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

PubMed

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

2017-11-30

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

Introns Protect Eukaryotic Genomes from Transcription-Associated Genetic Instability.

PubMed

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

2017-08-17

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

Fanconi anemia: causes and consequences of genetic instability.

PubMed

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

2006-01-01

Fanconi anemia (FA) is a rare recessive disease that reflects the cellular and phenotypic consequences of genetic instability: growth retardation, congenital malformations, bone marrow failure, high risk of neoplasia, and premature aging. At the cellular level, manifestations of genetic instability include chromosomal breakage, cell cycle disturbance, and increased somatic mutation rates. FA cells are exquisitely sensitive towards oxygen and alkylating drugs such as mitomycin C or diepoxybutane, pointing to a function of FA genes in the defense against reactive oxygen species and other DNA damaging agents. FA is caused by biallelic mutations in at least 12 different genes which appear to function in the maintenance of genomic stability. Eight of the FA proteins form a nuclear core complex with a catalytic function involving ubiquitination of the central FANCD2 protein. The posttranslational modification of FANCD2 promotes its accumulation in nuclear foci, together with known DNA maintenance proteins such as BRCA1, BRCA2, and the RAD51 recombinase. Biallelic mutations in BRCA2 cause a severe FA-like phenotype, as do biallelic mutations in FANCD2. In fact, only leaky or hypomorphic mutations in this central group of FA genes appear to be compatible with life birth and survival. The newly discovered FANCJ (= BRIP1) and FANCM (= Hef ) genes correspond to known DNA-maintenance genes (helicase resp. helicase-associated endonuclease for fork-structured DNA). These genes provide the most convincing evidence to date of a direct involvement of FA genes in DNA repair functions associated with the resolution of DNA crosslinks and stalled replication forks. Even though genetic instability caused by mutational inactivation of the FANC genes has detrimental effects for the majority of FA patients, around 20% of patients appear to benefit from genetic instability since genetic instability also increases the chance of somatic reversion of their constitutional mutations. Intragenic crossover, gene conversion, back mutation and compensating mutations in cis have all been observed in revertant, and, consequently, mosaic FA-patients, leading to improved bone marrow function. There probably is no other experiment of nature in our species in which causes and consequences of genetic instability, including the role of reactive oxygen species, can be better documented and explored than in FA.

Genetic Influence on the Expression of Hand Preferences in Chimpanzees (Pan Troglodytes): Evidence in Support of the Right-Shift Theory and Developmental Instability

PubMed Central

Hopkins, William D.; Dahl, Jeremy F.; Pilcher, Dawn

2007-01-01

Genetic mechanisms have been proposed to explain the pervasive representation of right-handedness in humans, whereas random, nongenetic factors have been posited to explain the lack of population-level right-handedness in nonhuman primates. We report evidence that hand preferences in chimpanzees are heritable, even among related individuals raised in different environments. Furthermore, we report that the degree of heritability is modified by factors associated with developmental instability, notably, offspring parity. The data are interpreted to reconcile both genetic models for handedness and hypotheses suggesting that developmental instability influences variation in handedness. PMID:11476096

DNA Damage as a Driver for Growth Delay: Chromosome Instability Syndromes with Intrauterine Growth Retardation

PubMed Central

Hernández-Gómez, Mariana

2017-01-01

DNA is constantly exposed to endogenous and exogenous mutagenic stimuli that are capable of producing diverse lesions. In order to protect the integrity of the genetic material, a wide array of DNA repair systems that can target each specific lesion has evolved. Despite the availability of several repair pathways, a common general program known as the DNA damage response (DDR) is stimulated to promote lesion detection, signaling, and repair in order to maintain genetic integrity. The genes that participate in these pathways are subject to mutation; a loss in their function would result in impaired DNA repair and genomic instability. When the DDR is constitutionally altered, every cell of the organism, starting from development, will show DNA damage and subsequent genomic instability. The cellular response to this is either uncontrolled proliferation and cell cycle deregulation that ensues overgrowth, or apoptosis and senescence that result in tissue hypoplasia. These diverging growth abnormalities can clinically translate as cancer or growth retardation; both features can be found in chromosome instability syndromes (CIS). The analysis of the clinical, cellular, and molecular phenotypes of CIS with intrauterine growth retardation allows inferring that replication alteration is their unifying feature. PMID:29238724

Chromosomal instability affects the tumorigenicity of glioblastoma tumor-initiating cells

PubMed Central

Godek, Kristina M.; Venere, Monica; Wu, Quilian; Mills, Kevin D.; Hickey, William F.; Rich, Jeremy N.; Compton, Duane A.

2016-01-01

Tumors are dynamic organs that evolve during disease progression with genetic, epigenetic, and environmental differences among tumor cells serving as the foundation for selection and evolution in tumors. Tumor-initiating cells (TICs) that are responsible for tumorigenesis are a source of functional cellular heterogeneity while chromosomal instability (CIN) is a source of karyotypic genetic diversity. However, the extent that CIN contributes to TIC genetic diversity and its relationship to TIC function remains unclear. Here we demonstrate that glioblastoma TICs display chromosomal instability with lagging chromosomes at anaphase and extensive non-clonal chromosome copy number variations. Elevating the basal chromosome mis-segregation rate in TICs both decreases proliferation and the stem-like phenotype of TICs in vitro. Consequently tumor formation is abolished in an orthotopic mouse model. These results demonstrate that TICs generate genetic heterogeneity within tumors but that TIC function is impaired if the rate of genetic change is elevated above a tolerable threshold. PMID:27001151

Radiation-induced transmissable chromosomal instability in haemopoietic stem cells

NASA Astrophysics Data System (ADS)

Kadhim, M. A.; Wright, E. G.

Heritable radiation-induced genetic alterations have long been assumed to be ``fixed'' within the first cell division. However, there is a growing body of evidence that a considerable fraction of cells surviving radiation exposure appear normal, but a variety of mutational changes arise in their progeny due to a transmissible genomic instability. In our investigations of G-banded metaphases, non-clonal cytogenetic aberrations, predominantly chromatid-type aberrations, have been observed in the clonal descendants of murine and human haemopoietic stem cells surviving low doses (~1 track per cell) of alpha-particle irradiations. The data are consistent with a transmissible genetic instability induced in a stem cell resulting in a diversity of chromosomal aberrations in its clonal progeny many cell divisions later. Recent studies have demonstrated that the instability phenotype persists in vivo and that the expression of chromosomal instability has a strong dependence on the genetic characteristics of the irradiated cell. At the time when cytogenetic aberrations are detected, an increased incidence of hprt mutations and apoptotic cells have been observed in the clonal descendants of alpha-irradiated murine haemopoietic stem cells. Thus, delayed chromosomal abnormalities, delayed cell death by apoptosis and late-arising specific gene mutations may reflect diverse consequences of radiation-induced genomic instability. The relationship, if any, between these effects is not established. Current studies suggest that expression of these delayed heritable effects is determined by the type of radiation exposure, type of cell and a variety of genetic factors.

Genetic changes of MLH1 and MSH2 genes could explain constant findings on microsatellite instability in intracranial meningioma.

PubMed

Pećina-Šlaus, Nives; Kafka, Anja; Bukovac, Anja; Vladušić, Tomislav; Tomas, Davor; Hrašćan, Reno

2017-07-01

Postreplicative mismatch repair safeguards the stability of our genome. The defects in its functioning will give rise to microsatellite instability. In this study, 50 meningiomas were investigated for microsatellite instability. Two major mismatch repair genes, MLH1 and MSH2, were analyzed using microsatellite markers D1S1611 and BAT26 amplified by polymerase chain reaction and visualized by gel electrophoresis on high-resolution gels. Furthermore, genes DVL3 (D3S1262), AXIN1 (D16S3399), and CDH1 (D16S752) were also investigated for microsatellite instability. Our study revealed constant presence of microsatellite instability in meningioma patients when compared to their autologous blood DNA. Altogether 38% of meningiomas showed microsatellite instability at one microsatellite locus, 16% on two, and 13.3% on three loci. The percent of detected microsatellite instability for MSH2 gene was 14%, and for MLH1, it was 26%, for DVL3 22.9%, for AXIN1 17.8%, and for CDH1 8.3%. Since markers also allowed for the detection of loss of heterozygosity, gross deletions of MLH1 gene were found in 24% of meningiomas. Genetic changes between MLH1 and MSH2 were significantly positively correlated (p = 0.032). We also noted a positive correlation between genetic changes of MSH2 and DVL3 genes (p = 0.034). No significant associations were observed when MLH1 or MSH2 was tested against specific histopathological meningioma subtype or World Health Organization grade. However, genetic changes in DVL3 were strongly associated with anaplastic histology of meningioma (χ 2  = 9.14; p = 0.01). Our study contributes to better understanding of the genetic profile of human intracranial meningiomas and suggests that meningiomas harbor defective cellular DNA mismatch repair mechanisms.

Biomarkers For Breast Cancer Based On Genetic Instability | NCI Technology Transfer Center | TTC

Cancer.gov

It is difficult to establish a prognosis for breast cancer because the clinical course and survival times of patients with the disease vary greatly.  The National Cancer Institute's Genetics Branch is seeking statements of capability or interest from parties interested in in-licensing or collaborative research to co-develop, evaluate, or commercialize prognostic tests for breast cancer based on a 12-gene expression signature.

A novel reverse genetics system for production of infectious West Nile virus using homologous recombination in mammalian cells.

PubMed

Kobayashi, Shintaro; Yoshii, Kentaro; Hirano, Minato; Muto, Memi; Kariwa, Hiroaki

2017-02-01

Reverse genetics systems facilitate investigation of many aspects of the life cycle and pathogenesis of viruses. However, genetic instability in Escherichia coli has hampered development of a reverse genetics system for West Nile virus (WNV). In this study, we developed a novel reverse genetics system for WNV based on homologous recombination in mammalian cells. Introduction of the DNA fragment coding for the WNV structural protein together with a DNA-based replicon resulted in the release of infectious WNV. The growth rate and plaque size of the recombinant virus were almost identical to those of the parent WNV. Furthermore, chimeric WNV was produced by introducing the DNA fragment coding for the structural protein and replicon plasmid derived from various strains. Here, we report development of a novel system that will facilitate research into WNV infection. Copyright © 2016 Elsevier B.V. All rights reserved.

Mutational Analysis of Mismatch Repair Genes, hMLH1 and hMSH2, in Sporadic Endometrial Carcinomas with Microsatellite Instability

PubMed Central

Kobayashi, Kanji; Matsushima, Mieko; Koi, Sumiko; Saito, Hiroko; Sagae, Satoru; Kudo, Ryuichi

1996-01-01

Microsatellite instability, monitored by replication error (RER), bas been observed in both sporadic and hereditary types of endometrial carcinoma. In the hereditary tumors, this instability is considered to be caused by a germline defect in the DNA mismatch‐repair system. We previously reported that nearly one‐quarter of sporadic endometrial carcinomas examined revealed an RER‐positive phenotype at multiple microsatellite loci. To investigate the role of genetic alterations of DNA mismatch‐repair genes in sporadic endometrial carcinomas, we screened 18 RER(+) endometrial carcinomas for mutations of hMLH1 and hMSH2. Although we found no germline mutations, we detected two somatic mutations of hMLH1 in a single endometrial cancer; these two mutations had occurred on different alleles, suggesting that two separate mutational events had affected both copies of hMLH1 in this particular tumor. These data implied that mutations of hMLH1 or hMSH2 play limited roles in the development of sporadic endometrial carcinomas, and that the tumors with genetic instability might have alterations of other mismatch‐repair genes, such as hPMS1 and hPMS2, or of unknown genes related to the mismatch‐repair system. PMID:8609062

Caspase 3 promotes genetic instability and carcinogenesis

PubMed Central

Liu, Xinjian; He, Yujun; Li, Fang; Huang, Qian; Kato, Takamitsu A.; Hall, Russell P; Li, Chuan-Yuan

2015-01-01

Summary Apoptosis is typically considered an anti-oncogenic process since caspase activation can promote the elimination of genetically unstable or damaged cells. We report that a central effector of apoptosis, caspase 3, facilitates, rather than suppresses, chemical and radiation-induced genetic instability and carcinogenesis. We found that a significant fraction of mammalian cells treated with ionizing radiation can survive, despite caspase 3 activation. Moreover, this sublethal activation of caspase 3 promoted persistent DNA damage and oncogenic transformation. In addition, chemically-induced skin carcinogenesis was significantly reduced in mice genetically deficient in caspase 3. Furthermore, attenuation of Endo G activity significantly reduced radiation-induced DNA damage and oncogenic transformation, identifying Endo G as a downstream effector of caspase 3 in this pathway. Our findings suggest that rather than acting as a broad inhibitor of carcinogenesis, caspase 3 activation may contribute to genome instability and play a pivotal role in tumor formation following damage. PMID:25866249

Evidence for possible non-canonical pathway(s) driven early-onset colorectal cancer in India

PubMed Central

Raman, Ratheesh; Kotapalli, Viswakalyan; Adduri, Raju; Gowrishankar, Swarnalata; Bashyam, Leena; Chaudhary, Ajay; Vamsy, Mohana; Patnaik, Sujith; Srinivasulu, Mukta; Sastry, Regulagadda; Rao, Subramanyeshwar; Vasala, Anjayneyulu; Kalidindi, NarasimhaRaju; Pollack, Jonathan; Murthy, Sudha; Bashyam, Murali

2012-01-01

Two genetic instability pathways viz. chromosomal instability, driven primarily by APC mutation induced deregulated Wnt signaling, and microsatellite instability (MSI) caused by mismatch repair (MMR) inactivation, together account for greater than 90% of late-onset colorectal cancer. Our understanding of early-onset sporadic CRC is however comparatively limited. In addition, most seminal studies have been performed in the western population and analyses of tumorigenesis pathway(s) causing CRC in developing nations have been rare. We performed a comparative analysis of early and late-onset CRC from India with respect to common genetic aberrations including Wnt, KRAS and p53 (constituting the classical CRC progression sequence) in addition to MSI. Our results revealed the absence of Wnt and MSI in a significant proportion of early-onset as against late-onset CRC in India. In addition, KRAS mutation frequency was significantly lower in early-onset CRC indicating that a significant proportion of CRC in India may follow tumorigenesis pathways distinct from the classical CRC progression sequence. Our study has therefore revealed the possible existence of non-canonical tumorigenesis pathways in early-onset CRC in India. PMID:23168910

Genetic Contributors to Intergenerational CAG Repeat Instability in Huntington's Disease Knock-In Mice.

PubMed

Neto, João Luís; Lee, Jong-Min; Afridi, Ali; Gillis, Tammy; Guide, Jolene R; Dempsey, Stephani; Lager, Brenda; Alonso, Isabel; Wheeler, Vanessa C; Pinto, Ricardo Mouro

2017-02-01

Huntington's disease (HD) is a neurodegenerative disorder caused by the expansion of a CAG trinucleotide repeat in exon 1 of the HTT gene. Longer repeat sizes are associated with increased disease penetrance and earlier ages of onset. Intergenerationally unstable transmissions are common in HD families, partly underlying the genetic anticipation seen in this disorder. HD CAG knock-in mouse models also exhibit a propensity for intergenerational repeat size changes. In this work, we examine intergenerational instability of the CAG repeat in over 20,000 transmissions in the largest HD knock-in mouse model breeding datasets reported to date. We confirmed previous observations that parental sex drives the relative ratio of expansions and contractions. The large datasets further allowed us to distinguish effects of paternal CAG repeat length on the magnitude and frequency of expansions and contractions, as well as the identification of large repeat size jumps in the knock-in models. Distinct degrees of intergenerational instability were observed between knock-in mice of six background strains, indicating the occurrence of trans-acting genetic modifiers. We also found that lines harboring a neomycin resistance cassette upstream of Htt showed reduced expansion frequency, indicative of a contributing role for sequences in cis, with the expanded repeat as modifiers of intergenerational instability. These results provide a basis for further understanding of the mechanisms underlying intergenerational repeat instability. Copyright © 2017 by the Genetics Society of America.

Chronic Fatigue and Personality: A Twin Study of Causal Pathways and Shared Liabilities

PubMed Central

Poeschla, Brian; Strachan, Eric; Dansie, Elizabeth; Buchwald, Dedra S.; Afari, Niloofar

2013-01-01

Background The etiology of chronic fatigue syndrome (CFS) remains unknown. Personality traits influence well-being and may play a role in CFS and unexplained chronic fatigue. Purpose To examine the association of emotional instability and extraversion with chronic fatigue and CFS in a genetically informative sample. Methods We evaluated 245 twin pairs for two definitions of chronic fatigue. They completed the Neuroticism and Extraversion subscales of the NEO-FFI. Using a co-twin control design, we examined the association between personality and chronic fatigue. Results Higher emotional instability was associated with both definitions of chronic fatigue and was confounded by shared genetics. Lower extraversion was also associated with both definitions of fatigue, but was not confounded by familial factors. Conclusions Both emotional instability and extraversion are related to chronic fatigue and CFS. Whereas emotional instability and chronic fatigue are linked by shared genetic mechanisms, the relationship with extraversion may be causal and bi-directional. PMID:23361410

[SOS response of DNA repair and genetic cell instability under hypoxic conditions].

