The Genomic Centre for Cancer Research and Diagnosis, University of Manitoba, Winnipeg, Manitoba, R3E 0V9 (Canada); Righolt, Christiaan [Manitoba Institute of Cell Biology, The Genomic Centre for Cancer Research and Diagnosis, University of Manitoba, Winnipeg, Manitoba, R3E 0V9 (Canada); Department of Imaging Science and Technology, Delft University of Technology, 2628 CJ Delft (Netherlands); Mai, Sabine [Manitoba Institute of Cell Biology, The Genomic Centre for Cancer Research and Diagnosis, University of Manitoba, Winnipeg, Manitoba, R3E 0V9 (Canada)

    2013-06-05

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

  18. 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.

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

    Directory of Open Access Journals (Sweden)

    Marshall Wallace F

    2005-05-01

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

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

    Directory of Open Access Journals (Sweden)

    Sabine Mai

    2013-06-01

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

  1. cGAS surveillance of micronuclei links genome instability to innate immunity.

    Science.gov (United States)

    Mackenzie, Karen J; Carroll, Paula; Martin, Carol-Anne; Murina, Olga; Fluteau, Adeline; Simpson, Daniel J; Olova, Nelly; Sutcliffe, Hannah; Rainger, Jacqueline K; Leitch, Andrea; Osborn, Ruby T; Wheeler, Ann P; Nowotny, Marcin; Gilbert, Nick; Chandra, Tamir; Reijns, Martin A M; Jackson, Andrew P

    2017-08-24

    DNA is strictly compartmentalized within the nucleus to prevent autoimmunity; despite this, cyclic GMP-AMP synthase (cGAS), a cytosolic sensor of double-stranded DNA, is activated in autoinflammatory disorders and by DNA damage. Precisely how cellular DNA gains access to the cytoplasm remains to be determined. Here, we report that cGAS localizes to micronuclei arising from genome instability in a mouse model of monogenic autoinflammation, after exogenous DNA damage and spontaneously in human cancer cells. Such micronuclei occur after mis-segregation of DNA during cell division and consist of chromatin surrounded by its own nuclear membrane. Breakdown of the micronuclear envelope, a process associated with chromothripsis, leads to rapid accumulation of cGAS, providing a mechanism by which self-DNA becomes exposed to the cytosol. cGAS is activated by chromatin, and consistent with a mitotic origin, micronuclei formation and the proinflammatory response following DNA damage are cell-cycle dependent. By combining live-cell laser microdissection with single cell transcriptomics, we establish that interferon-stimulated gene expression is induced in micronucleated cells. We therefore conclude that micronuclei represent an important source of immunostimulatory DNA. As micronuclei formed from lagging chromosomes also activate this pathway, recognition of micronuclei by cGAS may act as a cell-intrinsic immune surveillance mechanism that detects a range of neoplasia-inducing processes.

  2. The Role of MDM2 in Promoting Genome Stability versus Instability

    Directory of Open Access Journals (Sweden)

    M. Reza Saadatzadeh

    2017-10-01

    Full Text Available In cancer, the mouse double minute 2 (MDM2 is an oncoprotein that contributes to the promotion of cell growth, survival, invasion, and therapeutic resistance. The impact of MDM2 on cell survival versus cell death is complex and dependent on levels of MDM2 isoforms, p53 status, and cellular context. Extensive investigations have demonstrated that MDM2 protein–protein interactions with p53 and other p53 family members (p63 and p73 block their ability to function as transcription factors that regulate cell growth and survival. Upon genotoxic insults, a dynamic and intricately regulated DNA damage response circuitry is activated leading to release of p53 from MDM2 and activation of cell cycle arrest. What ensues following DNA damage, depends on the extent of DNA damage and if the cell has sufficient DNA repair capacity. The well-known auto-regulatory loop between p53-MDM2 provides an additional layer of control as the cell either repairs DNA damage and survives (i.e., MDM2 re-engages with p53, or undergoes cell death (i.e., MDM2 does not re-engage p53. Furthermore, the decision to live or die is also influenced by chromatin-localized MDM2 which directly interacts with the Mre11-Rad50-Nbs1 complex and inhibits DNA damage-sensing giving rise to the potential for increased genome instability and cellular transformation.

  3. 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.

  4. Genomic Instability in Human Lymphocytes from Male Users of Crack Cocaine

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    Thiago Aley Brites de Freitas

    2014-09-01

    Full Text Available Recent research suggests that crack cocaine use alters systemic biochemical markers, like oxidative damage and inflammation markers, but very few studies have assessed the potential effects of crack cocaine at the cellular level. We assessed genome instability by means of the comet assay and the cytokinesis-block micronucleus technique in crack cocaine users at the time of admission to a rehabilitation clinic and at two times after the beginning of withdrawal. Thirty one active users of crack cocaine and forty control subjects were evaluated. Comparison between controls and crack cocaine users at the first analysis showed significant differences in the rates of DNA damage (p = 0.037. The frequency of micronuclei (MN (p < 0.001 and nuclear buds (NBUDs (p < 0.001 was increased, but not the frequency of nucleoplasmic bridges (NPBs (p = 0.089. DNA damage decreased only after the end of treatment (p < 0.001. Micronuclei frequency did not decrease after treatment, and nuclear buds increased substantially. The results of this study reveal the genotoxic and mutagenic effects of crack cocaine use in human lymphocytes and pave the way for further research on cellular responses and the possible consequences of DNA damage, such as induction of irreversible neurological disease and cancer.

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

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    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.

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

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    Andrei Kuzminov

    2016-10-01

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

  7. 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.

  8. Non-homologous End-joining Genes are not Inactivated in Human Radiation-induced Sarcomas with Genomic Instability

    OpenAIRE

    Sandrine H., LEFEVRE; Arnaud, COQUELLE; Nathalie, GONIN LAURENT; Andrej, COR; Nicolas, VOGT; Laurent, CHAUVEINC; Philippe, ANRACT; Bernard, DUTRILLAUX; Sylvie, CHEVILLARD; Bernard, MALFOY; Institut for Histology and Embryology, Medical Faculty; Institut Curie, Service de Radiotherapie; Hopital Cochin. Service de Chirurgie Orthopedique et Oncologique; CEA, DSV DRR; Institut Curie-CNRS-UPMC UMR7147, CEA LRC38

    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 ...

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

    Energy Technology Data Exchange (ETDEWEB)

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

    2003-07-01

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

  10. 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.

  11. 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

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

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    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.

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

    Science.gov (United States)

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

    2015-10-01

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

  14. Targeting homologous recombination and telomerase in Barrett’s adenocarcinoma: Impact on telomere maintenance, genomic instability, and tumor growth

    Science.gov (United States)

    Lu, Renquan; Pal, Jagannath; Buon, Leutz; Nanjappa, Puru; Shi, Jialan; Fulciniti, Mariateresa; Tai, Yu-Tzu; Guo, Lin; Yu, Min; Gryaznov, Sergei; Munshi, Nikhil C.; Shammas, Masood A.

    2014-01-01

    Homologous recombination (HR), a mechanism to accurately repair DNA in normal cells, is deregulated in cancer. Elevated/deregulated HR is implicated in genomic instability and telomere maintenance, which are critical lifelines of cancer cells. We have previously shown that HR activity is elevated and significantly contributes to genomic instability in BAC. The purpose of this study was to evaluate therapeutic potential of HR inhibition, alone and in combination with telomerase inhibition, in BAC. We demonstrate that telomerase inhibition in BAC cells increases HR activity, RAD51 expression, and association of RAD51 to telomeres. Suppression of HR leads to shorter telomeres as well as markedly reduced genomic instability in BAC cells over time. Combination of HR suppression (whether transgenic or chemical) with telomerase inhibition, causes a significant increase in telomere attrition and apoptotic death in all BAC cell lines tested, relative to either treatment alone. A subset of treated cells also stain positive for β-galactosidase, indicating senescence. The combined treatment is also associated with decline in S-phase and a strong G2/M arrest, indicating massive telomere attrition. In a subcutaneous tumor model, the combined treatment resulted in the smallest tumors, which were even smaller (P=0.001) than those resulted from either treatment alone. Even the tumors removed from these mice had significantly reduced telomeres and evidence of apoptosis. We therefore conclude that although telomeres are elongated by telomerase, elevated RAD51/HR assist in their maintenance/stabilization in BAC cells. Telomerase inhibitor prevents telomere elongation but induces RAD51/HR, which contribute to telomere maintenance/stabilization and prevention of apoptosis, reducing the efficacy of treatment. Combining HR inhibition with telomerase, makes telomeres more vulnerable to degradation and significantly increases/expedites their attrition, leading to apoptosis. We therefore

  15. Targeting homologous recombination and telomerase in Barrett's adenocarcinoma: impact on telomere maintenance, genomic instability and tumor growth.

    Science.gov (United States)

    Lu, R; Pal, J; Buon, L; Nanjappa, P; Shi, J; Fulciniti, M; Tai, Y-T; Guo, L; Yu, M; Gryaznov, S; Munshi, N C; Shammas, M A

    2014-03-20

    Homologous recombination (HR), a mechanism to accurately repair DNA in normal cells, is deregulated in cancer. Elevated/deregulated HR is implicated in genomic instability and telomere maintenance, which are critical lifelines of cancer cells. We have previously shown that HR activity is elevated and significantly contributes to genomic instability in Barrett's esophageal adenocarcinoma (BAC). The purpose of this study was to evaluate therapeutic potential of HR inhibition, alone and in combination with telomerase inhibition, in BAC. We demonstrate that telomerase inhibition in BAC cells increases HR activity, RAD51 expression, and association of RAD51 to telomeres. Suppression of HR leads to shorter telomeres as well as markedly reduced genomic instability in BAC cells over time. Combination of HR suppression (whether transgenic or chemical) with telomerase inhibition, causes a significant increase in telomere attrition and apoptotic death in all BAC cell lines tested, relative to either treatment alone. A subset of treated cells also stain positive for β-galactosidase, indicating senescence. The combined treatment is also associated with decline in S-phase and a strong G2/M arrest, indicating massive telomere attrition. In a subcutaneous tumor model, the combined treatment resulted in the smallest tumors, which were even smaller (P=0.001) than those that resulted from either treatment alone. Even the tumors removed from these mice had significantly reduced telomeres and evidence of apoptosis. We therefore conclude that although telomeres are elongated by telomerase, elevated RAD51/HR assist in their maintenance/stabilization in BAC cells. Telomerase inhibitor prevents telomere elongation but induces RAD51/HR, which contributes to telomere maintenance/stabilization and prevention of apoptosis, reducing the efficacy of treatment. Combining HR inhibition with telomerase renders telomeres more vulnerable to degradation and significantly increases/expedites their

  16. Replication in mammalian cells recapitulates the locus-specific differences in somatic instability of genomic GAA triplet-repeats.

    Science.gov (United States)

    M Rindler, Paul; Clark, Rhonda M; Pollard, Laura M; De Biase, Irene; Bidichandani, Sanjay I

    2006-01-01

    Friedreich ataxia is caused by an expanded (GAA.TTC)n sequence in intron 1 of the FXN gene. Small pool PCR analysis showed that pure (GAA.TTC)44+ sequences at the FXN locus are unstable in somatic cells in vivo, displaying both expansions and contractions. On searching the entire human and mouse genomes we identified three other genomic loci with pure (GAA.TTC)44+ sequences. Alleles at these loci showed mutation loads of GAA.TTC)n sequences. Repeat instability was evaluated following replication of a (GAA.TTC)115 sequence in transfected COS1 cells under the control of the SV40 origin of replication located at one of five different distances from the repeat. Indeed, depending on the location of the SV40 origin relative to the (GAA.TTC)n sequence, we noted either no instability, predominant expansion or both expansion and contraction. These data suggest that mammalian DNA replication is a possible mechanism underlying locus-specific differences in instability of GAA triplet-repeat sequences.

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

    Science.gov (United States)

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

    2013-01-01

    Sequences that have the capacity to adopt alternative (i.e. non-B) DNA structures in the human genome have been implicated in stimulating genomic instability. Previously, we found that a naturally occurring intra-molecular triplex (H-DNA) caused genetic instability in mammals largely in the form of DNA double-strand breaks. Thus, it is of interest to determine the mechanism(s) involved in processing H-DNA. Recently, we demonstrated that human DHX9 helicase preferentially unwinds inter-molecular triplex DNA in vitro. Herein, we used a mutation-reporter system containing H-DNA to examine the relevance of DHX9 activity on naturally occurring H-DNA structures in human cells. We found that H-DNA significantly increased mutagenesis in small-interfering siRNA-treated, DHX9-depleted cells, affecting mostly deletions. Moreover, DHX9 associated with H-DNA in the context of supercoiled plasmids. To further investigate the role of DHX9 in the recognition/processing of H-DNA, we performed binding assays in vitro and chromatin immunoprecipitation assays in U2OS cells. DHX9 recognized H-DNA, as evidenced by its binding to the H-DNA structure and enrichment at the H-DNA region compared with a control region in human cells. These composite data implicate DHX9 in processing H-DNA structures in vivo and support its role in the overall maintenance of genomic stability at sites of alternatively structured DNA. PMID:24049074

  18. Genomic instability of I elements of Drosophila melanogaster in absence of dysgenic crosses.

    Directory of Open Access Journals (Sweden)

    Roberta Moschetti

    Full Text Available Retrotranspostion of I factors in the female germline of Drosophila melanogaster is responsible for the so called I-R hybrid dysgenesis, a phenomenon that produces a broad spectrum of genetic abnormalities including reduced fertility, increased frequency of mutations and chromosome loss. Transposition of I factor depends on cellular conditions that are established in the oocytes of the reactive females and transmitted to their daughters. The so-called reactivity is a cellular state that may exhibit variable levels of expression and represents a permissive condition for I transposition at high levels. Defective I elements have been proposed to be the genetic determinants of reactivity and, through their differential expression, to modulate transposition of active copies in somatic and/or germ line cells. Recently, control of transposable element activity in the germ line has been found to depend on pi-RNAs, small repressive RNAs interacting with Piwi-family proteins and derived from larger transposable elements (TE-derived primary transcripts. In particular, maternally transmitted I-element piRNAs originating from the 42AB region of polytene chromosomes were found to be involved in control of I element mobility. In the present work, we use a combination of cytological and molecular approaches to study the activity of I elements in three sublines of the inducer y; cn bw; sp isogenic strain and in dysgenic and non-dysgenic genetic backgrounds. Overall, the results of FISH and Southern blotting experiments clearly show that I elements are highly unstable in the Montpellier subline in the absence of classical dysgenic conditions. Such instability appears to be correlated to the amount of 5' and 3' I element transcripts detected by quantitative and real-time RT-PCR. The results of this study indicate that I elements can be highly active in the absence of a dysgenic crosses. Moreover, in the light of our results caution should be taken to assimilate

  19. Parental gamma irradiation induces reprotoxic effects accompanied by genomic instability in zebrafish (Danio rerio) embryos.

    Science.gov (United States)

    Hurem, Selma; Gomes, Tânia; Brede, Dag A; Lindbo Hansen, Elisabeth; Mutoloki, Stephen; Fernandez, Cristian; Mothersill, Carmel; Salbu, Brit; Kassaye, Yetneberk A; Olsen, Ann-Karin; Oughton, Deborah; Aleström, Peter; Lyche, Jan L

    2017-11-01

    increased in the E line compared to controls, but not in progeny of irradiated parents (G and GE lines). Overall, this study showed that irradiation of parents can result in multigenerational oxidative stress and genomic instability in irradiated (GE) and non-irradiated (G) progeny of irradiated parents, including increases in ROS formation, LPO, DNA damage and bystander effects. The results therefore highlight the necessity for multi- and transgenerational studies to assess the environmental impact of gamma radiation. Copyright © 2017 Elsevier Inc. All rights reserved.

  20. 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.

  1. 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

  2. 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.

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

    Science.gov (United States)

    Shima, Naoko; Pederson, Kayla D

    2017-08-01

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

  4. Tolerance of Deregulated G1/S Transcription Depends on Critical G1/S Regulon Genes to Prevent Catastrophic Genome Instability

    Directory of Open Access Journals (Sweden)

    Catia Caetano

    2014-12-01

    Full Text Available Expression of a G1/S regulon of genes that are required for DNA replication is a ubiquitous mechanism for controlling cell proliferation; moreover, the pathological deregulated expression of E2F-regulated G1/S genes is found in every type of cancer. Cellular tolerance of deregulated G1/S transcription is surprising because this regulon includes many dosage-sensitive proteins. Here, we used the fission yeast Schizosaccharomyces pombe to investigate this issue. We report that deregulating the MBF G1/S regulon by eliminating the Nrm1 corepressor increases replication errors. Homology-directed repair proteins, including MBF-regulated Ctp1CtIP, are essential to prevent catastrophic genome instability. Surprisingly, the normally inconsequential MBF-regulated S-phase cyclin Cig2 also becomes essential in the absence of Nrm1. This requirement was traced to cyclin-dependent kinase inhibition of the MBF-regulated Cdc18Cdc6 replication origin-licensing factor. Collectively, these results establish that, although deregulation of G1/S transcription is well tolerated by cells, nonessential G1/S target genes become crucial for preventing catastrophic genome instability.

  5. 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.

  6. 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.

  7. TP53 mutation-mediated genomic instability induces the evolution of chemoresistance and recurrence in epithelial ovarian cancer.

    Science.gov (United States)

    Zhang, Meiying; Zhuang, Guanglei; Sun, Xiangjun; Shen, Yanying; Wang, Wenjing; Li, Qing; Di, Wen

    2017-02-02

    Genomic instability caused by mutation of the checkpoint molecule TP53 may endow cancer cells with the ability to undergo genomic evolution to survive stress and treatment. We attempted to gain insight into the potential contribution of ovarian cancer genomic instability resulted from TP53 mutation to the aberrant expression of multidrug resistance gene MDR1. TP53 mutation status was assessed by performing nucleotide sequencing and immunohistochemistry. Ovarian cancer cell DNA ploidy was determined using Feulgen-stained smears or flow cytometry. DNA copy number was analyzed by performing fluorescence in situ hybridization (FISH). In addition to performing nucleotide sequencing for 5 cases of ovarian cancer, TP53 mutations were analyzed via immunohistochemical staining for P53. Both intensive P53 immunohistochemical staining and complete absence of signal were associated with the occurrence of TP53 mutations. HE staining and the quantification of DNA content indicated a significantly higher proportion of polyploidy and aneuploidy cells in the TP53 mutant group than in the wild-type group (p ovarian cancer patients, multivariate logistic analysis identified late FIGO (International Federation of Gynecology and Obstetrics) stage, serous histotype, G3 grade and TP53 mutation as independent risk factors for ovarian cancer recurrence. In relapse patients, the proportion of chemoresistant cases in the TP53 wild-type group was significantly lower than in the mutant group (63.6% vs. 91.8%, p 6 MDR1 copies and chromosome 7 amplication in the TP53 mutant group than in the wild-type group [11.7 ± 2.3% vs. 3.0 ± 0.7% and 2.1 ± 0.7% vs. 0.3 ± 0.05%, (p ovarian cancer chemoresistance and recurrence. Our findings lay the foundation for the development of promising chemotherapeutic approaches to treat aggressive and recurrent ovarian cancer.

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

    Directory of Open Access Journals (Sweden)

    Nestor Luis Lopez Corrales

    2012-12-01

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

  9. 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 TH cell deficiency and genomic instability in the XLT/WAS clinical spectrum. In human TH1- or TH2-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 TH1 cells relative to TH2 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 (TH1 genes) in TH1 cells. These aberrations accompany increased unspliced (intron-retained) and decreased spliced mRNA of IFNG and TBX21 but not IL13 (TH2 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 TH1 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 and could be

  10. 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

  11. 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.

  12. 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.

  13. 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.

  14. Targeting TPX2 Suppresses the Tumorigenesis of Hepatocellular Carcinoma Cells Resulting in Arrested Mitotic Phase Progression and Increased Genomic Instability.

    Science.gov (United States)

    Hsu, Chao-Wen; Chen, Yu-Chia; Su, Hsing-Hao; Huang, Guan-Jin; Shu, Chih-Wen; Wu, Tony Tong-Lin; Pan, Hung-Wei

    2017-01-01

    Hepatocellular carcinoma (HCC) remains one of the most difficult cancers to treat, with chemotherapies being relatively ineffective. Therefore, a better knowledge of molecular hepatocarcinogenesis will provide opportunities for designing targeted therapies. TPX2 (targeting protein for Xklp2) is overexpressed as a consequence of oncogenic alterations and is likely to alter the proper regulation of chromosome segregation in cancer cells. Disrupting the machinery which is responsible for mitosis and chromosome instability in cancer cells can be one of the most successful strategies for cancer therapy. Therefore, we consider the targeting TPX2 could provide novel therapeutic strategies for cancer. In this study, increased TPX2 protein expression was present in 16 (42%) of 38 primary HCCs and was associated with advanced stage, distant metastatic HCCs and poor prognosis. Knockdown of TPX2 inhibited cancer cell growth and downregulation of cyclin A, cyclin E and CDK2 proteins. However, over-expressed EGFP-TPX2 protein enhanced the in vitro tumor spheroid formation and rescued the TPX2 depleted cell growth. Targeting TPX2 caused a rising impaired chromosomal instability resulting in multinuclearity, cell cycle progression arrest, apotosis, senescence and an increased polyploidy in cells. An image-cytometry analysis revealed cell cycle progression arrest after TPX2 inhibition. A correlation was observed between the downregulation of the protein levels of genes related to chromosomal segregation and spindle assembly checkpoint (securin, seprase, Aurora A, Aurora B, Cyclin B1, Cyclin B2, MPS1, BUB1, BUB3, MAD1 and MAD2) and increased cell ploidy, indicating mitotic progression failure and the loss of the balance of genomic instability. In vitro tumor spheroid assay and in vivo xenografts mouse model showed a therapeutic opportunity. Our findings indicate that targeting TPX2 lead to suppress tumorigenicity in liver cancer cells, suggesting that TPX2 is a potential target for

  15. Accumulation and Phosphorylation of RecQ-Mediated Genome Instability Protein 1 (RMI1 at Serine 284 and Serine 292 during Mitosis

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    Chang Xu

    2015-11-01

    Full Text Available Chromosome instability usually leads to tumorigenesis. Bloom syndrome (BS is a genetic disease associated with chromosome instability. The BS gene product, BLM, has been reported to function in the spindle assembly checkpoint (SAC to prevent chromosome instability. BTR complex, composed of BLM, topoisomerase IIIα (Topo IIIα, RMI1 (RecQ-mediated genome instability protein 1, BLAP75 and RMI2 (RecQ-mediated genome instability protein 2, BLAP18, is crucial for maintaining genome stability. Recent work has demonstrated that RMI2 also plays critical role in SAC. However, little is know about RMI1 regulation during the cell cycle. Here we present that RMI1 protein level does not change through G1, S and G2 phases, but significantly increases in M phase. Moreover, phosphorylation of RMI1 occurs in mitosis. Upon microtubule-disturbing agent, RMI1 is phosphorylated primarily at the sites of Serine 284 and Serine 292, which does not interfere with the formation of BTR complex. Additionally, this phosphorylation is partially reversed by roscovitine treatment, implying cycling-dependent kinase 1 (CDK1 might be one of the upstream kinases.

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

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    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.

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

    Science.gov (United States)

    Patterson, Melissa N; Maxwell, Patrick H

    2014-10-16

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

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

    DEFF Research Database (Denmark)

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

    2006-01-01

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

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

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    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

  20. 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.

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

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    Lentini Laura

    2009-12-01

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

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

    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

  3. Nucleosome loss leads to global transcriptional up-regulation and genomic instability during yeast aging.

    Science.gov (United States)

    Hu, Zheng; Chen, Kaifu; Xia, Zheng; Chavez, Myrriah; Pal, Sangita; Seol, Ja-Hwan; Chen, Chin-Chuan; Li, Wei; Tyler, Jessica K

    2014-02-15

    All eukaryotic cells divide a finite number of times, although the mechanistic basis of this replicative aging remains unclear. Replicative aging is accompanied by a reduction in histone protein levels, and this is a cause of aging in budding yeast. Here we show that nucleosome occupancy decreased by 50% across the whole genome during replicative aging using spike-in controlled micrococcal nuclease digestion followed by sequencing. Furthermore, nucleosomes became less well positioned or moved to sequences predicted to better accommodate histone octamers. The loss of histones during aging led to transcriptional induction of all yeast genes. Genes that are normally repressed by promoter nucleosomes were most induced, accompanied by preferential nucleosome loss from their promoters. We also found elevated levels of DNA strand breaks, mitochondrial DNA transfer to the nuclear genome, large-scale chromosomal alterations, translocations, and retrotransposition during aging.

  4. p16(INK4a prevents centrosome dysfunction and genomic instability in primary cells.

    Directory of Open Access Journals (Sweden)

    Kimberly M McDermott

    2006-03-01

    Full Text Available Aneuploidy, frequently observed in premalignant lesions, disrupts gene dosage and contributes to neoplastic progression. Theodor Boveri hypothesized nearly 100 years ago that aneuploidy was due to an increase in centrosome number (multipolar mitoses and the resultant abnormal segregation of chromosomes. We performed immunocytochemistry, quantitative immunofluorescence, karyotypic analysis, and time-lapse microscopy on primary human diploid epithelial cells and fibroblasts to better understand the mechanism involved in the production of supernumerary centrosomes (more than two microtubule nucleating bodies to directly demonstrate that the presence of supernumerary centrosomes in genomically intact cells generates aneuploid daughter cells. We show that loss of p16(INK4a generates supernumerary centrosomes through centriole pair splitting. Generation of supernumerary centrosomes in human diploid epithelial cells was shown to nucleate multipolar spindles and directly drive production of aneuploid daughter cells as a result of unequal segregation of the genomic material during mitosis. Finally, we demonstrate that p16(INK4a cooperates with p21 through regulation of cyclin-dependent kinase activity to prevent centriole pair splitting. Cells with loss of p16(INK4a activity have been found in vivo in histologically normal mammary tissue from a substantial fraction of healthy, disease-free women. Demonstration of centrosome dysfunction in cells due to loss of p16(INK4a suggests that, under the appropriate conditions, these cells can become aneuploid. Gain or loss of genomic material (aneuploidy may provide the necessary proproliferation and antiapoptotic mechanisms needed for the earliest stages of tumorigenesis.

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

    Science.gov (United States)

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

    2017-10-15

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

  6. [Genomic instability in chidren born after the Chernobyl nuclear accident (in vivo and in vitro studies)].

    Science.gov (United States)

    Agadzhanian, A V; Suskov, I I

    2010-06-01

    Analysis of peripheral blood lymphocytes in children born after the accident at the Chernobyl Nuclear Power Plant in the period from 1987 to 2004 (permanent residents of territories contaminated with radionuclides, n = 92; and children of irradiated fathers-liquidators, n = 88)) revealed increased levels of aberrant cells (ACs) and aberrations of the chromosomal type as compared to the control (P or = 3%; children with medium AC frequencies, 2%; and children with low AC frequencies, > or = 1%), the levels of aberrations of the chromosomal type are increased as compared to the control (P or = 3% frequencies significantly differ from those in the subgroup of children with > or = 1% AC frequencies. No dependence of the AC and CA frequencies on the year of birth after the Chernobyl accident was revealed. After fractional and single gamma-irradiation (137Cs) of blood in vitro in the 10-30 cGy dose range, the average CA frequencies in the first and second mitoses increased in a similar way depending on the initial AC frequencies in the children and parents. All these results suggest an individual character ofgenomic instability induced by low radiation doses and its transgenerational phenomenon in the organisms of children.

  7. T-cell-specific deletion of Mof blocks their differentiation and results in genomic instability in mice.

    Science.gov (United States)

    Gupta, Arun; Hunt, Clayton R; Pandita, Raj K; Pae, Juhee; Komal, K; Singh, Mayank; Shay, Jerry W; Kumar, Rakesh; Ariizumi, Kiyoshi; Horikoshi, Nobuo; Hittelman, Walter N; Guha, Chandan; Ludwig, Thomas; Pandita, Tej K

    2013-05-01

    Ataxia telangiectasia patients develop lymphoid malignancies of both B- and T-cell origin. Similarly, ataxia telangiectasia mutated (Atm)-deficient mice exhibit severe defects in T-cell maturation and eventually develop thymomas. The function of ATM is known to be influenced by the mammalian orthologue of the Drosophila MOF (males absent on the first) gene. Here, we report the effect of T-cell-specific ablation of the mouse Mof (Mof) gene on leucocyte trafficking and survival. Conditional Mof(Flox/Flox) (Mof (F/F)) mice expressing Cre recombinase under control of the T-cell-specific Lck proximal promoter (Mof(F/F)/Lck-Cre(+)) display a marked reduction in thymus size compared with Mof(F/F)/Lck-Cre(-) mice. In contrast, the spleen size of Mof(F/F)/Lck-Cre(+) mice was increased compared with control Mof(F/F)/Lck-Cre(-) mice. The thymus of Mof(F/F)/Lck-Cre(+) mice contained significantly reduced T cells, whereas thymic B cells were elevated. Within the T-cell population, CD4(+)CD8(+) double-positive T-cell levels were reduced, whereas the immature CD4(-)CD8(-) double-negative (DN) population was elevated. Defective T-cell differentiation is also evident as an increased DN3 (CD44(-)CD25(+)) population, the cell stage during which T-cell receptor rearrangement takes place. The differentiation defect in T cells and reduced thymus size were not rescued in a p53-deficient background. Splenic B-cell distributions were similar between Mof(F/F)/Lck-Cre(+) and Mof(F/F)/Lck-Cre(-) mice except for an elevation of the κ light-chain population, suggestive of an abnormal clonal expansion. T cells from Mof(F/F)/Lck-Cre(+) mice did not respond to phytohaemagglutinin (PHA) stimulation, whereas LPS-stimulated B cells from Mof(F/F)/Lck-Cre(+) mice demonstrated spontaneous genomic instability. Mice with T-cell-specific loss of MOF had shorter lifespans and decreased survival following irradiation than did Mof(F/F)/Lck-Cre(-) mice. These observations suggest that Mof plays a critical

  8. 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

    ). In this study, we show that the localization of EXO1 to DSBs depends on both CtIP and MRN. We also establish that CtIP interacts with EXO1 and restrains its exonucleolytic activity in vitro. Finally, we show that on exposure to camptothecin, depletion of EXO1 in CtIP-deficient cells increases the frequency......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....

  9. Polytene chromosomes of Chironomidae (Diptera as a bioassay of trace-metal-induced genome instability

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    Paraskeva Vladimirova Michailova

    2012-10-01

    Full Text Available Chironomids are a ubiquitous group of aquatic insects that are very sensitive to environmental stress. Due to the presence of polytene (‘giant’ salivary gland chromosomes, it is possible to define the genome response of several Chironomid species to various stress agents. The aim of this study was to assess the genotoxic changes in populations of widely distributed chironomid species from aquatic basins in Bulgaria, Italy, Russia, U.K. and Poland, which were exposed to high concentrations of trace metals. We analyzed the structural and functional alterations of polytene chromosomes of the salivary glands of larvae belonging to three different cytocomplexes of the genus Chironomus (“thummi”, “lacunarius”, “pseudothummi”, and genera Glyptotendipes and Kiefferulus. Somatic structural chromosome rearrangements (para- and pericentric heterozygous inversions, deletions, deficiencies and amplifications were used to estimate a Somatic index (S for each population. The highest S indexes were detected in Chironomus riparius populations from locations with high concentrations of trace metals in the sediment. Each species showed specific genome responses to stress agents which we discussed in the light of the specific DNA structures and cytogenetic characteristics of the species. In larvae from polluted sediments two key structures of the salivary gland chromosomes (Balbiani Rings and Nucleolar Organizer sharply reduced their activity to levels below those observed under non-polluted conditions. It is concluded that polytene chromosomes can be used as tools for evaluating the genotoxicity of the aquatic environment. Structural and functional chromosome alterations provide cost-effective early-warning signals of genotoxic concentrations of environmental pollutants.doi: 10.5324/fn.v31i0.1355.Published online: 17 October 2012.

  10. 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.

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

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    Diletta Edifizi

    2017-11-01

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

  12. 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.

  13. The RNA binding protein RNPS1 alleviates ASF/SF2 depletion-induced genomic instability.

    Science.gov (United States)

    Li, Xialu; Niu, Tianhui; Manley, James L

    2007-12-01

    Formation of transcription-induced R-loops poses a critical threat to genomic integrity throughout evolution. We have recently shown that the SR protein ASF/SF2 prevents R-loop formation in vertebrates by cotranscriptionally binding to nascent mRNA precursors to prevent their reassociation with template DNA. Here, we identify another RNA binding protein, RNPS1, that when overexpressed strongly suppresses the high molecular weight (HMW) DNA fragmentation, hypermutation, and G2 cell cycle arrest phenotypes of ASF/SF2-depleted cells. Furthermore, ablation of RNPS1 by RNA interference in HeLa cells leads to accumulation of HMW DNA fragments. As ASF/SF2 depletion does not influence RNPS1 expression, and RNPS1 cannot compensate for ASF/SF2 function in splicing, our data suggest that RNPS1 is able to function together with ASF/SF2 to form RNP complexes on nascent transcripts, and thereby prevent formation of transcriptional R-loops.

  14. A germline polymorphism of DNA polymerase beta induces genomic instability and cellular transformation.

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    Jennifer Yamtich

    Full Text Available Several germline single nucleotide polymorphisms (SNPs have been identified in the POLB gene, but little is known about their cellular and biochemical impact. DNA Polymerase β (Pol β, encoded by the POLB gene, is the main gap-filling polymerase involved in base excision repair (BER, a pathway that protects the genome from the consequences of oxidative DNA damage. In this study we tested the hypothesis that expression of the POLB germline coding SNP (rs3136797 in mammalian cells could induce a cancerous phenotype. Expression of this SNP in both human and mouse cells induced double-strand breaks, chromosomal aberrations, and cellular transformation. Following treatment with an alkylating agent, cells expressing this coding SNP accumulated BER intermediate substrates, including single-strand and double-strand breaks. The rs3136797 SNP encodes the P242R variant Pol β protein and biochemical analysis showed that P242R protein had a slower catalytic rate than WT, although P242R binds DNA similarly to WT. Our results suggest that people who carry the rs3136797 germline SNP may be at an increased risk for cancer susceptibility.

  15. Genome instability and epigenetic modification--heritable responses to environmental stress?

    Science.gov (United States)

    Boyko, Alex; Kovalchuk, Igor

    2011-06-01

    As sessile organisms, plants need to continuously adjust their responses to external stimuli to cope with changing growth conditions. Since the seed dispersal range is often rather limited, exposure of progeny to the growth conditions of parents is very probable. The plasticity of plant phenotypes cannot be simply explained by genetic changes such as point mutations, deletions, insertions and gross chromosomal rearrangements. Since many environmental stresses persist for only one or several plant generations, other mechanisms of adaptation must exist. The heritability of reversible epigenetic modifications that regulate gene expression without changing DNA sequence makes them an attractive alternative mechanism. In this review, we discuss recent advances in understanding how changes in genome stability and epigenetically mediated changes in gene expression could contribute to plant adaptation. We provide examples of environmentally induced transgenerational epigenetic effects that include the appearance of new phenotypes in successive generations of stressed plants. We also describe several cases in which exposure to stress leads to nonrandom heritable but reversible changes in stress tolerance in the progeny of stressed plants. Copyright © 2011 Elsevier Ltd. All rights reserved.

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

    Science.gov (United States)

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

    2017-09-11

    Germline mutations in ATM (encoding the DNA-damage signaling kinase, ataxia-telangiectasia-mutated) increase Familial Pancreatic Cancer (FPC) susceptibility, and ATM somatic mutations have been identified in resected human pancreatic tumors. Here we investigated how Atm contributes to pancreatic cancer by deleting this gene in a murine model of the disease expressing oncogenic Kras (KrasG12D). We show that partial or total ATM deficiency cooperates with KrasG12D to promote highly metastatic pancreatic cancer. We also reveal that ATM is activated in pancreatic precancerous lesions in the context of DNA damage and cell proliferation, and demonstrate that ATM deficiency leads to persistent DNA damage in both precancerous lesions and primary tumors. Using low passage cultures from primary tumors and liver metastases we show that ATM loss accelerates Kras-induced carcinogenesis without conferring a specific phenotype to pancreatic tumors or changing the status of the tumor suppressors p53, p16Ink4a and p19Arf. However, ATM deficiency markedly increases the proportion of chromosomal alterations in pancreatic primary tumors and liver metastases. More importantly, ATM deficiency also renders murine pancreatic tumors highly sensitive to radiation. These and other findings in our study conclusively establish that ATM activity poses a major barrier to oncogenic transformation in the pancreas via maintaining genomic stability.

  17. 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.

  18. Multilevel genomics of colorectal cancers with microsatellite instability-clinical impact of JAK1 mutations and consensus molecular subtype 1.

    Science.gov (United States)

    Sveen, Anita; Johannessen, Bjarne; Tengs, Torstein; Danielsen, Stine A; Eilertsen, Ina A; Lind, Guro E; Berg, Kaja C G; Leithe, Edward; Meza-Zepeda, Leonardo A; Domingo, Enric; Myklebost, Ola; Kerr, David; Tomlinson, Ian; Nesbakken, Arild; Skotheim, Rolf I; Lothe, Ragnhild A

    2017-05-24

    Approximately 15% of primary colorectal cancers have DNA mismatch repair deficiency, causing a complex genome with thousands of small mutations-the microsatellite instability (MSI) phenotype. We investigated molecular heterogeneity and tumor immunogenicity in relation to clinical endpoints within this distinct subtype of colorectal cancers. A total of 333 primary MSI+ colorectal tumors from multiple cohorts were analyzed by multilevel genomics and computational modeling-including mutation profiling, clonality modeling, and neoantigen prediction in a subset of the tumors, as well as gene expression profiling for consensus molecular subtypes (CMS) and immune cell infiltration. Novel, frequent frameshift mutations in four cancer-critical genes were identified by deep exome sequencing, including in CRTC1, BCL9, JAK1, and PTCH1. JAK1 loss-of-function mutations were validated with an overall frequency of 20% in Norwegian and British patients, and mutated tumors had up-regulation of transcriptional signatures associated with resistance to anti-PD-1 treatment. Clonality analyses revealed a high level of intra-tumor heterogeneity; however, this was not associated with disease progression. Among the MSI+ tumors, the total mutation load correlated with the number of predicted neoantigens (P = 4 × 10(-5)), but not with immune cell infiltration-this was dependent on the CMS class; MSI+ tumors in CMS1 were highly immunogenic compared to MSI+ tumors in CMS2-4. Both JAK1 mutations and CMS1 were favorable prognostic factors (hazard ratios 0.2 [0.05-0.9] and 0.4 [0.2-0.9], respectively, P = 0.03 and 0.02). Multilevel genomic analyses of MSI+ colorectal cancer revealed molecular heterogeneity with clinical relevance, including tumor immunogenicity and a favorable patient outcome associated with JAK1 mutations and the transcriptomic subgroup CMS1, emphasizing the potential for prognostic stratification of this clinically important subtype. See related research highlight

  19. 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.

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

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    Marta Viana-Pereira

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

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

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    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. 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.

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

    Science.gov (United States)

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

    2017-10-01

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

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

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    Ulises Urzúa

    2016-10-01

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

  5. 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.

  6. Comments on Rithidech, K.N.; et al. Lack of Genomic Instability in Bone Marrow Cells of SCID Mice Exposed Whole-Body to Low-Dose Radiation. Int. J. Environ. Res. Public Health 2013, 10, 1356–1377

    Directory of Open Access Journals (Sweden)

    Keith Baverstock

    2013-07-01

    Full Text Available I would like to take issue with Rithidech et al., authors of the paper entitled “Lack of genomic instability in mice at low doses” [1] who claim to have shown that their results on the measurement of late occurring chromosome aberrations after irradiation of SCID mice with X-rays show that lower doses (0.05 Gy do not induce genomic instability. Their earlier work at higher doses (0.1 and 1.0 Gy on the same strain of mouse indicated that de novo chromosome aberrations were detected at 6 months post-irradiation. This was taken, almost certainly correctly, to be an indication of the presence of genomic instability: late appearing chromosome damage, as the authors note, seems to be a reliable indicator of the process. The lack of de novo chromosome aberrations at 6 months post-irradiation, however, cannot be taken as evidence of the absence of genomic instability. In drawing their conclusion of a “lack of genomic instability ….” the authors have committed two category errors.

  7. Oligodeoxynucleotide binding to (CTG) · (CAG) microsatellite repeats inhibits replication fork stalling, hairpin formation, and genome instability.

    Science.gov (United States)

    Liu, Guoqi; Chen, Xiaomi; Leffak, Michael

    2013-02-01

    (CTG)(n) · (CAG)(n) trinucleotide repeat (TNR) expansion in the 3' untranslated region of the dystrophia myotonica protein kinase (DMPK) gene causes myotonic dystrophy type 1. However, a direct link between TNR instability, the formation of noncanonical (CTG)(n) · (CAG)(n) structures, and replication stress has not been demonstrated. In a human cell model, we found that (CTG)(45) · (CAG)(45) causes local replication fork stalling, DNA hairpin formation, and TNR instability. Oligodeoxynucleotides (ODNs) complementary to the (CTG)(45) · (CAG)(45) lagging-strand template eliminated DNA hairpin formation on leading- and lagging-strand templates and relieved fork stalling. Prolonged cell culture, emetine inhibition of lagging-strand synthesis, or slowing of DNA synthesis by low-dose aphidicolin induced (CTG)(45) · (CAG)(45) expansions and contractions. ODNs targeting the lagging-strand template blocked the time-dependent or emetine-induced instability but did not eliminate aphidicolin-induced instability. These results show directly that TNR replication stalling, replication stress, hairpin formation, and instability are mechanistically linked in vivo.

  8. The Roles of Chromosome Breaks and Telomere Dynamics in the Genomic Instability Associated With Human Breast Cancer

    National Research Council Canada - National Science Library

    Wilson, John

    1998-01-01

    .... Loss of telomeres allows chromosomes to fuse end-to-end, triggering chromosome fusion- bridge-breakage cycles that lead to genome rearrangements, loss of heterozygosity, and gene amplification...

  9. The Roles of Chromosome Breaks and Telomere Dynamics in the Genomic Instability Associated with Human Breast Cancer

    National Research Council Canada - National Science Library

    Wilson, John

    2000-01-01

    ... of telomeres from chromosome ends. Loss of telomeres allows chromosomes to fuse end-to-end, triggering chromosome fusion-bridge-breakage cycles that lead to genome rearrangements, loss of heterozygosity, and gene amplification...

  10. 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.

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

    Directory of Open Access Journals (Sweden)

    Wei Dai

    2009-12-01

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

  12. An array CGH based genomic instability index (G2I is predictive of clinical outcome in breast cancer and reveals a subset of tumors without lymph node involvement but with poor prognosis

    Directory of Open Access Journals (Sweden)

    Bonnet Françoise

    2012-11-01

    Full Text Available Abstract Background Despite entering complete remission after primary treatment, a substantial proportion of patients with early stage breast cancer will develop metastases. Prediction of such an outcome remains challenging despite the clinical use of several prognostic parameters. Several reports indicate that genomic instability, as reflected in specific chromosomal aneuploidies and variations in DNA content, influences clinical outcome but no precise definition of this parameter has yet been clearly established. Methods To explore the prognostic value of genomic alterations present in primary tumors, we performed a comparative genomic hybridization study on BAC arrays with a panel of breast carcinomas from 45 patients with metastatic relapse and 95 others, matched for age and axillary node involvement, without any recurrence after at least 11 years of follow-up. Array-CGH data was used to establish a two-parameter index representative of the global level of aneusomy by chromosomal arm, and of the number of breakpoints throughout the genome. Results Application of appropriate thresholds allowed us to distinguish three classes of tumors highly associated with metastatic relapse. This index used with the same thresholds on a published set of tumors confirms its prognostic significance with a hazard ratio of 3.24 [95CI: 1.76-5.96] p = 6.7x10-5 for the bad prognostic group with respect to the intermediate group. The high prognostic value of this genomic index is related to its ability to individualize a specific group of breast cancers, mainly luminal type and axillary node negative, showing very high genetic instability and poor outcome. Indirect transcriptomic validation was obtained on independent data sets. Conclusion Accurate evaluation of genetic instability in breast cancers by a genomic instability index (G2I helps individualizing specific tumors with previously unexpected very poor prognosis.

  13. 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

  14. Extract of bulbus Fritillaria cirrhosa perturbs spindle assembly checkpoint, induces mitotic aberrations and genomic instability in human colon epithelial cell line.

    Science.gov (United States)

    Guo, Xihan; Ni, Juan; Xue, Jinglun; Wang, Xu

    2017-03-02

    Bulbus Fritillaria cirrhosa D. Don (BFC) has been used in China as a folk medicine for the treatment of cough and asthma for more than 2000 years. The antitussive and antiasthmatic effects of BFC have been reported before, nevertheless its toxicity and safety have not been documented. This study investigated the possible effects of BFC on spindle assembly checkpoint (SAC), mitotic fidelity and genomic stability in human NCM460 colon epithelial cells. Cells were treated with BFC (0, 20, 40, 80 and 160μg/ml) for 24, 48 and 72h and harvested differently according to the biomarkers observed. Mitotic aberrations were assessed by the biomarkers of chromosome misalignment (CMA), chromosome lagging (CL) and chromatin bridge (CB). Frequencies of micronuclei (MN), nucleoplasmic bridge and nuclear bud (NB) in cytokinesis-block micronucleus assay were used as indicators of genomic instability (GIN). SAC activity was determined by anaphase to metaphase ratio (AMR) and the expression of several SAC genes, including CENP-E, Mps1, Bub1, Mad-1, BubR1 and Mad-2. Compared with the control, cells in BFC treated groups (80 and 160μg/ml) showed: 1) increased AMR (pMps1, Bub1 and Mad-1 (p<0.05) and down-regulated expression of CENP-E, BubR1 and Mad-2 (p<0.05); 2) increased frequencies of CMA, CL and CB (p<0.01); 3) increased incidences of MN and NB (p<0.01). This study revealed for the first time that BFC causes mitotic aberrations and GIN in human colon epithelial cells and these effects maybe the result of SAC dysfunction. Copyright © 2017 Elsevier GmbH. All rights reserved.

  15. Common chromosome fragile sites in human and murine epithelial cells and FHIT/FRA3B loss-induced global genome instability.

    Science.gov (United States)

    Hosseini, Seyed Ali; Horton, Susan; Saldivar, Joshua C; Miuma, Satoshi; Stampfer, Martha R; Heerema, Nyla A; Huebner, Kay

    2013-11-01

    Chromosomal positions of common fragile sites differ in lymphoblasts and fibroblasts, with positions dependent on the epigenetically determined density of replication origins at these loci. Because rearrangement of fragile loci and associated loss of fragile gene products are hallmarks of cancers, we aimed to map common fragile sites in epithelial cells, from which most cancers derive. Among the five most frequently activated sites in human epithelial cells were chromosome bands 2q33 and Xq22.1, which are not among top fragile sites identified in lymphoblasts or fibroblasts. FRA16D at 16q23 was among the top three fragile sites in the human epithelial cells examined, as it is in lymphoblasts and fibroblasts, while FRA3B at 3p14.2, the top fragile locus in lymphoblasts, was not fragile in most epithelial cell lines tested. Epithelial cells exhibited varying hierarchies of fragile sites; some frequent epithelial cell fragile sites are apparently not frequently altered in epithelial cancers and sites that are frequently deleted in epithelial cancers are not necessarily among the most fragile. Since we have reported that loss of expression of the FRA3B-encoded FHIT protein causes increased replication stress-induced DNA damage, we also examined the effect of FHIT-deficiency on markers of genome instability in epithelial cells. FHIT-deficient cells exhibited increases in fragile breaks and in γH2AX and 53BP1 foci in G1 phase cells, confirming in epithelial cells that the FHIT gene and encompassing FRA3B, is a "caretaker gene" necessary for maintenance of genome stability. © 2013 Wiley Periodicals, Inc.

  16. N-methyl-N'-nitro-N-nitrosoguanidine induces and cooperates with 12-O-tetradecanoylphorbol-1,3-acetate/sodium butyrate to enhance Epstein-Barr virus reactivation and genome instability in nasopharyngeal carcinoma cells.

    Science.gov (United States)

    Huang, Sheng-Yen; Fang, Chih-Yeu; Tsai, Ching-Hwa; Chang, Yao; Takada, Kenzo; Hsu, Tsuey-Ying; Chen, Jen-Yang

    2010-12-05

    Seroepidemiological studies implicate a correlation between Epstein-Barr virus (EBV) reactivation and the development of nasopharyngeal carcinoma (NPC). Moreover, N-nitroso compounds are known chemical carcinogens in preserved foodstuffs and cigarettes and have been implicated as risk factors contributing to the development of NPC. Here, NPC cell lines latently infected with EBV, NA and HA, and the corresponding EBV-negative NPC cell lines, NPC-TW01 and HONE-1, were used as the model system in this study. We demonstrate that the reactivation of EBV increases with increasing concentrations of N-methyl-N'-nitro-N-nitrosoguanidine (MNNG). MNNG at a single non-toxic concentration (0.1μg/ml) did not induce discernible reactivation of EBV, but repeated treatment with this concentration of MNNG significantly induced viral reactivation. Furthermore, low dose MNNG (0.1μg/ml) had a synergistic effect with 12-O-tetradecanoylphorbol-1,3-acetate (TPA)/sodium butyrate (SB) (10ng/ml and 0.75mM, respectively) on EBV reactivation. Through promoter activity assay, MNNG was found to enhance the transcriptional activity of Rta on Rta and Zta promoters. Using siZta to block EBV reactivation, the concomitant induction of genome instability was diminished indicating that reactivation is critical for enhancing genome instability. Co-treatment with TPA/SB and MNNG markedly increased the levels of γH2AX and ROS formation in NPC cells, which may be responsible for the increase of genome instability. Our findings offer a possible mechanism by which N-nitroso compounds induce reactivation of EBV and contribute to malignant progression by enhancing genome instability in NPC cells. Copyright © 2010 Elsevier Ireland Ltd. All rights reserved.

  17. The effect of growth architecture on the induction and decay of bleomycin and X-ray-induced bystander response and genomic instability in lung adenocarcinoma cells and blood lymphocytes.

    Science.gov (United States)

    Chinnadurai, Mani; Paul, Solomon F D; Venkatachalam, Perumal

    2013-02-01

    Cancer patients treated with radiomimetic drug bleomycin (BLM) have shown incidence of 7% second malignancy. Studies regarding BLM-induced genomic instability in bystander cells are scarce, and experiments with cells grown on three-dimensional (3D) cultures to mimic the in-vivo condition have never been attempted. A549 and NCI-H23 (human lung adenocarcinoma) cells were grown as 3D cultures using Cytomatrix(™), exposed to BLM or X-radiation and co-cultured with their respective unexposed cells. The DNA damage in direct and bystander cells were assessed by the induction of micronuclei (MN) or phosphorylated serine-15 residue in protein 53 (p53(ser-15)), a reflection of DNA damage, and by up-regulation of protein 21 (p21Waf1). The persistence of DNA damage was measured using MN assay and fluorescence in situ hybridization (FISH) in cancer cells and human peripheral blood lymphocytes (PBL) respectively. BLM or X-irradiation induced DNA damage in both A549 and NCI-H23 cells and their respective bystander cells grown in 2D or 3D cultures. Further persistence of these damages in bystander PBL at delayed times indicated genomic instability in these cells. BLM-induced genomic instability in the progeny of bystander cells and their significance in therapy-induced second malignancy may not be eliminated completely.

  18. Influence of the antifolate drug Methotrexate on the development of murine neural tube defects and genomic instability.

    Science.gov (United States)

    Zhao, Jie; Guan, Tao; Wang, Jianhua; Xiang, Qian; Wang, Mingsheng; Wang, Xiuwei; Guan, Zhen; Xie, Qiu; Niu, Bo; Zhang, Ting

    2013-09-01

    Impaired folate metabolism is considered a risk factor for neural tube defects (NTDs). However, the relationship between folate deficiency and the risk of NTDs remains unclear, because experimentally induced dietary folate deficiency is insufficient to cause NTDs in non-mutant mice. Methotrexate (MTX) is a specific folate antagonist that competitively inhibits dihydrofolate reductase (DHFR) activity. The objective of this study was to develop a folate dysmetabolism murine model, and study the development of NTDs and its mechanism. Pregnant mice were injected with different doses of MTX [0, 0.5, 1.0, 3.0, 4.5 and 6.0 mg kg(-1) body weight (b/w) intraperitoneally (i.p.)] on gestational day 7.5 and sacrificed on gestational day 11.5. DHFR activity in embryonic tissues was detected, and folate concentrations were analyzed using LC/MS/MS. Copy number variations (CNVs) in neural tube tissues were detected using array comparative genomic hybridization (aCGH). A dose of MTX 4.5 mg kg(-1) b/w, resulted in the highest incidence of NTDs (31.4%) compared with the other groups, and DHFR activities, 5-MeTHF and 5-FoTHF concentrations in embryonic tissues decreased significantly after MTX injection. Furthermore, we found three high-confidence CNVs on chromosome X using aCGH, which was confirmed by RT-PCR and MassARRAY. These results indicate that MTX could cause a folate-associated dysmetabolism, which is similar to that of dietary folate deficiency in mice. The presence of CNVs in neural tube tissues was associated with the development of NTDs. Copyright © 2012 John Wiley & Sons, Ltd.

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

    Energy Technology Data Exchange (ETDEWEB)

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

    2011-04-08

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

  20. 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.)

  1. 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

  2. Shoulder Instability

    Science.gov (United States)

    ... Causes & Risk FactorsIs shoulder instability the same as shoulder dislocation?No. The signs of dislocation and instability might ... the same to you–weakness and pain. However, dislocation occurs when your shoulder goes completely out of place. The shoulder ligaments ...

  3. Alpha-Particle-Induced Complex Chromosome Exchanges Transmitted through Extra-Thymic Lymphopoiesis In Vitro Show Evidence of Emerging Genomic Instability.

    Directory of Open Access Journals (Sweden)

    Natalia Sumption

    Full Text Available Human exposure to high-linear energy transfer α-particles includes environmental (e.g. radon gas and its decay progeny, medical (e.g. radiopharmaceuticals and occupational (nuclear industry sources. The associated health risks of α-particle exposure for lung cancer are well documented however the risk estimates for leukaemia remain uncertain. To further our understanding of α-particle effects in target cells for leukaemogenesis and also to seek general markers of individual exposure to α-particles, this study assessed the transmission of chromosomal damage initially-induced in human haemopoietic stem and progenitor cells after exposure to high-LET α-particles. Cells surviving exposure were differentiated into mature T-cells by extra-thymic T-cell differentiation in vitro. Multiplex fluorescence in situ hybridisation (M-FISH analysis of naïve T-cell populations showed the occurrence of stable (clonal complex chromosome aberrations consistent with those that are characteristically induced in spherical cells by the traversal of a single α-particle track. Additionally, complex chromosome exchanges were observed in the progeny of irradiated mature T-cell populations. In addition to this, newly arising de novo chromosome aberrations were detected in cells which possessed clonal markers of α-particle exposure and also in cells which did not show any evidence of previous exposure, suggesting ongoing genomic instability in these populations. Our findings support the usefulness and reliability of employing complex chromosome exchanges as indicators of past or ongoing exposure to high-LET radiation and demonstrate the potential applicability to evaluate health risks associated with α-particle exposure.

  4. SUMO-targeted ubiquitin ligase activity can either suppress or promote genome instability, depending on the nature of the DNA lesion.

    Directory of Open Access Journals (Sweden)

    Minghua Nie

    2017-05-01

    Full Text Available The posttranslational modifiers SUMO and ubiquitin critically regulate the DNA damage response (DDR. Important crosstalk between these modifiers at DNA lesions is mediated by the SUMO-targeted ubiquitin ligase (STUbL, which ubiquitinates SUMO chains to generate SUMO-ubiquitin hybrids. These SUMO-ubiquitin hybrids attract DDR proteins able to bind both modifiers, and/or are degraded at the proteasome. Despite these insights, specific roles for SUMO chains and STUbL in the DDR remain poorly defined. Notably, fission yeast defective in SUMO chain formation exhibit near wild-type resistance to genotoxins and moreover, have a greatly reduced dependency on STUbL activity for DNA repair. Based on these and other data, we propose that a critical role of STUbL is to antagonize DDR-inhibitory SUMO chain formation at DNA lesions. In this regard, we identify a SUMO-binding Swi2/Snf2 translocase called Rrp2 (ScUls1 as a mediator of the DDR defects in STUbL mutant cells. Therefore, in support of our proposal, SUMO chains attract activities that can antagonize STUbL and other DNA repair factors. Finally, we find that Taz1TRF1/TRF2-deficiency triggers extensive telomeric poly-SUMOylation. In this setting STUbL, together with its cofactor Cdc48p97, actually promotes genomic instability caused by the aberrant processing of taz1Δ telomeres by DNA repair factors. In summary, depending on the nature of the initiating DNA lesion, STUbL activity can either be beneficial or harmful.

  5. Genomic Instability and Breast Cancer

    Science.gov (United States)

    2009-10-01

    activity in Xenopus eggs . Mol. Biol. Cell 9, 1847–1861 (1998). 30. McNally, K., Audhya, A., Oegema, K. & McNally, F. J. Katanin controls mitotic and...17 18 20 22 24 26 28 30 32 33 34 35 36 38 40 42 44 46 48 Blue dextran (2MDa) Ferritin (440kDa) Catalase (232kDa) Albumin (43kDa) G H I His-Flag-BRCA1...2 Serum albumin precursor 2 Signal recognition particle 14 kda protein 2 3

  6. Genomic Instability and Breast Cancer

    Science.gov (United States)

    2007-10-01

    cancer related proteins. 293T cells were transfected respectively with constructs encoding triple tagged (SFB- tagged) Cockayne syndrome protein 1 (CKN1...checkpoint protein 1 (MDC1), Nijmegen break- age syndrome 1 (NBS1), BRCA1, and checkpoint kinases 1 and 2 (Chk1 and Chk2)] are involved in the ionizing...this surveillance system has been demonstrated by the finding that inactivation of the DNA damage response can lead to cancer-susceptibility syndromes

  7. Genomic Instability and Breast Cancer

    Science.gov (United States)

    2011-06-01

    domains. The accession numbers of SWI5 orthologues are: NP_001035100.1 for Homo sapiens , XP_001144446.1 for Pan troglodytes, NP_780399.1 for Mus musculus...siRNA Control #6 Control #6 Control #6 RPA2 DAPI Vector Homo sapiens (1–954) Pan troglodytes (1–954) Canis familiaris (1–961) Bos taurus (1–941) Mus...Schizosaccharomyces pombe, and NP_011947.2 for Saccharomyces cerevisiae. The accession numbers of MEI5 orthologues are: NP_660290.3 for H. sapiens , XP_001135759.1 for P

  8. Genome instability in Alzheimer disease

    DEFF Research Database (Denmark)

    Hou, Yujun; Song, Hyundong; Croteau, Deborah L

    2017-01-01

    Alzheimer's disease (AD) is a progressive neurodegenerative disorder and the most common form of dementia. Autosomal dominant, familial AD (fAD) is very rare and caused by mutations in amyloid precursor protein (APP), presenilin-1 (PSEN-1), and presenilin-2 (PSEN-2) genes. The pathogenesis...

  9. Shoulder instability

    African Journals Online (AJOL)

    2011-09-02

    Sep 2, 2011 ... Honorary Consultant, Shoulder and Elbow Unit, Department of Orthopaedic Surgery, University of Cape Town. Basil Vrettos is a shoulder ... Head, Shoulder and Elbow Unit, Princess Alice Orthopaedic Unit, Groote Schuur Hospital. Steve Roche heads ..... tidirectional instability is physiotherapy. • Surgery for ...

  10. Chromium and Genomic Stability

    Science.gov (United States)

    Wise, Sandra S.; Wise, John Pierce

    2014-01-01

    Many metals serve as micronutrients which protect against genomic instability. Chromium is most abundant in its trivalent and hexavalent forms. Trivalent chromium has historically been considered an essential element, though recent data indicate that while it can have pharmacological effects and value, it is not essential. There are no data indicating that trivalent chromium promotes genomic stability and, instead may promote genomic instability. Hexavalent chromium is widely accepted as highly toxic and carcinogenic with no nutritional value. Recent data indicate that it causes genomic instability and also has no role in promoting genomic stability. PMID:22192535

  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. Factor-induced Reprogramming and Zinc Finger Nuclease-aided Gene Targeting Cause Different Genome Instability in β-Thalassemia Induced Pluripotent Stem Cells (iPSCs)*

    Science.gov (United States)

    Ma, Ning; Shan, Yongli; Liao, Baojian; Kong, Guanyi; Wang, Cheng; Huang, Ke; Zhang, Hui; Cai, Xiujuan; Chen, Shubin; Pei, Duanqing; Chen, Nansheng; Pan, Guangjin

    2015-01-01

    The generation of personalized induced pluripotent stem cells (iPSCs) followed by targeted genome editing provides an opportunity for developing customized effective cellular therapies for genetic disorders. However, it is critical to ascertain whether edited iPSCs harbor unfavorable genomic variations before their clinical application. To examine the mutation status of the edited iPSC genome and trace the origin of possible mutations at different steps, we have generated virus-free iPSCs from amniotic cells carrying homozygous point mutations in β-hemoglobin gene (HBB) that cause severe β-thalassemia (β-Thal), corrected the mutations in both HBB alleles by zinc finger nuclease-aided gene targeting, and obtained the final HBB gene-corrected iPSCs by excising the exogenous drug resistance gene with Cre recombinase. Through comparative genomic hybridization and whole-exome sequencing, we uncovered seven copy number variations, five small insertions/deletions, and 64 single nucleotide variations (SNVs) in β-Thal iPSCs before the gene targeting step and found a single small copy number variation, 19 insertions/deletions, and 340 single nucleotide variations in the final gene-corrected β-Thal iPSCs. Our data revealed that substantial but different genomic variations occurred at factor-induced somatic cell reprogramming and zinc finger nuclease-aided gene targeting steps, suggesting that stringent genomic monitoring and selection are needed both at the time of iPSC derivation and after gene targeting. PMID:25795783

  13. Chromium and Genomic Stability

    OpenAIRE

    Wise, Sandra S.; Wise, John Pierce

    2011-01-01

    Many metals serve as micronutrients which protect against genomic instability. Chromium is most abundant in its trivalent and hexavalent forms. Trivalent chromium has historically been considered an essential element, though recent data indicate that while it can have pharmacological effects and value, it is not essential. There are no data indicating that trivalent chromium promotes genomic stability and, instead may promote genomic instability. Hexavalent chromium is widely accepted as high...

  14. Yeast Assay Highlights the Intrinsic Genomic Instability of Human PML Intron 6 over Intron 3 and the Role of Replication Fork Proteins.

    Directory of Open Access Journals (Sweden)

    Roland Chanet

    Full Text Available Human acute promyelocytic leukemia (APL is characterized by a specific balanced translocation t(15;17(q22;q21 involving the PML and RARA genes. In both de novo and therapy-related APL, the most frequent PML breakpoints are located within intron 6, and less frequently in intron 3; the precise mechanisms by which these breakpoints arise and preferentially in PML intron 6 remain unsolved. To investigate the intrinsic properties of the PML intron sequences in vivo, we designed Saccharomyces cerevisiae strains containing human PML intron 6 or intron 3 sequences inserted in yeast chromosome V and measured gross chromosomal rearrangements (GCR. This approach provided evidence that intron 6 had a superior instability over intron 3 due to an intrinsic property of the sequence and identified the 3' end of intron 6 as the most susceptible to break. Using yeast strains invalidated for genes that control DNA replication, we show that this differential instability depended at least upon Rrm3, a DNA helicase, and Mrc1, the human claspin homolog. GCR induction by hydrogen peroxide, a general genotoxic agent, was also dependent on genetic context. We conclude that: 1 this yeast system provides an alternative approach to study in detail the properties of human sequences in a genetically controlled situation and 2 the different susceptibility to produce DNA breaks in intron 6 versus intron 3 of the human PML gene is likely due to an intrinsic property of the sequence and is under replication fork genetic control.

  15. 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

  16. Electron heat flux instability

    Science.gov (United States)

    Saeed, Sundas; Sarfraz, M.; Yoon, P. H.; Lazar, M.; Qureshi, M. N. S.

    2017-02-01

    The heat flux instability is an electromagnetic mode excited by a relative drift between the protons and two-component core-halo electrons. The most prominent application may be in association with the solar wind where drifting electron velocity distributions are observed. The heat flux instability is somewhat analogous to the electrostatic Buneman or ion-acoustic instability driven by the net drift between the protons and bulk electrons, except that the heat flux instability operates in magnetized plasmas and possesses transverse electromagnetic polarization. The heat flux instability is also distinct from the electrostatic counterpart in that it requires two electron species with relative drifts with each other. In the literature, the heat flux instability is often called the 'whistler' heat flux instability, but it is actually polarized in the opposite sense to the whistler wave. This paper elucidates all of these fundamental plasma physical properties associated with the heat flux instability starting from a simple model, and gradually building up more complexity towards a solar wind-like distribution functions. It is found that the essential properties of the instability are already present in the cold counter-streaming electron model, and that the instability is absent if the protons are ignored. These instability characteristics are highly reminiscent of the electron firehose instability driven by excessive parallel temperature anisotropy, propagating in parallel direction with respect to the ambient magnetic field, except that the free energy source for the heat flux instability resides in the effective parallel pressure provided by the counter-streaming electrons.

  17. TIN: An R Package for Transcriptome Instability Analysis.

    Science.gov (United States)

    Johannessen, Bjarne; Sveen, Anita; Skotheim, Rolf I

    2015-01-01

    Alternative splicing is a key regulatory mechanism for gene expression, vital for the proper functioning of eukaryotic cells. Disruption of normal pre-mRNA splicing has the potential to cause and reinforce human disease. Owing to rapid advances in high-throughput technologies, it is now possible to identify novel mRNA isoforms and detect aberrant splicing patterns on a genome scale, across large data sets. Analogous to the genomic types of instability describing cancer genomes (eg, chromosomal instability and microsatellite instability), transcriptome instability (TIN) has recently been proposed as a splicing-related genome-wide characteristic of certain solid cancers. We present the R package TIN, available from Bioconductor, which implements a set of methods for TIN analysis based on exon-level microarray expression profiles. TIN provides tools for estimating aberrant exon usage across samples and for analyzing correlation patterns between TIN and splicing factor expression levels.

  18. Evaluating shoulder instability treatment

    NARCIS (Netherlands)

    van der Linde, J.A.

    2016-01-01

    Shoulder instability common occurs. When treated nonoperatively, the resulting societal costs based on health care utilization and productivity losses are significant. Shoulder function can be evaluated using patient reported outcome measurements (PROMs). For shoulder instability, these include the

  19. Response to Baverstock, K. Comments on Rithidech, K.N.; et al. Lack of Genomic Instability in Bone Marrow Cells of SCID Mice Exposed Whole-Body to Low-Dose Radiation. Int. J. Environ. Res. Public Health 2013, 10, 1356–1377.