PubMed

Vasil'eva, S V; Strel'tsova, D A

2011-01-01

The SOS DNA repair pathway is induced in E. coli as a multifunctional cell response to a wide variety of signals: UV, X or gamma-irradiation, mitomycin C or nalidixic acid treatment, thymine starvation, etc. Triggering of the system can be used as a general and early sign of DNA damage. Additionally, the SOS-response is known to be an "error-prone" DNA repair pathway and one of the sources of genetic instability. Hypoxic conditions are established to be the major factor of genetic instability as well. In this paper we for the first time studied the SOS DNA repair response under hypoxic conditions induced by the well known aerobic SOS-inducers. The SOS DNA repair response was examined as a reaction of E. coli PQ37 [sfiA::lacZ] cells to UVC, NO-donating agents and 4NQO. Here we provide evidence that those agents were able to induce the SOS DNA repair response in E. coli at anaerobic growth conditions. The process does not depend on the transcriptional activity of the universal protein of E. col anaerobic growth Fnr [4Fe-4S]2+ or can not be referred to as an indicator of genetic instability in hypoxic conditions.

Trisomy 21 and facial developmental instability.

PubMed

Starbuck, John M; Cole, Theodore M; Reeves, Roger H; Richtsmeier, Joan T

2013-05-01

The most common live-born human aneuploidy is trisomy 21, which causes Down syndrome (DS). Dosage imbalance of genes on chromosome 21 (Hsa21) affects complex gene-regulatory interactions and alters development to produce a wide range of phenotypes, including characteristic facial dysmorphology. Little is known about how trisomy 21 alters craniofacial morphogenesis to create this characteristic appearance. Proponents of the "amplified developmental instability" hypothesis argue that trisomy 21 causes a generalized genetic imbalance that disrupts evolutionarily conserved developmental pathways by decreasing developmental homeostasis and precision throughout development. Based on this model, we test the hypothesis that DS faces exhibit increased developmental instability relative to euploid individuals. Developmental instability was assessed by a statistical analysis of fluctuating asymmetry. We compared the magnitude and patterns of fluctuating asymmetry among siblings using three-dimensional coordinate locations of 20 anatomic landmarks collected from facial surface reconstructions in four age-matched samples ranging from 4 to 12 years: (1) DS individuals (n = 55); (2) biological siblings of DS individuals (n = 55); 3) and 4) two samples of typically developing individuals (n = 55 for each sample), who are euploid siblings and age-matched to the DS individuals and their euploid siblings (samples 1 and 2). Identification in the DS sample of facial prominences exhibiting increased fluctuating asymmetry during facial morphogenesis provides evidence for increased developmental instability in DS faces. We found the highest developmental instability in facial structures derived from the mandibular prominence and lowest in facial regions derived from the frontal prominence. Copyright © 2013 Wiley Periodicals, Inc.

Mechanisms underlying cellular responses of cells from haemopoietic tissue to low

DOE Office of Scientific and Technical Information (OSTI.GOV)

Kadhim, Munira A

2012-08-22

The above studies will provide fundamental mechanistic information relating genetic predisposition to important low dose phenomena, and will aid in the development of Department of Energy policy, as well as radiation risk policy for the public and the workplace. We believe the proposed studies accurately reflect the goals of the DOE low dose program. To accurately define the risks associated with human exposure to relevant environmental doses of low LET ionizing radiation, it is necessary to completely understand the biological effects at very low doses (i.e. less than 0.1 Gy), including the lowest possible dose, that of a single electronmore » track traversal. At such low doses, a range of studies have shown responses in biological systems which are not related to the direct interaction of radiation tracks with DNA. The role of these "non-targeted responses in critical tissues is poorly understood and little is known regarding the underlying mechanisms. Although critical for dosimetry and risk assessment, the role of individual genetic susceptibility in radiation risk is not satisfactorily defined at present. The aim of the proposed grant is to critically evaluate non-targeted effects of ionizing radiation with a focus on the induction of genomic instability (GI) in key stem cell populations from haemopoietic tissue. Using stem cells from two mouse strains (CBA/CaH and C57BL/6J) known to differ in their susceptibility to radiation effects, we plan to carefully dissect the role of genetic predisposition in these models on genomic instability. We will specifically focus on the effects of low doses of low LET radiation, down to the dose of 10mGy (0.01Gy) X-rays. Using conventional X-ray and we will be able to assess the role of genetic variation under various conditions at a range of doses down to the very low dose of 0.01Gy. Irradiations will be carried out using facilities in routine operation for such studies. Mechanistic studies of instability in different cell lineages will include the role of cytokines which have been shown to be in the initiation of instability. These studies also aim to uncover the possible mechanism of the initiation, perpetuation and delayed pathways of the instability response using relevant biological endpoints i.e. chromosomal instability, apoptosis induction, cytokine and gene array analysis. Integral to these studies will be an assessment of the role of genetic susceptibility in these responses, using CBA/CaH and C57BL/6J mice. The overall results suggest that low dose low LET X-irradiation induced delayed GI in both CBA/CaH and C57BL/6J haemopoeitic tissue. Using several biological approaches, some key strain and dose-specific differences have been identified in radiation-induced signalling in the initiation and perpetuation of the instability process. Furthermore, the induction of non-targeted radiation effects and genetic dependency may be linked to the use of alternative signalling pathways and mechanisms which have potential implications on evaluation of non-targeted effects in radiation risk assessment.« less

Navigating yeast genome maintenance with functional genomics.

PubMed

Measday, Vivien; Stirling, Peter C

2016-03-01

Maintenance of genome integrity is a fundamental requirement of all organisms. To address this, organisms have evolved extremely faithful modes of replication, DNA repair and chromosome segregation to combat the deleterious effects of an unstable genome. Nonetheless, a small amount of genome instability is the driver of evolutionary change and adaptation, and thus a low level of instability is permitted in populations. While defects in genome maintenance almost invariably reduce fitness in the short term, they can create an environment where beneficial mutations are more likely to occur. The importance of this fact is clearest in the development of human cancer, where genome instability is a well-established enabling characteristic of carcinogenesis. This raises the crucial question: what are the cellular pathways that promote genome maintenance and what are their mechanisms? Work in model organisms, in particular the yeast Saccharomyces cerevisiae, has provided the global foundations of genome maintenance mechanisms in eukaryotes. The development of pioneering genomic tools inS. cerevisiae, such as the systematic creation of mutants in all nonessential and essential genes, has enabled whole-genome approaches to identifying genes with roles in genome maintenance. Here, we review the extensive whole-genome approaches taken in yeast, with an emphasis on functional genomic screens, to understand the genetic basis of genome instability, highlighting a range of genetic and cytological screening modalities. By revealing the biological pathways and processes regulating genome integrity, these analyses contribute to the systems-level map of the yeast cell and inform studies of human disease, especially cancer. © The Author 2015. Published by Oxford University Press. All rights reserved. For permissions, please email: journals.permissions@oup.com.

Genetics and epigenetics of small bowel adenocarcinoma: the interactions of CIN, MSI, and CIMP.

PubMed

Warth, Arne; Kloor, Matthias; Schirmacher, Peter; Bläker, Hendrik

2011-04-01

Characterization of tumor genetics and epigenetics allows to stratify a tumor entity according to molecular pathways and may shed light on the interactions of different types of DNA alterations during tumorigenesis. Small intestinal adenocarcinoma is rare, and to date the interrelation of genomic instability and epigenetics has not been investigated in this tumor type. We therefore analyzed 37 primary small bowel carcinomas with known microsatellite instability and KRAS status for chromosomal instability using comparative genomic hybridization, for the presence of aberrant methylation (CpG island methylation phenotype) by methylation-specific polymerase chain reaction, and for BRAF mutations. Chromosomal instability was detected in 22 of 37 (59%) tumors (3 of 9 microsatellite instable, and 19 of 28 microsatellite stable carcinomas). Nine carcinomas (24%) were microsatellite and chromosomally stable. High-level DNA methylation was found in 16% of chromosomal instable tumors and in 44% of both microsatellite instable and microsatellite and chromosomally stable carcinomas. KRAS was mutated in 55, 0, and 10% of chromosomal instable, microsatellite instable, and microsatellite and chromosomally stable tumors, respectively whereas the frequencies of BRAF mutations were 6% for chromosomal instable and 22% for both microsatellite instable and microsatellite and chromosomally stable carcinomas. In conclusion, in this study we show that chromosomal instable carcinomas of the small intestine are distinguished from microsatellite instable and microsatellite and chromosomally stable tumors by a high frequency of KRAS mutations, low frequencies of CpG island methylation phenotype, and BRAF mutations. In microsatellite instable and microsatellite and chromosomally stable cancers, CpG island methylation phenotype and BRAF/KRAS mutations are similarly distributed, indicating common mechanisms of tumor initiation or progression in their molecular pathogenesis.

PTEN in the maintenance of genome integrity: From DNA replication to chromosome segregation.

PubMed

Hou, Sheng-Qi; Ouyang, Meng; Brandmaier, Andrew; Hao, Hongbo; Shen, Wen H

2017-10-01

Faithful DNA replication and accurate chromosome segregation are the key machineries of genetic transmission. Disruption of these processes represents a hallmark of cancer and often results from loss of tumor suppressors. PTEN is an important tumor suppressor that is frequently mutated or deleted in human cancer. Loss of PTEN has been associated with aneuploidy and poor prognosis in cancer patients. In mice, Pten deletion or mutation drives genomic instability and tumor development. PTEN deficiency induces DNA replication stress, confers stress tolerance, and disrupts mitotic spindle architecture, leading to accumulation of structural and numerical chromosome instability. Therefore, PTEN guards the genome by controlling multiple processes of chromosome inheritance. Here, we summarize current understanding of the PTEN function in promoting high-fidelity transmission of genetic information. We also discuss the PTEN pathways of genome maintenance and highlight potential targets for cancer treatment. © 2017 WILEY Periodicals, Inc.

Genetics of Streptomyces rimosus, the Oxytetracycline Producer

PubMed Central

Petković, Hrvoje; Cullum, John; Hranueli, Daslav; Hunter, Iain S.; Perić-Concha, Nataša; Pigac, Jasenka; Thamchaipenet, Arinthip; Vujaklija, Dušica; Long, Paul F.

2006-01-01

From a genetic standpoint, Streptomyces rimosus is arguably the best-characterized industrial streptomycete as the producer of oxytetracycline and other tetracycline antibiotics. Although resistance to these antibiotics has reduced their clinical use in recent years, tetracyclines have an increasing role in the treatment of emerging infections and noninfective diseases. Procedures for in vivo and in vitro genetic manipulations in S. rimosus have been developed since the 1950s and applied to study the genetic instability of S. rimosus strains and for the molecular cloning and characterization of genes involved in oxytetracycline biosynthesis. Recent advances in the methodology of genome sequencing bring the realistic prospect of obtaining the genome sequence of S. rimosus in the near term. PMID:16959966

Malignant Tumors and Forensics – Dilemmas and Proposals

PubMed Central

Budimlija, Zoran; Lu, Connie; Axler-DiPerte, Grace; Seifarth, Jessica; Popiolek, Dorota; Fogt, Franz; Prinz, Mechthild

2009-01-01

Aim To evaluate the effect of genetic instability and degradation in archived histology samples from cancerous tumors and to investigate the validity of short tandem repeat (STR) typing of these samples and its potential effect on human identification. Methods Two hundred and twenty eight slides of archival pathology tissues from 13 different types of malignant tumors were compared with healthy tissues from the same individuals. DNA analysis was performed using standard techniques for forensic STR analysis, PowerPlex®16 and Identifiler® on 2 distinct sample sets. Genetic instability was assessed by comparing reference tissues with cancerous tissues derived from the same individual. Loss of heterozygosity, a ≥50% reduction in heterozygosity ratio between healthy and diseased samples, and microsatellite instability, the presence of an additional allele not present in reference tissue, were assessed. The quality of profiles obtained with respect to completeness among the archived samples and degradation using the 2 platforms were also compared. Results Profiles obtained using the Identifiler® system were generally more complete, but showed 3-fold higher levels of instability (86%) than those obtained using PowerPlex® 16 (27%). Instances of genetic instability were distributed throughout all loci in both multiplex STR systems. Conclusion After having compared 2 widely used forensic chemistries, we suggest individual validation of each kit for use with samples likely to exhibit instability combined with fixation induced degradation or artifact. A “one size fits all” approach for interpretation of these samples among commercially available multiplexes is not recommended. PMID:19480018

Temporal Dependence of Chromosomal Aberration on Radiation Quality and Cellular Genetic Background

NASA Technical Reports Server (NTRS)

Lu, Tao; Zhang, Ye; Krieger, Stephanie; Yeshitla, Samrawit; Goss, Rosalin; Bowler, Deborah; Kadhim, Munira; Wilson, Bobby; Wu, Honglu

2017-01-01

Radiation induced cancer risks are driven by genetic instability. It is not well understood how different radiation sources induce genetic instability in cells with different genetic background. Here we report our studies on genetic instability, particularly chromosome instability using fluorescence in situ hybridization (FISH), in human primary lymphocytes, normal human fibroblasts, and transformed human mammary epithelial cells in a temporal manner after exposure to high energy protons and Fe ions. The chromosome spread was prepared 48 hours, 1 week, 2 week, and 1 month after radiation exposure. Chromosome aberrations were analyzed with whole chromosome specific probes (chr. 3 and chr. 6). After exposure to protons and Fe ions of similar cumulative energy (??), Fe ions induced more chromosomal aberrations at early time point (48 hours) in all three types of cells. Over time (after 1 month), more chromosome aberrations were observed in cells exposed to Fe ions than in the same type of cells exposed to protons. While the mammary epithelial cells have higher intrinsic genetic instability and higher rate of initial chromosome aberrations than the fibroblasts, the fibroblasts retained more chromosomal aberration after long term cell culture (1 month) in comparison to their initial frequency of chromosome aberration. In lymphocytes, the chromosome aberration frequency at 1 month after exposure to Fe ions was close to unexposed background, and the chromosome aberration frequency at 1 month after exposure to proton was much higher. In addition to human cells, mouse bone marrow cells isolated from strains CBA/CaH and C57BL/6 were irradiated with proton or Fe ions and were analyzed for chromosome aberration at different time points. Cells from CBA mice showed similar frequency of chromosome aberration at early and late time points, while cells from C57 mice showed very different chromosome aberration rate at early and late time points. Our results suggest that relative biological effectiveness (RBE) of radiation are different for different radiation sources, for different cell types, and for the same cell type with different genetic background at different times after radiation exposure. Caution must be taken in using RBE value to estimate biological effects from radiation exposure.

Investigation of microsatellite instability in Turkish breast cancer patients.

PubMed

Demokan, Semra; Muslumanoglu, Mahmut; Yazici, H; Igci, Abdullah; Dalay, Nejat

2002-01-01

Multiple somatic and inherited genetic changes that lead to loss of growth control may contribute to the development of breast cancer. Microsatellites are tandem repeats of simple sequences that occur abundantly and at random throughout most eucaryotic genomes. Microsatellite instability (MI), characterized by the presence of random contractions or expansions in the length of simple sequence repeats or microsatellites, is observed in a variety of tumors. The aim of this study was to compare tumor DNA fingerprints with constitutional DNA fingerprints to investigate changes specific to breast cancer and evaluate its correlation with clinical characteristics. Tumor and normal tissue samples of 38 patients with breast cancer were investigated by comparing PCR-amplified microsatellite sequences D2S443 and D21S1436. Microsatellite instability at D21S1436 and D2S443 was found in 5 (13%) and 7 (18%) patients, respectively. Two patients displayed instability at both marker loci. No association was found between MI and age, family history, lymph node involvement and other clinical parameters.

The genetic and phenotypic variability of interspecific hybrid bermudagrasses (Cynodon dactylon (L.) Pers. × C. transvaalensis Burtt-Davy) used on golf course putting greens.

PubMed

Reasor, Eric H; Brosnan, James T; Trigiano, Robert N; Elsner, J Earl; Henry, Gerald M; Schwartz, Brian M

2016-10-01

Some interspecific hybrid bermudagrass cultivars used on golf course putting greens are genetically unstable, which has caused phenotypically different off-type grasses to occur in production nurseries and putting surfaces. Management practices to reduce the occurrence of off-type grasses in putting green surfaces and the effect they can have on putting quality and performance need to be researched until genetically stable cultivars are developed. Golf course putting green surfaces in subtropical and tropical climates are typically planted with an interspecific hybrid bermudagrass (Cynodon dactylon (L.) Pers. × C. transvaalensis Burtt-Davy), because of the superior putting quality and performance of these cultivars. 'Tifgreen' was one of the first interspecific hybrids developed for putting green use in lieu of common bermudagrass. However, off-type grasses began appearing in established Tifgreen stands soon after commercial release. Off-type grasses are those with different morphology and performance when compared to the surrounding, desirable cultivar. Off-types have the potential to decrease surface uniformity, which negatively affects putting surface quality. However, several unique off-types from Tifgreen have been selected as commercial cultivars, the first being 'Tifdwarf'; then 'Floradwarf', 'MS-Supreme', 'Pee Dee-102', and 'TL-2', identified later. The cultivars 'Champion Dwarf', 'P-18', 'RJT', and 'Emerald Dwarf' were subsequently selected as off-types in Tifdwarf. The naturally occurring off-types and cultivars that have been identified within the Tifgreen family have widely differing phenotypes; however, they are reported to be genetically similar, supporting the hypothesis that their occurrence is a result of somatic mutations. Genetic instability in currently available commercial cultivars is likely to lead to the continued presence of off-types in production nurseries and putting greens. Additional research is needed to understand the nature of genetic instability in Tifgreen-derived cultivars and how to manage its consequences to develop new cultivars, but also strategies for eradication of off-types in pedigree nursery production and end-site putting greens.