    Directory of Open Access Journals (Sweden)

    Elbert Whorton

    2013-07-01

    Full Text Available We thank Dr. Baverstock [1] for his interest in reading our article and his time in writing his comments for our work [2]. We, however, respectfully disagree with his statement that we made “two category errors” associated with the assessment of the occurrence of “genomic instability” by determining the frequencies of delayed- or late-occurring chromosomal damage. Our disagreement is based upon the well-known fact that radiation-induced genomic instability (or delayed/late-occurring damage can be manifested in many ways. These include late-occurring chromosomal damage, or mutations, or gene expression, or gene amplifications, or transformation, or microsatellite instability, or cell killing [3–9]. Such phenomena have been detected many cell generations after irradiation. We agree that genomic instability may well be the consequence of epigenetic changes. Another mechanism mentioned by Dr. Bavertock as being probably unlikely is the reversibility of damage. This potential may not be discarded off-hand, as Dr. Baverstock prefers to do. There is much reproducible evidence of adaptive protection that depending on absorbed dose precisely may reverse early damage, and damage appearing late may be due to some form of residual damage letting the cell become genetically unstable. In other words, the argument by Dr. Baverstock regarding upward or downward causation appears to be rather speculative and far from being settled.

  20. 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.

  1. 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.

  2. Shoulder instability; Schulterinstabilitaeten

    Energy Technology Data Exchange (ETDEWEB)

    Kreitner, Karl-Friedrich [Mainiz Univ. (Germany). Klinik und Poliklinik fuer Diagnostische und Interventionelle Radiologie

    2014-06-15

    In the shoulder, the advantages of range of motion are traded for the disadvantages of vulnerability to injury and the development of instability. Shoulder instability and the lesion it produces represent one of the main causes of shoulder discomfort and pain. Shoulder instability is defined as a symptomatic abnormal motion of the humeral head relative to the glenoid during active shoulder motion. Glenohumeral instabilities are classified according to their causative factors as the pathogenesis of instability plays an important role with respect to treatment options: instabilities are classified in traumatic and atraumatic instabilities as part of a multidirectional instability syndrome, and in microtraumatic instabilities. Plain radiographs ('trauma series') are performed to document shoulder dislocation and its successful reposition. Direct MR arthrography is the most important imaging modality for delineation the different injury patterns on the labral-ligamentous complex and bony structures. Monocontrast CT-arthrography with use of multidetector CT scanners may be an alternative imaging modality, however, regarding the younger patient age, MR imaging should be preferred in the diagnostic work-up of shoulder instabilities. (orig.)

  3. 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...... of the specimens was recorded. The reproducibility of the instability pattern suggests that this model is suitable for evaluating stabilizing procedures aimed at correction of elbow joint instability before these procedures are introduced into patient care....

  4. Lecture on beam instabilities

    Energy Technology Data Exchange (ETDEWEB)

    Chao, A.

    1999-12-21

    These lectures treat some of the common collective beam instability effects encountered in accelerators. In choosing the material for these lectures, it is attempted to introduce this subject with a more practical approach, instead of a more theoretical approach starting with first principles. After introducing the terminologies, emphasis will be placed on how to apply the lecture material to perform calculations and to make estimates of various instability effects. In the first half of the lectures, after briefly introducing the concepts of impedance and wake field, the authors will discuss a selected list of formulas for the impedances of various accelerator components. Detailed derivations are omitted, allowing time for the students to think through the process of how to apply the knowledge learned. The list of impedances to be covered include: space charge, resistive wall, resonator, wall roughness, and small perturbation on the vacuum chamber wall. Assuming impedances are known, the second half of the lectures addresses the question of how to calculate the power of beam heating, the growth rates, and the thresholds for a list of selected beam instability effects. Again with minimal detailed derivations, the aim is to introduce a collection of formulas, and apply them to linear as well as circular accelerators. The list of beam instability effects to be covered include: loss factor, beam break-up, BNS damping, bunch lengthening, resistive wall instability, head-tail instability, longitudinal head-tail instability, Landau damping, microwave instability, and mode coupling instability.

  5. Imaging of shoulder instability

    Science.gov (United States)

    Martínez Martínez, Alberto; Tomás Muñoz, Pablo; Pozo Sánchez, José; Zarza Pérez, Antonio

    2017-01-01

    This extended review tries to cover the imaging findings of the wide range of shoulder injuries secondary to shoulder joint instability. Usefulness of the different imaging methods is stressed, including radiography, computed tomography (CT) and magnetic resonance. The main topics to be covered include traumatic, atraumatic and minor instability syndromes. Radiography may show bone abnormalities associated to instability, including developmental and post-traumatic changes. CT is the best technique depicting and quantifying skeletal changes. MR-arthrography is the main tool in diagnosing the shoulder instability injuries. PMID:28932699

  6. 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.

  7. Posterior Shoulder Instability.

    Science.gov (United States)

    Antosh, Ivan J; Tokish, John M; Owens, Brett D

    Posterior shoulder instability has become more frequently recognized and treated as a unique subset of shoulder instability, especially in the military. Posterior shoulder pathology may be more difficult to accurately diagnose than its anterior counterpart, and commonly, patients present with complaints of pain rather than instability. "Posterior instability" may encompass both dislocation and subluxation, and the most common presentation is recurrent posterior subluxation. Arthroscopic and open treatment techniques have improved as understanding of posterior shoulder instability has evolved. Electronic databases including PubMed and MEDLINE were queried for articles relating to posterior shoulder instability. Clinical review. Level 4. In low-demand patients, nonoperative treatment of posterior shoulder instability should be considered a first line of treatment and is typically successful. Conservative treatment, however, is commonly unsuccessful in active patients, such as military members. Those patients with persistent shoulder pain, instability, or functional limitations after a trial of conservative treatment may be considered surgical candidates. Arthroscopic posterior shoulder stabilization has demonstrated excellent clinical outcomes, high patient satisfaction, and low complication rates. Advanced techniques may be required in select cases to address bone loss, glenoid dysplasia, or revision. Posterior instability represents about 10% of shoulder instability and has become increasingly recognized and treated in military members. Nonoperative treatment is commonly unsuccessful in active patients, and surgical stabilization can be considered in patients who do not respond. Isolated posterior labral repairs constitute up to 24% of operatively treated labral repairs in a military population. Arthroscopic posterior stabilization is typically considered as first-line surgical treatment, while open techniques may be required in complex or revision settings.

  8. Microsatellite Instability Markers Status in Colorectal Cancer

    Directory of Open Access Journals (Sweden)

    Giti Esmailnia

    2014-12-01

    Full Text Available Background: Colorectal cancer (CRC is the third most prevalent and the third leading cause of cancer-related deaths in Iran. Our aim was to investigate five mononucleotide statuses among Iranian patients with sporadic colorectal cancer. Materials and Methods: In this experimental study 80 sporadic CRC patients were evaluated for microsatellite instability (MSI. The pentaplex panel including 5 quasi mononucleotide microsatellite markers (NR-21, BAT-26, BAT-25, NR-27 and NR-24 was used. The MSI analysis was performed on paired tumoral DNA from cancerous tissues and genomic DNA from whole blood. MSI carriers were identified by analysis of tumor tissue using polymerase chain reaction. Results: Our findings showed that microsatellite instability was detected in 36 of 80 cases (45% with colorectal cancer. MSI analysis revealed that 17 cases of MSI-H (21%, 19 MSI-L (23% and 44 microsatellite stable tumors (55%. Instability is observed in the tumoral DNA compared to the DNA from the normal DNA sample. The most instable markers were NR-21, NR-24 in which instability was detected in 45% of patients. Conclusion: Using a panel including 3 mentioned MSI markers should be more promising markers for identifying MSI status in patients with sporadic colorectal cancer.

  9. 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.

  10. Propagating Instabilities in Solids

    Science.gov (United States)

    Kyriakides, Stelios

    1998-03-01

    Instability is one of the factors which limit the extent to which solids can be loaded or deformed and plays a pivotal role in the design of many structures. Such instabilities often result in localized deformation which precipitates catastrophic failure. Some materials have the capacity to recover their stiffness following a certain amount of localized deformation. This local recovery in stiffness arrests further local deformation and spreading of the instability to neighboring material becomes preferred. Under displacement controlled loading the propagation of the transition fronts can be achieved in a steady-state manner at a constant stress level known as the propagation stress. The stresses in the transition fronts joining the highly deformed zone to the intact material overcome the instability nucleation stresses and, as a result, the propagation stress is usually much lower than the stress required to nucleate the instability. The classical example of this class of material instabilities is L/"uders bands which tend to affect mild steels and other metals. Recent work has demonstrated that propagating instabilities occur in several other materials. Experimental and analytical results from four examples will be used to illustrate this point: First the evolution of L=FCders bands in mild steel strips will be revisited. The second example involves the evolution of stress induced phase transformations (austenite to martensite phases and the reverse) in a shape memory alloy under displacement controlled stretching. The third example is the crushing behavior of cellular materials such as honeycombs and foams made from metals and polymers. The fourth example involves the axial broadening/propagation of kink bands in aligned fiber/matrix composites under compression. The microstructure and, as a result, the micromechanisms governing the onset, localization, local arrest and propagation of instabilities in each of the four materials are vastly different. Despite this

  11. Handbook on plasma instabilities

    CERN Document Server

    Cap, Ferdinand F

    1982-01-01

    Handbook on Plasma Instabilities, Volume 3, is primarily intended to serve as a sourcebook for obtaining quick information and literature references pertaining to a specific topic. Such a handbook has to be formulated in a way that enables understanding of any one section without requiring full understanding of any other section. Volume 1 (Chapters 1-13) presents the fundamental concepts of plasma physics with applications, and has more the nature of a textbook treating basic plasma physics, containment, waves, and macroscopic instabilities. Volume 2 (Chapters 14-17) covers various aspects of

  12. 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 ...

  13. Chronic Ankle Instability

    Science.gov (United States)

    ... was not rehabilitated completely. When you sprain your ankle, the connective tissues (ligaments) are stretched or torn. The ability to balance ... Repeated ankle sprains often cause—and perpetuate—chronic ankle ... of the ligaments, resulting in greater instability and the likelihood of ...

  14. 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...

  15. Neurodegeneration-associated instability of ribosomal DNA.

    Science.gov (United States)

    Hallgren, Justin; Pietrzak, Maciej; Rempala, Grzegorz; Nelson, Peter T; Hetman, Michal

    2014-06-01

    Homologous recombination (HR)-mediated instability of the repetitively organized ribosomal DNA (rDNA) has been proposed as a mediator of cell senescence in yeast triggering the DNA damage response. High individual variability in the content of human rDNA suggests that this genomic region remained relatively unstable throughout evolution. Therefore, quantitative real-time polymerase chain reaction was used to determine the genomic content of rDNA in post mortem samples of parietal cortex from 14 young and 9 elderly individuals with no diagnosis of a chronic neurodegenerative/neurological disease. In addition, rDNA content in that brain region was compared between 10 age-matched control individuals and 10 patients with dementia with Lewy bodies (DLB) which involves neurodegeneration of the cerebral cortex. Probing rRNA-coding regions of rDNA revealed no effects of aging on the rDNA content. Elevated rDNA content was observed in DLB. Conversely, in the DLB pathology-free cerebellum, lower genomic content of rDNA was present in the DLB group. In the parietal cortex, such a DLB-associated instability of rDNA was not accompanied by any major changes of cytosine-phosphate-guanine methylation of the rDNA promoter. As increased cerebro-cortical rDNA content was previously reported in Alzheimer's disease, neurodegeneration appears to be associated with instability of rDNA. The hypothetical origins and consequences of this phenomenon are discussed including possibilities that the DNA damage-induced recombination destabilizes rDNA and that differential content of rDNA affects heterochromatin formation, gene expression and/or DNA damage response. This article is part of a Special Issue entitled: Role of the Nucleolus in Human Disease. Copyright © 2014 Elsevier B.V. All rights reserved.

  16. HA novel approach to investigate tissue-specific trinucleotide repeat instability

    Directory of Open Access Journals (Sweden)

    Boily Marie-Josee

    2010-03-01

    Full Text Available Abstract Background In Huntington's disease (HD, an expanded CAG repeat produces characteristic striatal neurodegeneration. Interestingly, the HD CAG repeat, whose length determines age at onset, undergoes tissue-specific somatic instability, predominant in the striatum, suggesting that tissue-specific CAG length changes could modify the disease process. Therefore, understanding the mechanisms underlying the tissue specificity of somatic instability may provide novel routes to therapies. However progress in this area has been hampered by the lack of sensitive high-throughput instability quantification methods and global approaches to identify the underlying factors. Results Here we describe a novel approach to gain insight into the factors responsible for the tissue specificity of somatic instability. Using accurate genetic knock-in mouse models of HD, we developed a reliable, high-throughput method to quantify tissue HD CAG repeat instability and integrated this with genome-wide bioinformatic approaches. Using tissue instability quantified in 16 tissues as a phenotype and tissue microarray gene expression as a predictor, we built a mathematical model and identified a gene expression signature that accurately predicted tissue instability. Using the predictive ability of this signature we found that somatic instability was not a consequence of pathogenesis. In support of this, genetic crosses with models of accelerated neuropathology failed to induce somatic instability. In addition, we searched for genes and pathways that correlated with tissue instability. We found that expression levels of DNA repair genes did not explain the tissue specificity of somatic instability. Instead, our data implicate other pathways, particularly cell cycle, metabolism and neurotransmitter pathways, acting in combination to generate tissue-specific patterns of instability. Conclusion Our study clearly demonstrates that multiple tissue factors reflect the level of

  17. Diagnostic Role of Chromosomal Instability in Melanoma

    Directory of Open Access Journals (Sweden)

    Nitika Dabas

    2012-01-01

    Full Text Available Early diagnosis gives melanoma patients the best chance for long term survival. However discrimination of an early melanoma from an unusual/atypical benign nevus can represent a significant challenge. There are no current pathological markers to definitively define malignant potential in these indeterminate lesions. Thus, there is a need for improved diagnostic tools. Chromosomal instability (CIN is a hallmark of cancer and is markedly prevalent in melanoma. Advances in genomics have opened the door for the development of molecular tools to better segregate benign and malignant lesions. This paper focuses on CIN in melanoma and the role of current diagnostic approaches.

  18. Molecular Dissection of Microsatellite Instable Colorectal Cancer

    Science.gov (United States)

    Vilar, Eduardo; Tabernero, Josep

    2013-01-01

    Colorectal cancer was one of the first solid tumors to be classified based on molecular profiling. Microsatellite instability has allowed researchers to distinguish a specific subtype of colorectal cancer that has a clearly identified molecular origin (mismatch repair deficiency), arises on a hereditary and sporadic basis, is linked to a clear clinicopathological profile and has prognostic implications. Inconclusive predictive data along with a paucity of targeted drug development have prevented this molecular classification system from being implemented in the clinical setting. New high-throughput genomic data have validated it, thus stressing the fact that it is ready to be applied clinically. PMID:23454900

  19. 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.

  20. Beam-beam instability

    Energy Technology Data Exchange (ETDEWEB)

    Chao, A.W.

    1983-08-01

    The subject of beam-beam instability has been studied since the invention of the colliding beam storage rings. Today, with several colliding beam storage rings in operation, it is not yet fully understood and remains an outstanding problem for the storage ring designers. No doubt that good progress has been made over the years, but what we have at present is still rather primitive. It is perhaps possible to divide the beam-beam subject into two areas: one on luminosity optimization and another on the dynamics of the beam-beam interaction. The former area concerns mostly the design and operational features of a colliding beam storage ring, while the later concentrates on the experimental and theoretical aspects of the beam-beam interaction. Although both areas are of interest, our emphasis is on the second area only. In particular, we are most interested in the various possible mechanisms that cause the beam-beam instability.

  1. Evaporation and Antievaporation instabilities

    OpenAIRE

    Addazi, Andrea; Marciano, Antonino

    2017-01-01

    We review (anti)evaporation phenomena within the context of quantum gravity and extended theories of gravity. The (anti)evaporation 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...

  2. 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.

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

    Directory of Open Access Journals (Sweden)

    Mitsuko Masutani

    2012-05-01

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

  4. 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.

  5. R loops stimulate genetic instability of CTG.CAG repeats.

    Science.gov (United States)

    Lin, Yunfu; Dent, Sharon Y R; Wilson, John H; Wells, Robert D; Napierala, Marek

    2010-01-12

    Transcription stimulates the genetic instability of trinucleotide repeat sequences. However, the mechanisms leading to transcription-dependent repeat length variation are unclear. We demonstrate, using biochemical and genetic approaches, that the formation of stable RNA.DNA hybrids enhances the instability of CTG.CAG repeat tracts. In vitro transcribed CG-rich repeating sequences, unlike AT-rich repeats and nonrepeating sequences, form stable, ribonuclease A-resistant structures. These RNA.DNA hybrids are eliminated by ribonuclease H treatment. Mutation in the rnhA1 gene that decreases the activity of ribonuclease HI stimulates the instability of CTG.CAG repeats in E. coli. Importantly, the effect of ribonuclease HI depletion on repeat instability requires active transcription. We also showed that transcription-dependent CTG.CAG repeat instability in human cells is stimulated by siRNA knockdown of RNase H1 and H2. In addition, we used bisulfite modification, which detects single-stranded DNA, to demonstrate that the nontemplate DNA strand at transcribed CTG.CAG repeats remains partially single-stranded in human genomic DNA, thus indicating that it is displaced by an RNA.DNA hybrid. These studies demonstrate that persistent hybrids between the nascent RNA transcript and the template DNA strand at CTG.CAG tracts promote instability of DNA trinucleotide repeats.

  6. Size effects on cavitation instabilities

    DEFF Research Database (Denmark)

    Niordson, Christian Frithiof; Tvergaard, Viggo

    2006-01-01

    In metal-ceramic systems the constraint on plastic flow leads to so high stress triaxialities that cavitation instabilities may occur. If the void radius is on the order of magnitude of a characteristic length for the metal, the rate of void growth is reduced, and the possibility of unstable cavity...... triaxiality, where cavitation instabilities are predicted by conventional plasticity theory, such instabilities are also found for the nonlocal theory, but the effects of gradient hardening delay the onset of the instability. Furthermore, in some cases the cavitation stress reaches a maximum and then decays...

  7. Instability of enclosed horizons

    CERN Document Server

    Kay, Bernard S

    2013-01-01

    We study the classical massless scalar wave equation on the region of 1+1-dimensional Minkowski space between the two branches of the hyperbola $x^2-t^2=1$ with vanishing boundary conditions on it. We point out that there are initially finite-energy initially, say, right-going waves for which the stress-energy tensor becomes singular on the null-line $t+x=0$. We also construct the quantum theory of this system and show that, while there is a regular Hartle-Hawking-Israel-like state, there are coherent states built on this for which there is a similar singularity in the expectation value of the renormalized stress-energy tensor. We conjecture that in 1+3-dimensional situations with 'enclosed horizons' such as a (maximally extended) Schwarzschild black hole in equilibrium in a stationary box or the (maximally extended) Schwarzschild-AdS spacetime, there will be a similar singularity at the horizon and that would signal an instability when matter perturbations and/or gravity are switched on. Such an instability ...

  8. Instability and Information

    CERN Document Server

    Patzelt, Felix

    2015-01-01

    Many complex systems exhibit extreme events far more often than expected for a normal distribution. This work examines how self-similar bursts of activity across several orders of magnitude can emerge from first principles in systems that adapt to information. Surprising connections are found between two apparently unrelated research topics: hand-eye coordination in balancing tasks and speculative trading in financial markets. Seemingly paradoxically, locally minimising fluctuations can increase a dynamical system's sensitivity to unpredictable perturbations and thereby facilitate global catastrophes. This general principle is studied in several domain-specific models and in behavioural experiments. It explains many findings in both fields and resolves an apparent antinomy: the coexistence of stabilising control or market efficiency and perpetual instabilities resembling critical phenomena in physical systems.

  9. Saturation of equatorial inertial instability

    NARCIS (Netherlands)

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

    2015-01-01

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

  10. Microsatellite instability in bladder cancer

    DEFF Research Database (Denmark)

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

    1993-01-01

    Somatic instability at microsatellite repeats was detected in 6 of 200 transitional cell carcinomas of the bladder. Instabilities were apparent as changes in (GT)n repeat lengths on human chromosome 9 for four tumors and as alterations in a (CAG)n repeat in the androgen receptor gene on the X chr...

  11. Liquid propellant rocket combustion instability

    Science.gov (United States)

    Harrje, D. T.

    1972-01-01

    The solution of problems of combustion instability for more effective communication between the various workers in this field is considered. The extent of combustion instability problems in liquid propellant rocket engines and recommendations for their solution are discussed. The most significant developments, both theoretical and experimental, are presented, with emphasis on fundamental principles and relationships between alternative approaches.

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

    Science.gov (United States)

    Camats, Núria; García, Francisca; Parrilla, Juan José; Calaf, Joaquim; Martín, Miguel; Caldés, Montserrat Garcia

    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 (5Gy, 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 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 generational, radiation-induced chromosomal instability in the foetal cells from X-ray-treated female rats and that this RIGI enhances the chromosomal damage caused by the chemical agent aphidicolin.

  13. Beam instability Workshop - plenary sessions

    Energy Technology Data Exchange (ETDEWEB)

    NONE

    2001-07-01

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

  14. CTCF cis-regulates trinucleotide repeat instability in an epigenetic manner: a novel basis for mutational hot spot determination.

    Directory of Open Access Journals (Sweden)

    Randell T Libby

    2008-11-01

    Full Text Available At least 25 inherited disorders in humans result from microsatellite repeat expansion. Dramatic variation in repeat instability occurs at different disease loci and between different tissues; however, cis-elements and trans-factors regulating the instability process remain undefined. Genomic fragments from the human spinocerebellar ataxia type 7 (SCA7 locus, containing a highly unstable CAG tract, were previously introduced into mice to localize cis-acting "instability elements," and revealed that genomic context is required for repeat instability. The critical instability-inducing region contained binding sites for CTCF -- a regulatory factor implicated in genomic imprinting, chromatin remodeling, and DNA conformation change. To evaluate the role of CTCF in repeat instability, we derived transgenic mice carrying SCA7 genomic fragments with CTCF binding-site mutations. We found that CTCF binding-site mutation promotes triplet repeat instability both in the germ line and in somatic tissues, and that CpG methylation of CTCF binding sites can further destabilize triplet repeat expansions. As CTCF binding sites are associated with a number of highly unstable repeat loci, our findings suggest a novel basis for demarcation and regulation of mutational hot spots and implicate CTCF in the modulation of genetic repeat instability.

  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. 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.

  17. Dana-Farber Cancer Institute | Office of Cancer Genomics

    Science.gov (United States)

    Functional Annotation of Cancer Genomes Principal Investigator: William C. Hahn, M.D., Ph.D. The comprehensive characterization of cancer genomes has and will continue to provide an increasingly complete catalog of genetic alterations in specific cancers. However, most epithelial cancers harbor hundreds of genetic alterations as a consequence of genomic instability. Therefore, the functional consequences of the majority of mutations remain unclear.

  18. Simulations of Astrophysical fluid instabilities

    Science.gov (United States)

    Calder, A. C.; Fryxell, B.; Rosner, R.; Dursi, L. J.; Olson, K.; Ricker, P. M.; Timmes, F. X.; Zingale, M.; MacNeice, P.; Tufo, H. M.

    2001-10-01

    We present direct numerical simulations of mixing at Rayleigh-Taylor unstable interfaces performed with the FLASH code, developed at the ASCI/Alliances Center for Astrophysical Thermonuclear Flashes at the University of Chicago. We present initial results of single-mode studies in two and three dimensions. Our results indicate that three-dimensional instabilities grow significantly faster than two-dimensional instabilities and that grid resolution can have a significant effect on instability growth rates. We also find that unphysical diffusive mixing occurs at the fluid interface, particularly in poorly resolved simulations. .

  19. Lineage Switch Between B-Lymphoblastic Leukemia and Acute Myeloid Leukemia Intermediated by "Occult" Myelodysplastic Neoplasm: Two Cases of Adult Patients With Evidence of Genomic Instability and Clonal Selection by Chemotherapy.

    Science.gov (United States)

    Wu, Bin; Jug, Rachel; Luedke, Catherine; Su, Pu; Rehder, Catherine; McCall, Chad; Lagoo, Anand S; Wang, Endi

    2017-08-01

    Lineage switch occurs in rare leukemias, and the mechanism is unclear. We report two cases of B-lymphoblastic leukemia (B-ALL) relapsed as acute myeloid leukemia (AML). Retrospective review of clinical and laboratory data. Complex cytogenetic abnormalities were detected in B-ALL for both cases with subclone heterogeneity. Postchemotherapy marrow biopsies showed trilineage hematopoiesis without detectable B-ALL. Cytogenetics in both showed stemline abnormalities. The cases were considered "occult" myelodysplastic syndrome (MDS) preceding B-ALL. The patients relapsed 6.5 and 9 months following induction, respectively. Case 1 relapsed as AML-M5 initially, was treated as such, and then relapsed again as B-ALL. Case 2 relapsed as AML-M6. Cytogenetics demonstrated persistent abnormalities. Both patients died soon after relapse. Lineage switch between B-ALL and AML could be intermediated by occult MDS. A pluripotent progenitor likely undergoes neoplastic transformation, resulting in a genomically unstable clone. This leads to a repertoire of heterogeneous subclones that may be selected by chemotherapy. Lineage switch heralds a dismal clinical outcome.

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

    Energy Technology Data Exchange (ETDEWEB)

    Moore, Stephen R. [Environmental Toxicology Graduate Program, Department of Cell Biology and Neuroscience, University of California, Riverside, CA (United States); Radiation and Genome Stability Unit, Medical Research Council, Harwell, Oxfordshire (United Kingdom); Papworth, David [Radiation and Genome Stability Unit, Medical Research Council, Harwell, Oxfordshire (United Kingdom); Grosovsky, Andrew J. [Environmental Toxicology Graduate Program, Department of Cell Biology and Neuroscience, University of California, Riverside, CA (United States)]. E-mail: Grosovsky@ucr.edu

    2006-08-30

    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.

  1. WELLBORE INSTABILITY: CAUSES AND CONSEQUENCES

    Directory of Open Access Journals (Sweden)

    Borivoje Pašić

    2007-12-01

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

  2. Edge instabilities of topological superconductors

    Energy Technology Data Exchange (ETDEWEB)

    Hofmann, Johannes S. [Institut fuer Theoretische Physik und Astrophysik, Universitaet Wuerzburg (Germany); Max-Planck-Institut fuer Festkoerperforschung, Stuttgart (Germany); Assaad, Fakher F. [Institut fuer Theoretische Physik und Astrophysik, Universitaet Wuerzburg (Germany); Schnyder, Andreas P. [Max-Planck-Institut fuer Festkoerperforschung, Stuttgart (Germany)

    2016-07-01

    Nodal topological superconductors display zero-energy Majorana flat bands at generic edges. The flatness of these edge bands, which is protected by time-reversal and translation symmetry, gives rise to an extensive ground state degeneracy and a diverging density of states. Therefore, even arbitrarily weak interactions lead to an instability of the flat-band edge states towards time-reversal and translation-symmetry broken phases, which lift the ground-state degeneracy. Here, we employ Monte Carlo simulations combined with mean-field considerations to examine the instabilities of the flat-band edge states of d{sub xy}-wave superconductors. We find that attractive interactions induce a complex s-wave pairing instability together with a density wave instability. Repulsive interactions, on the other hand, lead to ferromagnetism mixed with spin-triplet pairing at the edge. We discuss the implications of our findings for experiments on cuprate high-temperature superconductors.

  3. Beam Instabilities in Hadron Synchrotrons

    CERN Document Server

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

    2016-01-01

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

  4. Microsatellite instability in bladder cancer

    DEFF Research Database (Denmark)

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

    1993-01-01

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

  5. Material Instabilities in Particulate Systems

    Science.gov (United States)

    Goddard, J. D.

    1999-01-01

    Following is a brief summary of a theoretical investigation of material (or constitutive) instability associated with shear induced particle migration in dense particulate suspensions or granular media. It is shown that one can obtain a fairly general linear-stability analysis, including the effects of shear-induced anisotropy in the base flow as well as Reynolds dilatancy. A criterion is presented here for simple shearing instability in the absence of inertia and dilatancy.

  6. History of shoulder instability surgery.

    Science.gov (United States)

    Randelli, Pietro; Cucchi, Davide; Butt, Usman

    2016-02-01

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

  7. Transcriptome instability in colorectal cancer identified by exon microarray analyses: Associations with splicing factor expression levels and patient survival.

    Science.gov (United States)

    Sveen, Anita; Agesen, Trude H; Nesbakken, Arild; Rognum, Torleiv O; Lothe, Ragnhild A; Skotheim, Rolf I

    2011-05-27

    Colorectal cancer (CRC) is a heterogeneous disease that, on the molecular level, can be characterized by inherent genomic instabilities; chromosome instability and microsatellite instability. In the present study we analyze genome-wide disruption of pre-mRNA splicing, and propose transcriptome instability as a characteristic that is analogous to genomic instability on the transcriptome level. Exon microarray profiles from two independent series including a total of 160 CRCs were investigated for their relative amounts of exon usage differences. Each exon in each sample was assigned an alternative splicing score calculated by the FIRMA algorithm. Amounts of deviating exon usage per sample were derived from exons with extreme splicing scores. There was great heterogeneity within both series in terms of sample-wise amounts of deviating exon usage. This was strongly associated with the expression levels of approximately half of 280 splicing factors (54% and 48% of splicing factors were significantly correlated to deviating exon usage amounts in the two series). Samples with high or low amounts of deviating exon usage, associated with overall transcriptome instability, were almost completely separated into their respective groups by hierarchical clustering analysis of splicing factor expression levels in both sample series. Samples showing a preferential tendency towards deviating exon skipping or inclusion were associated with skewed transcriptome instability. There were significant associations between transcriptome instability and reduced patient survival in both sample series. In the test series, patients with skewed transcriptome instability showed the strongest prognostic association (P = 0.001), while a combination of the two characteristics showed the strongest association with poor survival in the validation series (P = 0.03). We have described transcriptome instability as a characteristic of CRC. This transcriptome instability has associations with splicing

  8. Instability Prediction and Disruption Avoidance

    Science.gov (United States)

    Turnbull, A. D.; Liu, Y. Q.; Hanson, J. M.; Turco, F.; Ferraro, N. M.

    2017-10-01

    Disruption avoidance requires both a prediction of the instability proximity and an estimate of the `disruptability' - the likelihood that the instability will ultimately result in a disruptive event. MHD spectroscopy is a promising option for obtaining information on the proximity of instabilities. Both the direct response and the antenna impedance provide valuable information on the low frequency global normal modes corresponding to stabilized kink modes. Data from DIII-D experiments and available nonlinear simulations are used to define quantitative criteria that signify when instabilities ultimately disrupt and when they saturate or dissipate. The key distinction in this approach is the use of physical characteristics of the modes rather than more accessible operation parameters. Simple characteristics of the linear instability for example include the linear growth or damping rate and the mode spatial extent. Criteria can also involve identifying sources of free energy in the nonlinear evolution. Work supported in part by the US DOE under DE-FC02-04ER54698 & DE-FG02-95ER54309.

  9. Telomere dysfunction and chromosome instability

    Energy Technology Data Exchange (ETDEWEB)

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

    2012-02-01

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

  10. Political instability and illegal immigration.

    Science.gov (United States)

    Campos, J E; Lien, D

    1995-01-01

    "Economic theory suggests that transnational migration results from the push-pull effect of wage differentials between host and source countries. In this paper, we argue that political instability exacerbates the migration flow, with greater instability leading to relatively larger flows. We conclude then that an optimal solution to the illegal immigration problem requires proper coordination of immigration and foreign policies by the host country. A narrow preoccupation with tougher immigration laws is wasteful and may be marginally effective." Emphasis is on the United States as a host country. excerpt

  11. Stringy bounces and gradient instabilities

    CERN Document Server

    Giovannini, Massimo

    2017-01-01

    Bouncing solutions are obtained from a generally covariant action characterized by a potential which is a nonlocal functional of the dilaton field at two separated space-time points. Gradient instabilities are shown to arise in this context but they are argued to be nongeneric. After performing a gauge-invariant and frame-invariant derivation of the evolution equations of the fluctuations, a heuristic criterium for the avoidance of pathological instabilities is proposed and corroborated by a number of explicit examples that turn out to be compatible with a quasi-flat spectrum of curvature inhomogeneities for typical wavelengths larger than the Hubble radius.

  12. 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.

  13. Modulational instability of nematic phase

    Indian Academy of Sciences (India)

    2014-02-08

    Feb 8, 2014 ... Abstract. We numerically observe the effect of homogeneous magnetic field on the modulation- ally stable case of polar phase in F = 2 spinor Bose–Einstein condensates (BECs). Also we investigate the modulational instability of uniaxial and biaxial (BN) states of polar phase. Our observations show that ...

  14. Modulational instability of nematic phase

    Indian Academy of Sciences (India)

    2014-02-08

    Feb 8, 2014 ... We numerically observe the effect of homogeneous magnetic field on the modulationally stable case of polar phase in = 2 spinor Bose–Einstein condensates (BECs). Also we investigate the modulational instability of uniaxial and biaxial (BN) states of polar phase. Our observations show that the magnetic ...

  15. The Chemistry of Beer Instability

    Science.gov (United States)

    Stewart, Graham G.

    2004-01-01

    Brewing of beer, one of the oldest biotechnology industries was one of the earliest processes to be undertaken on commercial basis. Biological instability involves contamination of bacteria, yeast, or mycelia fungi and there is always a risk in brewing that beer can become contaminated by micro-organisms.

  16. Edge instabilities of topological superconductors

    Science.gov (United States)

    Hofmann, Johannes S.; Assaad, Fakher F.; Schnyder, Andreas P.

    2016-05-01

    Nodal topological superconductors display zero-energy Majorana flat bands at generic edges. The flatness of these edge bands, which is protected by time-reversal and translation symmetry, gives rise to an extensive ground-state degeneracy. Therefore, even arbitrarily weak interactions lead to an instability of the flat-band edge states towards time-reversal and translation-symmetry-broken phases, which lift the ground-state degeneracy. We examine the instabilities of the flat-band edge states of dx y-wave superconductors by performing a mean-field analysis in the Majorana basis of the edge states. The leading instabilities are Majorana mass terms, which correspond to coherent superpositions of particle-particle and particle-hole channels in the fermionic language. We find that attractive interactions induce three different mass terms. One is a coherent superposition of imaginary s -wave pairing and current order, and another combines a charge-density-wave and finite-momentum singlet pairing. Repulsive interactions, on the other hand, lead to ferromagnetism together with spin-triplet pairing at the edge. Our quantum Monte Carlo simulations confirm these findings and demonstrate that these instabilities occur even in the presence of strong quantum fluctuations. We discuss the implications of our results for experiments on cuprate high-temperature superconductors.