Trisomy 21 and Facial Developmental Instability

PubMed Central

Starbuck, John M.; Cole, Theodore M.; Reeves, Roger H.; Richtsmeier, Joan T.

2013-01-01

The most common live-born human aneuploidy is trisomy 21, which causes Down syndrome (DS). Dosage imbalance of genes on chromosome 21 (Hsa21) affects complex gene-regulatory interactions and alters development to produce a wide range of phenotypes, including characteristic facial dysmorphology. Little is known about how trisomy 21 alters craniofacial morphogenesis to create this characteristic appearance. Proponents of the “amplified developmental instability” hypothesis argue that trisomy 21 causes a generalized genetic imbalance that disrupts evolutionarily conserved developmental pathways by decreasing developmental homeostasis and precision throughout development. Based on this model, we test the hypothesis that DS faces exhibit increased developmental instability relative to euploid individuals. Developmental instability was assessed by a statistical analysis of fluctuating asymmetry. We compared the magnitude and patterns of fluctuating asymmetry among siblings using three-dimensional coordinate locations of 20 anatomic landmarks collected from facial surface reconstructions in four age-matched samples ranging from 4 to 12 years: 1) DS individuals (n=55); 2) biological siblings of DS individuals (n=55); 3) and 4) two samples of typically developing individuals (n=55 for each sample), who are euploid siblings and age-matched to the DS individuals and their euploid siblings (samples 1 and 2). Identification in the DS sample of facial prominences exhibiting increased fluctuating asymmetry during facial morphogenesis provides evidence for increased developmental instability in DS faces. We found the highest developmental instability in facial structures derived from the mandibular prominence and lowest in facial regions derived from the frontal prominence. PMID:23505010

Genetic Contributors to Intergenerational CAG Repeat Instability in Huntington’s Disease Knock-In Mice

PubMed Central

Neto, João Luís; Lee, Jong-Min; Afridi, Ali; Gillis, Tammy; Guide, Jolene R.; Dempsey, Stephani; Lager, Brenda; Alonso, Isabel; Wheeler, Vanessa C.; Pinto, Ricardo Mouro

2017-01-01

Huntington’s disease (HD) is a neurodegenerative disorder caused by the expansion of a CAG trinucleotide repeat in exon 1 of the HTT gene. Longer repeat sizes are associated with increased disease penetrance and earlier ages of onset. Intergenerationally unstable transmissions are common in HD families, partly underlying the genetic anticipation seen in this disorder. HD CAG knock-in mouse models also exhibit a propensity for intergenerational repeat size changes. In this work, we examine intergenerational instability of the CAG repeat in over 20,000 transmissions in the largest HD knock-in mouse model breeding datasets reported to date. We confirmed previous observations that parental sex drives the relative ratio of expansions and contractions. The large datasets further allowed us to distinguish effects of paternal CAG repeat length on the magnitude and frequency of expansions and contractions, as well as the identification of large repeat size jumps in the knock-in models. Distinct degrees of intergenerational instability were observed between knock-in mice of six background strains, indicating the occurrence of trans-acting genetic modifiers. We also found that lines harboring a neomycin resistance cassette upstream of Htt showed reduced expansion frequency, indicative of a contributing role for sequences in cis, with the expanded repeat as modifiers of intergenerational instability. These results provide a basis for further understanding of the mechanisms underlying intergenerational repeat instability. PMID:27913616

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

NASA Astrophysics Data System (ADS)

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. I became interested in creating learning environments that encourage students to make interdisciplinary connections in a way that provides comprehensible learning experiences that they can relate to their daily lives. Resulting from these studies, I developed an interdisciplinary, stories-based curriculum that is described in chapter four of this thesis.

Intra-tumor heterogeneity of cancer cells and its implications for cancer treatment

PubMed Central

Sun, Xiao-xiao; Yu, Qiang

2015-01-01

Recent studies have revealed extensive genetic and non-genetic variation across different geographical regions of a tumor or throughout different stages of tumor progression, which is referred to as intra-tumor heterogeneity. Several causes contribute to this phenomenon, including genomic instability, epigenetic alteration, plastic gene expression, signal transduction, and microenvironmental differences. These variables may affect key signaling pathways that regulate cancer cell growth, drive phenotypic diversity, and pose challenges to cancer treatment. Understanding the mechanisms underlying this heterogeneity will support the development of effective therapeutic strategies. PMID:26388155

[Microsatellite instability and human papilloma virus genotypes in preneoplastic and neoplastic uterine cervix lesions].

PubMed

Roa S, Juan Carlos; Martínez S, Ricardo; Montenegro, Sonia; Roa E, Iván; Capurro V, Italo; Ibacache S, Gilda; Melo A, Angélica

2007-01-01

The association between some specific human papilloma virus (HPV) types and cervix cancer is well known. However, the genetic conditions that favor the development of cervical cancer are less well known. To determine the presence of satellite instability (MSI) in preneoplastic and neoplastic lesions of the cervix and correlate these findings with HPV genotypes. Biopsy samples of cervical lesions were studied. Sixteen had low grade lesions, 22 had high grade lesions and 28 had an epidermoid cancer. Viral types were identified with polymerase chain reaction, dot-blot hybridization and restriction fragment length polymorphism. MSI was determined using a panel of eight highly informative microsatellites. Microsatellite instability in at least one locus was observed in 91, 56 and 69% of low grade lesions, high grade lesions and epidermoid carcinomas, respectively. MSI-High grade, MSI-Low grade instability and microsatellite stability were observed in 5, 60 and 46% of samples, respectively. Two of three samples with high grade instability had HPV 52 genotype. Other viral subtypes had frequencies that ranged from 78% to 100%, with the exception of HPV16 that was present in only 53% of samples with low grade instability. Two thirds of biopsy samples from cervical lesions had MSI, mechanism that can be involved in the first stages of cervical carcinogenesis. The low frequency of high grade instability, its association with HPV52 and the low frequency of HPV16 in samples with low grade instability, suggest different coadjutant mechanisms in cervical carcinogenesis.

Microsatellite instability and MLH1 promoter hypermethylation in colorectal cancer

PubMed Central

Niv, Yaron

2007-01-01

Colorectal cancer (CRC) is caused by a series of genetic or epigenetic changes, and in the last decade there has been an increased awareness that there are multiple forms of colorectal cancer that develop through different pathways. Microsatellite instability is involved in the genesis of about 15% of sporadic colorectal cancers and most of hereditary nonpolyposis cancers. Tumors with a high frequency of microsatellite instability tend to be diploid, to possess a mucinous histology, and to have a surrounding lymphoid reaction. They are more prevalent in the proximal colon and have a fast pass from polyp to cancer. Nevertheless, they are associated with longer survival than stage-matched tumors with microsatellite stability. Resistance of colorectal cancers with a high frequency of microsatellite instability to 5-fluorouracil-based chemotherapy is well established. Silencing the MLH1 gene expression by its promoter methylation stops the formation of MLH1 protein, and prevents the normal activation of the DNA repair gene. This is an important cause for genomic instability and cell proliferation to the point of colorectal cancer formation. Better knowledge of this process will have a huge impact on colorectal cancer management, prevention, treatment and prognosis. PMID:17465465

Growth, morphology, and developmental instability of rainbow trout, Yellowstone cutthroat trout, and four hybrid generations

USGS Publications Warehouse

Ostberg, C.O.; Duda, J.J.; Graham, J.H.; Zhang, S.; Haywood, K. P.; Miller, B.; Lerud, T.L.

2011-01-01

Hybridization of cutthroat trout Oncorhynchus clarkii with nonindigenous rainbow trout O. mykiss contributes to the decline of cutthroat trout subspecies throughout their native range. Introgression by rainbow trout can swamp the gene pools of cutthroat trout populations, especially if there is little selection against hybrids. We used rainbow trout, Yellowstone cutthroat trout O. clarkii bouvieri, and rainbow trout × Yellowstone cutthroat trout F1 hybrids as parents to construct seven different line crosses: F1 hybrids (both reciprocal crosses), F2 hybrids, first-generation backcrosses (both rainbow trout and Yellowstone cutthroat trout), and both parental taxa. We compared growth, morphology, and developmental instability among these seven crosses reared at two different temperatures. Growth was related to the proportion of rainbow trout genome present within the crosses. Meristic traits were influenced by maternal, additive, dominant, overdominant, and (probably) epistatic genetic effects. Developmental stability, however, was not disturbed in F1 hybrids, F2 hybrids, or backcrosses. Backcrosses were morphologically similar to their recurrent parent. The lack of developmental instability in hybrids suggests that there are few genetic incompatibilities preventing introgression. Our findings suggest that hybrids are not equal: that is, growth, development, character traits, and morphology differ depending on the genomic contribution from each parental species as well as the hybrid generation.

Modeling dynamics for oncogenesis encompassing mutations and genetic instability.

PubMed

Fassoni, Artur C; Yang, Hyun M

2018-06-27

Tumorigenesis has been described as a multistep process, where each step is associated with a genetic alteration, in the direction to progressively transform a normal cell and its descendants into a malignant tumour. Into this work, we propose a mathematical model for cancer onset and development, considering three populations: normal, premalignant and cancer cells. The model takes into account three hallmarks of cancer: self-sufficiency on growth signals, insensibility to anti-growth signals and evading apoptosis. By using a nonlinear expression to describe the mutation from premalignant to cancer cells, the model includes genetic instability as an enabling characteristic of tumour progression. Mathematical analysis was performed in detail. Results indicate that apoptosis and tissue repair system are the first barriers against tumour progression. One of these mechanisms must be corrupted for cancer to develop from a single mutant cell. The results also show that the presence of aggressive cancer cells opens way to survival of less adapted premalignant cells. Numerical simulations were performed with parameter values based on experimental data of breast cancer, and the necessary time taken for cancer to reach a detectable size from a single mutant cell was estimated with respect to some parameters. We find that the rates of apoptosis and mutations have a large influence on the pace of tumour progression and on the time it takes to become clinically detectable.

Development of surrogate endpoint biomarkers for clinical trials of cancer chemopreventive agents: relationships to fundamental properties of preinvasive (intraepithelial) neoplasia.

PubMed

Boone, C W; Kelloff, G J

1994-01-01

The tissue changes offering the greatest immediate potential for development as surrogate endpoint biomarkers (SEBs) to be used in Phase II trials of cancer chemopreventive agents are those derived from the microscopic tissue changes pathologists use to make the diagnosis of preinvasive (intraepithelial) neoplasia. These changes comprise four categories: proliferative index, ploidy, nuclear morphometry (size, shape, texture, and pleomorphism), and nucleolar morphometry (number, size, shape, position, and pleomorphism). Computer-assisted image analysis (CIA) permits dozens of additional morphometric parameters to be developed. Other categories of candidate SEBs are: DNA and chromosomal structural changes associated with genomic instability, activation of oncogenes and inactivation of tumor suppressor genes, structural changes in differentiated molecules, and aberrations of growth factor/receptor structure and function. Self-perpetuating DNA breakage with secondary mutator mutations in genomic stability genes is a major mechanism by which the genomic instability characteristic of neoplasia occurs, and from which stem other basic neoplastic properties, including clonal evolution, along multiple pathways of genetic variation that are stochastically determined, continuously increasing proliferation, rate and extent of phenotypic heterogeneity. SEBs resulting from genomic instability include homogeneously staining regions, double minute chromosomes, micronuclei, dicentrics, gene amplification, loss of heterozygosity, and alterations in chromosome number. Newly developed assays for detecting genomic instability include comparative genomic hybridization using fluorescence in situ hybridization on > 20 micron-thick sections monitored by confocal laser scanning microscopy, assays for microsatellite instability, and restriction landmark genomic scanning. These assays offer promise for detecting the earliest molecular changes of neoplasia in normal-appearing epithelium prior to the onset of the dysplastic phase of intraepithelial neoplasia.

Understanding the role of epigenomic, genomic and genetic alterations in the development of endometriosis (review).

PubMed

Kobayashi, Hiroshi; Imanaka, Shogo; Nakamura, Haruki; Tsuji, Ayumi

2014-05-01

Endometriosis is a complex disease influenced by genetic, epigenetic and environmental factors. The aim of the present study was to describe genomic instability, genetic polymorphisms and their haplotype, epigenetic alterations associated with predisposition to endometriosis, and the key factors associated with endometriosis-related ovarian neoplasms. Focus has been given on the developing paradigm that epigenetic alterations or genetic mutations in endometriosis may start in utero or in adolescent and young adults. A search was conducted between 1966 and 2010 through the English language literature (online Medline PubMed database) using the keywords endometriosis combined with epigenetic, genetic and environment. Genetic/epigenetic alterations include single‑nucleotide polymorphisms (SNPs), copy number variation, loss of heterozygosity (LOH), and promoter methylation. Several genes with genetic polymorphisms analyzed in the present study tended to overlap previously reported endometriosis susceptibility genes. Retrograde menstruation leads to iron overload, which facilitates the accumulation of somatic mutations through Fenton reaction-mediated oxidative stress. The epigenetic disruption of gene expression plays an important role in the development of endometriosis through interaction with environmental changes. There seems to be at least three spatiotemporally distinct phases of the development of endometriosis: the initial phase of genetic background inherited from parents; followed by epigenetic modifications in the female offspring; and iron overload, which is subject to dynamic modulation later in life. In conclusion, the marked regulation of endometriosis susceptibility genes may stem from a mechanism responsible for epigenetic and genetic mutations based on the microenvironmental changes.

Genetic Diversity of Pancreatic Ductal Adenocarcinoma and Opportunities for Precision Medicine.

PubMed

Knudsen, Erik S; O'Reilly, Eileen M; Brody, Jonathan R; Witkiewicz, Agnieszka K

2016-01-01

Patients with pancreatic ductal adenocarcinoma (PDA) have a poor prognosis despite new treatments; approximately 7% survive for 5 years. Although there have been advances in systemic, primarily cytotoxic, therapies, it has been a challenge to treat patients with PDA using targeted therapies. Sequence analyses have provided a wealth of information about the genetic features of PDA and have identified potential therapeutic targets. Preclinical and early-phase clinical studies have found specific pathways could be rationally targeted; it might also be possible to take advantage of the genetic diversity of PDAs to develop therapeutic agents. The genetic diversity and instability of PDA cells have long been thought of as obstacles to treatment, but are now considered exploitable features. We review the latest findings in pancreatic cancer genetics and the promise of targeted approaches in PDA therapy. Copyright © 2016 AGA Institute. Published by Elsevier Inc. All rights reserved.

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

PubMed

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 as much genome damage as that induced by exposure to a high dose of ionizing radiation. Even moderate folate deficiency causes very severe damage to the genome in the general population. All these accentuate the susceptibility of populations in these nations to environmental toxic assault requiring preventive measures employing the science of Nutrigenomics, probably augmented with adaptive response pathways such as the Nrf2 signaling pathway. Human populations in developing countries are increasingly exposed to a diverse array of industrial chemicals, which adversely modify the genome, the precursor of many diseases especially cancer. Nutrigenomics encompasses nutritional factors that protect the genome from damage and is a promising new field that can be exploited, perhaps augmented with the Nrf2 signaling pathway with international collaboration in these nations as an antidote to chemical-induced genome instability.

Up-regulation of mismatch repair genes MSH6, PMS2 and MLH1 parallels development of genetic instability and is linked to tumor aggressiveness and early PSA recurrence in prostate cancer.

PubMed

Wilczak, Waldemar; Rashed, Semin; Hube-Magg, Claudia; Kluth, Martina; Simon, Ronald; Büscheck, Franziska; Clauditz, Till Sebastian; Grupp, Katharina; Minner, Sarah; Tsourlakis, Maria Christina; Möller-Koop, Christina; Graefen, Markus; Adam, Meike; Haese, Alexander; Wittmer, Corinna; Sauter, Guido; Izbicki, Jakob Robert; Huland, Hartwig; Schlomm, Thorsten; Steurer, Stefan; Krech, Till; Lebok, Patrick

2017-01-01

DNA mismatch repair (MMR) is integral to the maintenance of genetic stability. We aimed to evaluate the clinical impact of MMR gene expression in prostate cancer. The MMR genes MSH6, MLH1 and PMS2 were analyzed by immunohistochemistry on a tissue microarray containing 11152 prostate cancer specimens. Results were compared with ETS-related gene status and deletions of PTEN, 3p13, 5q21 and 6q15. MSH6, MLH1 and PMS2 expression was detectable in 89.5%, 85.4% and 85.0% of cancers and was particularly strong in cancers with advanced pathological tumor stage (P < 0.0001 each), high Gleason grade (P < 0.0001 each), nodal metastasis (P ≤ 0.0083) and early biochemical recurrence (P < 0.0001). High levels of MMR gene expression paralleled features of genetic instability, such as the number of genomic deletions per cancer; strong expression of all three MMR genes was found in 24%, 29%, 30%, 33% and 42% of cancers with no, one, two, three or four to five deletions (P < 0.0001). The prognostic value of the analyzed MMR genes was largely driven by the subset of cancers lacking ERG fusion (P < 0.0001), while the prognostic impact of MMR gene overexpression was only marginal in ERG-positive cancers. Multivariate analyses suggested an independent prognostic relevance of MMR genes in ERG-negative prostate cancers when compared with prognostic parameters available at the time of initial biopsy. In conclusion, MMR overexpression is common in prostate cancer and is linked to poor outcome as well as features indicating genetic instability. ERG fusion should be analyzed along with MMR gene expression in potential clinical tests. © The Author 2016. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oup.com.