  17. Lending sociodynamics and economic instability

    Science.gov (United States)

    Hawkins, Raymond J.

    2011-11-01

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

  18. Arthroscopic Management of Scapholunate Instability

    Science.gov (United States)

    Geissler, William B.

    2013-01-01

    Wrist arthroscopy plays a valuable role in the management of scapholunate instability. A spectrum of injuries can occur to the scapholunate interosseous ligament, which may be difficult to detect with imaging studies. Wrist arthroscopy enables detection and management of injury to the scapholunate ligament under bright light and magnified conditions, in both acute and chronic situations. PMID:24436805

  19. Singlet and triplet instability theorems

    Science.gov (United States)

    Yamada, Tomonori; Hirata, So

    2015-09-01

    A useful definition of orbital degeneracy—form-degeneracy—is introduced, which is distinct from the usual energy-degeneracy: Two canonical spatial orbitals are form-degenerate when the energy expectation value in the restricted Hartree-Fock (RHF) wave function is unaltered upon a two-electron excitation from one of these orbitals to the other. Form-degenerate orbitals tend to have isomorphic electron densities and occur in the highest-occupied and lowest-unoccupied molecular orbitals (HOMOs and LUMOs) of strongly correlated systems. Here, we present a mathematical proof of the existence of a triplet instability in a real or complex RHF wave function of a finite system in the space of real or complex unrestricted Hartree-Fock wave functions when HOMO and LUMO are energy- or form-degenerate. We also show that a singlet instability always exists in a real RHF wave function of a finite system in the space of complex RHF wave functions, when HOMO and LUMO are form-degenerate, but have nonidentical electron densities, or are energy-degenerate. These theorems provide Hartree-Fock-theory-based explanations of Hund's rule, a singlet instability in Jahn-Teller systems, biradicaloid electronic structures, and a triplet instability during some covalent bond breaking. They also suggest (but not guarantee) the spontaneous formation of a spin density wave (SDW) in a metallic solid. The stability theory underlying these theorems extended to a continuous orbital-energy spectrum proves the existence of an oscillating (nonspiral) SDW instability in one- and three-dimensional homogeneous electron gases, but only at low densities or for strong interactions.

  20. Singlet and triplet instability theorems

    Energy Technology Data Exchange (ETDEWEB)

    Yamada, Tomonori; Hirata, So, E-mail: sohirata@illinois.edu [Department of Chemistry, University of Illinois at Urbana-Champaign, 600 South Mathews Avenue, Urbana, Illinois 61801 (United States); CREST, Japan Science and Technology Agency, 4-1-8 Honcho, Kawaguchi, Saitama 332-0012 (Japan)

    2015-09-21

    A useful definition of orbital degeneracy—form-degeneracy—is introduced, which is distinct from the usual energy-degeneracy: Two canonical spatial orbitals are form-degenerate when the energy expectation value in the restricted Hartree–Fock (RHF) wave function is unaltered upon a two-electron excitation from one of these orbitals to the other. Form-degenerate orbitals tend to have isomorphic electron densities and occur in the highest-occupied and lowest-unoccupied molecular orbitals (HOMOs and LUMOs) of strongly correlated systems. Here, we present a mathematical proof of the existence of a triplet instability in a real or complex RHF wave function of a finite system in the space of real or complex unrestricted Hartree–Fock wave functions when HOMO and LUMO are energy- or form-degenerate. We also show that a singlet instability always exists in a real RHF wave function of a finite system in the space of complex RHF wave functions, when HOMO and LUMO are form-degenerate, but have nonidentical electron densities, or are energy-degenerate. These theorems provide Hartree–Fock-theory-based explanations of Hund’s rule, a singlet instability in Jahn–Teller systems, biradicaloid electronic structures, and a triplet instability during some covalent bond breaking. They also suggest (but not guarantee) the spontaneous formation of a spin density wave (SDW) in a metallic solid. The stability theory underlying these theorems extended to a continuous orbital-energy spectrum proves the existence of an oscillating (nonspiral) SDW instability in one- and three-dimensional homogeneous electron gases, but only at low densities or for strong interactions.

  1. Genomic Testing

    Science.gov (United States)

    ... Counseling Genomic Testing Pathogen Genomics Epidemiology Resources Genomic Testing Recommend on Facebook Tweet Share Compartir Fact Sheet: ... Page The Need for Reliable Information on Genetic Testing In 2008, the former Secretary’s Advisory Committee on ...

  2. Treatment of glenohumeral instability in rugby players

    OpenAIRE

    Funk, Lennard

    2016-01-01

    Rugby is a high-impact collision sport, with impact forces. Shoulder injuries are common and result in the longest time off sport for any joint injury in rugby. The most common injuries are to the glenohumeral joint with varying degrees of instability. The degree of instability can guide management. The three main types of instability presentations are: (1) frank dislocation, (2) subluxations and (3) subclinical instability with pain and clicking. Understanding the exact mechanism of injury c...

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

    Energy Technology Data Exchange (ETDEWEB)

    Dynan, William S. [Georgia Regents University

    2013-05-31

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

  4. Genome instability : Lessons from single-cell sequencing studies

    NARCIS (Netherlands)

    van Wietmarschen, Niek

    2016-01-01

    Bloom syndrome (BS) is a genetic disorder caused by mutations in the BLM gene, which encodes for a protein with multiple functions in DNA repair. Symptoms include sensitivity to sunlight and cancer development at an early age. The average life expectancy is 26 years and cancer is frequently the

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

    African Journals Online (AJOL)

    Random amplified polymorphic DNA (RAPD) markers were used to evaluate genetic stability of regenerants of cucumber plants obtained through somatic embryogenesis. Somatic embryo plants and plants of F1 hybrids, from which they were derived, were compared during weaning, early growth, flowering, fruiting and at ...

  6. Evaluation of Genomic Instability in the Abnormal Prostate

    Science.gov (United States)

    2007-12-01

    Jeffrey K Griffith, Ph D CONTRACTING ORGANIZATION: University of New Mexico...Jeffrey K Griffith, Ph D 5f. WORK UNIT NUMBER 7. PERFORMING ORGANIZATION NAME(S) AND ADDRESS(ES) 8. PERFORMING ORGANIZATION REPORT...NUMBER University of New Mexico Health Sciences Center 915 Camino De Salud , NE Albuquerque, New Mexico 87131-5221 9. SPONSORING

  7. Spartan deficiency causes genomic instability and progeroid phenotypes

    NARCIS (Netherlands)

    Maskey, R.S.; Kim, M.S.; Baker, D.J.; Childs, B.; Malureanu, L.A.; Jeganathan, K.B.; Machida, Y.; Deursen, J.M.A. van; Machida, Y.J.

    2014-01-01

    Spartan (also known as DVC1 and C1orf124) is a PCNA-interacting protein implicated in translesion synthesis, a DNA damage tolerance process that allows the DNA replication machinery to replicate past nucleotide lesions. However, the physiological relevance of Spartan has not been established. Here

  8. Evaluation of Genomic Instability in the Abnormal Prostate

    Science.gov (United States)

    2008-12-01

    should include molecular, in addition to histological , techniques , thus war- ranting further investigations. Acknowledgements We thank Myra Zucker from...ABSTRACT The aim of this study is to investigate field effect in prostate cancer, the relationship between tumor and nearby histologically normal...expression changes occurring between tumor and histologically normal tissues compared to truly disease free tissue. While telomere length and allelic

  9. The Adaptive Response, Genetic Haplo-Insufficiency and Genomic Instability

    Energy Technology Data Exchange (ETDEWEB)

    Geard, Charles R. [Columbia Univ., New York, NY (United States). Center for Radiological Research

    2014-12-12

    The linear no-threshold (LNT) hypothesis is the driving force in the establishment of radiation protection standards. However, the scientific basis for linearity has been brought into question, particularly due to the concerns about induced radiation resistance as it pertains to oxidative stress. Specifically, we investigated the observation that tumor hypoxia is associated with malignant progression, increased metastases, chemo- and radioresistance and poor prognosis. Experiments were conducted with non-malignant 3T3/NIH cells and normal human lung fibroblasts (NHLF) that were subjected to γ-irradiation under the levels of oxygen resembling those in growing tumors, and related our data to the concentrations of dissolved oxygen (DO), which is a better indicator of the amounts of residual oxygen inside the cells cultured in the hypoxic or anoxic atmosphere. We found that at DO levels about 0.5 mg/L cells subjected to both short-term (17 hours) and prolonged (48-72 hours) hypoxia continued to proliferate, and that apoptotic events were decreased at the early hours of hypoxic treatment. We showed that the short-term hypoxia up-regulated p53-binding protein 1 (53BP1) and resulted in facilitated 53BP1 nuclear foci formation and disappearance, thus indicating the higher efficiency of DNA double strand breaks repair processes. The latter was confirmed by the lower micronuclei incidence in irradiated hypoxic cells.

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

    African Journals Online (AJOL)

    STORAGESEVER

    2009-07-20

    Jul 20, 2009 ... ce their effectiveness for genetic diversity analysis of cucumber (Horejsi and Staub, 1999). ... logy has proven effective for genetic analysis of diverse cucumber germplasm (Staub et al., 1997), ... powdered with a mortar and pestle and transferred into 3 volumes of extraction buffer (500 mM NaCl, 50 mM ...

  11. APC/C Dysfunction Limits Excessive Cancer Chromosomal Instability.

    Science.gov (United States)

    Sansregret, Laurent; Patterson, James O; Dewhurst, Sally; López-García, Carlos; Koch, André; McGranahan, Nicholas; Chao, William Chong Hang; Barry, David J; Rowan, Andrew; Instrell, Rachael; Horswell, Stuart; Way, Michael; Howell, Michael; Singleton, Martin R; Medema, René H; Nurse, Paul; Petronczki, Mark; Swanton, Charles

    2017-02-01

    Intercellular heterogeneity, exacerbated by chromosomal instability (CIN), fosters tumor heterogeneity and drug resistance. However, extreme CIN correlates with improved cancer outcome, suggesting that karyotypic diversity required to adapt to selection pressures might be balanced in tumors against the risk of excessive instability. Here, we used a functional genomics screen, genome editing, and pharmacologic approaches to identify CIN-survival factors in diploid cells. We find partial anaphase-promoting complex/cyclosome (APC/C) dysfunction lengthens mitosis, suppresses pharmacologically induced chromosome segregation errors, and reduces naturally occurring lagging chromosomes in cancer cell lines or following tetraploidization. APC/C impairment caused adaptation to MPS1 inhibitors, revealing a likely resistance mechanism to therapies targeting the spindle assembly checkpoint. Finally, CRISPR-mediated introduction of cancer somatic mutations in the APC/C subunit cancer driver gene CDC27 reduces chromosome segregation errors, whereas reversal of an APC/C subunit nonsense mutation increases CIN. Subtle variations in mitotic duration, determined by APC/C activity, influence the extent of CIN, allowing cancer cells to dynamically optimize fitness during tumor evolution. We report a mechanism whereby cancers balance the evolutionary advantages associated with CIN against the fitness costs caused by excessive genome instability, providing insight into the consequence of CDC27 APC/C subunit driver mutations in cancer. Lengthening of mitosis through APC/C modulation may be a common mechanism of resistance to cancer therapeutics that increase chromosome segregation errors. Cancer Discov; 7(2); 218-33. ©2017 AACR.See related commentary by Burkard and Weaver, p. 134This article is highlighted in the In This Issue feature, p. 115. ©2017 American Association for Cancer Research.

  12. Interface instability modes in freezing colloidal suspensions: revealed from onset of planar instability

    Science.gov (United States)

    Wang, Lilin; You, Jiaxue; Wang, Zhijun; Wang, Jincheng; Lin, Xin

    2016-03-01

    Freezing colloidal suspensions widely exists in nature and industry. Interface instability has attracted much attention for the understandings of the pattern formation in freezing colloidal suspensions. However, the interface instability modes, the origin of the ice banding or ice lamellae, are still unclear. In-situ experimental observation of the onset of interface instability remains absent up to now. Here, by directly imaging the initial transient stage of planar interface instability in directional freezing colloidal suspensions, we proposed three interface instability modes, Mullins-Sekerka instability, global split instability and local split instability. The intrinsic mechanism of the instability modes comes from the competition of the solute boundary layer and the particle boundary layer, which only can be revealed from the initial transient stage of planar instability in directional freezing.

  13. Genomics and proteomics in cancer.

    Science.gov (United States)

    Baak, J P A; Path, F R C; Hermsen, M A J A; Meijer, G; Schmidt, J; Janssen, E A M

    2003-06-01

    Cancer development is driven by the accumulation of DNA changes in the approximately 40000 chromosomal genes. In solid tumours, chromosomal numerical/structural aberrations are common. DNA repair defects may lead to genome-wide genetic instability, which can drive further cancer progression. The genes code the actual players in the cellular processes, the 100000-10 million proteins, which in (pre)malignant cells can also be altered in a variety of ways. Over the past decade, our knowledge of the human genome and Genomics (the study of the human genome) in (pre)malignancies has increased enormously and Proteomics (the analysis of the protein complement of the genome) has taken off as well. Both will play an increasingly important role. In this article, a short description of the essential molecular biological cell processes is given. Important genomic and proteomic research methods are described and illustrated. Applications are still limited, but the evidence so far is exciting. Will genomics replace classical diagnostic or prognostic procedures? In breast cancers, the gene expression array is stronger than classical criteria, but in endometrial hyperplasia, quantitative morphological features are more cost-effective than genetic testing. It is still too early to make strong statements, the more so because it is expected that genomics and proteomics will expand rapidly. However, it is likely that they will take a central place in the understanding, diagnosis, monitoring and treatment of (pre)cancers of many different sites.

  14. Fluctuations and Instability in Sedimentation

    KAUST Repository

    Guazzelli, Élisabeth

    2011-01-21

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

  15. Quad-Bike Operational Instability

    Directory of Open Access Journals (Sweden)

    Ross H. Macmillan

    2017-05-01

    Full Text Available The stake-holders in the quad-bike (QB industry in Australia have failed to reach a satisfactory resolution of the present impasse that exists with respect to the causes and mitigation of the trauma suffered by riders due to QB instability. In an effort to provide purchasers with data enabling them to discriminate between safer and less safe machines, static longitudinal and lateral tests have been conducted by various interested parties; quasi-static lateral tests have also been conducted under some operational conditions. It is argued that while these static tests are valid, under many operating conditions QBs will not reach such unstable slopes due to poor traction. Further, these tests do not include the quasi-static and dynamic factors which also influence the processes associated with operational instability. For these reasons, the static tests do not provide an adequate basis for discrimination between safer and less safe machines.

  16. Instability of ties in compression

    DEFF Research Database (Denmark)

    Buch-Hansen, Thomas Cornelius

    2013-01-01

    Masonry cavity walls are loaded by wind pressure and vertical load from upper floors. These loads results in bending moments and compression forces in the ties connecting the outer and the inner wall in a cavity wall. Large cavity walls are furthermore loaded by differential movements from...... the temperature gradient between the outer and the inner wall, which results in critical increase of the bending moments in the ties. Since the ties are loaded by combined compression and moment forces, the loadbearing capacity is derived from instability equilibrium equations. Most of them are iterative, since......-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....

  17. Placing Marangoni instabilities under arrest

    CERN Document Server

    Bhamla, M Saad

    2016-01-01

    Soap bubbles occupy the rare position of delighting and fascinating both young children and scientific minds alike. Sir Isaac Newton, Joseph Plateau, Carlo Marangoni, and Pierre-Gilles de Gennes, not to mention countless others, have discovered remarkable results in optics, molecular forces and fluid dynamics from investigating this seemingly simple system. We present here a compilation of curiosity-driven experiments that systematically investigate the surface flows on a rising soap bubble. From childhood experience, we are familiar with the vibrant colors and mesmerizing display of chaotic flows on the surface of a soap bubble. These flows arise due to surface tension gradients, also known as Marangoni flows or instabilities. In Figure 1, we show the surprising effect of layering multiple instabilities on top of each other, highlighting that unexpected new phenomena are still waiting to be discovered, even in the simple soap bubble.

  18. Effect of Hecogenin on DNA instability

    Directory of Open Access Journals (Sweden)

    Marina Sampaio Cruz

    2016-01-01

    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.

  19. Instability of colliding metastable strings

    Energy Technology Data Exchange (ETDEWEB)

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

    2013-04-15

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

  20. Morphological instabilities of lamellar eutectics

    Energy Technology Data Exchange (ETDEWEB)

    Karma, A.; Sarkissian, A. [Northeastern Univ., Boston, MA (United States). Physics Dept.

    1996-03-01

    The authors present the results of a numerical study based on the boundary integral technique of interfacial pattern formation in directional solidification of thin-film lamellar eutectics at low velocity. Microstructure selection maps that identify the stability domains of various steady-state and nonsteady-state growth morphologies in the spacing-composition ({lambda} {minus} C{sub 0}) plane are constructed for the transparent organic alloy CBr{sub 4}-C{sub 2}Cl{sub 6} and for a model eutectic alloy with two solid phases of identical physical properties. In CBr{sub 4}-C{sub 2}Cl{sub 6}, the basic set of instabilities that limit steady-state growth is richer than expected. It consists of three primary instabilities, two of which are oscillatory, which bound the domain of the commonly observed axisymmetric lamellar morphology, and two secondary oscillatory instabilities, which bound the domain of the nonaxisymmetric (tilted) lamellar morphology. Four stable oscillatory microstructures, at least three of which have been seen experimentally, are predicted to occur in unstable regimes. In the model alloy, the structure is qualitatively similar, except that a stable domain of tilted steady-state growth is not found, in agreement with previous random-walk simulations. Furthermore, the composition range of stability of the axisymmetric morphology decreases sharply with increasing spacing away from minimum undercooling but extends further off-eutectic than predicted by the competitive growth criterion. In addition, oscillations with a wavelength equal to two {lambda} lead to lamella termination at a small distance above the onset of instability. The implications of these two features for the eutectic to dendrite transition are examined with the conclusion that in the absence of heterogeneous nucleation, this transition should be histeritic at small velocity and temperature gradient.

  1. Atlantoaxial instability in Down's synarome

    OpenAIRE

    Kafadar, Ali; Hanci, Murat; Tuysuz, Beyhan; Sarioglu, Ali Cetin; Erginel, Ayten; Cenani, Asim

    2004-01-01

    9-31 % of children with Down syndrome have atlantoaxial instability. These children might have the risk of atlantoaxial dislocation and spinal cord compression if they play sport or take part actively in daily Iife. The purpose of our study was to assess the presumed risk. We examined and followed up one year Iong 35 children with Down syndrome through a series of Iateral cervical spine x-ray and neurological examination. Those children with an atlantoaxial distance => 5mm were considered uns...

  2. Atlantoaxial instability in Down's synarome

    OpenAIRE

    Kafadar, Ali; Hanci, Murat; Tuysuz, Beyhan; Sarioglu, Ali; Erginel, Ayten; Cenani, Asim

    2004-01-01

    9-31 % of children with Down syndrome have atlantoaxial instability. These children might have the risk of atlantoaxial dislocation and spinal cord compression if they play sport or take part actively in daily Iife. The purpose of our study was to assess the presumed risk. We examined and followed up one year Iong 35 children with Down syndrome through a series of Iateral cervical spine x-ray and neurological examination. Those children with an atlantoaxial distance => 5mm were considered ...

  3. Hydrodynamic instabilities in miscible fluids

    Science.gov (United States)

    Truzzolillo, Domenico; Cipelletti, Luca

    2018-01-01

    Hydrodynamic instabilities in miscible fluids are ubiquitous, from natural phenomena up to geological scales, to industrial and technological applications, where they represent the only way to control and promote mixing at low Reynolds numbers, well below the transition from laminar to turbulent flow. As for immiscible fluids, the onset of hydrodynamic instabilities in miscible fluids is directly related to the physics of their interfaces. The focus of this review is therefore on the general mechanisms driving the growth of disturbances at the boundary between miscible fluids, under a variety of forcing conditions. In the absence of a regularizing mechanism, these disturbances would grow indefinitely. For immiscible fluids, interfacial tension provides such a regularizing mechanism, because of the energy cost associated to the creation of new interface by a growing disturbance. For miscible fluids, however, the very existence of interfacial stresses that mimic an effective surface tension is debated. Other mechanisms, however, may also be relevant, such as viscous dissipation. We shall review the stabilizing mechanisms that control the most common hydrodynamic instabilities, highlighting those cases for which the lack of an effective interfacial tension poses deep conceptual problems in the mathematical formulation of a linear stability analysis. Finally, we provide a short overview on the ongoing research on the effective, out of equilibrium interfacial tension between miscible fluids.

  4. Microsatellite Instability Pathway and EMAST in Colorectal Cancer.

    Science.gov (United States)

    Carethers, John M

    2017-02-01

    Microsatellite instability (MSI) refers to the biochemical detection of frameshifted microsatellite sequences from genomic DNA. Genesis of MSI is due to defective DNA mismatch repair (MMR) that fails to correct post DNA replicative slippage mistakes at microsatellites. Most of the estimated 100,000 genomic microsatellites are non-coding; however, ~150-300 microsatellites are coding such that, when frameshifted during the pathogenesis of an MSI tumor, can generate immunogenic neopeptide antigens that limit the growth of tumor and prolong patient survival. In addition to the immune reaction and longer survival, patients with MSI colorectal cancers tend to have poorly differentiated tumors with mucinous features that are located in the right colon. Patients with MSI tumors are more resistant to 5-fluorouracil-based adjuvant chemotherapy but may be responsive to PD-1 immune checkpoint blockade. Specific defects of MMR function not only drive MSI but also elevate microsatellite alterations at selected tetranucleotide repeats that may further modify patient outcome.

  5. Genome constraint through sexual reproduction: application of 4D-Genomics in reproductive biology.

    Science.gov (United States)

    Horne, Steven D; Abdallah, Batoul Y; Stevens, Joshua B; Liu, Guo; Ye, Karen J; Bremer, Steven W; Heng, Henry H Q

    2013-06-01

    Assisted reproductive technologies have been used to achieve pregnancies since the first successful test tube baby was born in 1978. Infertile couples are at an increased risk for multiple miscarriages and the application of current protocols are associated with high first-trimester miscarriage rates. Among the contributing factors of these higher rates is a high incidence of fetal aneuploidy. Numerous studies support that protocols including ovulation-induction, sperm cryostorage, density-gradient centrifugation, and embryo culture can induce genome instability, but the general mechanism is less clear. Application of the genome theory and 4D-Genomics recently led to the establishment of a new paradigm for sexual reproduction; sex primarily constrains genome integrity that defines the biological system rather than just providing genetic diversity at the gene level. We therefore propose that application of assisted reproductive technologies can bypass this sexual reproduction filter as well as potentially induce additional system instability. We have previously demonstrated that a single-cell resolution genomic approach, such as spectral karyotyping to trace stochastic genome level alterations, is effective for pre- and post-natal analysis. We propose that monitoring overall genome alteration at the karyotype level alongside the application of assisted reproductive technologies will improve the efficacy of the techniques while limiting stress-induced genome instability. The development of more single-cell based cytogenomic technologies are needed in order to better understand the system dynamics associated with infertility and the potential impact that assisted reproductive technologies have on genome instability. Importantly, this approach will be useful in studying the potential for diseases to arise as a result of bypassing the filter of sexual reproduction.

  6. Mapping of microsatellite instability in endoscopic normal colon.

    Science.gov (United States)

    Tug, Esra; Balaban, Yasemin H; Sahin, Ebru Kaplan

    2012-05-01

    Genomic instability in colorectal cancer (CRC) occurs as either microsatellite instability (MSI) or chromosomal instability. The present study was aimed at examining the MSI for the MLH1 and MSH2 genes in normal colon and polyps, if detected. Four segments of the colon were sampled in 102 subjects during colonoscopy. DNA samples were analyzed for the MSI status according to the Bethesda consensus panel. Family history of any type of cancer or for colon cancer was present in 44.8% and 9.4% of the individuals, respectively. Forty-eight percent of individuals were microsatellite stable for all five markers at all locations, 20% had low MSI status (MSI-L), and 32% had high MSI status (MSI-H). The frequencies of MSI markers differed significantly from each other (p=0.003). The most frequent positive marker was D17S250. This is the first study which revealed that MSI is present in endoscopically normal-looking colon of normal individuals and, more frequently, in individuals with family histories of CRC. The detection of very early-stage CRC is possible by MSI analysis of DNA mismatch repair genes in colon tissues. This study has revealed crucial information for the use of molecular tests in CRC screening, such as high frequencies of MSI in endoscopically normal colon, which might cause false positivity.

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

    Directory of Open Access Journals (Sweden)

    M Fukuda

    2009-06-01

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

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

    Energy Technology Data Exchange (ETDEWEB)

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

    2008-04-02

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

  10. instability

    Directory of Open Access Journals (Sweden)

    Magdalena Czubaszek

    2014-06-01

    Full Text Available The basic method for analyzing the degree of DNA fragmentation caused by genotoxic factors is gel electrophoresis of single cells (single cell gel electrophoresis, also called the comet assay. The comet assay enables the analysis of the level of several different DNA modifications. The basic testing procedure has been only slightly modified. This method helps identify single-strand and double-strand DNA cracks, as well as any chemical and enzymatic modifications that can potentially turn into cracks in DNA or chromatids. The comet assay makes it possible to detect DNA damage at the level of single cells. It can be employed in analyses of any tissues which provide cellular suspensions. Analysed cells are submerged in agarose on a microscope slide. DNA is what is left after proteins have been broken down. The slide is then subjected to electrophoresis and stained with a fluorescent dye. A “comet-like” image is obtained. The “head” is the cell fixation site prior to lysis; the “tail” represents damaged DNA fragments. The extent of DNA damage is reflected in the length of the tail and the amount of DNA contained in it. The assay finds research applications in the following fields: genetic toxicology, monitoring of DNA repair following chemotherapy and radiotherapy, ecotoxicology, animal and human nourishment, biomonitoring of genotoxicity, epidemiology and assessment of material deposited in sperm and blood banks.

  11. Modes of storage ring coherent instabilities

    Energy Technology Data Exchange (ETDEWEB)

    Wang, J.M.

    1986-12-01

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

  12. Karyotypic Determinants of Chromosome Instability in Aneuploid Budding Yeast

    Science.gov (United States)

    Bradford, William D.; Li, Rong

    2012-01-01

    Recent studies in cancer cells and budding yeast demonstrated that aneuploidy, the state of having abnormal chromosome numbers, correlates with elevated chromosome instability (CIN), i.e. the propensity of gaining and losing chromosomes at a high frequency. Here we have investigated ploidy- and chromosome-specific determinants underlying aneuploidy-induced CIN by observing karyotype dynamics in fully isogenic aneuploid yeast strains with ploidies between 1N and 2N obtained through a random meiotic process. The aneuploid strains exhibited various levels of whole-chromosome instability (i.e. chromosome gains and losses). CIN correlates with cellular ploidy in an unexpected way: cells with a chromosomal content close to the haploid state are significantly more stable than cells displaying an apparent ploidy between 1.5 and 2N. We propose that the capacity for accurate chromosome segregation by the mitotic system does not scale continuously with an increasing number of chromosomes, but may occur via discrete steps each time a full set of chromosomes is added to the genome. On top of such general ploidy-related effect, CIN is also associated with the presence of specific aneuploid chromosomes as well as dosage imbalance between specific chromosome pairs. Our findings potentially help reconcile the divide between gene-centric versus genome-centric theories in cancer evolution. PMID:22615582

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

    Directory of Open Access Journals (Sweden)

    Rabindra N Bhattacharjee

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

  14. Microsatellite instability in prostate cancer

    Energy Technology Data Exchange (ETDEWEB)

    Shan, A.L.; Wick, M.J.; Persons, D.L. [Mayo Clinic and Foundation, Rochester, MN (United States)] [and others

    1994-09-01

    Microsatellite instability (MIN) has been documented in hereditary nonpolyposis colorectal cancer (HNPCC) as well as in sporadic forms of human cancers. Two of the genes which appear to be responsible for this particular tumor phenotype, hMSH2 and hMLH1, have now been identified. To determine the potential role of these mutator genes in prostate cancer, we have examined 95 prostate adenocarcinomas (40 paraffin embedded and 55 fresh frozen) for the presence of genetic instability at four microsatellite markers. The markers are localized to chromosome arms 5q(APC-CA1), 8p(Mfd 210Z), 15q(635/636), and 17q(p53-CA). Patients from whom paraffin embedded material was obtained were divided into short term (<3 years, n=18), and long term (>3 years, n=22) survivors. Of the 95 tumors examined, only four tumors (4%) demonstrated MIN: two tumors demonstrated MIN at 3 loci (p53-CA, APC-CA1, 635/636), one tumor demonstrated MIN at 2 loci (APC-CA1 and 635/636), and one tumor demonstrated instability at 635/636 only. All tumors exhibiting MIN had Gleason scores of {ge} 4+4. A correlation between MIN and survival was not observed. Information on family history was limited. However, of the two patients demonstrating MIN at three loci, one patient was diagnosed with a second malignancy (TCC of the ureter), but otherwise had a negative family history, while the second patient had one first degree relative with esophageal cancer. The patient demonstrating MIN at two loci had a negative family history, while the remaining patient had two first degree relatives with cancer (prostate and stomach). These results suggest that hMSH2 and hMLH1 (as reflected by the small percentage of tumors displaying MIN) do not play a prominent role in the process of prostate tumorigenesis.

  15. Transverse Instabilities in the Fermilab Recycler

    Energy Technology Data Exchange (ETDEWEB)

    Prost, L.R.; Burov, A.; Shemyakin, A.; Bhat, C.M.; Crisp, J.; Eddy, N.; /Fermilab

    2011-07-01

    Transverse instabilities of the antiproton beam have been observed in the Recycler ring soon after its commissioning. After installation of transverse dampers, the threshold for the instability limit increased significantly but the instability is still found to limit the brightness of the antiprotons extracted from the Recycler for Tevatron shots. In this paper, we describe observations of the instabilities during the extraction process as well as during dedicated studies. The measured instability threshold phase density agrees with the prediction of the rigid beam model within a factor of 2. Also, we conclude that the instability threshold can be significantly lowered for a bunch contained in a narrow and shallow potential well due to effective exclusion of the longitudinal tails from Landau damping.

  16. Mode-locking via dissipative Faraday instability.

    Science.gov (United States)

    Tarasov, Nikita; Perego, Auro M; Churkin, Dmitry V; Staliunas, Kestutis; Turitsyn, Sergei K

    2016-08-09

    Emergence of coherent structures and patterns at the nonlinear stage of modulation instability of a uniform state is an inherent feature of many biological, physical and engineering systems. There are several well-studied classical modulation instabilities, such as Benjamin-Feir, Turing and Faraday instability, which play a critical role in the self-organization of energy and matter in non-equilibrium physical, chemical and biological systems. Here we experimentally demonstrate the dissipative Faraday instability induced by spatially periodic zig-zag modulation of a dissipative parameter of the system-spectrally dependent losses-achieving generation of temporal patterns and high-harmonic mode-locking in a fibre laser. We demonstrate features of this instability that distinguish it from both the Benjamin-Feir and the purely dispersive Faraday instability. Our results open the possibilities for new designs of mode-locked lasers and can be extended to other fields of physics and engineering.

  17. Asymptotic Behavior of the Electron Cloud Instability

    Energy Technology Data Exchange (ETDEWEB)

    Heifets, Samuel; /SLAC

    2007-06-06

    The fast beam-ion instability and the single bunch electron-cloud instability are substantially nonlinear phenomena and can be analyzed in a similar way. The initial exponential growth of the amplitudes known for both instabilities takes place only in the linear approximation. Later, in the nonlinear regime, amplitudes grow according to a power law or even decrease. We analyze the nonlinear regime describing the growth of amplitudes in time and along the train of bunches. Analytic analysis is compared with simulations.

  18. Evaluation and Management of Posterior Shoulder Instability

    Science.gov (United States)

    Tannenbaum, Eric; Sekiya, Jon K.

    2011-01-01

    Context: Posterior shoulder instability is a commonly misdiagnosed disorder in many competitive athletes. Type of Study: Clinical review. Evidence Acquisition: Relevant studies on posterior shoulder instability from 1950 to 2010 in PubMed and Cochrane databases were reviewed. Results: A total of 107 studies were reviewed. Conclusion: Patients who have undergone at least 6 months of physical therapy and still experience instability symptoms should be considered for surgical stabilization directed at their underlying pathology. PMID:23016015

  19. Instabilities of flows and transition to turbulence

    CERN Document Server

    Sengupta, Tapan K

    2012-01-01

    Introduction to Instability and TransitionIntroductionWhat Is Instability?Temporal and Spatial InstabilitySome Instability MechanismsComputing Transitional and Turbulent FlowsFluid Dynamical EquationsSome Equilibrium Solutions of the Basic EquationBoundary Layer TheoryControl Volume Analysis of Boundary LayersNumerical Solution of the Thin Shear Layer (TSL) EquationLaminar Mixing LayerPlane Laminar JetIssues of Computing Space-Time Dependent FlowsWave Interaction: Group Velocity and Energy FluxIssues of Space-Time Scale Resolution of FlowsTemporal Scales in Turbulent FlowsComputing Time-Averag

  20. Size-effects on cavitation instabilities

    DEFF Research Database (Denmark)

    Niordson, Christian Frithiof; Tvergaard, Viggo

    2005-01-01

    In metal-ceramic systems the constraint on plastic flow leads to so high stress triaxialities that cavitation instabilities may occur. If the void radius is on the order of magnitude of a characteristic length for the metal, the rate of void growth is reduced, and the possibility of unstable cavity...... triaxiality, where cavitation instabilities are predicted by conventional plasticity theory, such instabilities are also found for the nonlocal theory, but the effects of gradient hardening delay the onset of the instability. Furthermore, in some cases the cavitation stress reaches a maximum and then decays...