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

PubMed

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

2018-01-30

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

Family Structure Instability, Genetic Sensitivity and Child Wellbeing

PubMed Central

Mitchell, Colter; McLanahan, Sara; Hobcraft, John; Brooks-Gunn, Jeanne; Garfinkel, Irwin; Notterman, Daniel

2016-01-01

The association between family structure instability and children’s life chances is well documented, with children reared in stable, two-parent families experiencing more favorable outcomes than children reared in other family arrangements. This study extends prior research by distinguishing between father-entrances into and father-exits from the household, by distinguishing between the entrance of a biological father and a social-father, and by testing for interactions between family structure instability and children’s age, gender and genetic characteristics. Using data from the Fragile Families and Child Wellbeing Study (n=2493) and focusing on changes in family structure between birth and age 9, we find that father-exits are associated with increases in children’s anti-social behavior, which is a strong predictor of health and wellbeing in adulthood. The pattern for father-entrances is more complicated, with biological father entrances being associated with lower anti-social behavior among boys, and social-father entrances being associated with higher anti-social behavior among boys with certain genetic variants. Child’s age at the time of family change does not moderate the association with children’s behavior. However, incorporating genetic information into our models sharpens the findings substantially, showing how such data can enrich our understanding of the intergenerational mobility process. PMID:26046228

Increased Risk of Genetic and Epigenetic Instability in Human Embryonic Stem Cells Associated with Specific Culture Conditions

PubMed Central

Garitaonandia, Ibon; Amir, Hadar; Boscolo, Francesca Sesillo; Wambua, Gerald K.; Schultheisz, Heather L.; Sabatini, Karen; Morey, Robert; Waltz, Shannon; Wang, Yu-Chieh; Tran, Ha; Leonardo, Trevor R.; Nazor, Kristopher; Slavin, Ileana; Lynch, Candace; Li, Yingchun; Coleman, Ronald; Gallego Romero, Irene; Altun, Gulsah; Reynolds, David; Dalton, Stephen; Parast, Mana; Loring, Jeanne F.; Laurent, Louise C.

2015-01-01

The self-renewal and differentiation capacities of human pluripotent stem cells (hPSCs) make them a promising source of material for cell transplantation therapy, drug development, and studies of cellular differentiation and development. However, the large numbers of cells necessary for many of these applications require extensive expansion of hPSC cultures, a process that has been associated with genetic and epigenetic alterations. We have performed a combinatorial study on both hESCs and hiPSCs to compare the effects of enzymatic vs. mechanical passaging, and feeder-free vs. mouse embryonic fibroblast feeder substrate, on the genetic and epigenetic stability and the phenotypic characteristics of hPSCs. In extensive experiments involving over 100 continuous passages, we observed that both enzymatic passaging and feeder-free culture were associated with genetic instability, higher rates of cell proliferation, and persistence of OCT4/POU5F1-positive cells in teratomas, with enzymatic passaging having the stronger effect. In all combinations of culture conditions except for mechanical passaging on feeder layers, we noted recurrent deletions in the genomic region containing the tumor suppressor gene TP53, which was associated with decreased mRNA expression of TP53, as well as alterations in the expression of several downstream genes consistent with a decrease in the activity of the TP53 pathway. Among the hESC cultures, we also observed culture-associated variations in global gene expression and DNA methylation. The effects of enzymatic passaging and feeder-free conditions were also observed in hiPSC cultures. Our results highlight the need for careful assessment of the effects of culture conditions on cells intended for clinical therapies. PMID:25714340

Expression levels of DNA replication and repair genes predict regional somatic repeat instability in the brain but are not altered by polyglutamine disease protein expression or age.

PubMed

Mason, Amanda G; Tomé, Stephanie; Simard, Jodie P; Libby, Randell T; Bammler, Theodor K; Beyer, Richard P; Morton, A Jennifer; Pearson, Christopher E; La Spada, Albert R

2014-03-15

Expansion of CAG/CTG trinucleotide repeats causes numerous inherited neurological disorders, including Huntington's disease (HD), several spinocerebellar ataxias and myotonic dystrophy type 1. Expanded repeats are genetically unstable with a propensity to further expand when transmitted from parents to offspring. For many alleles with expanded repeats, extensive somatic mosaicism has been documented. For CAG repeat diseases, dramatic instability has been documented in the striatum, with larger expansions noted with advancing age. In contrast, only modest instability occurs in the cerebellum. Using microarray expression analysis, we sought to identify the genetic basis of these regional instability differences by comparing gene expression in the striatum and cerebellum of aged wild-type C57BL/6J mice. We identified eight candidate genes enriched in cerebellum, and validated four--Pcna, Rpa1, Msh6 and Fen1--along with a highly associated interactor, Lig1. We also explored whether expression levels of mismatch repair (MMR) proteins are altered in a line of HD transgenic mice, R6/2, that is known to show pronounced regional repeat instability. Compared with wild-type littermates, MMR expression levels were not significantly altered in R6/2 mice regardless of age. Interestingly, expression levels of these candidates were significantly increased in the cerebellum of control and HD human samples in comparison to striatum. Together, our data suggest that elevated expression levels of DNA replication and repair proteins in cerebellum may act as a safeguard against repeat instability, and may account for the dramatically reduced somatic instability present in this brain region, compared with the marked instability observed in the striatum.

Cancer-related inflammation, the seventh hallmark of cancer: links to genetic instability.

PubMed

Colotta, Francesco; Allavena, Paola; Sica, Antonio; Garlanda, Cecilia; Mantovani, Alberto

2009-07-01

Inflammatory conditions in selected organs increase the risk of cancer. An inflammatory component is present also in the microenvironment of tumors that are not epidemiologically related to inflammation. Recent studies have begun to unravel molecular pathways linking inflammation and cancer. In the tumor microenvironment, smoldering inflammation contributes to proliferation and survival of malignant cells, angiogenesis, metastasis, subversion of adaptive immunity, reduced response to hormones and chemotherapeutic agents. Recent data suggest that an additional mechanism involved in cancer-related inflammation (CRI) is induction of genetic instability by inflammatory mediators, leading to accumulation of random genetic alterations in cancer cells. In a seminal contribution, Hanahan and Weinberg [(2000) Cell, 100, 57-70] identified the six hallmarks of cancer. We surmise that CRI represents the seventh hallmark.

The CpG island methylator phenotype (CIMP) in colorectal cancer

PubMed Central

Mojarad, Ehsan Nazemalhosseini; Kuppen, Peter JK; Aghdaei, Hamid Asadzadeh

2013-01-01

It is clear that colorectal cancer (CRC) develops through multiple genetic and epigenetic pathways. These pathways may be determined on the basis of three molecular features: (i) mutations in DNA mismatch repair genes, leading to a DNA microsatellite instability (MSI) phenotype, (ii) mutations in APC and other genes that activate Wnt pathway, characterized by chromosomal instability (CIN) phenotype, and (iii) global genome hypermethylation, resulting in switch off of tumor suppressor genes, indicated as CpG island methylator phenotype (CIMP). Each of these pathways is characterized by specific pathological features, mechanisms of carcinogenesis and process of tumor development. The molecular aspects of these pathways have been used clinically in the diagnosis, screening and management of patients with colorectal cancer. In this review we especially describe various aspects of CIMP, one of the important and rather recently discovered pathways that lead to colorectal cancer. PMID:24834258

The CpG island methylator phenotype (CIMP) in colorectal cancer.

PubMed

Nazemalhosseini Mojarad, Ehsan; Kuppen, Peter Jk; Aghdaei, Hamid Asadzadeh; Zali, Mohammad Reza

2013-01-01

It is clear that colorectal cancer (CRC) develops through multiple genetic and epigenetic pathways. These pathways may be determined on the basis of three molecular features: (i) mutations in DNA mismatch repair genes, leading to a DNA microsatellite instability (MSI) phenotype, (ii) mutations in APC and other genes that activate Wnt pathway, characterized by chromosomal instability (CIN) phenotype, and (iii) global genome hypermethylation, resulting in switch off of tumor suppressor genes, indicated as CpG island methylator phenotype (CIMP). Each of these pathways is characterized by specific pathological features, mechanisms of carcinogenesis and process of tumor development. The molecular aspects of these pathways have been used clinically in the diagnosis, screening and management of patients with colorectal cancer. In this review we especially describe various aspects of CIMP, one of the important and rather recently discovered pathways that lead to colorectal cancer.

Transposable Elements and Genetic Instabilities in Crop Plants

DOE R&D Accomplishments Database

Burr, B.; Burr, F.

1981-04-10

Transposable elements have long been associated with certain unstable loci in maize and have been intensively studied by McClintock and others. It is known that a transposable element can control the expression of the structural genes at the locus where it resides. These controlling elements in maize are now beginning to be studied at the molecular level. Using recombinant molecular probes we have been able to describe the changes induced by the controlling element Ds at the shrunken locus. Ds elements appear to be large and dissimilar insertions into the wild-type locus - two elements actually map within the transcribed region of the gene. Genetic instabilities have been described in other economically important plants but the bases for these phenomena have not been understood. We believe that it is likely that some of these instabilities are the result of transposable element activity much as in the case of maize.

Glutathione S-transferase gene polymorphisms in celiac disease and their correlation with genomic instability phenotype.

PubMed

Fundia, Ariela F; Weich, Natalia; Crivelli, Adriana; La Motta, Graciela; Larripa, Irene B; Slavutsky, Irma

2014-06-01

Genomic instability and reduced glutathione S-transferase (GST) activity have been identified as potential risk factors for malignant complications in celiac disease (CD). In this study, we assessed the possible influence of GST polymorphisms on genome instability phenotypes in a genetically characterised group of celiac patients from previous studies. The deletion polymorphisms in GSTM1 and GSTT1 genes and the single-nucleotide polymorphism GSTP1 c.313A>G were genotyped using PCR in a set of 20 untreated adult patients with a known genomic instability phenotype and 69 age- and sex-matched healthy individuals. The frequencies of variant genotypes in patients were GSTM1-null (30%), GSTT1-null (5%), GSTP1-AG (60%) and GSTP1-GG (15%), and they showed no differences from controls. No significant differences were found in the genotype distribution based on telomere length. Cases with GSTM1-null genotype (83%) and microsatellite stability were more frequent than those with genomic instability. Moreover, carriers of GSTP1-variant genotype (73%) and stable phenotype were significantly increased compared to unstable patients (27%) (P=0.031). No differences were found according to the clinical-pathological characteristics of celiac cases. No association between GST polymorphic variants and celiac-associated genomic instability was proven in our cohort. Future studies should explore the usefulness of other biomarkers to distinguish celiac patients who are susceptible to cancer development. Copyright © 2014 Elsevier Masson SAS. All rights reserved.

[Study on genetic instability of nm23H1 gene in Chinese with original gallbladder tumor].

PubMed

Lu, Hai Ying; Zhang, Guo Qiang; Li, Ji Cheng

2006-06-01

The aim of this study was to examine the microsatellite instability (MSI) and loss of heterozygosity (LOH) of locus D17S396 on chromosome 17 and their influence on the expression of nm23H1 in gallbladder tumors, which may provide experimental basis for the tumor occurrence and metastasis. Techniques such as DNA extraction from formalin-fixed paraffin-embedded tissues, polymerase chain reaction-single strand conformation polymorphism (PCR-SSCP), ordinary silver stain were used to study MSI and LOH of locus D17S396. Envision immunohistochemistry and Leica-Qwin computer imaging techniques were used to assess the expression of gene nm23H1. In our experiment, the frequency of genetic instability of malignant gallbladder tumors was 42.55%, which was higher than that of gallbladder adenomas, while there were no genetic instability occurred in chronic cholecystitis tissue. The frequency of LOH seemed higher with the deteriorism of gallbladder tumor. Among 47 gallbladder carcinomas, the frequency of LOH and MSI were different between different differentiation cases (P < 0.05), and the frequency of LOH in liver and lymph node metastasis cases was significantly higher than those without metastasis (P < 0.01). Moreover, the frequency of LOH was higher in stage Nevin IV and V when compared with stage I, II and III. However, the frequency of MSI showed contrary correlation with some clinicopathologic characteristics. The expression of nm23H1 in gallbladder carcinoma, gallbladder adenoma and chronic cholecystitis tissue were different (P < 0.05). The case with lymph node metastasis showed significantly lower nm23H1 expression than those without lymph node metastasis (P < 0.01). Nevin stage IV and V also exhibited lower nm23H1 expression levels compared with stage I, II and Ill. Furthermore, there was no difference in nm23H1 protein expression intensity analyzed by computer imaging techniques. In gallbladder carcinomas, the positive frequency of nm23H1 protein in LOH positive group was lower than that of LOH negative group (P < 0.05). The results indicated that the genetic instability of nm23H1 gene might be implicated in pathogenesis and progression of gallbladder tumor. Both MSI and LOH of nm23H1 gene controlled the development of gallbladder tumor independently in different paths. MSI may be an early stage molecule marker of gallbladder carcinoma. LOH may be molecule marker for the deteriorism of gallbladder tissue, which could inhibit the expression of nm23H1 in local tissue of gallbladder carcinoma and endow it with high aggressive and poor prognosis. Increasing the amount of nm23H1 protein expression could effectively restrain gallbladder carcinoma metastasis and improve prognosis of patients.

Chromosome instability on children with asthma.

PubMed

Lialiaris, Theodore; Polyzou, Aggeliki; Mpountoukas, Panagiotis; Tsiggene, Anthi; Kouskoukis, Alexandros; Pouliliou, Stamatia; Paraskakis, Emmanouil; Tentes, Ioannis; Trypsianis, Grigorios; Chatzimichail, Athanasios

2009-10-01

Asthma is a complex disease with multiple interactions between genetic and environmental factors. The aim of our study was to investigate the possible genetic instability in asthmatic patients (AP) with asthma in human cultured peripheral blood lymphocytes. Furthermore, the presence of either cytostaticity or cytotoxicity was demonstrated. Human peripheral blood lymphocytes were cultured from 18 admitted children to the Pediatric Clinic of the University Hospital of Alexandroupolis (average age 7.2 years), and 9 healthy blood donors were used as control subjects (average age 6.5 years), none of whom was receiving drugs for medical or other reasons. A significant (p < 0.05) increase in spontaneous sister chromatid exchanges (SCEs) frequency in asthmatic patients compared with control subjects was observed. No statistically significant modification in the spontaneous proliferation rate index (PRI) in AP compared with the controls was demonstrated. Finally, MMC induced a statistically significant increase in SCEs frequency both to controls and to AP, with the MMC-induced SCEs rates in AP being statistically (p < 0.01) higher compared to the MMC-induced SCEs in controls. We try to improve a new diagnostic process of possible genetic instability by a combination of genotoxic, cytostatic and cytotoxic effects of asthma on human peripheral lymphocytes.

Radiation-induced genomic instability: radiation quality and dose response

NASA Technical Reports Server (NTRS)

Smith, Leslie E.; Nagar, Shruti; Kim, Grace J.; Morgan, William F.

2003-01-01

Genomic instability is a term used to describe a phenomenon that results in the accumulation of multiple changes required to convert a stable genome of a normal cell to an unstable genome characteristic of a tumor. There has been considerable recent debate concerning the importance of genomic instability in human cancer and its temporal occurrence in the carcinogenic process. Radiation is capable of inducing genomic instability in mammalian cells and instability is thought to be the driving force responsible for radiation carcinogenesis. Genomic instability is characterized by a large collection of diverse endpoints that include large-scale chromosomal rearrangements and aberrations, amplification of genetic material, aneuploidy, micronucleus formation, microsatellite instability, and gene mutation. The capacity of radiation to induce genomic instability depends to a large extent on radiation quality or linear energy transfer (LET) and dose. There appears to be a low dose threshold effect with low LET, beyond which no additional genomic instability is induced. Low doses of both high and low LET radiation are capable of inducing this phenomenon. This report reviews data concerning dose rate effects of high and low LET radiation and their capacity to induce genomic instability assayed by chromosomal aberrations, delayed lethal mutations, micronuclei and apoptosis.

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

PubMed Central

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

2016-01-01

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

Macro-environment of breast carcinoma: frequent genetic alterations in the normal appearing skins of patients with breast cancer.

PubMed

Moinfar, Farid; Beham, Alfred; Friedrich, Gerhard; Deutsch, Alexander; Hrzenjak, Andelko; Luschin, Gero; Tavassoli, Fattaneh A

2008-05-01

Genetic abnormalities in microenvironmental tissues with subsequent alterations of reciprocal interactions between epithelial and mesenchymal cells play a key role in the breast carcinogenesis. Although a few reports have demonstrated abnormal fibroblastic functions in normal-appearing fibroblasts taken from the skins of breast cancer patients, the genetic basis of this phenomenon and its implication for carcinogenesis are unexplored. We analyzed 12 mastectomy specimens showing invasive ductal carcinomas. In each case, morphologically normal epidermis and dermis, carcinoma, normal stroma close to carcinoma, and stroma at a distant from carcinoma were microdissected. Metastatic-free lymphatic tissues from lymph nodes served as a control. Using PCR, DNA extracts were examined with 11 microsatellite markers known for a high frequency of allelic imbalances in breast cancer. Losses of heterozygosity and/or microsatellite instability were detected in 83% of the skin samples occurring either concurrently with or independently from the cancerous tissues. In 80% of these cases at least one microsatellite marker displayed loss of heterozygosity or microsatellite instability in the skin, which was absent in carcinoma. A total of 41% of samples showed alterations of certain loci observed exclusively in the carcinoma but not in the skin compartments. Our study suggests that breast cancer is not just a localized genetic disorder, but rather part of a larger field of genetic alterations/instabilities affecting multiple cell populations in the organ with various cellular elements, ultimately contributing to the manifestation of the more 'localized' carcinoma. These data indicate that more global assessment of tumor micro- and macro-environment is crucial for our understanding of breast carcinogenesis.

Longitudinal Associations between Marital Instability and Child Sleep Problems across Infancy and Toddlerhood in Adoptive Families

ERIC Educational Resources Information Center

Mannering, Anne M.; Harold, Gordon T.; Leve, Leslie D.; Shelton, Katherine H.; Shaw, Daniel S.; Conger, Rand D.; Neiderhiser, Jenae M.; Scaramella, Laura V.; Reiss, David

2011-01-01

This study examined the longitudinal association between marital instability and child sleep problems at ages 9 and 18 months in 357 families with a genetically unrelated infant adopted at birth. This design eliminates shared genes as an explanation for similarities between parent and child. Structural equation modeling indicated that T1 marital…

Mechanisms underlying cellular responses of cells from haemopoietic tissue to low dose/low LET radiation

DOE Office of Scientific and Technical Information (OSTI.GOV)

Munira A Kadhim

2010-03-05

To accurately define the risks associated with human exposure to relevant environmental doses of low LET ionizing radiation, it is necessary to completely understand the biological effects at very low doses (i.e., less than 0.1 Gy), including the lowest possible dose, that of a single electron track traversal. At such low doses, a range of studies have shown responses in biological systems which are not related to the direct interaction of radiation tracks with DNA. The role of these “non-targeted” responses in critical tissues is poorly understood and little is known regarding the underlying mechanisms. Although critical for dosimetry andmore » risk assessment, the role of individual genetic susceptibility in radiation risk is not satisfactorily defined at present. The aim of the proposed grant is to critically evaluate radiation-induced genomic instability and bystander responses in key stem cell populations from haemopoietic tissue. Using stem cells from two mouse strains (CBA/H and C57BL/6J) known to differ in their susceptibility to radiation effects, we plan to carefully dissect the role of genetic predisposition on two non-targeted radiation responses in these models; the bystander effect and genomic instability, which we believe are closely related. We will specifically focus on the effects of low doses of low LET radiation, down to doses approaching a single electron traversal. Using conventional X-ray and γ-ray sources, novel dish separation and targeted irradiation approaches, we will be able to assess the role of genetic variation under various bystander conditions at doses down to a few electron tracks. Irradiations will be carried out using facilities in routine operation for bystander targeted studies. Mechanistic studies of instability and the bystander response in different cell lineages will focus initially on the role of cytokines which have been shown to be involved in bystander signaling and the initiation of instability. These studies also aim to uncover protein mediators of the bystander responses using advanced proteomic screening of factors released from irradiated, bystander and unstable cells. Integral to these studies will be an assessment of the role of genetic susceptibility in these responses, using CBA/H and C57BL/6J mice. The relevance of in vivo interactions between stem cells and the stem cell niche will be explored in the future by re-implantation techniques of previously irradiated cells. The above studies will provide fundamental mechanistic information relating genetic predisposition to important low dose phenomena, and will aid in the development of Department of Energy policy, as well as radiation risk policy for the public and the workplace. We believe the proposed studies accurately reflect the goals of the DOE low dose program.« less

Molecular Genetics and Genetic Testing in Myotonic Dystrophy Type 1

PubMed Central

Savić Pavićević, Dušanka; Miladinović, Jelena; Brkušanin, Miloš; Šviković, Saša; Djurica, Svetlana; Brajušković, Goran; Romac, Stanka

2013-01-01

Myotonic dystrophy type 1 (DM1) is the most common adult onset muscular dystrophy, presenting as a multisystemic disorder with extremely variable clinical manifestation, from asymptomatic adults to severely affected neonates. A striking anticipation and parental-gender effect upon transmission are distinguishing genetic features in DM1 pedigrees. It is an autosomal dominant hereditary disease associated with an unstable expansion of CTG repeats in the 3′-UTR of the DMPK gene, with the number of repeats ranging from 50 to several thousand. The number of CTG repeats broadly correlates with both the age-at-onset and overall severity of the disease. Expanded DM1 alleles are characterized by a remarkable expansion-biased and gender-specific germline instability, and tissue-specific, expansion-biased, age-dependent, and individual-specific somatic instability. Mutational dynamics in male and female germline account for observed anticipation and parental-gender effect in DM1 pedigrees, while mutational dynamics in somatic tissues contribute toward the tissue-specificity and progressive nature of the disease. Genetic test is routinely used in diagnostic procedure for DM1 for symptomatic, asymptomatic, and prenatal testing, accompanied with appropriate genetic counseling and, as recommended, without predictive information about the disease course. We review molecular genetics of DM1 with focus on those issues important for genetic testing and counseling. PMID:23586035

Estimating parametric phenotypes that determine anthesis date in Zea mays: Challenges in combining ecophysiological models with genetics

PubMed Central

Welch, Stephen M.; White, Jeffrey W.; Thorp, Kelly R.; Bello, Nora M.

2018-01-01

Ecophysiological crop models encode intra-species behaviors using parameters that are presumed to summarize genotypic properties of individual lines or cultivars. These genotype-specific parameters (GSP’s) can be interpreted as quantitative traits that can be mapped or otherwise analyzed, as are more conventional traits. The goal of this study was to investigate the estimation of parameters controlling maize anthesis date with the CERES-Maize model, based on 5,266 maize lines from 11 plantings at locations across the eastern United States. High performance computing was used to develop a database of 356 million simulated anthesis dates in response to four CERES-Maize model parameters. Although the resulting estimates showed high predictive value (R2 = 0.94), three issues presented serious challenges for use of GSP’s as traits. First (expressivity), the model was unable to express the observed data for 168 to 3,339 lines (depending on the combination of site-years), many of which ended up sharing the same parameter value irrespective of genetics. Second, for 2,254 lines, the model reproduced the data, but multiple parameter sets were equally effective (equifinality). Third, parameter values were highly dependent (p<10−6919) on the sets of environments used to estimate them (instability), calling in to question the assumption that they represent fundamental genetic traits. The issues of expressivity, equifinality and instability must be addressed before the genetic mapping of GSP’s becomes a robust means to help solve the genotype-to-phenotype problem in crops. PMID:29672629

Predisposition to Cancer Caused by Genetic and Functional Defects of Mammalian Atad5

PubMed Central

Bell, Daphne W.; Chatterjee, Raghunath; Park, Hee-Dong; Fox, Jennifer; Ishiai, Masamichi; Rudd, Meghan L.; Pollock, Lana M.; Fogoros, Sarah K.; Mohamed, Hassan; Hanigan, Christin L.; Zhang, Suiyuan; Cruz, Pedro; Renaud, Gabriel; Hansen, Nancy F.; Cherukuri, Praveen F.; Borate, Bhavesh; McManus, Kirk J.; Stoepel, Jan; Sipahimalani, Payal; Godwin, Andrew K.; Sgroi, Dennis C.; Merino, Maria J.; Elliot, Gene; Elkahloun, Abdel; Vinson, Charles; Takata, Minoru; Mullikin, James C.; Wolfsberg, Tyra G.; Hieter, Philip; Lim, Dae-Sik; Myung, Kyungjae

2011-01-01

ATAD5, the human ortholog of yeast Elg1, plays a role in PCNA deubiquitination. Since PCNA modification is important to regulate DNA damage bypass, ATAD5 may be important for suppression of genomic instability in mammals in vivo. To test this hypothesis, we generated heterozygous (Atad5+/m) mice that were haploinsuffficient for Atad5. Atad5+/m mice displayed high levels of genomic instability in vivo, and Atad5+/m mouse embryonic fibroblasts (MEFs) exhibited molecular defects in PCNA deubiquitination in response to DNA damage, as well as DNA damage hypersensitivity and high levels of genomic instability, apoptosis, and aneuploidy. Importantly, 90% of haploinsufficient Atad5+/m mice developed tumors, including sarcomas, carcinomas, and adenocarcinomas, between 11 and 20 months of age. High levels of genomic alterations were evident in tumors that arose in the Atad5+/m mice. Consistent with a role for Atad5 in suppressing tumorigenesis, we also identified somatic mutations of ATAD5 in 4.6% of sporadic human endometrial tumors, including two nonsense mutations that resulted in loss of proper ATAD5 function. Taken together, our findings indicate that loss-of-function mutations in mammalian Atad5 are sufficient to cause genomic instability and tumorigenesis. PMID:21901109

Role of microsatellite instability-low as a diagnostic biomarker of Lynch syndrome in colorectal cancer.

PubMed

Vilar, Eduardo; Mork, Maureen E; Cuddy, Amanda; Borras, Ester; Bannon, Sarah A; Taggart, Melissa W; Ying, Jun; Broaddus, Russell R; Luthra, Rajyalakshmi; Rodriguez-Bigas, Miguel A; Lynch, Patrick M; You, Yi-Qian Nancy

2014-01-01

Lynch syndrome is the most common Mendelian disorder predisposing persons to hereditary colorectal cancer. Carriers of MSH6 mutations constitute less than 10% of the total of cases with Lynch syndrome and present with a weaker clinical phenotype, including low levels of microsatellite instability (MSI-L) in colorectal tumors. The frequency of MSH6 mutation carriers among patients presenting with MSI-L colorectal cancer has yet to be determined, as has the appropriate genetic workup in this context. We have reviewed here the clinicopathologic characteristics, immunohistochemistry, and genetic testing results for 71 patients at a single institution diagnosed with MSI-L colorectal cancers. Of 71 patients with MSI-L tumors, 21 underwent genetic testing for MSH6 mutations, three of whom presented with loss of staining of MSH6 and only one of whom carried a pathogenic germline MSH6 mutation in exon 4 (c.2677_2678delCT; p.Leu893Alafs*6). This latter patient had a significant family history of cancer and had a rectal primary tumor that showed instability only in mononucleotide markers. In this cohort of MSI-L patients, we detected no notable clinicopathologic or molecular characteristic that would help to distinguish a group most likely to harbor germline MSH6 mutations. Therefore, we conclude that the prevalence of MSH6 mutations among patients with MSI-L tumors is very low. Microsatellite instability analysis combined with immunohistochemistry of mismatch repair proteins adequately detects potential MSH6 mutation carriers among MSI-L colorectal cancers. Copyright © 2014 Elsevier Inc. All rights reserved.

[Molecular biology in clinical cancer research: the example of digestive cancers].

PubMed

Lièvre, A; Laurent-Puig, P

2005-06-01

Cancer is a DNA disease characterized by uncontrolled cell proliferation due to the accumulation of genetic alterations. Recent progress in molecular biology allowed the identification of markers potentially usefull for patients management through the identification of these genetic alterations and a best understanding of chemotherapy molecular targets. Several examples in digestive oncology underline the relevance of molecular biology in clinical research. If almost all colorectal cancers (CRC) correspond to the same histopathological type (adenocarcinoma), molecular biology allowed the identification of two different molecular mechanisms of colorectal carcinogenesis: chromosomal instability characterized by recurrent allelic losses on chromosomes 17, 5, 18, 8 and 22 that contribute to the inactivation of tumor suppressor genes, and genetic instability characterized by the instability of microsatellite loci due to an alteration of DNA mismatch repair leading to the accumulation of mutations in genes involved in the control of cell cycle and apoptosis. These data are potentially interesting for the management of CRC patients. Indeed, microsatellite instability seems not only to be a good prognostic factor but also a molecular factor that can predict response to adjuvant 5-fluorouracil based chemotherapy. Therapeutic clinical trials taking into account these molecular parameters are still going on. DNA microarray-based gene expression profiling technology that allows the simultaneous analysis of thousand of tumor genes represents also an interesting approach in oncology with the recent identification of a "genetic signature" as a risk factor of tumor recurrence in stage II CRC, a setting in which the benefit of adjuvant chemotherapy remains on debate. At last, a best understanding of chemotherapy molecular targets allowed the identification of genetic markers that can predict the response and/or the toxicity of anti-cancer drugs used in gastrointestinal cancers, which could be helpful in the future to propose for each patient a personalized treatment. Mutations that can predict the response of new target therapies such as the inhibitors of the c-KIT tyrosine kinase activity in gastrointestinal stromal tumors have also been found and will allow the selection of patients who can have benefit from these new therapeutic drugs.

Multifocality of transitional cell carcinoma results from genetic instability of entire transitional epithelium.

PubMed

Pycha, A; Mian, C; Hofbauer, J; Brössner, C; Haitel, A; Wiener, H; Marberger, M

1999-01-01

Multifocality of transitional cell carcinoma (TCC) has been attributed to seeding of exfoliated tumor cells or to a general sensitivity of the entire urothelium to carcinogenic stimuli. By contrast, TCC has been shown to evolve as a consequence of genetic defects and chromosomal instability. We analyzed chromosomal patterns, total DNA content, and p53 and Ki67 expression in malignant and normal transitional cells to evaluate their relationship to the development of multifocal TCC. Included in the study were 47 patients, 16 women and 31 men, with a mean age of 70.04 years (range 37 to 83). Of 47 patients, 45 had TCC of the urinary bladder and 7 of those had synchronous ureteral involvement. Two patients had ureteral TCC and a history of TCC of the bladder. Using fluorescence in situ hybridization, numerical aberrations of chromosomes 7, 9, and 17 were detected in imprint specimens of histologically verified tumor and "normal" urothelium and were compared with static ploidy and p53 and Ki67 expression. Chromosome 7 was altered in 93.6%, chromosome 9 in 63.8% (including monosomy), and chromosome 17 in 87.2% of the 47 analyzed tumor and normal imprints. Differences between tumor and normal epithelium were observed in aberrational frequencies (number of cells showing chromosomal aberrations calculated on 200 cells counted, given in percentages). DNA content was aneuploid in all tumor specimens, but diploid in 20 (42.5%) of 47 normal specimens, according to lower aberration frequencies in these patients. p53 detection was positive in 82.9% of the tumor specimens and 76.6% of the normal specimens. Ki67 was positive in 87.2% of the tumor imprints and in 72.3% of the normal specimens. These data suggest a general genetic instability as a reason for multifocality in the entire transitional epithelium.

Guidelines for the use of cell lines in biomedical research

PubMed Central

Geraghty, R J; Capes-Davis, A; Davis, J M; Downward, J; Freshney, R I; Knezevic, I; Lovell-Badge, R; Masters, J R W; Meredith, J; Stacey, G N; Thraves, P; Vias, M

2014-01-01

Cell-line misidentification and contamination with microorganisms, such as mycoplasma, together with instability, both genetic and phenotypic, are among the problems that continue to affect cell culture. Many of these problems are avoidable with the necessary foresight, and these Guidelines have been prepared to provide those new to the field and others engaged in teaching and instruction with the information necessary to increase their awareness of the problems and to enable them to deal with them effectively. The Guidelines cover areas such as development, acquisition, authentication, cryopreservation, transfer of cell lines between laboratories, microbial contamination, characterisation, instability and misidentification. Advice is also given on complying with current legal and ethical requirements when deriving cell lines from human and animal tissues, the selection and maintenance of equipment and how to deal with problems that may arise. PMID:25117809

Guidelines for the use of cell lines in biomedical research.

PubMed

Geraghty, R J; Capes-Davis, A; Davis, J M; Downward, J; Freshney, R I; Knezevic, I; Lovell-Badge, R; Masters, J R W; Meredith, J; Stacey, G N; Thraves, P; Vias, M

2014-09-09

Cell-line misidentification and contamination with microorganisms, such as mycoplasma, together with instability, both genetic and phenotypic, are among the problems that continue to affect cell culture. Many of these problems are avoidable with the necessary foresight, and these Guidelines have been prepared to provide those new to the field and others engaged in teaching and instruction with the information necessary to increase their awareness of the problems and to enable them to deal with them effectively. The Guidelines cover areas such as development, acquisition, authentication, cryopreservation, transfer of cell lines between laboratories, microbial contamination, characterisation, instability and misidentification. Advice is also given on complying with current legal and ethical requirements when deriving cell lines from human and animal tissues, the selection and maintenance of equipment and how to deal with problems that may arise.

Loss of Elongation-Like Factor 1 Spontaneously Induces Diverse, RNase H-Related Suppressor Mutations in Schizosaccharomyces pombe.