  1. Review of two-phase instabilities

    Energy Technology Data Exchange (ETDEWEB)

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

    1997-06-01

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

  2. Two-Beam Instability in Electron Cooling

    Energy Technology Data Exchange (ETDEWEB)

    Burov, Alexey V.; /Fermilab

    2006-04-01

    The drift motion of cooling electrons makes them able to respond to transverse perturbations of a cooled ion beam. This response may lead to dipole or quadrupole transverse instabilities at specific longitudinal wave numbers. While the dipole instabilities can be suppressed by a combination of the Landau damping, machine impedance, and the active damper, the quadrupole and higher order modes can lead to either emittance growth, or a lifetime degradation, or both. The growth rates of these instabilities are strongly determined by the machine x-y coupling. Thus, tuning out of the coupling resonance and/or reduction of the machine coupling can be an efficient remedy for these instabilities.

  3. Systems and methods for controlling flame instability

    KAUST Repository

    Cha, Min Suk

    2016-07-21

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

  4. Combustion instability modeling and analysis

    Energy Technology Data Exchange (ETDEWEB)

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

    1995-10-01

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

  5. Option price and market instability

    Science.gov (United States)

    Baaquie, Belal E.; Yu, Miao

    2017-04-01

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

  6. Manual testing for ankle instability.

    Science.gov (United States)

    Wilkin, Emily Jane; Hunt, Adrienne; Nightingale, Elizabeth Jean; Munn, Joanne; Kilbreath, Sharon Lynne; Refshauge, Kathryn Margaret

    2012-12-01

    To assess inter-rater reliability of ankle manual tests. We also correlated the manual tests with the Cumberland Ankle Instability Tool (CAIT). One ankle from each of 60 participants was assessed using four different manual tests (anterior drawer in supine and crook lying, talar tilt, inversion tilt). Three different raters, varying in experience, tested each participant. The CAIT questionnaire was also administered. The study received ethics approval from the University of Sydney Human Research Ethics Committee. Intraclass correlation coefficients (ICC), standard error of the mean (SEM) and percent close agreement (PCA) were used to determine reliability of the four tests. Pearson's correlation coefficients were used to determine relationships between the manual tests and CAIT scores. Inter-rater reliability for the four manual tests was poor regardless of therapist's experience (ICC([1,1]) -0.12 to 0.33; SEM 0.93-1.69). Correlations between the CAIT and manual tests were also low varying between r = -0.12 and -0.42. Inter-rater reliability was poor for manual tests of ankle stability. Reliability may be improved by using a grading scale with fewer intervals. The CAIT scores and manual tests correlated poorly, potentially reflecting the variety of conditions leading to ankle instability. Crown Copyright © 2012. Published by Elsevier Ltd. All rights reserved.

  7. Adhesional instabilities and gecko locomotion

    Science.gov (United States)

    Williams, John A.

    2015-01-01

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

  8. Hydrodynamic instability of meandering channels

    Science.gov (United States)

    Ali, Sk Zeeshan; Dey, Subhasish

    2017-12-01

    In this paper, we explore the hydrodynamic instability of meandering channels driven by the turbulent flow. The governing equations of channel dynamics with suitable boundary conditions are closed with the fluid and granular constitutive relationships. A regular expansion of the fundamental variables is employed to linearize the parent equations by superimposing the perturbations on the basic unperturbed flow. The channel dynamics reveal a resonance phenomenon which occurs when the key variables fall in the vicinity of the distinct critical values. The resonance phenomenon preserves its distinctive signature in different flow regimes which are guided by the characteristic values of the shear Reynolds number. The hydrodynamic analysis indicates that the fluid friction and the volumetric sediment flux play a decisive role to characterize the channel instability in different flow regimes. The growths of azimuthal velocity perturbation in phase with curvature, bed topography perturbation, bend amplification rate, and meander propagation speed in different flow regimes are investigated by varying the meander wavenumber, Shields number, channel aspect ratio, and relative roughness number. The analysis is capable to capture the effects of grain size on azimuthal velocity perturbation, bed topography perturbation, bend amplification rate, and meandering propagation speed over a wide range of shear Reynolds numbers. The variations of resonant wavenumbers in different flow regimes with the Shields number, channel aspect ratio, and relative roughness number are addressed. For a specific flow regime, the upstream and downstream migrations of meandering channels are typically governed by the Shields number, channel aspect ratio, and relative roughness number.

  9. The effects of in utero irradiation on mutation induction and transgenerational instability in mice

    Energy Technology Data Exchange (ETDEWEB)

    Barber, Ruth C.; Hardwick, Robert J.; Shanks, Morag E.; Glen, Colin D.; Mughal, Safeer K.; Voutounou, Mariel [Department of Genetics, University of Leicester, University Road, Leicester, LE1 7RH (United Kingdom); Dubrova, Yuri E., E-mail: yed2@le.ac.uk [Department of Genetics, University of Leicester, University Road, Leicester, LE1 7RH (United Kingdom)

    2009-05-12

    Epidemiological evidence suggests that the deleterious effects of prenatal irradiation can manifest during childhood, resulting in an increased risk of leukaemia and solid cancers after birth. However, the mechanisms underlying the long-term effects of foetal irradiation remain poorly understood. This study was designed to analyse the impact of in utero irradiation on mutation rates at expanded simple tandem repeat (ESTR) DNA loci in directly exposed mice and their first-generation (F{sub 1}) offspring. ESTR mutation frequencies in the germline and somatic tissues of male and female mice irradiated at 12 days of gestation remained highly elevated during adulthood, which was mainly attributed to a significant increase in the frequency of singleton mutations. The prevalence of singleton mutations in directly exposed mice suggests that foetal irradiation results in genomic instability manifested both in utero and during adulthood. The frequency of ESTR mutation in the F{sub 1} offspring of prenatally irradiated male mice was equally elevated across all tissues, which suggests that foetal exposure results in transgenerational genomic instability. In contrast, maternal in utero exposure did not affect the F{sub 1} stability. Our data imply that the passive erasure of epigenetic marks in the maternal genome can diminish the transgenerational effects of foetal irradiation and therefore provide important clues to the still unknown mechanisms of radiation-induced genomic instability. The results of this study offer a plausible explanation for the effects of in utero irradiation on the risk of leukaemia and solid cancers after birth.

  10. Comparative Genomics

    Indian Academy of Sciences (India)

    tory motifs and other non-coding DNA motifs, and genome flux and dynamics. Finally the article describes how the information one can extract from a comparative analysis of genomes depends to a large extent, on the specific aspect of the genomes that is being compared and the phylogenetic distances of the organisms ...

  11. Cancer genomics

    DEFF Research Database (Denmark)

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

    2007-01-01

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

  12. Interface instability modes in freezing colloidal suspensions - revealed from onset of planar instability

    OpenAIRE

    Lilin Wang; Jiaxue You; Zhijun Wang; Jincheng Wang; Xin Lin

    2015-01-01

    Freezing colloidal suspensions widely exists in nature and industry. Interface instability has attracted much attention for the understandings of the pattern formation in freezing colloidal suspensions. However, the interface instability modes, the origin of the ice banding or ice lamellae, are still unclear. In-situ experimental observation of the onset of interface instability remains absent up to now. Here, by directly imaging the initial transient stage of planar interface instability in ...

  13. Genetic instability is associated with histological transformation of follicle center lymphoma.

    Science.gov (United States)

    Nagy, M; Balázs, M; Adám, Z; Petkó, Z; Tímár, B; Szereday, Z; László, T; Warnke, R A; Matolcsy, A

    2000-12-01

    Follicle center lymphoma (FCL) is an indolent B cell non-Hodgkin's lymphoma (NHL) characterized genetically by the t(14;18) translocation. Histological transformation and clinical progression of FCLs are frequently associated with secondary genetic alterations at both nucleic acid and chromosomal levels. To determine the type and pattern of genomic instability occurring in histological transformation of FCLs and the role of DNA mismatch repair defects in this procedure, we have performed microsatellite analysis, comparative genomic hybridization (CGH) and mutational analysis of hMLH1 and hMSH2 genes on serial biopsy specimens from patients with FCL transformed to diffuse large cell lymphoma (DLCL). Paired biopsy samples of eight patients were analyzed for microsatellite instability and structural alterations for hMLH1 and hMSH2 genes, and tumor samples of five patients were subjected to CGH analysis. A high level of microsatellite instability was associated with histological transformation of two cases of FCL, but no mutations of the hMLH1 and hMSH2 genes were detected in any of the lymphoma samples. In the five cases subjected to CGH analysis, the histological transformation of FCLs was associated with genomic imbalances at 21 chromosomal regions. The genomic abnormalities found were rather heterogeneous and none of the genetic changes were overrepresented in the transformed DLCLs. These data suggest that histological transformation of FCLs to DLCL is frequently associated with genome wide instability at both nucleic acid and chromosomal levels, although mutations of the hMSH1 and hMLH2 genes are not involved in this process.

  14. Instability of vortex pair leapfrogging

    DEFF Research Database (Denmark)

    Tophøj, Laust; Aref, Hassan

    2013-01-01

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

  15. Instability Threshold “Hysteresis”

    Directory of Open Access Journals (Sweden)

    Agnes Muszynska

    1999-01-01

    Full Text Available The transient process which starts at the instability threshold of a rotor rotating in a fluid environment, and ends up in the limit cycle of self-excited vibrations known as fluid whirl or fluid whip, is discussed in this paper. A one-lateral-mode, isotropic, nonlinear model of the rotor with fluid interaction allows for exact particular solutions and an estimation of the transient process. The fluid interacting with the rotor is contained in a small radial clearance area, such as in bearings, seals, or rotor-to-stator clearances, and its effects are represented by fluid film radial stiffness, damping, and fluid inertia rotating at a different angular velocities.

  16. Instabilities in coaxial rotating jets

    Science.gov (United States)

    Ivanic, Tanja; Foucault, Eric; Pecheux, Jean; Gilard, Virginie

    2000-12-01

    The aim of this study is the characterization of the cylindrical mixing layer resulting from the interaction of two coaxial swirling jets. The experimental part of this study was performed in a cylindrical water tunnel, permitting an independent rotation of two coaxial jets. The rotations are generated by means of 2×36 blades localized in two swirling chambers. As expected, the evolution of the main instability modes presents certain differences compared to the plane-mixing-layer case. Experimental results obtained by tomography showed the existence of vortex rings and streamwise vortex pairs in the near field region. This method also permitted the observation of the evolution and interaction of different modes. PIV velocity measurements realized in the meridian plans and the plans perpendicular to the jet axis show that rotation distorts the typical top-hat axial velocity profile. The transition of the axial velocity profile from jet-like into wake-like is also observed.

  17. Plasma instabilities in high electric fields

    DEFF Research Database (Denmark)

    Morawetz, K.; Jauho, Antti-Pekka

    1994-01-01

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

  18. Cultural diversity, economic development and societal instability.

    Science.gov (United States)

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

    2007-09-26

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

  19. Recurrent Shoulder Instability After Primary Bankart Repair.

    Science.gov (United States)

    Donohue, Michael A; Mauntel, Timothy C; Dickens, Jonathan F

    2017-09-01

    The glenohumeral joint is one of the most frequently dislocated joints and occurs with increasing frequency in collision and contact athletes, especially those in sports that repeatedly place the glenohumeral joint in a position of vulnerability. Nonoperative management of shoulder instability especially in young contact athletes results in unacceptably high recurrence rates; thus, early surgical stabilization has become commonplace. Surgical stabilization typically yields acceptable outcomes. However, recurrent anterior instability may occur following a previous stabilization procedure at rates of 7% to 12%. Recurrent glenohumeral instability represents a treatment challenge for orthopedic surgeons as it not only has the potential to result in subsequent surgery, therapy, and missed activity time, but also has been associated with long-term degenerative joint changes. Thus, recurrent instability requires close examination to determine underlying pathology leading to failure. Evaluation of underlying pathology requires consideration of patient activity-related factors, hyperlaxity and multidirectional instability, glenoid bone loss, glenoid track lesions, and other pathologic lesions. Revision surgical stabilization approaches include arthroscopic and open stabilization, as well as glenoid osseous augmentation procedures. Postoperative rehabilitation and release to sports and activity must be tailored to protect the shoulder from continued instability. Understanding that risk of recurrent glenohumeral instability and the risk factors associated with it are essential so that these factors may be mitigated and recurrent instability prevented.

  20. Energetic particle instabilities in fusion plasmas

    NARCIS (Netherlands)

    Sharapov, S. E.; Alper, B.; Berk, H. L.; Borba, D. N.; Breizman, B. N.; Challis, C. D.; Classen, I.G.J.; Edlund, E. M.; Eriksson, J.; Fasoli, A.; Fredrickson, E. D.; Fu, G. Y.; M. García-Muñoz,; Gassner, T.; Ghantous, K.; Goloborodko, V.; Gorelenkov, N. N.; Gryaznevich, M. P.; Hacquin, S.; Heidbrink, W. W.; Hellesen, C.; Kiptily, V. G.; Kramer, G. J.; Lauber, P.; Lilley, M. K.; Lisak, M.; Nabais, F.; Nazikian, R.; Nyqvist, R.; Osakabe, M.; C. Perez von Thun,; Pinches, S. D.; Podesta, M.; Porkolab, M.; Shinohara, K.; Schoepf, K.; Todo, Y.; Toi, K.; VanZeeland, M. A.; Voitsekhovich, I.; White, R. B.; Yavorskij, V.; ITPA EP TG Contributors,; JET-EFDA Contributors,

    2013-01-01

    Remarkable progress has been made in diagnosing energetic particle instabilities on present-day machines and in establishing a theoretical framework for describing them. This overview describes the much improved diagnostics of Alfvén instabilities and modelling tools developed world-wide, and

  1. The short circuit instability in protoplanetary disks

    DEFF Research Database (Denmark)

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

    2013-01-01

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

  2. Instabilities and transition in boundary layers

    Indian Academy of Sciences (India)

    Abstract. Some recent developments in boundary layer instabilities and transition are reviewed. Background disturbance levels determine the instability mechanism that ulti- mately leads to turbulence. At low noise levels, the traditional Tollmien–Schlichting route is followed, while at high levels, a 'by-pass' route is more ...

  3. Gravitational Instability of Cylindrical Viscoelastic Medium ...

    Indian Academy of Sciences (India)

    field on the gravitational instability of strongly coupled plasma and observed that instability criterion gets modified due to the presence of non uniform magnetic field in transverse mode of wave propagation under both the kinetic and hydrodynamic limits, when the viscoelastic medium is infinitely electrically conducting.

  4. Genetically determined chromosome instability syndromes.

    Science.gov (United States)

    Schroeder, T M

    1982-01-01

    Spontaneously increased chromosomal instability is well documented in the three autosomal recessive diseases, Fanconi's anemia (FA), Bloom's syndrome (BS), and ataxia telangiectasia (AT). Other conditions have been reported to be associated with chromosomal breakage. Some are still single observations: in Werner's syndrome only fibroblasts are affected, and systemic sclerosis may not be an inherited disease. Various aspects of FA, BS, and AT are discussed which have emerged since recent reviews have been published. The differential diagnosis in FA has become more important than it was in the past. Proven heterogeneity in FA demands definition of what to name FA and FA variants. The analysis of cancer frequencies and types in FA and AT lacks important clues. This should stimulate all of us to mutual exchange of data and creation of registries not only of patients and follow-ups, but also of characterized cell strains. A synopsis of results from cell and cytogenetic studies demonstrates similarities and differences in detail of the general phenomenon of chromosomal instability which FA, BS, and AT share. Results from biochemical studies at the DNA level together with cytogenetic findings indicate different but still undefined failures in DNA metabolism or DNA repair mechanisms due to the different genes. A new approach to analyzing the impairment of DNA repair in FA is briefly described. DNA related enzymes are produced in the cytoplasm and have to be transported to the nucleus. The subcellular distribution of topoisomerase activity was found to be unusual in three placentas of FA patients. Other DNA enzymes were distributed normally. Thus, a specific mechanism for movement of the enzyme through the nuclear membrane seems to be defective.

  5. Surface instabilities during straining of anisotropic materials

    DEFF Research Database (Denmark)

    Legarth, Brian Nyvang; Richelsen, Ann Bettina

    2006-01-01

    The development of instabilities in traction-free surfaces is investigated numerically using a unit cell model. Full finite strain analyses are conducted using isotropic as well as anisotropic yield criteria and both plane strain tension and compression are considered. In the load range of tension...... of principal overall strain. For other orientations surface instabilities are seen when non-associated plastic flow is taken into account. Compared to tension, smaller compressive deformations are needed in order to initiate a surface instability....... investigated, it is found that isotropic plasticity can only predict surface instabilities if non-associated plastic flow is accounted for. However, for anisotropic plasticity a surface instability is observed for associated plastic flow if the principal axes of anisotropy coincide with the directions...

  6. 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.

  7. Taming contact line instability for pattern formation

    Science.gov (United States)

    Deblais, A.; Harich, R.; Colin, A.; Kellay, H.

    2016-08-01

    Coating surfaces with different fluids is prone to instability producing inhomogeneous films and patterns. The contact line between the coating fluid and the surface to be coated is host to different instabilities, limiting the use of a variety of coating techniques. Here we take advantage of the instability of a receding contact line towards cusp and droplet formation to produce linear patterns of variable spacings. We stabilize the instability of the cusps towards droplet formation by using polymer solutions that inhibit this secondary instability and give rise to long slender cylindrical filaments. We vary the speed of deposition to change the spacing between these filaments. The combination of the two gives rise to linear patterns into which different colloidal particles can be embedded, long DNA molecules can be stretched and particles filtered by size. The technique is therefore suitable to prepare anisotropic structures with variable properties.

  8. Tensile Instability in a Thick Elastic Body

    Science.gov (United States)

    Overvelde, Johannes; Dykstra, David; de Rooij, Rijk; Bertoldi, Katia

    A range of instabilities can occur in soft bodies that undergo large deformation. While most of them arise under compressive forces, it has previously been shown analytically that a tensile instability can occur in an elastic block subjected to equitriaxial tension. Guided by this result, we conducted centimeter-scale experiments on thick elastomeric samples under generalized plane strain conditions and observed for the first time this elastic tensile instability. We found that equibiaxial stretching leads to the formation of a wavy pattern, as regions of the sample alternatively flatten and extend in the out-of-plane direction. Our work uncovers a new type of instability that can be triggered in elastic bodies, enlarging the design space for smart structures that harness instabilities to enhance their functionality.

  9. Plasma electron hole oscillatory velocity instability

    Science.gov (United States)

    Zhou, Chuteng; Hutchinson, Ian H.

    2017-10-01

    In this paper, we report a new type of instability of electron holes (EHs) interacting with passing ions. The nonlinear interaction of EHs and ions is investigated using a new theory of hole kinematics. It is shown that the oscillation in the velocity of the EH parallel to the magnetic field direction becomes unstable when the hole velocity in the ion frame is slower than a few times the cold ion sound speed. This instability leads to the emission of ion-acoustic waves from the solitary hole and decay in its magnitude. The instability mechanism can drive significant perturbations in the ion density. The instability threshold, oscillation frequency and instability growth rate derived from the theory yield quantitative agreement with the observations from a novel high-fidelity hole-tracking particle-in-cell code.

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

    OpenAIRE

    Piqueras, Marta; Navarro, Samuel; Cañete, Adela; Castel, Victoria; Noguera, Rosa

    2011-01-01

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

  11. Genomic disorders: A window into human gene and genome evolution

    Science.gov (United States)

    Carvalho, Claudia M. B.; Zhang, Feng; Lupski, James R.

    2010-01-01

    Gene duplications alter the genetic constitution of organisms and can be a driving force of molecular evolution in humans and the great apes. In this context, the study of genomic disorders has uncovered the essential role played by the genomic architecture, especially low copy repeats (LCRs) or segmental duplications (SDs). In fact, regardless of the mechanism, LCRs can mediate or stimulate rearrangements, inciting genomic instability and generating dynamic and unstable regions prone to rapid molecular evolution. In humans, copy-number variation (CNV) has been implicated in common traits such as neuropathy, hypertension, color blindness, infertility, and behavioral traits including autism and schizophrenia, as well as disease susceptibility to HIV, lupus nephritis, and psoriasis among many other clinical phenotypes. The same mechanisms implicated in the origin of genomic disorders may also play a role in the emergence of segmental duplications and the evolution of new genes by means of genomic and gene duplication and triplication, exon shuffling, exon accretion, and fusion/fission events. PMID:20080665

  12. Anterior Shoulder Instability in the Military Athlete.

    Science.gov (United States)

    Waterman, Brian; Owens, Brett D; Tokish, John M

    Given its young, predominately male demographics and intense physical demands, the US military remains an ideal cohort for the study of anterior shoulder instability. A literature search of PubMed, MEDLINE, and the Cochrane Database was performed to identify all peer-reviewed publications from 1950 to 2016 from US military orthopaedic surgeons focusing on the management of anterior shoulder instability. Clinical review. Level 4. The incidence of anterior shoulder instability events in the military occurs at an order of magnitude greater than in civilian populations, with rates as high as 3% per year among high-risk groups. With more than 90% risk of a Bankart lesion and high risk for instability recurrence, the military has advocated for early intervention of first-time shoulder instability while documenting up to 76% relative risk reduction versus nonoperative treatment. Preoperative evaluation with advanced radiographic imaging should be used to evaluate for attritional bone loss or "off-track" engaging defects to guide comprehensive surgical management. With complex recurrent shoulder instability and/or cases of clinically significant osseous lesions, potential options such as remplissage, anterior open capsular procedures, or bone augmentation procedures may be preferentially considered. Careful risk stratification, clinical evaluation, and selective surgical management for at-risk military patients with anterior shoulder instability can optimize the recurrence risk and functional outcome in this population.

  13. The Relationship Between Spontaneous Telomere Loss and Chromosome Instability in a Human Tumor Cell Line

    Directory of Open Access Journals (Sweden)

    Bijan Fouladi

    2000-01-01

    Full Text Available Chromosome instability plays an important role in cancer by promoting the alterations in the genome required for tumor cell progression. The loss of telomeres that protect the ends of chromosomes and prevent chromosome fusion has been proposed as one mechanism for chromosome instability in cancer cells, however, there is little direct evidence to support this hypothesis. To investigate the relationship between spontaneous telomere loss and chromosome instability in human cancer cells, clones of the EJ-30 tumor cell line were isolated in which a herpes simplex virus thymidine kinase (HSV-tk gene was integrated immediately adjacent to a telomere. Selection for HSV-tkdeficient cells with ganciclovir demonstrated a high rate of loss of the end these "marked" chromosomes (10-4 events/cell per generation. DNA sequence and cytogenetic analysis suggests that the loss of function of the HSV-tk gene most often involves telomere loss, sister chromatid fusion, and prolonged periods of chromosome instability. In some HSV-tk-deficient cells, telomeric repeat sequences were added on to the end of the truncated HSV-tk gene at a new location, whereas in others, no telomere was detected on the end of the marked chromosome. These results suggest that spontaneous telomere loss is a mechanism for chromosome instability in human cancer cells.

  14. Genome Architecture and Its Roles in Human Copy Number Variation

    Directory of Open Access Journals (Sweden)

    Lu Chen

    2014-12-01

    Full Text Available Besides single-nucleotide variants in the human genome, large-scale genomic variants, such as copy number variations (CNVs, are being increasingly discovered as a genetic source of human diversity and the pathogenic factors of diseases. Recent experimental findings have shed light on the links between different genome architectures and CNV mutagenesis. In this review, we summarize various genomic features and discuss their contributions to CNV formation. Genomic repeats, including both low-copy and high-copy repeats, play important roles in CNV instability, which was initially known as DNA recombination events. Furthermore, it has been found that human genomic repeats can also induce DNA replication errors and consequently result in CNV mutations. Some recent studies showed that DNA replication timing, which reflects the high-order information of genomic organization, is involved in human CNV mutations. Our review highlights that genome architecture, from DNA sequence to high-order genomic organization, is an important molecular factor in CNV mutagenesis and human genomic instability.

  15. Serum Cartilage Biomarkers and Shoulder Instability.

    Science.gov (United States)

    Owens, Brett D; Cameron, Kenneth L; Bokshan, Steven L; Clifton, Kari B; Svoboda, Steven J; Wolf, Jennifer Moriatis

    2017-01-01

    Differences in cartilage biomarkers have been noted in patients with anterior cruciate ligament tears, but little is known about any similar relationship with shoulder instability. This study evaluated the relationship between serum cartilage biomarkers and shoulder instability. The authors present a prospective cohort study of young athletes followed from 2006 to 2010. A nested case-control analysis was conducted within this cohort to evaluate the association between preinjury collagen type II cleavage (a marker for type II collagen cleavage) and procollagen II carboxy propeptide (a marker of cartilage synthesis) and the subsequent likelihood of shoulder instability during the 4-year follow-up period. Preinjury collagen type II cleavage and procollagen II carboxy propeptide levels in 51 subjects who had shoulder instability were compared with levels in 210 subjects without documented anterior cruciate ligament or shoulder instability (control group) with commercially available enzyme-linked immunosorbent assay kits. Mean preinjury collagen type II cleavage levels in patients who subsequently had shoulder instability were significantly lower than those in the control group (73.91 vs 79.24 pg/mL, P=.03). No significant difference was found in preinjury procollagen II carboxy propeptide levels compared with the control group (359.94 vs 396.37, P=.24). This study is the first to examine the relationship between baseline collagen biomarkers and subsequent shoulder instability. The finding of lower baseline collagen type II cleavage levels in patients with subsequent shoulder instability may represent a genetic predisposition or a compensatory mechanism by which cartilage degradation is decreased in those who are more likely to have instability. [Orthopedics. 2017; 40(1):34-36.]. Copyright 2016, SLACK Incorporated.

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

    Directory of Open Access Journals (Sweden)

    A.L. Cisyk

    2015-03-01

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

  17. Somatic instability of the expanded allele of IT-15 from patients with Huntington disease

    Energy Technology Data Exchange (ETDEWEB)

    Stine, O.C.; Pleasant, N.; Ross, C.A. [Johns Hopkins Univ., Baltimore, MD (United States)] [and others

    1994-09-01

    Huntington`s disease (HD) is an inherited neurodegenerative disorder caused by an expanded trinucleotide repeat in the gene IT-15. Although the expanded allele of IT-15 is unstable during gametogenesis, particularly, spermatogenesis, it is not clear if there is somatic stability. There are two reports of stability and one of instability. In order to test whether somatic instability occurs in the expansions found in HD, we have compared amplified genomic DNA isolated from either blood or distinct regions of autopsied brains of persons with Huntington disease. We find that somatic variation occurs in at least two ways. First, in cases with longer repeats (n > 47), the cerebellum often (8 of 9 cases) has a smaller number of repeats (2 to 10 less) than other tested regions of the brain. The larger the expanded allele, the larger the reduction in size of the repeat in the cerebellum (r=0.94, p<0.0001, df=12). Second, regardless of the repeat size, the number of amplification products from genomic DNA isolated from the cerebellum is smaller than that from genomic DNA from other forebrain regions such as the dorsal parietal cortex. As the length of the expanded allele increases, the number of amplification products increase in either tissue (r=0.86, p<0.001, df=12). Therefore our data demonstrates somatic instability especially for longer repeats.

  18. Chromosomal instability in B-lymphoblasotoid cell lines from Werner and Bloom syndrome patients.

    Science.gov (United States)

    Honma, Masamitsu; Tadokoro, Satoshi; Sakamoto, Hiroko; Tanabe, Hideyuki; Sugimoto, Masanobu; Furuichi, Yasuhiro; Satoh, Takatomo; Sofuni, Toshio; Goto, Makoto; Hayashi, Makoto

    2002-09-26

    Werner's syndrome (WS) and Bloom's syndrome (BS) are rare autosomal genetic diseases that predispose to cancer and are associated with genomic instability. To characterize the genomic instability of WS and BS, we analyzed and compared the cytogenetics of B-lymphoblastoid cell lines (LCLs) from WS and BS patients and healthy donors. Although, similar spontaneous frequencies of micronuclei (MN) and sister chromatid exchanges (SCE) were observed in LCLs from WS patients and healthy donors, they were much higher in BS-LCLs. We also examined the cells' cytotoxic and cytogenetic formation (MN) response to camptothecin (CAM), etoposide (ETO), 4-nitroquinoline 1-oxide (4NQO), and mitomycin C (MMC). Compared to healthy donor LCLs, BS-LCLs but not WS-LCLs tended to be resistant to cytotoxicity and sensitive to MN induction by 4NQO and MMC. Spectrum karyotyping analysis revealed that most WS- and BS-LCLs generated "variegated translocation mosaicism" at high frequencies during cell culture. These findings support the idea that the basis of genomic instability in WS is different from that in BS.

  19. New instability strip for hot degenerates

    Energy Technology Data Exchange (ETDEWEB)

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

    1980-01-01

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

  20. Analyses of cavitation instabilities in ductile metals

    DEFF Research Database (Denmark)

    Tvergaard, Viggo

    2007-01-01

    Cavitation instabilities have been predicted for a single void in a ductile metal stressed under high triaxiality conditions. In experiments for a ceramic reinforced by metal particles a single dominant void has been observed on the fracture surface of some of the metal particles bridging a crack...... for the influence of such size-effects on cavitation instabilities are presented. When a metal contains a distribution of micro voids, and the void spacing compared to void size is not extremely large, the surrounding voids may affect the occurrence of a cavitation instability at one of the voids. This has been...

  1. Two stream instabilities in degenerate quantum plasmas

    CERN Document Server

    Son, S

    2013-01-01

    The quantum mechanical effect on the plasma two-stream instability is studied based on the dielectric function approach. The analysis suggests that the degenerate plasma relevant to the inertial confinement fusion behaves differently from classical plasmas when the electron drift velocity is comparable to the Fermi velocity. For high wave vector comparable to the Fermi wave vector, the degenerate quantum plasma has larger regime of the two-stream instabilities than the classical plasma. A regime, where the plasma waves with the frequency larger than 1.5 times of the Langmuir wave frequency become unstable to the two-stream instabilities, is identified.

  2. Turing instability in reaction-subdiffusion systems.

    Science.gov (United States)

    Yadav, A; Milu, Shane M; Horsthemke, Werner

    2008-08-01

    We determine the conditions for the occurrence of Turing instabilities in activator-inhibitor systems, where one component undergoes subdiffusion and the other normal diffusion. If the subdiffusing species has a nonlinear death rate, then coupling between the nonlinear kinetics and the memory effects of the non-Markovian transport process advances the Turing instability if the inhibitor subdiffuses and delays the Turing instability if the activator subdiffuses. We apply the results of our analysis to the Schnakenberg model, the Gray-Scott model, the Oregonator model of the Belousov-Zhabotinsky reaction, and the Lengyel-Epstein model of the chlorine dioxide-iodine-malonic acid reaction.

  3. Engineering adenovirus genome by bacterial artificial chromosome (BAC) technology.

    Science.gov (United States)

    Ruzsics, Zsolt; Lemnitzer, Frederic; Thirion, Christian

    2014-01-01

    Bacterial artificial chromosomes (BACs) are recombinant DNA molecules designed for propagation of large and instable foreign DNA fragment in Escherichia coli. BACs are used in genetics of large DNA viruses such as herpes and baculoviruses for propagation and manipulation of complex genomic regions or even entire viral genomes in one piece. Viral genomes in BACs are ready for the advanced tools of E. coli genetics. These techniques based on homologous or site-specific recombination allow engineering of virtually any kind of genetic changes. In the recent years, BAC technology was also adapted to manipulation of adenovirus genomes and became an effective alternative to traditional genetic engineering of recombinant adenoviruses.

  4. Careers in conditions of instability

    Directory of Open Access Journals (Sweden)

    Hohlova Valentina Vasil'evna

    2016-04-01

    Full Text Available The purpose of this work is the research of the social-economic phenomenon of a career as a result of conscious human position and behaviour in the field of employment, which is connected with job and professional growth, as a chain of events which are components of life, the sequence of professional activities and other biographical roles, which all together express the commitment of a person’s activity according to his generalized model of self-development. On the basis of the theoretical analysis the dependence of making a career in the condition of instability and indefiniteness on job market flexibility, erosion and even the destruction of the usual way of life and labor relations. The career concepts under the conditions of flexible capitalism and of career policy as the typology of empiric differences of job biographic models are considered. The peculiarity of the proposed career policy concept is that its individual alternatives of career making oppose to organization management and personal demands: the difference between a professional’s wishes and a specific strategy of the development phases are quite noticeable. According to the results of empiric research carried out through the methods of interview, polling, expert assessment, the analysis of the received results, the mathematical data processing the basic types of the career policy and its connection with the organization’s personal development are revealed.

  5. Genome Imprinting

    Indian Academy of Sciences (India)

    Home; Journals; Resonance – Journal of Science Education; Volume 5; Issue 9. Genome Imprinting - The Silencing of Genes and Genomes. H A Ranganath M T Tanuja. General Article Volume 5 Issue 9 September 2000 pp 49-57. Fulltext. Click here to view fulltext PDF. Permanent link:

  6. Baculovirus Genomics

    NARCIS (Netherlands)

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

    2007-01-01

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

  7. Genomic footprinting.

    Science.gov (United States)

    Vierstra, Jeff; Stamatoyannopoulos, John A

    2016-03-01

    The advent of DNA footprinting with DNase I more than 35 years ago enabled the systematic analysis of protein-DNA interactions, and the technique has been instrumental in the decoding of cis-regulatory elements and the identification and characterization of transcription factors and other DNA-binding proteins. The ability to analyze millions of individual genomic cleavage events via massively parallel sequencing has enabled in vivo DNase I footprinting on a genomic scale, offering the potential for global analysis of transcription factor occupancy in a single experiment. Genomic footprinting has opened unique vistas on the organization, function and evolution of regulatory DNA; however, the technology is still nascent. Here we discuss both prospects and challenges of genomic footprinting, as well as considerations for its application to complex genomes.