PubMed

Marayati, Bahjat F; Drayton, Alena L; Tucker, James F; Huckabee, Reid H; Anderson, Alicia M; Pease, James B; Zeyl, Clifford W; Zhang, Ke

2018-05-29

A healthy individual may carry a detrimental genetic trait that is masked by another genetic mutation. Such suppressive genetic interactions, in which a mutant allele either partially or completely restores the fitness defect of a particular mutant, tend to occur between genes that have a confined functional connection. Here we investigate a self-recovery phenotype in Schizosaccharomyces pombe , mediated by suppressive genetic interactions that can be amplified during cell culture. Cells without Elf1, an AAA+ family ATPase, have severe growth defects initially, but quickly recover growth rates near to those of wild-type strains by acquiring suppressor mutations. elf1Δ cells accumulate RNAs within the nucleus and display effects of genome instability such as sensitivity to DNA damage, increased incidence of lagging chromosomes, and mini-chromosome loss. Notably, the rate of phenotypic recovery was further enhanced in elf1Δ cells when RNase H activities were abolished and significantly reduced upon overexpression of RNase H1, suggesting that loss of Elf1-related genome instability can be resolved by RNase H activities, likely through eliminating the potentially mutagenic DNA-RNA hybrids caused by RNA nuclear accumulation. Using whole genome sequencing, we mapped a few consistent suppressors of elf1Δ including mutated Cue2, Rpl2702, and SPBPJ4664.02, suggesting previously unknown functional connections between Elf1 and these proteins. Our findings describe a mechanism by which cells bearing mutations that cause fitness defects and genome instability may accelerate the fitness recovery of their population through quickly acquiring suppressors. We propose that this mechanism may be universally applicable to all microorganisms in large-population cultures. Copyright © 2018, Genetics.

Chromosomal instability drives metastasis through a cytosolic DNA response.

PubMed

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

2018-01-25

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

Bacterial Genome Instability

PubMed Central

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

Molecular Mechanisms of Radiation-Induced Genomic Instability in Human Cells

DOE Office of Scientific and Technical Information (OSTI.GOV)

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 cellsmore » 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.« less

Genetic diversity and demographic instability in Riftia pachyptila tubeworms from eastern Pacific hydrothermal vents

PubMed Central

2011-01-01

Background Deep-sea hydrothermal vent animals occupy patchy and ephemeral habitats supported by chemosynthetic primary production. Volcanic and tectonic activities controlling the turnover of these habitats contribute to demographic instability that erodes genetic variation within and among colonies of these animals. We examined DNA sequences from one mitochondrial and three nuclear gene loci to assess genetic diversity in the siboglinid tubeworm, Riftia pachyptila, a widely distributed constituent of vents along the East Pacific Rise and Galápagos Rift. Results Genetic differentiation (FST) among populations increased with geographical distances, as expected under a linear stepping-stone model of dispersal. Low levels of DNA sequence diversity occurred at all four loci, allowing us to exclude the hypothesis that an idiosyncratic selective sweep eliminated mitochondrial diversity alone. Total gene diversity declined with tectonic spreading rates. The southernmost populations, which are subjected to superfast spreading rates and high probabilities of extinction, are relatively homogenous genetically. Conclusions Compared to other vent species, DNA sequence diversity is extremely low in R. pachyptila. Though its dispersal abilities appear to be effective, the low diversity, particularly in southern hemisphere populations, is consistent with frequent local extinction and (re)colonization events. PMID:21489281

Genetic diversity and demographic instability in Riftia pachyptila tubeworms from eastern Pacific hydrothermal vents

USGS Publications Warehouse

Coykendall, D.K.; Johnson, S.B.; Karl, S.A.; Lutz, R.A.; Vrijenhoek, R.C.

2011-01-01

Background: Deep-sea hydrothermal vent animals occupy patchy and ephemeral habitats supported by chemosynthetic primary production. Volcanic and tectonic activities controlling the turnover of these habitats contribute to demographic instability that erodes genetic variation within and among colonies of these animals. We examined DNA sequences from one mitochondrial and three nuclear gene loci to assess genetic diversity in the siboglinid tubeworm, Riftia pachyptila, a widely distributed constituent of vents along the East Pacific Rise and Galpagos Rift. Results: Genetic differentiation (FST) among populations increased with geographical distances, as expected under a linear stepping-stone model of dispersal. Low levels of DNA sequence diversity occurred at all four loci, allowing us to exclude the hypothesis that an idiosyncratic selective sweep eliminated mitochondrial diversity alone. Total gene diversity declined with tectonic spreading rates. The southernmost populations, which are subjected to superfast spreading rates and high probabilities of extinction, are relatively homogenous genetically. Conclusions: Compared to other vent species, DNA sequence diversity is extremely low in R. pachyptila. Though its dispersal abilities appear to be effective, the low diversity, particularly in southern hemisphere populations, is consistent with frequent local extinction and (re)colonization events. ?? 2011 Coykendall et al; licensee BioMed Central Ltd.

Integrative marker analysis allows risk assessment for metastasis in stage II colon cancer.

PubMed

Nitsche, Ulrich; Rosenberg, Robert; Balmert, Alexander; Schuster, Tibor; Slotta-Huspenina, Julia; Herrmann, Pia; Bader, Franz G; Friess, Helmut; Schlag, Peter M; Stein, Ulrike; Janssen, Klaus-Peter

2012-11-01

Individualized risk assessment in patients with UICC stage II colon cancer based on a panel of molecular genetic alterations. Risk assessment in patients with colon cancer and localized disease (UICC stage II) is not sufficiently reliable. Development of metachronous metastasis is assumed to be governed largely by individual tumor genetics. Fresh frozen tissue from 232 patients (T3-4, N0, M0) with complete tumor resection and a median follow-up of 97 months was analyzed for microsatellite stability, KRAS exon 2, and BRAF exon 15 mutations. Gene expression of the WNT-pathway surrogate marker osteopontin and the metastasis-associated genes SASH1 and MACC1 was determined for 179 patients. The results were correlated with metachronous distant metastasis risk (n = 22 patients). Mutations of KRAS were detected in 30% patients, mutations of BRAF in 15% patients, and microsatellite instability in 26% patients. Risk of recurrence was associated with KRAS mutation (P = 0.033), microsatellite stable tumors (P = 0.015), decreased expression of SASH1 (P = 0.049), and increased expression of MACC1 (P < 0.001). MACC1 was the only independent parameter for recurrence prediction (hazard ratio: 6.2; 95% confidence interval: 2.4-16; P < 0.001). Integrative 2-step cluster analysis allocated patients into 4 groups, according to their tumor genetics. KRAS mutation, BRAF wild type, microsatellite stability, and high MACC1 expression defined the group with the highest risk of recurrence (16%, 7 of 43), whereas BRAF wild type, microsatellite instability, and low MACC1 expression defined the group with the lowest risk (4%, 1 of 26). MACC1 expression predicts development of metastases, outperforming microsatellite stability status, as well as KRAS/BRAF mutation status.

Chromosomal instability and telomere shortening in long-term culture of hematopoietic stem cells: insights from a cell culture model of RPS14 haploinsufficiency.

PubMed

Thomay, K; Schienke, A; Vajen, B; Modlich, U; Schambach, A; Hofmann, W; Schlegelberger, B; Göhring, G

2014-01-01

The fate of cultivated primary hematopoietic stem cells (HSCs) with respect to genetic instability and telomere attrition has not yet been described in great detail. Thus, knowledge of the genetic constitution of HSCs is important when interpreting results of HSCs in culture. While establishing a cell culture model for myelodysplastic syndrome with a deletion in 5q by performing RPS14 knockdown, we found surprising data that may be of importance for any CD34+ cell culture experiments. We performed cytogenetic analyses and telomere length measurement on transduced CD34+ cells and untransduced control cells to observe the effects of long-term culturing. Initially, CD34+ cells had a normal median telomere length of about 12 kb and showed no signs of chromosomal instability. During follow-up, the median telomere length seemed to decrease and, simultaneously, increased chromosomal instability could be observed - in modified and control cells. One culture showed a clonal monosomy 7 - independent of prior RPS14 knockdown. During further culturing, it seemed that the telomeres re-elongated, and chromosomes stabilized, while TERT expression was not elevated. In summary, irrespective of our results of RPS14 knockdown in the long-term culture of CD34+ cells, it becomes clear that cell culture artefacts inducing telomere shortening and chromosomal instability have to be taken into account and regular cytogenetic analyses should always be performed. © 2013 S. Karger AG, Basel.

Extremely stringent activation of p16INK4a prevents immortalization of uterine cervical epithelial cells without human papillomavirus oncogene expression

PubMed Central

Hang, Su; Tiwari, Agnes F.Y.; Ngan, Hextan Y.S.; Yip, Yim-Ling; Cheung, Annie L.M.; Tsao, Sai Wah; Deng, Wen

2016-01-01

Cervical epithelial cell immortalization with defined genetic factors without viral oncogenes has never been reported. Here we report that HPV-negative cervical epithelial cells failed to be immortalized by telomerase activation or the combination of p53 knockdown and telomerase activation. Under those conditions, p16INK4a expression was always elevated during the late stage of limited cell lifespan, suggesting that cervical epithelial cells possess an intrinsic property of uniquely stringent activation of p16INK4a, which may offer an explanation for the rarity of HPV-negative cervical cancer. Combining p16INK4a knockdown with telomerase activation resulted in efficient immortalization of HPV-negative cervical epithelial cells under ordinary culture conditions. Compared with the HPV16-E6E7-immortalized cell lines derived from the same primary cell sources, the novel HPV-negative immortalized cell lines had lower degrees of chromosomal instability, maintained more sensitive p53/p21 response to DNA damage, exhibited more stringent G2 checkpoint function, and were more resistant to replication-stress-induced genomic instability. The newly immortalized HPV-negative cervical epithelial cell lines were non-tumorigenic in nude mice. The cell lines can be used not only as much-needed HPV-negative non-malignant cell models but also as starting models that can be genetically manipulated in a stepwise fashion to investigate the roles of defined genetic alterations in the development of HPV-negative cervical cancer. PMID:27344169

Genetic alterations in hepatocellular carcinoma: An update

PubMed Central

Niu, Zhao-Shan; Niu, Xiao-Jun; Wang, Wen-Hong

2016-01-01

Hepatocellular carcinoma (HCC) is one of the leading causes of cancer-related deaths worldwide. Although recent advances in therapeutic approaches for treating HCC have improved the prognoses of patients with HCC, this cancer is still associated with a poor survival rate mainly due to late diagnosis. Therefore, a diagnosis must be made sufficiently early to perform curative and effective treatments. There is a need for a deeper understanding of the molecular mechanisms underlying the initiation and progression of HCC because these mechanisms are critical for making early diagnoses and developing novel therapeutic strategies. Over the past decade, much progress has been made in elucidating the molecular mechanisms underlying hepatocarcinogenesis. In particular, recent advances in next-generation sequencing technologies have revealed numerous genetic alterations, including recurrently mutated genes and dysregulated signaling pathways in HCC. A better understanding of the genetic alterations in HCC could contribute to identifying potential driver mutations and discovering novel therapeutic targets in the future. In this article, we summarize the current advances in research on the genetic alterations, including genomic instability, single-nucleotide polymorphisms, somatic mutations and deregulated signaling pathways, implicated in the initiation and progression of HCC. We also attempt to elucidate some of the genetic mechanisms that contribute to making early diagnoses of and developing molecularly targeted therapies for HCC. PMID:27895396

Transcriptome-Derived Tetranucleotide Microsatellites and Their Associated Genes from the Giant Panda (Ailuropoda melanoleuca).

PubMed

Song, Xuhao; Shen, Fujun; Huang, Jie; Huang, Yan; Du, Lianming; Wang, Chengdong; Fan, Zhenxin; Hou, Rong; Yue, Bisong; Zhang, Xiuyue

2016-09-01

Recently, an increasing number of microsatellites or simple sequence repeats (SSRs) have been found and characterized from transcriptomes. Such SSRs can be employed as putative functional markers to easily tag corresponding genes, which play an important role in biomedical studies and genetic analysis. However, the transcriptome-derived SSRs for giant panda (Ailuropoda melanoleuca) are not yet available. In this work, we identified and characterized 20 tetranucleotide microsatellite loci from a transcript database generated from the blood of giant panda. Furthermore, we assigned their predicted transcriptome locations: 16 loci were assigned to untranslated regions (UTRs) and 4 loci were assigned to coding regions (CDSs). Gene identities of 14 transcripts contained corresponding microsatellites were determined, which provide useful information to study the potential contribution of SSRs to gene regulation in giant panda. The polymorphic information content (PIC) values ranged from 0.293 to 0.789 with an average of 0.603 for the 16 UTRs-derived SSRs. Interestingly, 4 CDS-derived microsatellites developed in our study were also polymorphic, and the instability of these 4 CDS-derived SSRs was further validated by re-genotyping and sequencing. The genes containing these 4 CDS-derived SSRs were embedded with various types of repeat motifs. The interaction of all the length-changing SSRs might provide a way against coding region frameshift caused by microsatellite instability. We hope these newly gene-associated biomarkers will pave the way for genetic and biomedical studies for giant panda in the future. In sum, this set of transcriptome-derived markers complements the genetic resources available for giant panda. © The American Genetic Association. 2016. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.

Universal Point of Care Testing for Lynch Syndrome in Patients with Upper Tract Urothelial Carcinoma.

PubMed

Metcalfe, Michael J; Petros, Firas G; Rao, Priya; Mork, Maureen E; Xiao, Lianchun; Broaddus, Russell R; Matin, Surena F

2018-01-01

Patients with Lynch syndrome are at risk for upper tract urothelial carcinoma. We sought to identify the incidence and most reliable means of point of care screening for Lynch syndrome in patients with upper tract urothelial carcinoma. A total of 115 consecutive patients with upper tract urothelial carcinoma without a history of Lynch syndrome were universally screened during followup from January 2013 through July 2016. We evaluated patient and family history using AMS (Amsterdam criteria) I and II, and tumor immunohistochemistry for mismatch repair proteins and microsatellite instability. Patients who were positive for AMS I/II, microsatellite instability or immunohistochemistry were classified as potentially having Lynch syndrome and referred for clinical genetic analysis and counseling. Patients with known Lynch syndrome served as positive controls. Of the 115 patients 16 (13.9%) screened positive for potential Lynch syndrome. Of these patients 7.0% met AMS II criteria, 11.3% had loss of at least 1 mismatch repair protein and 6.0% had high microsatellite instability. All 16 patients were referred for germline testing, 9 completed genetic analysis and counseling, and 6 were confirmed to have Lynch syndrome. All 7 patients with upper tract urothelial carcinoma who had a known history of Lynch syndrome were positive for AMS II criteria and at least a single mismatch repair protein loss while 5 of 6 had high microsatellite instability. We identified 13.9% of upper tract urothelial carcinoma cases as potential Lynch syndrome and 5.2% as confirmed Lynch syndrome at the point of care. These findings have important implications for universal screening of upper tract urothelial carcinoma, representing one of the highest rates of undiagnosed genetic disease in a urological cancer. Copyright © 2018 American Urological Association Education and Research, Inc. Published by Elsevier Inc. All rights reserved.

MSH3 polymorphisms and protein levels affect CAG repeat instability in Huntington's disease mice.

PubMed

Tomé, Stéphanie; Manley, Kevin; Simard, Jodie P; Clark, Greg W; Slean, Meghan M; Swami, Meera; Shelbourne, Peggy F; Tillier, Elisabeth R M; Monckton, Darren G; Messer, Anne; Pearson, Christopher E

2013-01-01

Expansions of trinucleotide CAG/CTG repeats in somatic tissues are thought to contribute to ongoing disease progression through an affected individual's life with Huntington's disease or myotonic dystrophy. Broad ranges of repeat instability arise between individuals with expanded repeats, suggesting the existence of modifiers of repeat instability. Mice with expanded CAG/CTG repeats show variable levels of instability depending upon mouse strain. However, to date the genetic modifiers underlying these differences have not been identified. We show that in liver and striatum the R6/1 Huntington's disease (HD) (CAG)∼100 transgene, when present in a congenic C57BL/6J (B6) background, incurred expansion-biased repeat mutations, whereas the repeat was stable in a congenic BALB/cByJ (CBy) background. Reciprocal congenic mice revealed the Msh3 gene as the determinant for the differences in repeat instability. Expansion bias was observed in congenic mice homozygous for the B6 Msh3 gene on a CBy background, while the CAG tract was stabilized in congenics homozygous for the CBy Msh3 gene on a B6 background. The CAG stabilization was as dramatic as genetic deficiency of Msh2. The B6 and CBy Msh3 genes had identical promoters but differed in coding regions and showed strikingly different protein levels. B6 MSH3 variant protein is highly expressed and associated with CAG expansions, while the CBy MSH3 variant protein is expressed at barely detectable levels, associating with CAG stability. The DHFR protein, which is divergently transcribed from a promoter shared by the Msh3 gene, did not show varied levels between mouse strains. Thus, naturally occurring MSH3 protein polymorphisms are modifiers of CAG repeat instability, likely through variable MSH3 protein stability. Since evidence supports that somatic CAG instability is a modifier and predictor of disease, our data are consistent with the hypothesis that variable levels of CAG instability associated with polymorphisms of DNA repair genes may have prognostic implications for various repeat-associated diseases.