  8. Parametric Instabilities of Electromagnetic Waves in Plasmas,

    Science.gov (United States)

    A simple formalism for the parametric decay of an intense, coherent electromagnetic wave into an electrostatic wave and scattered electromagnetic ... waves in a homogeneous plasma is developed. Various instabilities including Brillouin and Raman backscattering, Compton scattering, filamentation and

  9. Two-beam instability in electron cooling

    Directory of Open Access Journals (Sweden)

    A. Burov

    2006-12-01

    Full Text Available The drift motion of cooling electrons makes them able to respond to transverse perturbations of a cooled ion beam. This response may lead to dipole or quadrupole transverse instabilities at specific longitudinal wave numbers. While the dipole instabilities can be suppressed by a combination of the Landau damping, machine impedance, and the active damper, the quadrupole and higher order modes can lead to either emittance growth, or a lifetime degradation, or both. The growth rates of these instabilities are strongly determined by the machine x-y coupling. Thus, tuning out of the coupling resonance and/or reduction of the machine coupling can be an efficient remedy for these instabilities.

  10. Kelvin-Helmholtz instability in solar spicules

    Directory of Open Access Journals (Sweden)

    H Ebadi

    2016-12-01

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

  11. Cultural diversity, economic development and societal instability

    National Research Council Canada - National Science Library

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

    2007-01-01

    ..., and effects that are mediated by economic conditions. We assembled a large cross-national dataset with information on alpha and beta cultural diversity, economic conditions, and indices of societal instability...

  12. Overview of Rayleigh-Taylor instability

    Energy Technology Data Exchange (ETDEWEB)

    Sharp, D.H.

    1983-01-01

    The aim of this talk is to survey Rayleigh-Taylor instability, describing the phenomenology that occurs at a Taylor unstable interface, and reviewing attempts to understand these phenomena quantitatively.

  13. Stepper motor instabilities in an aerospace application

    Science.gov (United States)

    Kackley, Russell; Mccully, Sean

    1992-01-01

    Stepper motors are frequently used in positioning mechanisms because they have several advantages over ordinary DC motors. However, there is frequently no feedback loop and the motor may exhibit instabilities under some conditions. A stepper motor in an aerospace positioning mechanism was investigated. During testing, the motor exhibited unstable behavior, such as backrunning and forward running. The instability was dependent on voltage pulse characteristics, temperature, positioning angle, step rate, and interaction between the two motors in the system. Both testing and analysis results verified the instability. A special purpose FORTRAN code was written to simulate the system. This code was combined with another simpler code to show the performance of the system in the phase plane so that instability boundaries could be displayed along with the motor performance. The analysis was performed to verify that proposed modifications would produce stable performance before implementation in the hardware. Subsequent testing verified the analytic stability predictions.

  14. Single-mode coherent synchrotron radiation instability

    Directory of Open Access Journals (Sweden)

    S. Heifets

    2003-06-01

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

  15. Anisotropic instability of a stretching film

    Science.gov (United States)

    Xu, Bingrui; Li, Minhao; Deng, Daosheng

    2017-11-01

    Instability of a thin liquid film, such as dewetting arising from Van der Waals force, has been well studied, and is typically characterized by formation of many droplets. Interestingly, a thin liquid film subjected to an applied stretching during a process of thermal drawing is evolved into an array of filaments, i.e., continuity is preserved along the direction of stretching while breakup occurs exclusively in the plane of cross section. Here, to understand this anisotropic instability, we build a physical model by considering both Van der Waals force and the effect of stretching. By using the linear instability analysis method and then performing a numerical calculation, we find that the growth rate of perturbations at the cross section is larger than that along the direction of stretching, resulting in the anisotropic instability of the stretching film. These results may provide theoretical guidance to achieve more diverse structures for nanotechnology.

  16. [Cervical spine instability in the surgical patient].

    Science.gov (United States)

    Barbeito, A; Guerri-Guttenberg, R A

    2014-03-01

    Many congenital and acquired diseases, including trauma, may result in cervical spine instability. Given that airway management is closely related to the movement of the cervical spine, it is important that the anesthesiologist has detailed knowledge of the anatomy, the mechanisms of cervical spine instability, and of the effects that the different airway maneuvers have on the cervical spine. We first review the normal anatomy and biomechanics of the cervical spine in the context of airway management and the concept of cervical spine instability. In the second part, we review the protocols for the management of cervical spine instability in trauma victims and some of the airway management options for these patients. Copyright © 2013 Sociedad Española de Anestesiología, Reanimación y Terapéutica del Dolor. All rights reserved.

  17. Mirror Instability in the Turbulent Solar Wind

    Czech Academy of Sciences Publication Activity Database

    Hellinger, Petr; Landi, S.; Matteini, L.; Verdini, A.; Franci, L.

    2017-01-01

    Roč. 838, č. 2 (2017), 158/1-158/7 ISSN 0004-637X Institutional support: RVO:67985815 Keywords : instabilities * solar wind * waves Subject RIV: BN - Astronomy, Celestial Mechanics, Astrophysics Impact factor: 5.533, year: 2016

  18. On viscoelastic instability in polymeric filaments

    DEFF Research Database (Denmark)

    Rasmussen, Henrik Koblitz; Hassager, Ole

    1999-01-01

    The 3D Lagrangian Integral Method is used to simulate the effects of surface tension on the viscoelastic end-plate instability, occuring in the rapid extension of some polymeric filaments between parallel plates. It is shovn that the surface tension delays the onset of the instability. Furthermore...... it is demonstrated that surface tension plays a key role in the selection of the most unstable mode...

  19. Systematics of shoulder instability; Systematik der Schulterinstabilitaet

    Energy Technology Data Exchange (ETDEWEB)

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

    2015-03-01

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

  20. Elastic flow instability in nanotube suspensions.

    Science.gov (United States)

    Lin-Gibson, S; Pathak, J A; Grulke, E A; Wang, H; Hobbie, E K

    2004-01-30

    We report an elastic instability associated with flow-induced clustering in semidilute non-Brownian colloidal nanotubes. Rheo-optical measurements are compared with simulations of mechanical flocculation in sheared fiber suspensions, and the evolving structure is characterized as a function of confinement and shear stress. The transient rheology is correlated with the evolution of highly elastic vorticity-aligned aggregates, with the underlying instability being somewhat ubiquitous in complex fluids.

  1. Beam Instabilities in Circular Particle Accelerators

    CERN Document Server

    AUTHOR|(CDS)2067185

    2017-01-01

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

  2. Computational methods for probability of instability calculations

    Science.gov (United States)

    Wu, Y.-T.; Burnside, O. H.

    1990-01-01

    This paper summarizes the development of the methods and a computer program to compute the probability of instability of a dynamic system than can be represented by a system of second-order ordinary linear differential equations. Two instability criteria based upon the roots of the characteristics equation or Routh-Hurwitz test functions are investigated. Computational methods based on system reliability analysis methods and importance sampling concepts are proposed to perform efficient probabilistic analysis. Numerical examples are provided to demonstrate the methods.

  3. Topographic-driven instabilities in terrestrial bodies

    Science.gov (United States)

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

    2013-12-01

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

  4. Energetic particle instabilities in fusion plasmas

    Science.gov (United States)

    Sharapov, S. E.; Alper, B.; Berk, H. L.; Borba, D. N.; Breizman, B. N.; Challis, C. D.; Classen, I. G. J.; Edlund, E. M.; Eriksson, J.; Fasoli, A.; Fredrickson, E. D.; Fu, G. Y.; Garcia-Munoz, M.; Gassner, T.; Ghantous, K.; Goloborodko, V.; Gorelenkov, N. N.; Gryaznevich, M. P.; Hacquin, S.; Heidbrink, W. W.; Hellesen, C.; Kiptily, V. G.; Kramer, G. J.; Lauber, P.; Lilley, M. K.; Lisak, M.; Nabais, F.; Nazikian, R.; Nyqvist, R.; Osakabe, M.; Perez von Thun, C.; Pinches, S. D.; Podesta, M.; Porkolab, M.; Shinohara, K.; Schoepf, K.; Todo, Y.; Toi, K.; Van Zeeland, M. A.; Voitsekhovich, I.; White, R. B.; Yavorskij, V.; TG, ITPA EP; Contributors, JET-EFDA

    2013-10-01

    Remarkable progress has been made in diagnosing energetic particle instabilities on present-day machines and in establishing a theoretical framework for describing them. This overview describes the much improved diagnostics of Alfvén instabilities and modelling tools developed world-wide, and discusses progress in interpreting the observed phenomena. A multi-machine comparison is presented giving information on the performance of both diagnostics and modelling tools for different plasma conditions outlining expectations for ITER based on our present knowledge.

  5. Arthroscopic Findings in Anterior Shoulder Instability

    OpenAIRE

    Hantes, Michael; Raoulis, Vasilios

    2017-01-01

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

  6. Energetic particle instabilities in fusion plasmas

    CERN Document Server

    Sharapov, S E; Berk, H L; Borba, D N; Breizman, B N; Challis, C D; Classen, I G J; Edlund, E M; Eriksson, J; Fasoli, A; Fredrickson, E D; Fu, G Y; Garcia-Munoz, M; Gassner, T; Ghantous, K; Goloborodko, V; Gorelenkov, N N; Gryaznevich, M P; Hacquin, S; Heidbrink, W W; Hellesen, C; Kiptily, V G; Kramer, G J; Lauber, P; Lilley, M K; Lisak, M; Nabais, F; Nazikian, R; Nyqvist, R; Osakabe, M; von Thun, C Perez; Pinches, S D; Podesta, M; Porkolab, M; Shinohara, K; Schoepf, K; Todo, Y; Toi, K; Van Zeeland, M A; Voitsekhovich, I; White, R B; Yavorskij, V; TG, ITPA EP; Contributors, JET-EFDA

    2013-01-01

    Remarkable progress has been made in diagnosing energetic particle instabilities on present-day machines and in establishing a theoretical framework for describing them. This overview describes the much improved diagnostics of Alfven instabilities and modelling tools developed world-wide, and discusses progress in interpreting the observed phenomena. A multi-machine comparison is presented giving information on the performance of both diagnostics and modelling tools for different plasma conditions outlining expectations for ITER based on our present knowledge.

  7. Studies of elastic-plastic instabilities

    DEFF Research Database (Denmark)

    Tvergaard, Viggo

    1999-01-01

    Analyses of plastic instabilities are reviewed, with focus on results in structural mechanics as well as continuum mechanics. First the basic theories for bifurcation and post-bifurcation behavior are briefly presented. Then, localization of plastic flow is discussed, including shear band formation...... in solids, localized necking in biaxially stretched metal sheets, and the analogous phenomenon of buckling localization in structures. Also some recent results for cavitation instabilities in elastic-plastic solids are reviewed....

  8. Gigayear Instabilities in Planetary Systems

    Science.gov (United States)

    Fabrycky, Daniel

    One of the biggest modern discoveries about the Solar System is that it is chaotic (Laskar 1989, 1994). On million-year timescales, nearby trajectories exponentially diverge; on billion-year timescales, planets can develop large eccentricities and even collide. This is possible because our planets interact with enough energy and with the right (secular) timescales. This has the potential to put the planet Mercury on an unstable orbit in the future, before the Sun exhausts its fuel. Currently, as a standard step in the analysis, exoplanet observing teams check whether the planetary systems they are discovering are stable. This usually involves a few-Megayear numerical integration, and the system usually passes that test. However, the signatures of continuing instability have not been looked for in the exoplanet population, nor has its implications for planetary formation and evolution been fully recognized. We will study several specific evolutionary scenarios in which instability may manifest only on gigayear timescales, i.e. midway through the lives of the host stars. This is relevant to the solicitation in that it characterizes the dynamics of exoplanetary systems. In the first project, we will compare N-body, numerically-calculated secular, and Fourier-expansion secular theories to determine what essential ingredients go into the conclusion that a general planetary system is chaotic. We will apply these tools to specific realizations of Kepler-discovered close-in planetary systems consisting of three or more Neptunes or super-Earths, which is the most populous known exoplanet population. We will thus find the common ailments afflicting middle-age planetary systems. In the second project, we will consider how planets might get stranded in their Kuiper and Oort clouds during early system evolution, only to destabilize the inner system later on. Various investigators have wondered whether the Solar System is accompanied by a massive planetary companion, including a

  9. Interface instability modes in freezing colloidal suspensions: revealed from onset of planar instability

    National Research Council Canada - National Science Library

    Wang, Lilin; You, Jiaxue; Wang, Zhijun; Wang, Jincheng; Lin, Xin

    2016-01-01

    Freezing colloidal suspensions widely exists in nature and industry. Interface instability has attracted much attention for the understandings of the pattern formation in freezing colloidal suspensions...

  10. [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.

  11. Antarctic Genomics

    Directory of Open Access Journals (Sweden)

    Alex D. Rogers

    2006-03-01

    Full Text Available With the development of genomic science and its battery of technologies, polar biology stands on the threshold of a revolution, one that will enable the investigation of important questions of unprecedented scope and with extraordinary depth and precision. The exotic organisms of polar ecosystems are ideal candidates for genomic analysis. Through such analyses, it will be possible to learn not only the novel features that enable polar organisms to survive, and indeed thrive, in their extreme environments, but also fundamental biological principles that are common to most, if not all, organisms. This article aims to review recent developments in Antarctic genomics and to demonstrate the global context of such studies.

  12. CEP152 is a genome maintenance protein disrupted in Seckel syndrome

    NARCIS (Netherlands)

    Kalay, E.; Yigit, G.; Aslan, Y.; Brown, K.E.; Pohl, E.; Bicknell, L.S.; Kayserili, H.; Li, Y.; Tuysuz, B.; Nurnberg, G.; Kiess, W.; Koegl, M.; Baessmann, I.; Buruk, K.; Toraman, B.; Kayipmaz, S.; Kul, S.; Ikbal, M.; Turner, D.J.; Taylor, M.S.; Aerts, J.; Scott, C.; Milstein, K.; Dollfus, H.; Wieczorek, D.; Brunner, H.G.; Hurles, M.; Jackson, A.P.; Rauch, A.; Nurnberg, P.; Karaguzel, A.; Wollnik, B.

    2011-01-01

    Functional impairment of DNA damage response pathways leads to increased genomic instability. Here we describe the centrosomal protein CEP152 as a new regulator of genomic integrity and cellular response to DNA damage. Using homozygosity mapping and exome sequencing, we identified CEP152 mutations

  13. Instabilities in Interacting Binary Stars

    Science.gov (United States)

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

    2017-07-01

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

  14. Genomic Imprinting

    Indian Academy of Sciences (India)

    Home; Journals; Resonance – Journal of Science Education; Volume 5; Issue 9. Genomic Imprinting - Some Interesting Implications for the Evolution of Social Behaviour. Raghavendra Gadagkar. General Article Volume 5 Issue 9 September 2000 pp 58-68 ...

  15. Herbarium genomics

    DEFF Research Database (Denmark)

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

    2016-01-01

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

  16. Opportunities for immunotherapy in microsatellite instable colorectal cancer.

    Science.gov (United States)

    Westdorp, Harm; Fennemann, Felix L; Weren, Robbert D A; Bisseling, Tanya M; Ligtenberg, Marjolijn J L; Figdor, Carl G; Schreibelt, Gerty; Hoogerbrugge, Nicoline; Wimmers, Florian; de Vries, I Jolanda M

    2016-10-01

    Microsatellite instability (MSI), the somatic accumulation of length variations in repetitive DNA sequences called microsatellites, is frequently observed in both hereditary and sporadic colorectal cancer (CRC). It has been established that defects in the DNA mismatch repair (MMR) pathway underlie the development of MSI in CRC. After the inactivation of the DNA MMR pathway, misincorporations, insertions and deletions introduced by DNA polymerase slippage are not properly recognized and corrected. Specific genomic regions, including microsatellites, are more prone for DNA polymerase slippage and, therefore, more susceptible for the introduction of these mutations if the DNA MMR capacity is lost. Some of these susceptible genomic regions are located within the coding regions of genes. Insertions and deletions in these regions may alter their reading frame, potentially resulting in the transcription and translation of frameshift peptides with c-terminally altered amino acid sequences. These frameshift peptides are called neoantigens and are highly immunogenic, which explains the enhanced immunogenicity of MSI CRC. Neoantigens contribute to increased infiltration of tumor tissue with activated neoantigen-specific cytotoxic T lymphocytes, a hallmark of MSI tumors. Currently, neoantigen-based vaccination is being studied in a clinical trial for Lynch syndrome and in a trial for sporadic MSI CRC of advanced stage. In this Focussed Research Review, we summarize current knowledge on molecular mechanisms and address immunological features of tumors with MSI. Finally, we describe their implications for immunotherapeutic approaches and provide an outlook on next-generation immunotherapy involving neoantigens and combinatorial therapies in the setting of MSI CRC.

  17. Microsatellite instability at tetranucleotide repeats in sporadic colorectal cancer in Japan.

    Science.gov (United States)

    Yamada, Kanae; Kanazawa, Shinsaku; Koike, Junichi; Sugiyama, Hisahiko; Xu, Can; Funahashi, Kimihiko; Boland, C Richard; Koi, Minoru; Hemmi, Hiromichi

    2010-02-01

    Most tumors of patients with Lynch syndrome and a fraction of sporadic colorectal cancers (CRCs) exhibit high levels of microsatellite instability (MSI) at mono- and dinucleotide repeat loci. A different type of instability, elevated microsatellite alterations at selected tetranucleotide repeats (EMAST) has been found in non-colonic cancers. Our previous study demonstrated that EMAST is common in sporadic CRC. Here, we focused on the relationships between EMAST and other genomic instability parameters or clinicopathological features in an unselected series of 88 sporadic CRCs. Of the tumors in the sample, 4 (4.5%) were MSI-high (MSI-H), 9 (10.2%) were MSI-low (MSI-L) and 75 (85.2%) were microsatellite stable. EMAST status was determined using 7 EMAST markers. Fifty-three (60.2%) tumors without MSI-H showed instability at >or=1 EMAST loci. All 4 MSI-H tumors showed instability at several EMAST loci. Instability profiles of MSI-H tumors at EMAST loci were more complex than those of non-MSI-H tumors. A tendency of positive association was observed between MSI-L and EMAST (P=0.023). The frequency of loss of heterozygosity (LOH) for the 14 loci in EMAST-positive tumors was significantly higher than negative tumors (P=0.048). Among the clinicopathological parameters, only tumor location at the distal colon was associated with EMAST-negative tumors (P=0.0084, one-tailed). A relatively higher frequency of well-differentiated adenocarcinomas was observed in EMAST tumors as opposed to non-EMAST tumors, though the survival rate was similar. These results suggest that overlapping mechanisms that cause MSI-L, EMAST and LOH in CRCs may exist.

  18. Measurement properties of the Western Ontario Shoulder Instability Index in Dutch patients with shoulder instability

    NARCIS (Netherlands)

    van der Linde, J.A.; Willems, W.J.; van Kampen, D.A.; van Beers, L.W.A.H.; van Deurzen, D.F.P.; Terwee, C.B.

    2014-01-01

    Background: The Western Ontario Shoulder Instability index (WOSI) is a patient-reported outcome measure for patients with shoulder instability. The purpose of this study was to validate the WOSI in a Dutch population by evaluating its structural validity, internal consistency, measurement error,

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

    Science.gov (United States)

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

    2017-11-01

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

  20. Active Suppression of Instabilities in Engine Combustors

    Science.gov (United States)

    Kopasakis, George

    2004-01-01

    A method of feedback control has been proposed as a means of suppressing thermo-acoustic instabilities in a liquid- fueled combustor of a type used in an aircraft engine. The basic principle of the method is one of (1) sensing combustor pressure oscillations associated with instabilities and (2) modulating the rate of flow of fuel to the combustor with a control phase that is chosen adaptively so that the pressure oscillations caused by the modulation oppose the sensed pressure oscillations. The need for this method arises because of the planned introduction of advanced, lean-burning aircraft gas turbine engines, which promise to operate with higher efficiencies and to emit smaller quantities of nitrogen oxides, relative to those of present aircraft engines. Unfortunately, the advanced engines are more susceptible to thermoacoustic instabilities. These instabilities are hard to control because they include large dead-time phase shifts, wide-band noise characterized by amplitudes that are large relative to those of the instabilities, exponential growth of the instabilities, random net phase walks, and amplitude fluctuations. In this method (see figure), the output of a combustion-pressure sensor would be wide-band-pass filtered and then further processed to generate a control signal that would be applied to a fast-actuation valve to modulate the flow of fuel. Initially, the controller would rapidly take large phase steps in order to home in, within a fraction of a second, to a favorable phase region within which the instability would be reduced. Then the controller would restrict itself to operate within this phase region and would further restrict itself to operate within a region of stability, as long as the power in the instability signal was decreasing. In the phase-shifting scheme of this method, the phase of the control vector would be made to continuously bounce back and forth from one boundary of an effective stability region to the other. Computationally

  1. Genomic Stability: FANCJ-Dependent G4 DNA Repair

    OpenAIRE

    Maizels, Nancy

    2008-01-01

    G-rich regions have the potential to form G4 DNA upon replication, which can lead to genomic instability. FANCJ, a G4 DNA helicase, has been shown to be critical for the stability of regions that match the G4 signature motif by experiments analyzing its nematode homolog.

  2. Inertioelastic Flow Instability at a Stagnation Point

    Science.gov (United States)

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

    2017-10-01

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

  3. Bilateral, atraumatic, proximal tibiofibular joint instability.

    Science.gov (United States)

    Morrison, Troy D; Shaer, James A; Little, Jill E

    2011-01-01

    Dislocation of the tibiofibular joint is rare and usually results from a traumatic event. Only 1 case of atraumatic proximal tibiofibular joint instability in a 14-year-old girl has been reported in the literature, however this condition might occur more frequently than once thought. A wide range of treatment options exist for tibiofibular dislocations. Currently, the first choice is a conservative approach, and when this fails, surgical means such as resection of the fibula head, arthrodesis, and reconstruction are considered. However, no consensus exists on the most effective treatment. This article reports a unique case of bilateral, atraumatic, proximal tibia and fibular joint instability involving a 30-year-old man with a 20-year history of pain and laxity in the right knee. The patient had no trauma to his knees; he reported 2 immediate family members with similar complaints, which suggests that this case is likely congenital. After conservative approaches proved to be ineffective, the patient underwent capsular reconstruction using free autologous gracilis tendon. At 6-month postoperative follow-up, the patient was pain free with no locking and instability. He then underwent surgery on the left knee. At 1-year follow-up after the second surgery, the patient had no symptoms or restrictions in mobility. We provide an alternative surgical approach to arthrodesis and resection for the treatment of chronic proximal tibiofibular instability. In the treatment of chronic tibiofibular instability, we believe that reconstruction of the tibiofibular joint is a safe and effective choice. Copyright 2011, SLACK Incorporated.

  4. Inertioelastic Flow Instability at a Stagnation Point

    Directory of Open Access Journals (Sweden)

    Noa Burshtein

    2017-11-01

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

  5. Transverse mode coupling instability of colliding beams

    Directory of Open Access Journals (Sweden)

    S. White

    2014-04-01

    Full Text Available In high brightness circular colliders, coherent and incoherent beam dynamics are dominated by beam-beam interactions. It is generally assumed that the incoherent tune spread introduced by the beam-beam interactions is sufficiently large to cure any instabilities originating from impedance. However, as the two counterrotating beams interact they can give rise to coherent dipole modes and therefore modify the coherent beam dynamics and stability conditions. In this case, coherent beam-beam effects and impedance cannot be treated independently and their interplay should be taken into account in any realistic attempt to study the beam stability of colliding beams. Due to the complexity of these physics processes, numerical simulations become an important tool for the analysis of this system. Two approaches are proposed in this paper: a fully self-consistent multiparticle tracking including particle-in-cell Poisson solver for the beam-beam interactions and a linearized model taking into account finite bunch length effects. To ensure the validity of the results a detailed benchmarking of these models was performed. It will be shown that under certain conditions coherent beam-beam dipole modes can couple with higher order headtail modes and lead to strong instabilities with characteristics similar to the classical transverse mode coupling instability originating from impedance alone. Possible cures for this instability are explored both for single bunch and multibunch interactions. Simulation results and experimental evidences of the existence of this instability at the LHC will be presented for the specific case of offset collisions.

  6. Tidal instability in exoplanetary systems evolution

    Directory of Open Access Journals (Sweden)

    Le Gal P.

    2011-02-01

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

  7. Capillary instability on a hydrophilic stripe

    Energy Technology Data Exchange (ETDEWEB)

    Speth, Raymond L [Department of Mechanical Engineering, Massachusetts Institute of Technology, 77 Massachusetts Avenue, Cambridge, MA 02139 (United States); Lauga, Eric [Department of Mechanical and Aerospace Engineering, University of California, San Diego, 9500 Gilman Dr, La Jolla, CA 92093-0411 (United States)], E-mail: elauga@ucsd.edu

    2009-07-15

    A recent experiment showed that cylindrical segments of water filling a hydrophilic stripe on an otherwise hydrophobic surface display a capillary instability when their volume is increased beyond the critical volume at which their apparent contact angle on the surface reaches 90 deg. (Gau et al 1999 Science 283 46-9). Surprisingly, the fluid segments did not break up into droplets-as would be expected for a classical Rayleigh-Plateau instability-but instead displayed a long-wavelength instability where all excess fluid gathered in a single bulge along each stripe. We consider here the dynamics of the flow instability associated with this setup. We perform a linear stability analysis of the capillary flow problem in the inviscid limit. We first confirm previous work showing that all cylindrical segments are linearly unstable if (and only if) their apparent contact angle is larger than 90 deg. We then demonstrate that the most unstable wavenumber for the surface perturbation decreases to zero as the apparent contact angle of the fluid on the surface approaches 90 deg, allowing us to re-interpret the creation of bulges in the experiment as a zero-wavenumber capillary instability. A variation of the stability calculation is also considered for the case of a hydrophilic stripe located on a wedge-like geometry.

  8. 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.

  9. Frameshift mutations of poly(adenosine diphosphate-ribose) polymerase genes in gastric and colorectal cancers with microsatellite instability.

    Science.gov (United States)

    Kim, Min Sung; An, Chang Hyeok; Kim, Sung Soo; Yoo, Nam Jin; Lee, Sug Hyung

    2011-09-01

    Poly(adenosine diphosphate-ribose) polymerases consist of 16 members that modify nuclear proteins by building adenosine diphosphate-ribose polymers. Poly(adenosine diphosphate-ribose) polymerase 1, the prototype poly(adenosine diphosphate-ribose) polymerase, and some poly(adenosine diphosphate-ribose) polymerases are involved in many cellular processes including DNA damage response/repair, cell death, and inflammation. Inactivation of poly(adenosine diphosphate-ribose) polymerase proteins frequently enhances genomic instability and apoptosis inactivation, suggesting their roles in cancer development. However, genetic alterations of poly(adenosine diphosphate-ribose) polymerase genes have not been reported in cancers. In a public database, we found that poly(adenosine diphosphate-ribose) polymerase 1, poly(adenosine diphosphate-ribose) polymerase 11, poly(adenosine diphosphate-ribose) polymerase 14, poly(adenosine diphosphate-ribose) polymerase 15, tankyrase-1 (TNKS1), and tankyrase-2 (TNKS2) genes have mononucleotide repeats in coding DNA sequences. To see whether these genes are mutated in cancers with microsatellite instability, we analyzed the mononucleotide repeats in 30 gastric cancers with high microsatellite instability, 13 gastric cancers with low microsatellite instability, 45 gastric cancers with stable microsatellite instability, 40 colorectal cancers with high microsatellite instability, 14 colorectal cancers with low microsatellite instability, and 45 colorectal cancers with stable microsatellite instability by single-strand conformation polymorphism. We found poly(adenosine diphosphate-ribose) polymerase 14, TNKS1, and TNKS2 mutations in 8, 4, and 18 cancers, respectively. They were detected in cancers with high microsatellite instability but not in cancers with low microsatellite instability or stable microsatellite instability. The gastric cancers and colorectal cancers with high microsatellite instability harbored one or more mutations of the poly

  10. Induction of Chromosomal Instability via Telomere Dysfunction and Epigenetic Alterations in Myeloid Neoplasia

    Directory of Open Access Journals (Sweden)

    Brigitte Schlegelberger

    2013-07-01

    Full Text Available Chromosomal instability (CIN is a characteristic feature of cancer. In this review, we concentrate on mechanisms leading to CIN in myeloid neoplasia, i.e., myelodysplastic syndrome (MDS or acute myeloid leukemia (AML. The pathogenesis of myeloid neoplasia is complex and involves genetic and epigenetic alterations. Chromosome aberrations define specific subgroups and guide clinical decisions. Genomic instability may play an essential role in leukemogenesis by promoting the accumulation of genetic lesions responsible for clonal evolution. Indeed, disease progression is often driven by clonal evolution into complex karyotypes. Earlier studies have shown an association between telomere shortening and advanced MDS and underlined the important role of dysfunctional telomeres in the development of genetic instability and cancer. Several studies link chromosome rearrangements and aberrant DNA and histone methylation. Genes implicated in epigenetic control, like DNMT3A, ASXL1, EZH2 and TET2, have been discovered to be mutated in MDS. Moreover, gene-specific hypermethylation correlates highly significantly with the risk score according to the International Prognostic Scoring System. In AML, methylation profiling also revealed clustering dependent on the genetic status. Clearly, genetic instability and clonal evolution are driving forces for leukemic transformation. Understanding the mechanisms inducing CIN will be important for prevention and for novel approaches towards therapeutic interventions.

  11. Electromagnetic instability induced by neutrino interaction

    Science.gov (United States)

    Bhatt, Jitesh R.; George, Manu

    We consider the generation and evolution of magnetic field in a primordial plasma at temperature T ≤ 1MeV in the presence of asymmetric neutrino background, i.e. the number densities of right-handed and left-handed neutrinos are not the same. Semi-classical equations of motion of a charged fermion are derived using the effective low-energy Lagrangian. We show that the spin degree of freedom of the charged fermion couples with the neutrino background. Using this kinetic equation, we study the collective modes of the plasma. We find that there exist an unstable mode. This instability is closely related with the instability induced by chiral-anomaly in high temperature T ≥ 80TeV plasma where right and left-handed electrons are out of equilibrium. We find that at the temperatures below the neutrino decoupling this instability can produce magnetic field in the universe. We discuss cosmological implications of the results.

  12. Early Prevention Method for Power Systems Instability

    DEFF Research Database (Denmark)

    Dmitrova, Evgenia

    . The predicted effect of the suggested countermeasure application is in a good agreement with the results obtained by RMS dynamic simulation. Developed method enables adaptive preventive control for near real-time stability maintenance. The achieved results are opening promising perspective for power system......In the scope of this work, a method capable of fast identification of the proper countermeasure, that prevents emerging instability, has been developed. The focus is placed on the prevention of aperiodic small signal angular instability by means of manipulations applied to load nodes (nodes...... containing no voltage sources). The main functionality of the early prevention method is to deliver control solution allowing escape from instability on the basis of data obtained by PMU measurements. The developed algorithm performs identification of the optimal node for countermeasure application...

  13. Plasma instabilities of a charge breeder ECRIS

    Science.gov (United States)

    Tarvainen, O.; Angot, J.; Izotov, I.; Skalyga, V.; Koivisto, H.; Thuillier, T.; Kalvas, T.; Lamy, T.

    2017-10-01

    Experimental observation of plasma instabilities in a charge breeder electron cyclotron resonance ion source (CB-ECRIS) is reported. It is demonstrated that the injection of 133Cs+ or 85Rb+ ion beam into the oxygen discharge of the CB-ECRIS can trigger electron cyclotron instabilities, which restricts the parameter space available for the optimization of the charge breeding efficiency. It is concluded that the transition from a stable to unstable plasma regime is caused by gradual accumulation and ionization of Cs/Rb and simultaneous change of the discharge parameters in 10-100 ms time scale, not by a prompt interaction between the incident ion beam and the ECRIS plasma. The instabilities lead to loss of ion confinement, which results in the sputtering of the surfaces in contact with the plasma, followed by up to an order of magnitude increase of impurity currents in the extracted n+ ion beam.

  14. Nonlinear saturation of Weibel-type instabilities

    Science.gov (United States)

    Srinivasan, Bhuvana; Cagas, Petr; Hakim, Ammar

    2017-10-01

    Weibel-type instabilities, which grow in plasmas with anisotropic velocity distribution, have been studied for many years and drawn recent interest due to their broad applicability spanning from laboratory laser plasmas to origins of intergalactic magnetic fields in astrophysical plasmas. Magnetic particle trapping has been considered as the main mechanism of the nonlinear saturation of these instabilities. However, novel continuum kinetic and two-fluid five moment simulations show that there are additional effects - the transverse flow introduced by the magnetic field creates a secondary electrostatic two-stream instability which alters the saturation and is responsible for a quasi-periodic behavior in the nonlinear phase. This research was supported by the Air Force Office of Scientific Research under Grant Number FA9550-15-1-0193.

  15. Edge instability in incompressible planar active fluids

    Science.gov (United States)

    Nesbitt, David; Pruessner, Gunnar; Lee, Chiu Fan

    2017-12-01

    Interfacial instability is highly relevant to many important biological processes. A key example arises in wound healing experiments, which observe that an epithelial layer with an initially straight edge does not heal uniformly. We consider the phenomenon in the context of active fluids. Improving upon the approximation used by Zimmermann, Basan, and Levine [Eur. Phys. J.: Spec. Top. 223, 1259 (2014), 10.1140/epjst/e2014-02189-7], we perform a linear stability analysis on a two-dimensional incompressible hydrodynamic model of an active fluid with an open interface. We categorize the stability of the model and find that for experimentally relevant parameters, fingering instability is always absent in this minimal model. Our results point to the crucial role of density variation in the fingering instability in tissue regeneration.

  16. Pathways towards instability in financial networks

    Science.gov (United States)

    Bardoscia, Marco; Battiston, Stefano; Caccioli, Fabio; Caldarelli, Guido

    2017-02-01

    Following the financial crisis of 2007-2008, a deep analogy between the origins of instability in financial systems and complex ecosystems has been pointed out: in both cases, topological features of network structures influence how easily distress can spread within the system. However, in financial network models, the details of how financial institutions interact typically play a decisive role, and a general understanding of precisely how network topology creates instability remains lacking. Here we show how processes that are widely believed to stabilize the financial system, that is, market integration and diversification, can actually drive it towards instability, as they contribute to create cyclical structures which tend to amplify financial distress, thereby undermining systemic stability and making large crises more likely. This result holds irrespective of the details of how institutions interact, showing that policy-relevant analysis of the factors affecting financial stability can be carried out while abstracting away from such details.

  17. 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.

  18. Control and simulation of thermoacoustic instabilities

    Science.gov (United States)

    Poinsot, Thierry

    2014-11-01

    Combustion instabilities (CI), due to thermoacoustic coupling between acoustic waves and chemical reaction, constitute a major danger for all combustion systems. They can drive the system to unstable states where the whole combustor can oscillate, vibrate, quench or in extreme cases explode or burn. Such phenomena are commonly observed in the final phases of development programs, leading to major difficulties and significant additional costs. One of the most famous examples of combustion instabilities is the F1 engine of the Apollo program which required more than 1000 engine tests to obtain a stable regime satisfying all other constraints (performance, ignition, etc). CIs constitute one of the most challenging problems in fluid mechanics: they combine turbulence, acoustics, chemistry, unsteady two-phase flow in complex geometries. Since combustion instabilities have been identified (more than hundred years ago), the combustion community has followed two paths: (1) improve our understanding of the phenomena controlling stability to build engines which would be ``stable by design'' and (2) give up on a detailed understanding of mechanisms and add control systems either in open or closed loop devices to inhibit unstable modes. Of course, understanding phenomena driving combustion instabilities to suppress them would be the most satisfying approach but there is no fully reliable theory or numerical method today which can predict whether a combustor will be stable or not before it is fired. This talk will present an overview of combustion instabilities phenomenology before focusing on: (1) active control methods for combustion instabilities and (2) recent methods to predict unstable modes in combustors. These methods are based on recent Large Eddy Simulation codes for compressible reacting flows on HPC systems but we will also describe recent fully analytical methods which provide new insights into unstable modes in annular combustion chambers. Support: European

  19. Arthroscopic Findings in Anterior Shoulder Instability.

    Science.gov (United States)

    Hantes, Michael; Raoulis, Vasilios

    2017-01-01

    In the last years, basic research and arthroscopic surgery, have improved our understanding of shoulder anatomy and pathology. It is a fact that arthroscopic treatment of shoulder instability has evolved considerably over the past decades. The aim of this paper is to present the variety of pathologies that should be identified and treated during shoulder arthroscopy when dealing with anterior shoulder instability cases. A review of the current literature regarding arthroscopic shoulder anatomy, anatomic variants, and arthroscopic findings in anterior shoulder instability, is presented. In addition, correlation of arthroscopic findings with physical examination and advanced imaging (CT and MRI) in order to improve our understanding in anterior shoulder instability pathology is discussed. Shoulder instability represents a broad spectrum of disease and a thorough understanding of the pathoanatomy is the key for a successful treatment of the unstable shoulder. Patients can have a variety of pathologies concomitant with a traditional Bankart lesion, such as injuries of the glenoid (bony Bankart), injuries of the glenoid labrum, superiorly (SLAP) or anteroinferiorly ( e.g . anterior labroligamentous periosteal sleeve avulsion, and Perthes), capsular lesions (humeral avulsion of the glenohumeral ligament), and accompanying osseous-cartilage lesions (Hill-Sachs, glenolabral articular disruption). Shoulder arthroscopy allows for a detailed visualization and a dynamic examination of all anatomic structures, identification of pathologic findings, and treatment of all concomitant lesions. Surgeons must be well prepared and understanding the normal anatomy of the glenohumeral joint, including its anatomic variants to seek for the possible pathologic lesions in anterior shoulder instability during shoulder arthroscopy. Patient selection criteria, improved surgical techniques, and implants available have contributed to the enhancement of clinical and functional outcomes to the

  20. Nucleation versus instability race in strained films

    Science.gov (United States)

    Liu, Kailang; Berbezier, Isabelle; David, Thomas; Favre, Luc; Ronda, Antoine; Abbarchi, Marco; Voorhees, Peter; Aqua, Jean-Noël

    2017-10-01

    Under the generic term "Stranski-Krastanov" are grouped two different growth mechanisms of SiGe quantum dots. They result from the self-organized Asaro-Tiller-Grinfel'd (ATG) instability at low strain, while at high strain, from a stochastic nucleation. While these regimes are well known, we elucidate here the origin of the transition between these two pathways thanks to a joint theoretical and experimental work. Nucleation is described within the master equation framework. By comparing the time scales for ATG instability development and three-dimensional (3D) nucleation onset, we demonstrate that the transition between these two regimes is simply explained by the crossover between their divergent evolutions. Nucleation exhibits a strong exponential deviation at low strain while ATG behaves only algebraically. The associated time scale varies with exp(1 /x4) for nucleation, while it only behaves as 1 /x8 for the ATG instability. Consequently, at high (low) strain, nucleation (instability) occurs faster and inhibits the alternate evolution. It is then this different kinetic evolution which explains the transition from one regime to the other. Such a kinetic view of the transition between these two 3D growth regimes was not provided before. The crossover between nucleation and ATG instability is found to occur both experimentally and theoretically at a Ge composition around 50% in the experimental conditions used here. Varying the experimental conditions and/or the system parameters does not allow us to suppress the transition. This means that the SiGe quantum dots always grow via ATG instability at low strain and nucleation at high strain. This result is important for the self-organization of quantum dots.

  1. Imaging genomics.

    Science.gov (United States)

    Thompson, Paul M; Martin, Nicholas G; Wright, Margaret J

    2010-08-01

    Imaging genomics is an emerging field that is rapidly identifying genes that influence the brain, cognition, and risk for disease. Worldwide, thousands of individuals are being scanned with high-throughput genotyping (genome-wide scans), and new imaging techniques [high angular resolution diffusion imaging and resting state functional magnetic resonance imaging (MRI)] that provide fine-grained measures of the brain's structural and functional connectivity. Along with clinical diagnosis and cognitive testing, brain imaging offers highly reproducible measures that can be subjected to genetic analysis. Recent studies of twin, pedigree, and population-based datasets have discovered several candidate genes that consistently show small to moderate effects on brain measures. Many studies measure single phenotypes from the images, such as hippocampal volume, but voxel-wise genomic methods can plot the profile of genetic association at each 3D point in the brain. This exploits the full arsenal of imaging statistics to discover and replicate gene effects. Imaging genomics efforts worldwide are now working together to discover and replicate many promising leads. By studying brain phenotypes closer to causative gene action, larger gene effects are detectable with realistic sample sizes obtainable from meta-analysis of smaller studies. Imaging genomics has broad applications to dementia, mental illness, and public health.

  2. Combustion instability mitigation by magnetic fields

    Science.gov (United States)

    Jocher, Agnes; Pitsch, Heinz; Gomez, Thomas; Bonnety, Jérôme; Legros, Guillaume

    2017-06-01

    The present interdisciplinary study combines electromagnetics and combustion to unveil an original and basic experiment displaying a spontaneous flame instability that is mitigated as the non-premixed sooting flame experiences a magnetic perturbation. This magnetic instability mitigation is reproduced by direct numerical simulations to be further elucidated by a flow stability analysis. A key role in the stabilization process is attributed to the momentum and thermochemistry coupling that the magnetic force, acting mainly on paramagnetic oxygen, contributes to sustain. The spatial local stability analysis based on the numerical simulations shows that the magnetic field tends to reduce the growth rates of small flame perturbations.

  3. A fast beam-ion instability

    Energy Technology Data Exchange (ETDEWEB)

    Stupakov, G.V. [Stanford Linear Accelerator Center, Menlo Park, CA (United States)

    1996-08-01

    The ionization of residual gas by an electron beam in an accelerator generates ions that can resonantly couple to the beam through a wave propagating in the beam-ion system. Results of the study of a beam-ion instability are presented for a multi-bunch train taking into account the decoherence of ion oscillations due to the ion frequency spread and spatial variation of the ion frequency. It is shown that the combination of both effects can substantially reduce the growth rate of the instability. (author)

  4. Aeroelastic instability problems for wind turbines

    DEFF Research Database (Denmark)

    Hansen, Morten Hartvig

    2007-01-01

    This paper deals with the aeroelostic instabilities that have occurred and may still occur for modem commercial wind turbines: stall-induced vibrations for stall-turbines, and classical flutter for pitch-regulated turbines. A review of previous works is combined with derivations of analytical...... stability limits for typical blade sections that show the fundamental mechanisms of these instabilities. The risk of stall-induced vibrations is mainly related to blade airfoil characteristics, effective direction of blade vibrations and structural damping, whereas the blade tip speed, torsional blade...

  5. MHD thermal instabilities in cool inhomogeneous atmospheres

    Science.gov (United States)

    Bodo, G.; Ferrari, A.; Massaglia, S.; Rosner, R.

    1983-01-01

    The formation of a coronal state in a stellar atmosphere is investigated. A numerical code is used to study the effects of atmospheric gradients and finite loop dimension on the scale of unstable perturbations, solving for oscillatory perturbations as eigenfunctions of a boundary value problem. The atmosphere is considered as initially isothermal, with density and pressure having scale heights fixed by the hydrostatic equations. Joule mode instability is found to be an efficient mechanism for current filamentation and subsequent heating in initially cool atmospheres. This instability is mainly effective at the top of magnetic loops and is not suppressed by thermal conduction.

  6. Theory of electrohydrodynamic instabilities in electrolytic cells

    Science.gov (United States)

    Bruinsma, R.; Alexander, S.

    1990-01-01

    The paper develops the theory of the hydrodynamic stability of an electrolytic cell as a function of the imposed electric current. A new electrohydrodynamic instability is encountered when the current is forced to exceed the Nernst limit. The convection is driven by the volume force exerted by the electric field on space charges in the electrolyte. This intrinsic instability is found to be easily masked by extrinsic convection sources such as gravity or stirring. A linear stability analysis is performed and a dimensionless number Le is derived whose value determines the convection pattern.

  7. On cavitation instabilities with interacting voids

    DEFF Research Database (Denmark)

    Tvergaard, Viggo

    2012-01-01

    When a single void grows in an elastic–plastic material a cavitation instability may occur, if the stress triaxiality is sufficiently high. The effect of neighbouring voids on such unstable cavity growth is studied here by comparing two different models. The first model considers a periodic array...... voids so far apart that the radius of the plastic zone around each void is less than 1% of the current spacing between the voids, can still affect each others at the occurrence of a cavitation instability such that one void stops growing while the other grows in an unstable manner. On the other hand...

  8. IS POLARIS LEAVING THE CEPHEID INSTABILITY STRIP?

    OpenAIRE

    Turner, D. G.

    2017-01-01

    Although Polaris is generally regarded as an overtone pulsator that may soon switch to pulsation in the fundamental mode, it is argued that the variable is actually crossing the instability strip for the first time and is in the process of leaving the instability strip altogether. The luminosity of Polaris inferred from its optical F3 V companion, as well as from A, F, and G-type stars lying within a few degrees of it and populating a group main sequence coincident with that for Polaris B...

  9. Methods for Simulating the Heavy Core Instability

    Directory of Open Access Journals (Sweden)

    Chang Philip

    2013-04-01

    Full Text Available Vortices have been proposed as the sites of planet formation, where dust collects and grows into planetesimals, the building blocks of planets. However, for very small dust particles that can be treated as a pressure-less fluid, we have recently discovered the “heavy core” instability, driven by the density gradient in the vortex. In order to understand the eventual outcome of this instability, we need to study its non-linear development. Here, we describe our ongoing work to develop highly accurate numerical models of a vortex with a density gradient embedded within a protoplanetary disk.

  10. Heuristic explanation of journal bearing instability

    Science.gov (United States)

    Crandall, S. H.

    1982-01-01

    A fluid-filled journal bearing is viewed as a powerful pump circulating fluid around the annular space between the journal and the bearing. A small whirling motion of the journal generates a wave of thickness variation progressing around the channel. The hypothesis that the fluid flow drives the whirl whenever the mean of the pumped fluid velocity is greater than the peripheral speed of the thickness variation wave is discussed and compared with other simple explanations of journal bearing instability. It is shown that for non-cavitation long bearings the hypothesis predicts instability onset correctly for unloaded bearings but gradually overpredicts the onset speed as the load is increased.

  11. Efficiency Versus Instability in Plasma Accelerators

    Energy Technology Data Exchange (ETDEWEB)

    Lebedev, Valeri [Fermilab; Burov, Alexey [Fermilab; Nagaitsev, Sergei [Fermilab

    2017-01-05

    Plasma wake-field acceleration in a strongly nonlinear (a.k.a. the blowout) regime is one of the main candidates for future high-energy colliders. For this case, we derive a universal efficiency-instability relation, between the power efficiency and the key instability parameter of the witness bunch. We also show that in order to stabilize the witness bunch in a regime with high power efficiency, the bunch needs to have high energy spread, which is not presently compatible with collider-quality beam properties. It is unclear how such limitations could be overcome for high-luminosity linear colliders.

  12. Modulational instability in periodic quadratic nonlinear materials

    DEFF Research Database (Denmark)

    Corney, Joel Frederick; Bang, Ole

    2001-01-01

    We investigate the modulational instability of plane waves in quadratic nonlinear materials with linear and nonlinear quasi-phase-matching gratings. Exact Floquet calculations, confirmed by numerical simulations, show that the periodicity can drastically alter the gain spectrum but never completely...... removes the instability. The low-frequency part of the gain spectrum is accurately predicted by an averaged theory and disappears for certain gratings. The high-frequency part is related to the inherent gain of the homogeneous non-phase-matched material and is a consistent spectral feature....

  13. The Rossby wave instability in protoplanetary disks

    Directory of Open Access Journals (Sweden)

    Meheut H.

    2013-04-01

    Full Text Available The Rossby wave instability has been proposed as a mechanism to transport angular momentum in the dead zone of protoplanetary disks and to form vortices. These vortices are of particular interest to concentrate solids in their centres and eventually to form planetesimals. Here we summarize some recent results concerning the growth and structure of this instability in radially and vertically stratified disks, its saturation and non-linear evolution. We also discuss the concentration of solids in the Rossby vortices including vertical settling.

  14. Plasma wave instabilities in nonequilibrium graphene

    DEFF Research Database (Denmark)

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

    2016-01-01

    We study two-stream instabilities in a nonequilibrium system in which a stream of electrons is injected into doped graphene. As with equivalent nonequilibrium parabolic band systems, we find that the graphene systems can support unstable charge-density waves whose amplitudes grow with time. We...... determine the range of wave vectors q that are unstable, and their growth rates. We find no instability for waves with wave vectors parallel or perpendicular to the direction of the injected carriers. We find that, within the small-wave-vector approximation, the angle between q and the direction...

  15. Shape instability of a magnetic elastomer membrane

    Energy Technology Data Exchange (ETDEWEB)

    Raikher, Yu L; Stolbov, O V [Institute of Continuous Media Mechanics, Ural Branch of RAS, 614013 Perm (Russian Federation); Stepanov, G V [State Scientific Center ' Institute of Chemistry and Technology of Organoelement Compounds' , 11123 Moscow (Russian Federation)], E-mail: raikher@icmm.ru

    2008-08-07

    Shape instability occurring in a thin plate (membrane) made of a soft magnetoelastic material under a uniform magnetic field is predicted and analysed. The instability onset is shown to be similar to the second-order transition; the dependence of the threshold field on the magnetic and geometric parameters of the membrane is derived analytically; the membrane shapes (domes) are evaluated with the aid of numerical simulation. The theory proposed is in general agreement with experiments performed on a siloxane rubber/iron carbonyl composite. (fast track communication)

  16. Computing Instability In Combustion Of Liquid Propellants

    Science.gov (United States)

    Chen, Yen-Sen; Shang, Huan-Min

    1995-01-01

    Computational fluid dynamics (CFD) code developed for use in design analyses of flow instabilities associated with combustion of sprayed liquid propellants in rocket engines. Code also contributes to design of improved commercial sprayed-fuel combustors in furnaces and jet engines. Proves robust, user-friendly software tool with comprehensive analysis capability. Enables characterization of stability or instability of engine in terms of such physically meaningful parameters as initial conditions of spray, spatial distribution of ratio between concentrations of fuel and oxidizer at injector faces, geometry of combustor, and configurations of baffles.

  17. 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.

  18. Composition driven structural instability in perovskite ferroelectrics

    Directory of Open Access Journals (Sweden)

    Chao Xu

    2017-04-01

    Full Text Available Ferroelectric solid solutions usually exhibit enhanced functional properties at the morphotropic phase boundary separating two ferroelectric phases with different orientations of polarization. The underlying mechanism is generally associated with polarization rotational instability and the flattened free energy profile. In this work we show that the polarization extensional instability can also be induced at the morphotropic phase boundary beyond the reported polar-nonpolar phase boundary. The piezoelectricity enhanced by this mechanism exhibits excellent thermal stability, which helps to develop high performance piezoelectric materials with good temperature stability.

  19. White-light parametric instabilities in plasmas.

    Science.gov (United States)

    Santos, J E; Silva, L O; Bingham, R

    2007-06-08

    Parametric instabilities driven by partially coherent radiation in plasmas are described by a generalized statistical Wigner-Moyal set of equations, formally equivalent to the full wave equation, coupled to the plasma fluid equations. A generalized dispersion relation for stimulated Raman scattering driven by a partially coherent pump field is derived, revealing a growth rate dependence, with the coherence width sigma of the radiation field, scaling with 1/sigma for backscattering (three-wave process), and with 1/sigma1/2 for direct forward scattering (four-wave process). Our results demonstrate the possibility to control the growth rates of these instabilities by properly using broadband pump radiation fields.

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

    Directory of Open Access Journals (Sweden)

    Zhiliang Yu

    2017-07-01

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

  1. Role of intrinsic flame instability in the excitation of combustion chamber instability

    Science.gov (United States)

    Akkerman, V'yacheslav; Law, Chung K.

    2011-11-01

    While considerable progress was made on understanding the various modes of flame instability at the fundamental level, and substantial empirical information and phenomenological descriptions was also accumulated on combustion instability within combustion chambers such as those of rocket engines, few attempts were made to explore the possible macro-scale excitation of the latter through the micro-scale manifestation of the former. Here we present an initial attempt towards identifying such a possibility and the associated coupling mechanisms. We shall incorporate the flame parameters into the classical theories of liquid-propellant rocket engines, and then implement the rocket dynamics into the analyses of premixed and diffusion flame segments. The analyses are conducted for the various instability modes, including the diffusional-thermal, Darrieus-Landau, and Rayleigh-Taylor (body-force) instabilities for premixed flames, and the Kelvin-Helmholtz and body-force instabilities for diffusion flames. The role of chamber-generated sound on stabilizing the inherent flame instabilities and triggering the parametric instability is also considered.

  2. Marine genomics

    DEFF Research Database (Denmark)

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

    2017-01-01

    evolutionary biology of non-model organisms to species of commercial relevance for fishing, aquaculture and biomedicine. Instead of providing an exhaustive list of available genomic data, we rather set to present contextualized examples that best represent the current status of the field of marine genomics.......Marine ecosystems occupy 71% of the surface of our planet, yet we know little about their diversity. Although the inventory of species is continually increasing, as registered by the Census of Marine Life program, only about 10% of the estimated two million marine species are known. This lag......-throughput sequencing approaches have been helping to improve our knowledge of marine biodiversity, from the rich microbial biota that forms the base of the tree of life to a wealth of plant and animal species. In this review, we present an overview of the applications of genomics to the study of marine life, from...

  3. Listeria Genomics

    Science.gov (United States)

    Cabanes, Didier; Sousa, Sandra; Cossart, Pascale

    The opportunistic intracellular foodborne pathogen Listeria monocytogenes has become a paradigm for the study of host-pathogen interactions and bacterial adaptation to mammalian hosts. Analysis of L. monocytogenes infection has provided considerable insight into how bacteria invade cells, move intracellularly, and disseminate in tissues, as well as tools to address fundamental processes in cell biology. Moreover, the vast amount of knowledge that has been gathered through in-depth comparative genomic analyses and in vivo studies makes L. monocytogenes one of the most well-studied bacterial pathogens. This chapter provides an overview of progress in the exploration of genomic, transcriptomic, and proteomic data in Listeria spp. to understand genome evolution and diversity, as well as physiological aspects of metabolism used by bacteria when growing in diverse environments, in particular in infected hosts.

  4. Ancient genomics

    DEFF Research Database (Denmark)

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

    2015-01-01

    The past decade has witnessed a revolution in ancient DNA (aDNA) research. Although the field's focus was previously limited to mitochondrial DNA and a few nuclear markers, whole genome sequences from the deep past can now be retrieved. This breakthrough is tightly connected to the massive sequence...... by increasing the number of sequence reads to billions effectively means that contamination issues that have haunted aDNA research for decades, particularly in human studies, can now be efficiently and confidently quantified. At present, whole genomes have been sequenced from ancient anatomically modern humans......, archaic hominins, ancient pathogens and megafaunal species. Those have revealed important functional and phenotypic information, as well as unexpected adaptation, migration and admixture patterns. As such, the field of aDNA has entered the new era of genomics and has provided valuable information when...

  5. Cephalopod genomics

    DEFF Research Database (Denmark)

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

    2012-01-01

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

  6. MHD instabilities in astrophysical plasmas: very different from MHD instabilities in tokamaks!

    Science.gov (United States)

    Goedbloed, J. P.

    2018-01-01

    The extensive studies of MHD instabilities in thermonuclear magnetic confinement experiments, in particular of the tokamak as the most promising candidate for a future energy producing machine, have led to an ‘intuitive’ description based on the energy principle that is very misleading for most astrophysical plasmas. The ‘intuitive’ picture almost directly singles out the dominant stabilizing field line bending energy of the Alfvén waves and, consequently, concentrates on expansion schemes that minimize that contribution. This happens when the wave vector {{k}}0 of the perturbations, on average, is perpendicular to the magnetic field {B}. Hence, all macroscopic instabilities of tokamaks (kinks, interchanges, ballooning modes, ELMs, neoclassical tearing modes, etc) are characterized by satisfying the condition {{k}}0 \\perp {B}, or nearly so. In contrast, some of the major macroscopic instabilities of astrophysical plasmas (the Parker instability and the magneto-rotational instability) occur when precisely the opposite condition is satisfied: {{k}}0 \\parallel {B}. How do those instabilities escape from the dominance of the stabilizing Alfvén wave? The answer to that question involves, foremost, the recognition that MHD spectral theory of waves and instabilities of laboratory plasmas could be developed to such great depth since those plasmas are assumed to be in static equilibrium. This assumption is invalid for astrophysical plasmas where rotational and gravitational accelerations produce equilibria that are at best stationary, and the associated spectral theory is widely, and incorrectly, believed to be non-self adjoint. These complications are addressed, and cured, in the theory of the Spectral Web, recently developed by the author. Using this method, an extensive survey of instabilities of astrophysical plasmas demonstrates how the Alfvén wave is pushed into insignificance under these conditions to give rise to a host of instabilities that do not

  7. Clinical implications of microsatellite instability in T1 colorectal cancer.

    Science.gov (United States)

    Kang, Jeonghyun; Lee, Hak Woo; Kim, Im-kyung; Kim, Nam Kyu; Sohn, Seung-Kook; Lee, Kang Young

    2015-01-01

    The estimation of regional lymph node metastasis (LNM) risk in T1 colorectal cancer is based on histologic examination and imaging of the primary tumor. High-frequency microsatellite instability (MSI-H) is likely to decrease the possibility of metastasis to either regional lymph nodes or distant organs in colorectal cancers. This study evaluated the clinical implications of MSI in T1 colorectal cancer with emphasis on the usefulness of MSI as a predictive factor for regional LNM. A total of 133 patients who underwent radical resection for T1 colorectal cancer were included. Genomic DNA was extracted from normal and tumor tissues and amplified by polymerase chain reaction (PCR). Five microsatellite markers, BAT-25, BAT-26, D2S123, D5S346, and D17S250, were used. MSI and clinicopathological parameters were evaluated as potential predictors of LNM using univariate and multivariate analyses. Among 133 T1 colorectal cancer patients, MSI-H, low-frequency microsatellite instability (MSI-L), and microsatellite stable (MSS) colorectal cancers accounted for 7.5%, 6%, and 86.5%, respectively. MSI-H tumors showed a female predominance, a proximal location and more retrieved lymph nodes. Twenty-two patients (16.5%) had regional LNM. Lymphovascular invasion and depth of invasion were significantly associated with LNM. There was no LNM in 10 MSI-H patients; however, MSI status was not significantly correlated with LNM. Disease-free survival did not differ between patients with MSI-H and those with MSI-L/MSS. MSI status could serve as a negative predictive factor in estimating LNM in T1 colorectal cancer, given that LNM was not detected in MSI-H patients. However, validation of our result in a different cohort is necessary.

  8. Helicobacter pylori Infection Induces Genetic Instability of Nuclear and Mitochondrial DNA in Gastric Cells

    DEFF Research Database (Denmark)

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

    2009-01-01

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

  9. The Yin and Yang of Repair Mechanisms in DNA Structure-induced Genetic Instability

    Science.gov (United States)

    Vasquez, Karen M.; Wang, Guliang

    2013-01-01

    DNA can adopt a variety of secondary structures that deviate from the canonical Watson-Crick B-DNA form. More than 10 types of non-canonical or non-B DNA secondary structures have been characterized, and the sequences that have the capacity to adopt such structures are very abundant in the human genome. Non-B DNA structures have been implicated in many important biological processes and can serve as sources of genetic instability, implicating them in disease and evolution. Non-B DNA conformations interact with a wide variety of proteins involved in replication, transcription, DNA repair, and chromatin architectural regulation. In this review, we will focus on the interactions of DNA repair proteins with non-B DNA and their roles in genetic instability, as the proteins and DNA involved in such interactions may represent plausible targets for selective therapeutic intervention. PMID:23219604

  10. Aspects of electrohydrodynamic instabilities at polymer interfaces

    NARCIS (Netherlands)

    Russell, TP; Lin, ZQ; Schaffer, E; Steiner, U

    Electrospinning is emerging as a simple means of producing fibers with diameters ranging from 0.02 mum to many microns. Electrospinning, however, relies on the force generated by an electric field on the surface of a polymer solution to either enhance instabilities in a thinning jet or to rapidly

  11. Neutrino signal from pair-instability supernovae

    Science.gov (United States)

    Wright, Warren P.; Gilmer, Matthew S.; Fröhlich, Carla; Kneller, James P.

    2017-11-01

    A very massive star with a carbon-oxygen core in the range of 64M ⊙evolution at the extreme of stellar masses. Much will be sought within the electromagnetic radiation we detect from such a supernova but we should not forget that the neutrinos from a pair-instability supernova contain unique signatures of the event that unambiguously identify this type of explosion. We calculate the expected neutrino flux at Earth from two, one-dimensional pair-instability supernova simulations which bracket the mass range of stars which explode by this mechanism taking into account the full time and energy dependence of the neutrino emission and the flavor evolution through the outer layers of the star. We calculate the neutrino signals in five different detectors chosen to represent present or near future designs. We find the more massive progenitors explode as pair-instability supernova which can easily be detected in multiple different neutrino detectors at the "standard" supernova distance of 10 kpc producing several events in DUNE, JUNO, and Super-Kamiokande, while the lightest progenitors produce only a handful of events (if any) in the same detectors. The proposed Hyper-Kamiokande detector would detect neutrinos from a large pair-instability supernova as far as ˜50 kpc allowing it to reach the Megallanic Clouds and the several very high mass stars known to exist there.

  12. 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...

  13. Control of Coherent Instabilities by Linear Coupling

    CERN Document Server

    Cappi, R; Möhl, D

    2001-01-01

    One of the main challenges in the design of high-energy colliders is the very high luminosity necessary to provide significant event rates. This imposes strong constraints to achieve and preserve beams of high brightness, i.e. intensity to emittance ratio, all along the injector chain. Amongst the phenomena that can blow up and even destroy the beam are transverse coherent instabilities. Two methods are widely used to damp these instabilities. The first one is Landau damping by non-linearities. The second consists in using an electronic feedback system. However, non-linearities are harmful to single-particle motion due to resonance phenomena, and powerful wideband feedback systems are expensive. It is shown in this paper that linear coupling is a further method that can be used to damp transverse coherent instabilities. The theory of collective motion is outlined, including the coupling of instability rise and damping rates, chromaticity and Landau damping. Experimental results obtained at the CERN PS are rep...

  14. Understanding financial instability through complex systems

    NARCIS (Netherlands)

    in 't Veld, D.

    2011-01-01

    This article presents an outline and some early results of the research project Understanding inancial instability through complex systems, supported by the Dutch Science Foundation NWO. The project is carried out by the Center for Nonlinear Dynamics in Economics and Finance (CeNDEF) at the

  15. Plasmoid Instability in Forming Current Sheets

    Science.gov (United States)

    Comisso, L.; Lingam, M.; Huang, Y.-M.; Bhattacharjee, A.

    2017-12-01

    The plasmoid instability has revolutionized our understanding of magnetic reconnection in astrophysical environments. By preventing the formation of highly elongated reconnection layers, it is crucial in enabling the rapid energy conversion rates that are characteristic of many astrophysical phenomena. Most previous studies have focused on Sweet-Parker current sheets, which are unattainable in typical astrophysical systems. Here we derive a general set of scaling laws for the plasmoid instability in resistive and visco-resistive current sheets that evolve over time. Our method relies on a principle of least time that enables us to determine the properties of the reconnecting current sheet (aspect ratio and elapsed time) and the plasmoid instability (growth rate, wavenumber, inner layer width) at the end of the linear phase. After this phase the reconnecting current sheet is disrupted and fast reconnection can occur. The scaling laws of the plasmoid instability are not simple power laws, and they depend on the Lundquist number (S), the magnetic Prandtl number (P m ), the noise of the system ({\\psi }0), the characteristic rate of current sheet evolution (1/τ ), and the thinning process. We also demonstrate that previous scalings are inapplicable to the vast majority of astrophysical systems. We explore the implications of the new scaling relations in astrophysical systems such as the solar corona and the interstellar medium. In both of these systems, we show that our scaling laws yield values for the growth rate, wavenumber, and aspect ratio that are much smaller than the Sweet-Parker-based scalings.

  16. Instabilities in power law gradient hardening materials

    DEFF Research Database (Denmark)

    Niordson, Christian Frithiof; Tvergaard, Viggo

    2005-01-01

    Tension and compression instabilities are investigated for specimens with dimensions in the micron range. A finite strain generalization of a higher order strain gradient plasticity theory is implemented in a finite element scheme capable of modeling power law hardening materials. Effects...

  17. Greenscreen Teaching: Institutional Instability and Classroom Innovation

    Science.gov (United States)

    Perkins, Miriam Y.

    2017-01-01

    "Greenscreen Teaching" explores how the stresses of institutional and social change impact teaching and learning, and the creative resourcefulness born out of instability. In precarious institutions and social contexts, relevant outcomes for theological learning include developing attentiveness, robust moral discernment, and courageous…

  18. Treatment of glenohumeral instability in rugby players.

    Science.gov (United States)

    Funk, Lennard

    2016-02-01

    Rugby is a high-impact collision sport, with impact forces. Shoulder injuries are common and result in the longest time off sport for any joint injury in rugby. The most common injuries are to the glenohumeral joint with varying degrees of instability. The degree of instability can guide management. The three main types of instability presentations are: (1) frank dislocation, (2) subluxations and (3) subclinical instability with pain and clicking. Understanding the exact mechanism of injury can guide diagnosis with classical patterns of structural injuries. The standard clinical examination in a large, muscular athlete may be normal, so specific tests and techniques are needed to unearth signs of pathology. Taking these factors into consideration, along with the imaging, allows a treatment strategy. However, patient and sport factors need to be also considered, particularly the time of the season and stage of sporting career. Surgery to repair the structural damage should include all lesions found. In chronic, recurrent dislocations with major structural lesions, reconstruction procedures such as the Latarjet procedure yields better outcomes. Rehabilitation should be safe, goal-driven and athlete-specific. Return to sport is dependent on a number of factors, driven by the healing process, sport requirements and extrinsic pressures. Level of evidence V.

  19. Rodeo athletes: management of shoulder instability.

    Science.gov (United States)

    Figueiredo, Eduardo A; Belangero, Paulo S; Cohen, Carina; Louchard, Rafael L; Terra, Bernardo B; Pochini, Alberto C; Andreoli, Carlos V; Cohen, Moisés; Ejnisman, Benno

    2016-05-01

    The aim of this study was to describe epidemiological data and evaluate the clinical results of traumatic anterior glenohumeral instability in rodeo athletes. Thirteen patients, all male, with a mean age of 23.2 (18-31) years old, with anterior glenohumeral instability were include in this study. In 9 patients, the right side was affected. The mean time elapsed between injury and undergoing surgery was 56 months (24-120 months). The surgical technique used (arthroscopic or open bone block procedure) was chosen based on the ISIS (Instability Severity Index Score). Only professional athletes who had been in the sport for at least 60 months were included. Functional evaluation was conducted using the UCLA scale, after a 24-month follow-up period. The number of dislocation episodes varied from 10 to 100 (mean 27 episodes). All of the patients were submitted a surgical treatment open bone block procedure, due to their degree of sport participation, type of sport (forced overhead and collision) and the presence of associated bone defect lesions. According to UCLA criteria, the results were excellent in 12 patients and good in one. The mean time elapsed before returning to the sport was five months, varying between two and ten months. Complications included one patient developing axillary neuropraxia, which was completely resolved six months after the operation, and another patient developed a superficial skin infection. The rodeo athletes with anterior shoulder instability had serious associated bony lesions and has good outcome after bone block procedure.