MSH3 Polymorphisms and Protein Levels Affect CAG Repeat Instability in Huntington's Disease Mice

PubMed Central

Simard, Jodie P.; Clark, Greg W.; Slean, Meghan M.; Swami, Meera; Shelbourne, Peggy F.; Tillier, Elisabeth R. M.; Monckton, Darren G.; Messer, Anne; Pearson, Christopher E.

2013-01-01

Expansions of trinucleotide CAG/CTG repeats in somatic tissues are thought to contribute to ongoing disease progression through an affected individual's life with Huntington's disease or myotonic dystrophy. Broad ranges of repeat instability arise between individuals with expanded repeats, suggesting the existence of modifiers of repeat instability. Mice with expanded CAG/CTG repeats show variable levels of instability depending upon mouse strain. However, to date the genetic modifiers underlying these differences have not been identified. We show that in liver and striatum the R6/1 Huntington's disease (HD) (CAG)∼100 transgene, when present in a congenic C57BL/6J (B6) background, incurred expansion-biased repeat mutations, whereas the repeat was stable in a congenic BALB/cByJ (CBy) background. Reciprocal congenic mice revealed the Msh3 gene as the determinant for the differences in repeat instability. Expansion bias was observed in congenic mice homozygous for the B6 Msh3 gene on a CBy background, while the CAG tract was stabilized in congenics homozygous for the CBy Msh3 gene on a B6 background. The CAG stabilization was as dramatic as genetic deficiency of Msh2. The B6 and CBy Msh3 genes had identical promoters but differed in coding regions and showed strikingly different protein levels. B6 MSH3 variant protein is highly expressed and associated with CAG expansions, while the CBy MSH3 variant protein is expressed at barely detectable levels, associating with CAG stability. The DHFR protein, which is divergently transcribed from a promoter shared by the Msh3 gene, did not show varied levels between mouse strains. Thus, naturally occurring MSH3 protein polymorphisms are modifiers of CAG repeat instability, likely through variable MSH3 protein stability. Since evidence supports that somatic CAG instability is a modifier and predictor of disease, our data are consistent with the hypothesis that variable levels of CAG instability associated with polymorphisms of DNA repair genes may have prognostic implications for various repeat-associated diseases. PMID:23468640

Longitudinal Genetic Analysis of Early Reading: The Western Reserve Reading Project

ERIC Educational Resources Information Center

Petrill, Stephen A.; Deater-Deckard, Kirby; Thompson, Lee Anne; Schatschneider, Chris; DeThorne, Laura S.; Vandenbergh, David J.

2007-01-01

We examined the genetic and environmental contribution to the stability and instability of reading outcomes in early elementary school using a sample of 283 twin pairs drawn from the Western Reserve Reading Project. Twins were assessed across two measurement occasions. In Wave 1, children were either in kindergarten or first grade. Wave 2…

WD-repeat instability and diversification of the Podospora anserina hnwd non-self recognition gene family.

PubMed

Chevanne, Damien; Saupe, Sven J; Clavé, Corinne; Paoletti, Mathieu

2010-05-06

Genes involved in non-self recognition and host defence are typically capable of rapid diversification and exploit specialized genetic mechanism to that end. Fungi display a non-self recognition phenomenon termed heterokaryon incompatibility that operates when cells of unlike genotype fuse and leads to the cell death of the fusion cell. In the fungus Podospora anserina, three genes controlling this allorecognition process het-d, het-e and het-r are paralogs belonging to the same hnwd gene family. HNWD proteins are STAND proteins (signal transduction NTPase with multiple domains) that display a WD-repeat domain controlling recognition specificity. Based on genomic sequence analysis of different P. anserina isolates, it was established that repeat regions of all members of the gene family are extremely polymorphic and undergoing concerted evolution arguing for frequent recombination within and between family members. Herein, we directly analyzed the genetic instability and diversification of this allorecognition gene family. We have constituted a collection of 143 spontaneous mutants of the het-R (HNWD2) and het-E (hnwd5) genes with altered recognition specificities. The vast majority of the mutants present rearrangements in the repeat arrays with deletions, duplications and other modifications as well as creation of novel repeat unit variants. We investigate the extreme genetic instability of these genes and provide a direct illustration of the diversification strategy of this eukaryotic allorecognition gene family.

Bet-hedging as a complex interaction among developmental instability, environmental heterogeneity, dispersal, and life-history strategy.

PubMed

Scheiner, Samuel M

2014-02-01

One potential evolutionary response to environmental heterogeneity is the production of randomly variable offspring through developmental instability, a type of bet-hedging. I used an individual-based, genetically explicit model to examine the evolution of developmental instability. The model considered both temporal and spatial heterogeneity alone and in combination, the effect of migration pattern (stepping stone vs. island), and life-history strategy. I confirmed that temporal heterogeneity alone requires a threshold amount of variation to select for a substantial amount of developmental instability. For spatial heterogeneity only, the response to selection on developmental instability depended on the life-history strategy and the form and pattern of dispersal with the greatest response for island migration when selection occurred before dispersal. Both spatial and temporal variation alone select for similar amounts of instability, but in combination resulted in substantially more instability than either alone. Local adaptation traded off against bet-hedging, but not in a simple linear fashion. I found higher-order interactions between life-history patterns, dispersal rates, dispersal patterns, and environmental heterogeneity that are not explainable by simple intuition. We need additional modeling efforts to understand these interactions and empirical tests that explicitly account for all of these factors.

Current Progresses of Single Cell DNA Sequencing in Breast Cancer Research.

PubMed

Liu, Jianlin; Adhav, Ragini; Xu, Xiaoling

2017-01-01

Breast cancers display striking genetic and phenotypic diversities. To date, several hypotheses are raised to explain and understand the heterogeneity, including theories for cancer stem cell (CSC) and clonal evolution. According to the CSC theory, the most tumorigenic cells, while maintaining themselves through symmetric division, divide asymmetrically to generate non-CSCs with less tumorigenic and metastatic potential, although they can also dedifferentiate back to CSCs. Clonal evolution theory recapitulates that a tumor initially arises from a single cell, which then undergoes clonal expansion to a population of cancer cells. During tumorigenesis and evolution process, cancer cells undergo different degrees of genetic instability and consequently obtain varied genetic aberrations. Yet the heterogeneity in breast cancers is very complex, poorly understood and subjected to further investigation. In recent years, single cell sequencing (SCS) technology developed rapidly, providing a powerful new way to better understand the heterogeneity, which may lay foundations to some new strategies for breast cancer therapies. In this review, we will summarize development of SCS technologies and recent advances of SCS in breast cancer.

Chromosomal Instability Affects the Tumorigenicity of Glioblastoma Tumor-Initiating Cells.

PubMed

Godek, Kristina M; Venere, Monica; Wu, Quilian; Mills, Kevin D; Hickey, William F; Rich, Jeremy N; Compton, Duane A

2016-05-01

Tumors are dynamic organs that evolve during disease progression with genetic, epigenetic, and environmental differences among tumor cells serving as the foundation for selection and evolution in tumors. Tumor-initiating cells (TIC) that are responsible for tumorigenesis are a source of functional cellular heterogeneity, whereas chromosomal instability (CIN) is a source of karyotypic genetic diversity. However, the extent that CIN contributes to TIC genetic diversity and its relationship to TIC function remains unclear. Here, we demonstrate that glioblastoma TICs display CIN with lagging chromosomes at anaphase and extensive nonclonal chromosome copy-number variations. Elevating the basal chromosome missegregation rate in TICs decreases both proliferation and the stem-like phenotype of TICs in vitro Consequently, tumor formation is abolished in an orthotopic mouse model. These results demonstrate that TICs generate genetic heterogeneity within tumors, but that TIC function is impaired if the rate of genetic change is elevated above a tolerable threshold. Genetic heterogeneity among TICs may produce advantageous karyotypes that lead to therapy resistance and relapse; however, we found that TICs have an upper tolerable limit for CIN. Thus, increasing the chromosome missegregation rate offers a new therapeutic strategy to eliminate TICs from tumors. Cancer Discov; 6(5); 532-45. ©2016 AACR.This article is highlighted in the In This Issue feature, p. 461. ©2016 American Association for Cancer Research.

Loss of heterozygosity and microsatellite instability in chromosomal segments commonly deleted in squamous cell carcinoma

DOE Office of Scientific and Technical Information (OSTI.GOV)

Van Dyke, D.L.; Worsham, M.J.; Zarbo, R.J.

1994-09-01

To evaluate genetic loss in an unselected series of squamous cell carcinoma (SCC) of the head and neck region (SCCHN), including early stage tumors that do not proliferate aggressively in vitro, we have compared microsatellite repeat polymorphisms (MSRP) in normal blood DNA and tumor DNA from 44 patients with SCCHN, using nine MSRPs from 5q15-q21, proximal 8p, 9p21-p23, 18q21-qter, and 21q21. In previous cytogenetic studies, these chromosome segments were deleted in 40-60% of SCCHN and SCC of the female genital tract. Loss of heterozygosity (LOH) was observed from the ANK1 locus (8p21.1-p11.2) in 2/29 informative tumors. LOH was observed atmore » D5S98 (5q15-5q21) in 5/19, and at D21S11 (21q21) in 5/33 informative tumors. These LOH frequencies were lower than expected, which suggests that the critical region of deletion from these chromosome regions exludes the MSRPs studied here, especially for the 8p MSRP, which may reside in proximal 8p. Alternatively, the observed LOH rates may be appropriate for earlier pathologic stage tumors: total genetic loss increases with tumor stage, and the present study included more stage I and II tumors than did the cytogenetic studies. LOH was observed at D9S126, 1FN, and/or D9S199 (at 9p21, 9p22, & 9p23) in 16/38 informative tumors, and at D18S34 and/or MBP (at 18q21 & 18q22-qter) in 17/39 informative tumors. In addition, three tumors demonstrated microsatellite instability at the MBP locus, and one of these had an expansion at D9S199 as well. This tumor, HFH-SCC-20, also demonstrated microsatellite instability at many other MSRP loci. These results confirm that genetic loss from 9p and 18q is frequent in SCCHN, and demonstrate that microsatellite instability also occurs. Of 66 MSRP changes, 62 were LOH and 4 were microsatellite instabilities. These results also show the usefulness of analyses of MSRP LOH and microsatellite instability in squamous cell carcinoma.« less

The Role of Chromosomal Instability in Cancer and Therapeutic Responses

PubMed Central

Vargas-Rondón, Natalia

2017-01-01

Cancer is one of the leading causes of death, and despite increased research in recent years, control of advanced-stage disease and optimal therapeutic responses remain elusive. Recent technological improvements have increased our understanding of human cancer as a heterogeneous disease. For instance, four hallmarks of cancer have recently been included, which in addition to being involved in cancer development, could be involved in therapeutic responses and resistance. One of these hallmarks is chromosome instability (CIN), a source of genetic variation in either altered chromosome number or structure. CIN has become a hot topic in recent years, not only for its implications in cancer diagnostics and prognostics, but also for its role in therapeutic responses. Chromosomal alterations are mainly used to determine genetic heterogeneity in tumors, but CIN could also reveal treatment efficacy, as many therapies are based on increasing CIN, which causes aberrant cells to undergo apoptosis. However, it should be noted that contradictory findings on the implications of CIN for the therapeutic response have been reported, with some studies associating high CIN with a better therapeutic response and others associating it with therapeutic resistance. Considering these observations, it is necessary to increase our understanding of the role CIN plays not only in tumor development, but also in therapeutic responses. This review focuses on recent studies that suggest possible mechanisms and consequences of CIN in different disease types, with a primary focus on cancer outcomes and therapeutic responses. PMID:29283387

Mechanisms and consequences of aneuploidy and chromosome instability in the aging brain

PubMed Central

Andriani, Grasiella A.; Vijg, Jan; Montagna, Cristina

2017-01-01

Aneuploidy and polyploidy are a form of Genomic Instability (GIN) known as Chromosomal Instability (CIN) characterized by sporadic abnormalities in chromosome copy numbers. Aneuploidy is commonly linked to pathological states. It is a hallmark of spontaneous abortions and birth defects and it is observed virtually in every human tumor, therefore being generally regarded as detrimental for the development or the maturation of tissues under physiological conditions. Polyploidy however, occurs as part of normal physiological processes during maturation and differentiation of some mammalian cell types. Surprisingly, high levels of aneuploidy are present in the brain, and their frequency increases with age suggesting that the brain is able to maintain its functionality in the presence of high levels of mosaic aneuploidy. Because somatic aneuploidy with age can reach exceptionally high levels, it is likely to have long-term adverse effects in this organ. We describe the mechanisms accountable for an abnormal DNA content with a particular emphasis on the CNS where cell division is limited. Next, we briefly summarize the types of GIN known to date and discuss how they interconnect with CIN. Lastly we highlight how several forms of CIN may contribute to genetic variation, tissue degeneration and disease in the CNS. PMID:27013377

A Sleeping Beauty forward genetic screen identifies new genes and pathways driving osteosarcoma development and metastasis

PubMed Central

Moriarity, Branden S; Otto, George M; Rahrmann, Eric P; Rathe, Susan K; Wolf, Natalie K; Weg, Madison T; Manlove, Luke A; LaRue, Rebecca S; Temiz, Nuri A; Molyneux, Sam D; Choi, Kwangmin; Holly, Kevin J; Sarver, Aaron L; Scott, Milcah C; Forster, Colleen L; Modiano, Jaime F; Khanna, Chand; Hewitt, Stephen M; Khokha, Rama; Yang, Yi; Gorlick, Richard; Dyer, Michael A; Largaespada, David A

2016-01-01

Osteosarcomas are sarcomas of the bone, derived from osteoblasts or their precursors, with a high propensity to metastasize. Osteosarcoma is associated with massive genomic instability, making it problematic to identify driver genes using human tumors or prototypical mouse models, many of which involve loss of Trp53 function. To identify the genes driving osteosarcoma development and metastasis, we performed a Sleeping Beauty (SB) transposon-based forward genetic screen in mice with and without somatic loss of Trp53. Common insertion site (CIS) analysis of 119 primary tumors and 134 metastatic nodules identified 232 sites associated with osteosarcoma development and 43 sites associated with metastasis, respectively. Analysis of CIS-associated genes identified numerous known and new osteosarcoma-associated genes enriched in the ErbB, PI3K-AKT-mTOR and MAPK signaling pathways. Lastly, we identified several oncogenes involved in axon guidance, including Sema4d and Sema6d, which we functionally validated as oncogenes in human osteosarcoma. PMID:25961939

A Genome-Wide Survey of Genetic Instability by Transposition in Drosophila Hybrids

PubMed Central

Vela, Doris; Fontdevila, Antonio; Vieira, Cristina; García Guerreiro, María Pilar

2014-01-01

Hybridization between species is a genomic instability factor involved in increasing mutation rate and new chromosomal rearrangements. Evidence of a relationship between interspecific hybridization and transposable element mobilization has been reported in different organisms, but most studies are usually performed with particular TEs and do not discuss the real effect of hybridization on the whole genome. We have therefore studied whole genome instability of Drosophila interspecific hybrids, looking for the presence of new AFLP markers in hybrids. A high percentage (27–90%) of the instability markers detected corresponds to TEs belonging to classes I and II. Moreover, three transposable elements (Osvaldo, Helena and Galileo) representative of different families, showed an overall increase of transposition rate in hybrids compared to parental species. This research confirms the hypothesis that hybridization induces genomic instability by transposition bursts and suggests that genomic stress by transposition could contribute to a relaxation of mechanisms controlling TEs in the Drosophila genome. PMID:24586475

Dana-Farber Cancer Institute | Office of Cancer Genomics

Cancer.gov

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.

A Genetically Informed Study of the Processes Underlying the Association between Parental Marital Instability and Offspring Adjustment

ERIC Educational Resources Information Center

D'Onofrio, Brian M.; Turkheimer, Eric; Emery, Robert E.; Slutske, Wendy S.; Heath, Andrew C.; Madden, Pamela A.; Martin, Nicholas G.

2006-01-01

Parental divorce is associated with problematic offspring adjustment, but the relation may be due to shared genetic or environmental factors. One way to test for these confounds is to study offspring of twins discordant for divorce. The current analyses used this design to separate the mechanisms responsible for the association between parental…

ATRX Loss Promotes Tumor Growth and Impairs Non-Homologous End Joining DNA Repair in Glioma

PubMed Central

Koschmann, Carl; Calinescu, Anda-Alexandra; Nunez, Felipe J.; Mackay, Alan; Fazal-Salom, Janet; Thomas, Daniel; Mendez, Flor; Kamran, Neha; Dzaman, Marta; Mulpuri, Lakshman; Krasinkiewicz, Johnathon; Doherty, Robert; Lemons, Rosemary; Brosnan-Cashman, Jackie A.; Li, Youping; Roh, Soyeon; Zhao, Lili; Appelman, Henry; Ferguson, David; Gorbunova, Vera; Meeker, Alan; Jones, Chris; Lowenstein, Pedro R.; Castro, Maria G.