  20. Corruption, Governance and Political Instability in Nigeria ...

    African Journals Online (AJOL)

    The Nigerian State is a victim of high-level corruption, bad governance, political instability and cyclical legitimacy crisis. In the absence of support from civil society, the effective power of government was eroded and patron-client relationships took a prime role over the formal aspects of politics, such as the rule of law, ...

  1. Nonlinear Instabilities on an Axisymmetric Ferrofluid Jet

    Science.gov (United States)

    Cornish, Michael; Papageorgiou, Demetrios

    2017-11-01

    The stability properties of an inviscid axisymmetric ferrofluid jet running over a current carrying rod are investigated. The rod generates an azimuthal magnetic field which can fully stabilize the Rayleigh-plateau instability for a sufficiently large magnetic field. However, long wave instability can occur when the magnetic field is below critical; this regime has not been studied nonlinearly unlike the above critical regime where the magnetic stabilization property has led to theoretical and experimental discoveries of solitary waves on the ferrofluid jet. We study the flow asymptotically near the critical value of the magnetic field. In the stable regime, we derive the Boussinesq equation. Our interest is in the unstable regime, where magnetic forces are slightly smaller than capillary forces. The Rayleigh-plateau instability is no longer suppressed and a weakly nonlinear long wave model is derived and studied analytically and computationally. The final part of the study follows the nonlinear evolution of the free surface for magnetic fields away from the critical level. A fully nonlinear long-wave theory will be used to derive reduced model equations to evaluate the nonlinear competition between capillary instability of the liquid jet and the stabilizing magnetic field.

  2. Parametric instabilities in picosecond time scales

    Energy Technology Data Exchange (ETDEWEB)

    Baldis, H.A. [Lawrence Livermore National Lab., CA (United States); Rozmus, W. [Alberta Univ., Edmonton, AB (Canada). Dept. of Physics; Labaune, C.; Mounaix, Ph.; Pesme, D.; Baton, S. [Ecole Polytechnique, Palaiseau (France); Tikhonchuk, V.T. [P.N. Lebedev Physics Inst., Moscow (Russian Federation)

    1993-03-01

    The coupling of intense laser light with plasmas is a rich field of plasma physics, with many applications. Among these are inertial confinement fusion (ICF), x-ray lasers, particle acceleration, and x-ray sources. Parametric instabilities have been studied for many years because of their importance to ICF; with laser pulses with duration of approximately a nanosecond, and laser intensities in the range 10{sup 14}--10{sup 15}W/cm{sup 2} these instabilities are of crucial concern because of a number of detrimental effects. Although the laser pulse duration of interest for these studies are relatively long, it has been evident in the past years that to reach an understanding of these instabilities requires their characterization and analysis in picosecond time scales. At the laser intensities of interest, the growth rate for stimulated Brillouin scattering (SBS) is of the order of picoseconds, and of an order of magnitude shorter for stimulated Raman scattering (SRS). In this paper the authors discuss SBS and SRS in the context of their evolution in picosecond time scales. They describe the fundamental concepts associated with their growth and saturation, and recent work on the nonlinear treatment required for the modeling of these instabilities at high laser intensities.

  3. 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...

  4. Suppression of instability in rotatory hydromagnetic convection

    Indian Academy of Sciences (India)

    Recently discovered hydrodynamic instability [1], in a simple Bénard configuration in the parameter regime 02 > 1 under the action of a nonadverse temperature gradient, is shown to be suppressed by the simultaneous action of a uniform rotation and a uniform magnetic field both acting parallel to gravity for oscillatory ...

  5. The disruptive instability in Tokamak plasmas

    NARCIS (Netherlands)

    Salzedas, F.J.B.

    2000-01-01

    Studies performed in RTP (Rijnhuizen Tokamak Project) of the most violent and dangerous instability in tokamak plasmas, the major disruption, are presented. A particular class of disruptions is analyzed, namely the density limit disruption, which occur in high density plasmas. The radiative

  6. Theory and Experiments on Chemical Instabilities.

    Science.gov (United States)

    1983-12-31

    following institutions and conferences: 1981 Jan. 8 X Reunion de Fisica Estadistica , Cocoyoc, Mexico, Resonances and Control Features Feb. 13 Michigan State...Aeronautics and Astronautics, Invited Remarks, Palo Alto, CA 1982 Feb. 25,26 Industrial Affiliates Program ": .’ Hydrodynamic and Chemical Instabilities

  7. Capillary instability on a hydrophilic stripe

    Science.gov (United States)

    Speth, Raymond L.; Lauga, Eric

    2009-07-01

    A recent experiment showed that cylindrical segments of water filling a hydrophilic stripe on an otherwise hydrophobic surface display a capillary instability when their volume is increased beyond the critical volume at which their apparent contact angle on the surface reaches 90° (Gau et al 1999 Science 283 46-9). Surprisingly, the fluid segments did not break up into droplets—as would be expected for a classical Rayleigh-Plateau instability—but instead displayed a long-wavelength instability where all excess fluid gathered in a single bulge along each stripe. We consider here the dynamics of the flow instability associated with this setup. We perform a linear stability analysis of the capillary flow problem in the inviscid limit. We first confirm previous work showing that all cylindrical segments are linearly unstable if (and only if) their apparent contact angle is larger than 90°. We then demonstrate that the most unstable wavenumber for the surface perturbation decreases to zero as the apparent contact angle of the fluid on the surface approaches 90°, allowing us to re-interpret the creation of bulges in the experiment as a zero-wavenumber capillary instability. A variation of the stability calculation is also considered for the case of a hydrophilic stripe located on a wedge-like geometry.

  8. Upstream and Downstream Influence in STBLI Instability

    Science.gov (United States)

    Martin, Pino; Priebe, Stephan; Helm, Clara

    2016-11-01

    Priebe and Martín (JFM, 2012) show that the low-frequency unsteadiness in shockwave and turbulent boundary layer interactions (STBLI) is governed by an inviscid instability. Priebe, Tu, Martín and Rowley (JFM, 2016) show that the instability is an inviscid centrifugal one, i.e Görtlerlike vortices. Previous works had given differing conclusions as to whether the low-frequency unsteadiness in STBLI is caused by an upstream or downstream mechanism. In this paper, we reconcile these opposite views and show that upstream and downstream correlations co-exist in the context of the nature of Görtler vortices. We find that the instability is similar to that in separated subsonic and laminar flows. Since the turbulence is modulated but passive to the global mode, the turbulent separated flows are amenable to linear global analysis. As such, the characteristic length and time scales, and the receptivity of the global mode might be determined, and low-order models that represent the low-frequency dynamics in STBLI might be developed. The centrifugal instability persists even under hypersonic conditions. This work is funded by the AFOSR Grant Number AF9550-15-1-0284 with Dr. Ivett Leyva.

  9. Mix and hydrodynamic instabilities on NIF

    Science.gov (United States)

    Smalyuk, V. A.; Robey, H. F.; Casey, D. T.; Clark, D. S.; Döppner, T.; Haan, S. W.; Hammel, B. A.; MacPhee, A. G.; Martinez, D.; Milovich, J. L.; Peterson, J. L.; Pickworth, L.; Pino, J. E.; Raman, K.; Tipton, R.; Weber, C. R.; Baker, K. L.; Bachmann, B.; Berzak Hopkins, L. F.; Bond, E.; Caggiano, J. A.; Callahan, D. A.; Celliers, P. M.; Cerjan, C.; Dixit, S. N.; Edwards, M. J.; Felker, S.; Field, J. E.; Fittinghoff, D. N.; Gharibyan, N.; Grim, G. P.; Hamza, A. V.; Hatarik, R.; Hohenberger, M.; Hsing, W. W.; Hurricane, O. A.; Jancaitis, K. S.; Jones, O. S.; Khan, S.; Kroll, J. J.; Lafortune, K. N.; Landen, O. L.; Ma, T.; MacGowan, B. J.; Masse, L.; Moore, A. S.; Nagel, S. R.; Nikroo, A.; Pak, A.; Patel, P. K.; Remington, B. A.; Sayre, D. B.; Spears, B. K.; Stadermann, M.; Tommasini, R.; Widmayer, C. C.; Yeamans, C. B.; Crippen, J.; Farrell, M.; Giraldez, E.; Rice, N.; Wilde, C. H.; Volegov, P. L.; Gatu Johnson, M.

    2017-06-01

    Several new platforms have been developed to experimentally measure hydrodynamic instabilities in all phases of indirect-drive, inertial confinement fusion implosions on National Ignition Facility. At the ablation front, instability growth of pre-imposed modulations was measured with a face-on, x-ray radiography platform in the linear regime using the Hydrodynamic Growth Radiography (HGR) platform. Modulation growth of "native roughness" modulations and engineering features (fill tubes and capsule support membranes) were measured in conditions relevant to layered DT implosions. A new experimental platform was developed to measure instability growth at the ablator-ice interface. In the deceleration phase of implosions, several experimental platforms were developed to measure both low-mode asymmetries and high-mode perturbations near peak compression with x-ray and nuclear techniques. In one innovative technique, the self-emission from the hot spot was enhanced with argon dopant to "self-backlight" the shell in-flight. To stabilize instability growth, new "adiabat-shaping" techniques were developed using the HGR platform and applied in layered DT implosions.

  10. On Hydrodynamic Instabilities in Cylindrical Geometry

    Science.gov (United States)

    Proano, Erik; Rollin, Bertrand

    2017-11-01

    Recent research has suggested that hydrodynamic instabilities induced mixing is one of the last major hurdles toward achieving optimum conditions for ignition in confined fusion approaches for energy production. We leave aside the complexities of multiple interacting physics that lead to a fusion target ignition to be able to focus on understanding the development of these hydrodynamic instabilities, namely Richtmyer-Meshkov and Rayleigh-Taylor, in the context of a converging geometry. The problem is reformulated into the cleaner case of a cylindrical shock wave imploding onto a pocket of Sulfur Hexafluoride immersed in air. This numerical experiment aims at characterizing qualitatively and quantitatively the relation between the instabilities initial conditions and their development until late time. Starting from carefully designed single- and multimode disturbances at the initial density interface, our simulations track the evolution of the mixing layer through successive occurrences of the Richtmyer-Meshkov and Rayleigh-Taylor instabilities. Evolution of the mixing zone width and growth rate are presented for selected initial conditions, along with a quantification of mixing. Also, the effect of the converging shock strength is discussed.

  11. Snake venom instability | Willemse | African Zoology

    African Journals Online (AJOL)

    Egyptian cobra Naja haje haje) and puffadder (Bills arietans). Considerable differences in electrophoretic characteristics were found between fresh venom and commercial venom samples from the same species of snake. These differences could be attributed partly to the instability of snake venom under conditions of drying ...

  12. Galloping instability to chaos of cables

    CERN Document Server

    Luo, Albert C J

    2017-01-01

    This book provides students and researchers with a systematic solution for fluid-induced structural vibrations, galloping instability and the chaos of cables. They will also gain a better understanding of stable and unstable periodic motions and chaos in fluid-induced structural vibrations. Further, the results presented here will help engineers effectively design and analyze fluid-induced vibrations.

  13. Remittances, spending, and political instability in Ukraine

    Czech Academy of Sciences Publication Activity Database

    Kuntsevych, Iuliia

    2016-01-01

    Roč. 64, č. 1 (2016), s. 42-57 ISSN 0722-480X Institutional support: PRVOUK-P23 Keywords : Ukraine * remittances * political instability Subject RIV: AH - Economics http://www.degruyter.com/view/j/soeu.2016.64.issue-1/soeu-2016-0004/soeu-2016-0004.xml

  14. Genome Imprinting

    Indian Academy of Sciences (India)

    because of their maternal 'or paternal origin. Human homologies for the type of situation described above are naturally occurring placental malformation, the hydatidiform ..... drome, familial glomus tumors, psoriasis, neural tube defects, congenital heart disease and narcolepsy. Since genome imprint- ing is implicated in the ...

  15. Transport Properties of the Azimuthal Magnetorotational Instability

    Science.gov (United States)

    Guseva, Anna; Willis, Ashley P.; Hollerbach, Rainer; Avila, Marc

    2017-11-01

    The magnetorotational instability (MRI) is thought to be a powerful source of turbulence in Keplerian accretion disks. Motivated by recent laboratory experiments, we study the MRI driven by an azimuthal magnetic field in an electrically conducting fluid sheared between two concentric rotating cylinders. By adjusting the rotation rates of the cylinders, we approximate angular velocity profiles {ω }\\propto {r}q. We perform direct numerical simulations of a steep profile close to the Rayleigh line q≳ -2 and a quasi-Keplerian profile q≈ -3/2 and cover wide ranges of Reynolds ({{Re}} ≤slant 4× {10}4) and magnetic Prandtl numbers (0≤slant {{Pm}}≤slant 1). In the quasi-Keplerian case, the onset of instability depends on the magnetic Reynolds number, with {{{Rm}}}c≈ 50, and angular momentum transport scales as \\sqrt{{{Pm}}}{{{Re}}}2 in the turbulent regime. The ratio of Maxwell to Reynolds stresses is set by Rm. At the onset of instability both stresses have similar magnitude, whereas the Reynolds stress vanishes or becomes even negative as Rm increases. For the profile close to the Rayleigh line, the instability shares these properties as long as {{Pm}}≳ 0.1 but exhibits a markedly different character if {{Pm}}\\to 0, where the onset of instability is governed by the Reynolds number, with {{{Re}}}c ≈ 1250, and transport is via Reynolds stresses and scales as Re2. At intermediate Pm = 0.01 we observe a continuous transition from one regime to the other, with a crossover at {{Rm}}={ O }(100). Our results give a comprehensive picture of angular momentum transport of the MRI with an imposed azimuthal field.

  16. Prevalence of knee instability in relation to sports activity

    DEFF Research Database (Denmark)

    Hahn, Thomas; Foldspang, Anders; Hansen, Thorsten Ingemann

    2001-01-01

    The objective was to estimate the prevalence of knee instability among active athletes and to investigate potential associations to type, amount and duration of sports participation. Based on a questionnaire, 339 athletes provided information about different features of occupation, sports activity...... and knee instability. The 12-month period prevalence of knee instability and constant or recurrent knee instability, and absence from sport and absence from work due to knee instability, was 22%, 14%, 5% and 1%, respectively. Knee instability as such, and constant or recurrent knee instability were found...... to be positively associated with female gender and different features of occupational work. In conclusion, knee instability is a commonly reported phenomenon among active athletes. It was found to be independent of the type and the amount of sports activity but highly dependent on female gender, type and amount...

  17. Study of Electron Cloud Instability in Fermilab Main Injector

    Energy Technology Data Exchange (ETDEWEB)

    Zwaska, R. M. [Fermilab; Ohmi, K. [KEK, Tsukuba

    2012-05-01

    Electron cloud has been observed in Fermilab main injector. Electron signal is enhanced near the transition. The slippage factor which suppress instabilities approach to zero at the transition. Instabilities must be most serious near the trans ition. The instability caused by the electron cloud is an important issue for high intensity operation and the future toward Project-X. Simulations of electron cloud instability near the transition is presented.

  18. Helicobacter pylori infection generates genetic instability in gastric cells

    DEFF Research Database (Denmark)

    Machado, Ana Manuel; Figueiredo, C.; Seruca, R.

    2010-01-01

    The discovery that Helicobacter pylori is associated with gastric cancer has led to numerous studies that investigate the mechanisms by which H. pylori induces carcinogenesis. Gastric cancer shows genetic instability both in nuclear and mitochondrial DNA, besides impairment of important DNA repair...... of the host, such as oxidative damage, methylation, chromosomal instability, microsatellite instability, and mutations. Interestingly, H. pylori infection generates genetic instability in nuclear and mitochondrial DNA. Based on the reviewed literature we conclude that H. pylori infection promotes gastric...

  19. A Computational Study of Transverse Combustion Instability Mechanisms

    Science.gov (United States)

    2014-07-01

    Marshall Space Flight Center. References 1. Smith, D. A., Zukoski, E. E., “Combustion Instability Sustained by Unsteady Vortex Combustion,” 21st JPC ...Prediction in a Model Rocket Combustor,” 47th JPC , AIAA 2011-6030. 10. Harvazinski, M. E., Modeling Self-Excited Combustion Instabilities Using A...Instabilities,” 49th JPC , AIAA 2013-3992. 13. Smith, R., Xia, G., Anderson, W., Merkle, C. L., “Extraction of Combustion Instability Mechanisms form Detailed

  20. Transcriptome instability as a molecular pan-cancer characteristic of carcinomas.

    Science.gov (United States)

    Sveen, Anita; Johannessen, Bjarne; Teixeira, Manuel R; Lothe, Ragnhild A; Skotheim, Rolf I

    2014-08-10

    We have previously proposed transcriptome instability as a genome-wide, pre-mRNA splicing-related characteristic of colorectal cancer. Here, we explore the hypothesis of transcriptome instability being a general characteristic of cancer. Exon-level microarray expression data from ten cancer datasets were analyzed, including breast cancer, cervical cancer, colorectal cancer, gastric cancer, lung cancer, neuroblastoma, and prostate cancer (555 samples), as well as paired normal tissue samples from the colon, lung, prostate, and stomach (93 samples). Based on alternative splicing scores across the genomes, we calculated sample-wise relative amounts of aberrant exon skipping and inclusion. Strong and non-random (P < 0.001) correlations between these estimates and the expression levels of splicing factor genes (n = 280) were found in most cancer types analyzed (breast-, cervical-, colorectal-, lung- and prostate cancer). This suggests a biological explanation for the splicing variation. Surprisingly, these associations prevailed in pan-cancer analyses. This is in contrast to the tissue and cancer specific patterns observed in comparisons across healthy tissue samples from the colon, lung, prostate, and stomach, and between paired cancer-normal samples from the same four tissue types. Based on exon-level expression profiling and computational analyses of alternative splicing, we propose transcriptome instability as a molecular pan-cancer characteristic. The affected cancers show strong and non-random associations between low expression levels of splicing factor genes, and high amounts of aberrant exon skipping and inclusion, and vice versa, on a genome-wide scale.

  1. Current-Driven Filament Instabilities in Relativistic Plasmas. Final report

    Energy Technology Data Exchange (ETDEWEB)

    Ren, Chuang

    2013-02-13

    This grant has supported a study of some fundamental problems in current- and flow-driven instabilities in plasmas and their applications in inertial confinement fusion (ICF) and astrophysics. It addressed current-driven instabilities and their roles in fast ignition, and flow-driven instabilities and their applications in astrophysics.

  2. The cancer genome: from structure to function.

    Science.gov (United States)

    Geurts van Kessel, Ad

    2014-06-01

    The 2014 joint meeting of the International Society for Cellular Oncology (ISCO) and the European Workshop on Cytogenetics and Molecular Genetics of Solid Tumors (EWCMST), organized by Nick Gilbert, Juan Cigudosa and Bauke Ylstra, was held from 11 to 14 May in Malaga, Spain. Since the previous meeting in 2012, the ever increasing availability of new sequencing technologies has enabled the analysis of cancer genomes at an increasingly greater detail. In addition to structural changes in the genome (i.e., translocations, deletions, amplifications), frequent mutations in important regulatory genes have been found to occur, as also frequent alterations in a large number of epigenetic factors. The challenge now is to relate structural changes in cancer genomes to the underlying disease mechanisms and to reveal opportunities for the design of novel (targeted) therapies. During the meeting, various topics related to these challenges and opportunities were addressed, including those dealing with functional genomics, genome instability, biomarkers and diagnostics, cancer genetics and epigenomics. Special attention was paid to therapy-driven cancer evolution (keynote lecture) and relationships between DNA repair, cancer and ageing (Prof. Ploem lecture). Based on the information presented at the meeting, several aspects of the cancer genome and its functional implications are provided in this report.

  3. Personal genomics services: whose genomes?

    Science.gov (United States)

    Gurwitz, David; Bregman-Eschet, Yael

    2009-07-01

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

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

    KAUST Repository

    Baranasic, Damir

    2014-07-17

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

  5. On the measurement of political instability and its impact on economic growth

    NARCIS (Netherlands)

    Jong-A-Pin, R.

    We examine the multidimensionality of political instability using 25 political instability indicators in an Exploratory Factor Analysis. We find that political instability has four dimensions: politically motivated violence, mass civil protest. instability within the political regime. and

  6. Reprogramming to pluripotency can conceal somatic cell chromosomal instability.

    Directory of Open Access Journals (Sweden)

    Masakazu Hamada

    Full Text Available The discovery that somatic cells are reprogrammable to pluripotency by ectopic expression of a small subset of transcription factors has created great potential for the development of broadly applicable stem-cell-based therapies. One of the concerns regarding the safe use of induced pluripotent stem cells (iPSCs in therapeutic applications is loss of genomic integrity, a hallmark of various human conditions and diseases, including cancer. Structural chromosome defects such as short telomeres and double-strand breaks are known to limit reprogramming of somatic cells into iPSCs, but whether defects that cause whole-chromosome instability (W-CIN preclude reprogramming is unknown. Here we demonstrate, using aneuploidy-prone mouse embryonic fibroblasts (MEFs in which chromosome missegregation is driven by BubR1 or RanBP2 insufficiency, that W-CIN is not a barrier to reprogramming. Unexpectedly, the two W-CIN defects had contrasting effects on iPSC genomic integrity, with BubR1 hypomorphic MEFs almost exclusively yielding aneuploid iPSC clones and RanBP2 hypomorphic MEFs karyotypically normal iPSC clones. Moreover, BubR1-insufficient iPSC clones were karyotypically unstable, whereas RanBP2-insufficient iPSC clones were rather stable. These findings suggest that aneuploid cells can be selected for or against during reprogramming depending on the W-CIN gene defect and present the novel concept that somatic cell W-CIN can be concealed in the pluripotent state. Thus, karyotypic analysis of somatic cells of origin in addition to iPSC lines is necessary for safe application of reprogramming technology.

  7. Citrus Genomics

    Science.gov (United States)

    Talon, Manuel; Gmitter Jr., Fred G.

    2008-01-01

    Citrus is one of the most widespread fruit crops globally, with great economic and health value. It is among the most difficult plants to improve through traditional breeding approaches. Currently, there is risk of devastation by diseases threatening to limit production and future availability to the human population. As technologies rapidly advance in genomic science, they are quickly adapted to address the biological challenges of the citrus plant system and the world's industries. The historical developments of linkage mapping, markers and breeding, EST projects, physical mapping, an international citrus genome sequencing project, and critical functional analysis are described. Despite the challenges of working with citrus, there has been substantial progress. Citrus researchers engaged in international collaborations provide optimism about future productivity and contributions to the benefit of citrus industries worldwide and to the human population who can rely on future widespread availability of this health-promoting and aesthetically pleasing fruit crop. PMID:18509486

  8. Minimal genome: Worthwhile or worthless efforts toward being smaller?

    Science.gov (United States)

    Choe, Donghui; Cho, Suhyung; Kim, Sun Chang; Cho, Byung-Kwan

    2016-02-01

    Microbial cells are versatile hosts for the production of value-added products due to the well-established background knowledge, various genetic tools, and ease of manipulation. Despite those advantages, efficiency of newly incorporated synthetic pathways in microbial cells is frequently limited by innate metabolism, product toxicity, and growth-mediated genetic instability. To overcome those obstacles, a minimal genome harboring only the essential set of genes was proposed, which is a fascinating concept with potential for use as a platform strain. Here, we review the currently available artificial reduced genomes and discuss the prospects for extending use of the genome-reduced strains as programmable chasses. The genome-reduced strains generally showed comparable growth to and higher productivity than their ancestral strains. In Escherichia coli, about 300 genes are estimated as the minimal number of genes under laboratory conditions. However, recent advances revealed that there are non-essential components in essential genes, suggesting that the design principle of minimal genomes should be reconstructed. Current technology is not efficient enough to reduce large amount of interspaced genomic regions or to synthesize the genome. Furthermore, construction of minimal genome frequently has failed due to lack of genomic information. Technological breakthroughs and intense systematic studies on genomes remain tasks. Copyright © 2015 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

  9. Visualization for genomics: the Microbial Genome Viewer.

    NARCIS (Netherlands)

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

    2004-01-01

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

  10. Simulation of liquid propellant rocket engine combustion instabilities

    Science.gov (United States)

    Ventrice, M. B.; Fang, J. C.; Purdy, K. R.

    1979-01-01

    A simulation technique for studying the high frequency combustion instabilities of liquid propellant rocket engines has been developed and used to investigate various aspects of instability phenomena. Of importance was investigation of the significance of the method of coupling the combustion and the gas dynamics of the system. Two coupling processes were studied: linear response of the combustion process to pressure fluctuations, and the nature of the resulting instabilities; and nonlinear response of the combustion process to velocity fluctuations, and the nature of the resulting instabilities. For the combustion model studied, nonlinear (velocity) coupling was found to more closely characterize liquid propellant instabilities.

  11. Selected Topics in Microwave Instabilities and Linacs

    Energy Technology Data Exchange (ETDEWEB)

    Ng, K. Y. [Fermi National Accelerator Lab. (FNAL), Batavia, IL (United States)

    2013-06-01

    The Shanghai Institute of Applied Physics (SINAP) is embarking on its first X-ray free-electron laser (FEL) project. It is a cascading high-gain harmonic generation FEL. Microwave instabilities driven by various effects, especially the space-charge force, will degrade the qual- ity of the electron beam before entering into the undulator. However, inside the undulator, the occurrence of microbunching becomes an ut- most important ingredient for the generation of coherent radiation. In short, controlled and uncontrolled microwave instabilities must be fully understood in such a project. These are the slides of a series of eight-hour lectures given at the SINAP in June of 2013, with the intention of a fully understanding of the microbunching phenomenon. The sections of wake field and impedance theory are added as an in- troduction for those who are not familiar with the subject.

  12. Coulomb center instability in bilayer graphene

    Science.gov (United States)

    Oriekhov, D. O.; Sobol, O. O.; Gorbar, E. V.; Gusynin, V. P.

    2017-10-01

    In the low-energy two-band as well as four-band continuum models, we study the supercritical charge instability in gapped bilayer graphene in the field of an impurity charge when the lowest-energy bound state dives into the hole continuum. It is found that the screening effects are crucially important in bilayer graphene. If they are neglected, then the critical value for the impurity charge tends to zero as the gap Δ vanishes. If the screened Coulomb interaction is considered, then the critical charge tends to a finite value for Δ →0 . The different scalings of the kinetic energy of quasiparticles and the Coulomb interaction with respect to the distance to the charged impurity ensure that the wave function of the electron bound state does not shrink toward the impurity as its charge increases. This results in the absence of the fall-to-center phenomenon in bilayer graphene although the supercritical charge instability is realized.

  13. Instability in electromagnetically driven flows Part I

    CERN Document Server

    Gissinger, Christophe; Fauve, Stephan

    2016-01-01

    The MHD flow driven by a travelling magnetic field (TMF) in an annular channel is investigated numerically. For sufficiently large magnetic Reynolds number Rm, or if a large enough pressure gradient is externally applied, the system undergoes an instability in which the flow rate in the channel dramatically drops from synchronism with the wave to much smaller velocities. This transition takes the form of a saddle-node bifurcation for the time-averaged quantities. In this first paper, we characterize the bifurcation, and study the stability of the flow as a function of several parameters. We show that the bifurcation of the flow involves a bistability between Poiseuille-like and Hartman-like regimes, and relies on magnetic flux expulsion. Based on this observation, new predictions are made for the occurrence of this stalling instability.

  14. Microwave instability in electron storage rings

    CERN Document Server

    Mosnier, A

    1999-01-01

    Tracking simulations, with the aim of studying the microwave regime with short and intense bunches, suggest different instability mechanisms, according to the impedance model. In order to get a better insight of the source of the instability, i.e. azimuthal or radial mode coupling, we choose to follow the Sacherer (IEEE Trans. Nucl. Sci. NS-24, 1977 1393) approach to investigate the stability of the stationary solution. The generalized Sacherer's integral, including mode coupling and potential well distortion, is then solved by using the 'step function technique' for the expansion of the radial function, as proposed by Oide and Yokoya (KEK Preprint-90-10, April, 1990). For illustration, the effect of the resonant frequency of a broadband resonator in the SOLEIL storage ring is studied. When the resonator frequency is much higher than the bunch spectrum width, azimuthal mode coupling can occur before radial mode coupling. When the resonator frequency is lower, radial mode coupling comes usually first, but two ...

  15. Elastic instability in stratified core annular flow.

    Science.gov (United States)

    Bonhomme, Oriane; Morozov, Alexander; Leng, Jacques; Colin, Annie

    2011-06-01

    We study experimentally the interfacial instability between a layer of dilute polymer solution and water flowing in a thin capillary. The use of microfluidic devices allows us to observe and quantify in great detail the features of the flow. At low velocities, the flow takes the form of a straight jet, while at high velocities, steady or advected wavy jets are produced. We demonstrate that the transition between these flow regimes is purely elastic--it is caused by the viscoelasticity of the polymer solution only. The linear stability analysis of the flow in the short-wave approximation supplemented with a kinematic criterion captures quantitatively the flow diagram. Surprisingly, unstable flows are observed for strong velocities, whereas convected flows are observed for low velocities. We demonstrate that this instability can be used to measure the rheological properties of dilute polymer solutions that are difficult to assess otherwise.

  16. Rehabilitation for Shoulder Instability - Current Approaches.

    Science.gov (United States)

    Jaggi, Anju; Alexander, Susan

    2017-01-01

    The shoulder relies predominantly on dynamic muscular control to provide stability. Successful treatment is highly dependent upon the correct clinical diagnosis, identification of anatomical structural defects and abnormal movement patterns so that rehabilitation programs can be designed accordingly and individualised to the patient. A systematic outline is provided to guide the clinician on how to identify muscular insufficiencies both local to the shoulder joint and global muscles that can influence shoulder instability. Management is based on expert experience and current literature. The Stanmore classification helps to correctly diagnose the type of instability and prioritise management. Symptom modification tests can help to guide management, however assessing individual muscle groups local to glenohumeral control is also recommended. Physical and psychosocial factors can influence motor control in the presence of pain and injury. A multi-disciplinary approach is required to avoid recurrence of symptoms with rehabilitation focusing on kinetic chain, scapular and gleno-humeral control.

  17. Nanoemulsion Through Stretching-Folding Instability

    Science.gov (United States)

    Ohl, Claus-Dieter; Chan, Chon U.

    2009-11-01

    A new kind of instability sets in when a oil filament is focused by surrounding water-flow through a thin constriction commonly used in fluid focusing devices. At sufficiently high flow rates the oil filament is forced into harmonic oscillations through interfacial forces. Past the constriction the liquid is suddenly slowed down which leads to rapid shortening of the filament's wavelength. At sufficiently high amplitudes the co-flowing water stream breaks up and pinches off micrometer and sub-micrometer sized droplets in a very repeatable manner, thus producing a water-in-oil emulsion. This pinch off is caused by a stretching and folding instability when the oscillating flow impinges into the quasi stagnant reservoir past the constriction. We will present high-speed movies at up to 300,000 frames per second resolving details of the very fast events. A simple model based on restoring interfacial forces is able to predict the kilohertz oscillation frequency observed.

  18. Electrostatic instabilities in a mirror trap revisited

    Science.gov (United States)

    Kotelnikov, Igor A.; Chernoshtanov, Ivan S.; Prikhodko, Vadim V.

    2017-12-01

    The conditions for the stabilization of the Drift-Cyclotron Loss-Cone (DCLC) and Double-Humped (DH) microinstabilities in a mirror trap are critically revisited assuming the plasma is confined in the kinetic regime, which is characterized by an empty loss cone. The temperature of warm ions, necessary for stabilization of the DH instability, is calculated. The fraction of warm ions necessary to stabilize the DCLC instability at a given radial density gradient is calculated. Assuming the wavelength is much shorter than the Larmor radius, a simple criterion for the stability of drift-cyclotron loss-cone oscillations is derived whose accuracy is verified by comparison with the solution of the exact dispersion equation and with known experimental data obtained in the past decades in PR-6, 2XII, 2XIIB, TMX, and TMX-U devices for plasma confinement.

  19. Patellofemoral Pain and Instability in Adolescent Athletes.

    Science.gov (United States)

    Bessette, Matthew; Saluan, Paul

    2016-12-01

    Injuries and disorders of the patellofemoral joint in the adolescent athlete can encompass a wide spectrum of symptomatology and pathology. Anterior knee pain is a common presenting symptom in sports medicine clinics, and can have numerous underlying etiologies. This activity-related pain may be the manifestation of enthesopathy, tendinopathy, fat pad impingement, or numerous other conditions, but is more commonly related to more subtle skeletal and muscular imbalances. Treatment is typically nonoperative in nature, and excellent results are reported with physical therapy. Patellofemoral instability usually has a more dramatic onset in the form of dislocation or subluxation events, commonly experienced during athletics. Concomitant injuries to the patellofemoral articular cartilage are common. Again, treatment is typically nonoperative initially, but recurrent or recalcitrant instability may necessitate reconstructive or realignment procedures. Skeletal maturity often dictates what procedures can be safely attempted.

  20. Thermal instability in the interstellar medium

    Directory of Open Access Journals (Sweden)

    J. Ghanbari

    2000-06-01

    Full Text Available   This study demonstrates how thermal structures in the interstellar medium can emerge as a result of thermal instability. For a two-dimensional case, the steady state thermal structures was investigeted and it was shown that a large class of solutions exist. For a one –dimensional case the conductivity was found to be negligible. The effects of to cal cooling on the thermal instability were explored in some depth. In this case analytical results for time-dependent cooling function were presented, too. We studied nonlinear wave phenomena in thermal fluid systems, with a particular emphasis on presenting analytical results. When conductivity is proportional to temperature, the beliavior of thermal waves is soliton like. For slow thermal waves, approximate analytical results were presented. Extensions of this work are discussed briefly, together with possible astrophysical applications.