2017-01-01

Recent work in human glioblastoma (GBM) has documented recurrent mutations in the histone chaperone protein ATRX. We developed an animal model of ATRX-deficient GBM and show that loss of ATRX reduces median survival and increases genetic instability. Further, analysis of genome-wide data for human gliomas showed that ATRX mutation is associated with increased mutation rate at the single nucleotide variant (SNV) level. In mouse tumors, ATRX deficiency impairs non-homologous end joining (NHEJ) and increases sensitivity to DNA-damaging agents that induce double-stranded DNA breaks. We propose that ATRX loss results in a genetically unstable tumor, which is more aggressive when left untreated, but is more responsive to double-stranded DNA-damaging agents, resulting in improved overall survival. PMID:26936505

The various aspects of genetic and epigenetic toxicology: testing methods and clinical applications.

PubMed

Ren, Ning; Atyah, Manar; Chen, Wan-Yong; Zhou, Chen-Hao

2017-05-22

Genotoxicity refers to the ability of harmful substances to damage genetic information in cells. Being exposed to chemical and biological agents can result in genomic instabilities and/or epigenetic alterations, which translate into a variety of diseases, cancer included. This concise review discusses, from both a genetic and epigenetic point of view, the current detection methods of different agents' genotoxicity, along with their basic and clinical relation to human cancer, chemotherapy, germ cells and stem cells.

Genetics Home Reference: spondyloepiphyseal dysplasia congenita

MedlinePlus

... feet. Abnormal curvature of the spine ( kyphoscoliosis and lordosis ) becomes more severe during childhood. Instability of the ... Resources (4 links) MedlinePlus Encyclopedia: Clubfoot MedlinePlus Encyclopedia: ... Detachment MedlinePlus Encyclopedia: Scoliosis General ...

A substitution in the transmembrane region of the glycoprotein leads to an unstable attenuation of Machupo virus.

PubMed

Patterson, Michael; Koma, Takaaki; Seregin, Alexey; Huang, Cheng; Miller, Milagros; Smith, Jennifer; Yun, Nadezhda; Smith, Jeanon; Paessler, Slobodan

2014-09-01

Machupo virus (MACV) is the etiologic agent of Bolivian hemorrhagic fever (BHF). Utilizing a reverse-genetics system recently developed, we report the rescue of a rationally modified recombinant MACV containing a single mutation in the transmembrane region of the glycoprotein. Following challenge of susceptible mice, we identified a significant reduction in virulence in the novel virus. We also identified an instability leading to reversion of the single mutation to a wild-type genotype. Copyright © 2014, American Society for Microbiology. All Rights Reserved.

Factors associated with ATXN2 CAG/CAA repeat intergenerational instability in Spinocerebellar Ataxia type 2.

PubMed

Almaguer-Mederos, L E; Mesa, J M L; González-Zaldívar, Y; Almaguer-Gotay, D; Cuello-Almarales, D; Aguilera-Rodríguez, R; Falcón, N S; Gispert, S; Auburger, G; Velázquez-Pérez, L

2018-05-14

Spinocerebellar ataxia type 2 (SCA2) is a neurodegenerative disorder caused by the unstable expansion of a CAG/CAA repeat in the ATXN2 gene, which normally encodes 22 glutamines (Q22). A large study was conducted to characterize the CAG/CAA repeat intergenerational instability in SCA2 families. Large normal alleles (LNA, Q24-31) were significantly more unstable upon maternal transmissions. In contrast, expanded alleles (EA, Q32-750) were significantly more unstable during paternal transmissions, in correlation with repeat length. Significant correlations were found between the instability and the age at conception in paternal transmissions. In conclusion, intergenerational instability at ATXN2 locus is influenced by the sex, repeat length and age at conception of the transmitting parent. These results have profound implications for genetic counseling services. This article is protected by copyright. All rights reserved. This article is protected by copyright. All rights reserved.

Radiation-induced chromosomal instability in human mammary epithelial cells

NASA Technical Reports Server (NTRS)

Durante, M.; Grossi, G. F.; Yang, T. C.

1996-01-01

Karyotypes of human cells surviving X- and alpha-irradiation have been studied. Human mammary epithelial cells of the immortal, non-tumorigenic cell line H184B5 F5-1 M/10 were irradiated and surviving clones isolated and expanded in culture. Cytogenetic analysis was performed using dedicated software with an image analyzer. We have found that both high- and low-LET radiation induced chromosomal instability in long-term cultures, but with different characteristics. Complex chromosomal rearrangements were observed after X-rays, while chromosome loss predominated after alpha-particles. Deletions were observed in both cases. In clones derived from cells exposed to alpha-particles, some cells showed extensive chromosome breaking and double minutes. Genomic instability was correlated to delayed reproductive death and neoplastic transformation. These results indicate that chromosomal instability is a radiation-quality-dependent effect which could determine late genetic effects, and should therefore be carefully considered in the evaluation of risk for space missions.

Radiation-induced chromosomal instability in human mammary epithelial cells

NASA Astrophysics Data System (ADS)

Durante, M.; Grossi, G. F.; Yang, T. C.

Karyotypes of human cells surviving X- and alpha-irradiation have been studied. Human mammary epithelial cells of the immortal, non-tumorigenic cell line H184B5 F5-1 M/10 were irradiated and surviving clones isolated and expanded in culture. Cytogenetic analysis was performed using dedicated software with an image analyzer. We have found that both high- and low-LET radiation induced chromosomal instability in long-term cultures, but with different characteristics. Complex chromosomal rearrangements were observed after X-rays, while chromosome loss predominated after alpha-particles. Deletions were observed in both cases. In clones derived from cells exposed to alpha-particles, some cells showed extensive chromosome breaking and double minutes. Genomic instability was correlated to delayed reproductive death and neoplastic transformation. These results indicate that chromosomal instability is a radiation-quality-dependent effect which could determine late genetic effects, and should therefore be carefully considered in the evaluation of risk for space missions.

Genetic and Epigenetic Changes in Chromosomally Stable and Unstable Progeny of Irradiated Cells

DOE Office of Scientific and Technical Information (OSTI.GOV)

Baulch, Janet E.; Aypar, Umut; Waters, Katrina M.

2014-09-24

Radiation induced genomic instability is a well-studied phenomenon, the underlying mechanisms of which are poorly understood. Persistent oxidative stress, mitochondrial dysfunction, elevated cytokine levels and epigenetic changes are among the mechanisms invoked in the perpetuation of the phenotype. To determine whether epigenetic aberrations affect genomic instability we measured DNA methylation, mRNA and microRNA (miR) levels in well characterized chromosomally stable and unstable clonally expanded single cell survivors of irradiation. While no changes in DNA methylation were observed for the gene promoters evaluated, increased LINE-1 methylation was observed for two unstable clones (LS12, CS9) and decreased Alu element methylation was observedmore » for the other two unstable clones (115, Fe5.0-8). These relationships also manifested for mRNA and miR expression. mRNA identified for the LS12 and CS9 clones were most similar to each other (261 mRNA), while the 115 and Fe5.0-8 clones were more similar to each other, and surprisingly also similar to the two stable clones, 114 and 118 (286 mRNA among these four clones). Pathway analysis showed enrichment for pathways involved in mitochondrial function and cellular redox, themes routinely invoked in genomic instability. The commonalities between the two subgroups of clones were also observed for miR. The number of miR for which anti-correlated mRNA were identified suggests that these miR exert functional effects in each clone. The results of this study demonstrate significant genetic and epigenetic changes in unstable cells, but similar changes almost equally common in chromosomally stable cells. Possible conclusions might be that the chromosomally stable clones have some other form of instability, or that some of the observed changes represent a sort of radiation signature for and that other changes are related to genomic instability. Irrespective, these findings again suggest that a spectrum of changes both drive genomic instability and permit unstable cells to persist and proliferate.« less

Genetics Home Reference: multiple system atrophy

MedlinePlus

... inability to hold the body upright and balanced (postural instability). The other type of multiple system atrophy , ... cells in parts of the nervous system that control movement, balance and coordination, and autonomic functioning. The ...

Role of microsatellite instability-low as a diagnostic biomarker of Lynch syndrome in colorectal cancer

PubMed Central

Vilar, Eduardo; Mork, Maureen E.; Cuddy, Amanda; Borras, Ester; Bannon, Sarah A.; Taggart, Melissa W.; Ying, Jun; Broaddus, Russell R.; Luthra, Rajyalakshmi; Rodriguez-Bigas, Miguel A.; Lynch, Patrick M.; You, Y. Nancy

2014-01-01

Lynch syndrome is the most common Mendelian disorder predisposing to hereditary colorectal cancer. Carriers of MSH6 mutations constitute less than 10% of total cases and present with a weaker clinical phenotype, including low levels of microsatellite instability (MSI-L) in colorectal tumors. The frequency of MSH6 mutation carriers among patients presenting with MSI-L colorectal cancer has yet to be determined, as has the appropriate genetic work-up in this context. We have reviewed here the clinicopathological characteristics, immunohistochemistry and genetic testing results for 71 patients at a single institution diagnosed with MSI-L colorectal cancers. Of 71 patients with MSI-L tumors, 21 underwent genetic testing for MSH6 mutations, three of them presented with loss of staining of MSH6 and only one carried a pathogenic germline MSH6 mutation in exon 4 (c.2677_2678delCT; p.Leu893Alafs*6). This latter patient had a significant family history and had a rectal primary that showed instability only in mononucleotide markers. In this cohort of MSI-L patients, we detected no notable clinicopathological and molecular characteristics that would help to distinguish a group most likely to harbor germline MSH6 mutations. Therefore, we conclude that the prevalence of MSH6 mutations among subjects with MSI-L tumors is very low. MSI analysis combined with immunohistochemistry of mismatch repair proteins adequately detects potential MSH6 carriers among MSI-L colorectal cancers. PMID:25432668

Turtle Carapace Anomalies: The Roles of Genetic Diversity and Environment

PubMed Central

Velo-Antón, Guillermo; Becker, C. Guilherme; Cordero-Rivera, Adolfo

2011-01-01

Background Phenotypic anomalies are common in wild populations and multiple genetic, biotic and abiotic factors might contribute to their formation. Turtles are excellent models for the study of developmental instability because anomalies are easily detected in the form of malformations, additions, or reductions in the number of scutes or scales. Methodology/Principal Findings In this study, we integrated field observations, manipulative experiments, and climatic and genetic approaches to investigate the origin of carapace scute anomalies across Iberian populations of the European pond turtle, Emys orbicularis. The proportion of anomalous individuals varied from 3% to 69% in local populations, with increasing frequency of anomalies in northern regions. We found no significant effect of climatic and soil moisture, or climatic temperature on the occurrence of anomalies. However, lower genetic diversity and inbreeding were good predictors of the prevalence of scute anomalies among populations. Both decreasing genetic diversity and increasing proportion of anomalous individuals in northern parts of the Iberian distribution may be linked to recolonization events from the Southern Pleistocene refugium. Conclusions/Significance Overall, our results suggest that developmental instability in turtle carapace formation might be caused, at least in part, by genetic factors, although the influence of environmental factors affecting the developmental stability of turtle carapace cannot be ruled out. Further studies of the effects of environmental factors, pollutants and heritability of anomalies would be useful to better understand the complex origin of anomalies in natural populations. PMID:21533278

Induction of Chromosome Instability by Activation of Yes-Associated Protein and Forkhead Box M1 in Liver Cancer.

PubMed

Weiler, Sofia M E; Pinna, Federico; Wolf, Thomas; Lutz, Teresa; Geldiyev, Aman; Sticht, Carsten; Knaub, Maria; Thomann, Stefan; Bissinger, Michaela; Wan, Shan; Rössler, Stephanie; Becker, Diana; Gretz, Norbert; Lang, Hauke; Bergmann, Frank; Ustiyan, Vladimir; Kalin, Tatiana V; Singer, Stephan; Lee, Ju-Seog; Marquardt, Jens U; Schirmacher, Peter; Kalinichenko, Vladimir V; Breuhahn, Kai

2017-06-01

Many different types of cancer cells have chromosome instability. The hippo pathway leads to phosphorylation of the transcriptional activator yes-associated protein 1 (YAP1, YAP), which regulates proliferation and has been associated with the development of liver cancer. We investigated the effects of hippo signaling via YAP on chromosome stability and hepatocarcinogenesis in humans and mice. We analyzed transcriptome data from 242 patients with hepatocellular carcinoma (HCC) to search for gene signatures associated with chromosomal instability (CIN); we investigated associations with overall survival time and cancer recurrence using Kaplan-Meier curves. We analyzed changes in expression of these signature genes, at mRNA and protein levels, after small interfering RNA-mediated silencing of YAP in Sk-Hep1, SNU182, HepG2, or pancreatic cancer cells, as well as incubation with thiostrepton (an inhibitor of forkhead box M1 [FOXM1]) or verteporfin (inhibitor of the interaction between YAP and TEA domain transcription factor 4 [TEAD4]). We performed co-immunoprecipitation and chromatin immunoprecipitation experiments. We collected liver tissues from mice that express a constitutively active form of YAP (YAP S127A ) and analyzed gene expression signatures and histomorphologic parameters associated with chromosomal instability. Mice were given injections of thiostrepton and livers were collected and analyzed by immunoblotting, immunohistochemistry, histology, and real-time polymerase chain reaction. We performed immunohistochemical analyses on tissue microarrays of 105 HCCs and 7 nontumor liver tissues. Gene expression patterns associated with chromosome instability, called CIN25 and CIN70, were detected in HCCs from patients with shorter survival time or early cancer recurrence. TEAD4 and YAP were required for CIN25 and CIN70 signature expression via induction and binding of FOXM1. Disrupting the interaction between YAP and TEAD4 with verteporfin, or inhibiting FOXM1 with thiostrepton, reduced the chromosome instability gene expression patterns. Hyperplastic livers and tumors from YAP S127A mice had increased CIN25 and CIN70 gene expression patterns, aneuploidy, and defects in mitosis. Injection of YAP S127A mice with thiostrepton reduced liver overgrowth and signs of chromosomal instability. In human HCC tissues, high levels of nuclear YAP correlated with increased chromosome instability gene expression patterns and aneuploidy. By analyzing cell lines, genetically modified mice, and HCC tissues, we found that YAP cooperates with FOXM1 to contribute to chromosome instability. Agents that disrupt this pathway might be developed as treatments for liver cancer. Transcriptome data are available in the Gene Expression Omnibus public database (accession numbers: GSE32597 and GSE73396). Copyright © 2017 AGA Institute. Published by Elsevier Inc. All rights reserved.

Inhibition of oxidative metabolism leads to p53 genetic inactivation and transformation in neural stem cells

PubMed Central

Bartesaghi, Stefano; Graziano, Vincenzo; Galavotti, Sara; Henriquez, Nick V.; Betts, Joanne; Saxena, Jayeta; Minieri, Valentina; A, Deli; Karlsson, Anna; Martins, L. Miguel; Capasso, Melania; Nicotera, Pierluigi; Brandner, Sebastian; De Laurenzi, Vincenzo; Salomoni, Paolo

2015-01-01

Alterations of mitochondrial metabolism and genomic instability have been implicated in tumorigenesis in multiple tissues. High-grade glioma (HGG), one of the most lethal human neoplasms, displays genetic modifications of Krebs cycle components as well as electron transport chain (ETC) alterations. Furthermore, the p53 tumor suppressor, which has emerged as a key regulator of mitochondrial respiration at the expense of glycolysis, is genetically inactivated in a large proportion of HGG cases. Therefore, it is becoming evident that genetic modifications can affect cell metabolism in HGG; however, it is currently unclear whether mitochondrial metabolism alterations could vice versa promote genomic instability as a mechanism for neoplastic transformation. Here, we show that, in neural progenitor/stem cells (NPCs), which can act as HGG cell of origin, inhibition of mitochondrial metabolism leads to p53 genetic inactivation. Impairment of respiration via inhibition of complex I or decreased mitochondrial DNA copy number leads to p53 genetic loss and a glycolytic switch. p53 genetic inactivation in ETC-impaired neural stem cells is caused by increased reactive oxygen species and associated oxidative DNA damage. ETC-impaired cells display a marked growth advantage in the presence or absence of oncogenic RAS, and form undifferentiated tumors when transplanted into the mouse brain. Finally, p53 mutations correlated with alterations in ETC subunit composition and activity in primary glioma-initiating neural stem cells. Together, these findings provide previously unidentified insights into the relationship between mitochondria, genomic stability, and tumor suppressive control, with implications for our understanding of brain cancer pathogenesis. PMID:25583481

Colorectal Liver Metastases: Does the Future of Precision Medicine Lie in Genetic Testing?

PubMed

Barbon, Carlotta; Margonis, Georgios Antonios; Andreatos, Nikolaos; Rezaee, Neda; Sasaki, Kazunari; Buettner, Stefan; Damaskos, Christos; Pawlik, Timothy M; He, Jin; Wolfgang, Christopher L; Weiss, Matthew J

2018-04-11

Colorectal liver metastases (CRLM) present an important clinical challenge in both surgical and medical oncology. Despite improvements in management, survival among patients undergoing resection of CRLM is still very variable and there is a paucity of clinical trial data and reliable biomarkers that could guide prognostic forecasts, treatment selection, and follow-up. Fortunately, recent advances in molecular biology and tumor sequencing have identified a number of critical genetic loci and proliferation markers that may hold the key to understanding the biologic behavior of CRLM; specifically, mutations of KRAS, BRAF, TP53, PIK3CA, APC, expression of Ki-67, and the presence of microsatellite instability appear to have a decisive impact on prognosis and response to treatment in patients with CRLM. While the applicability of genetic biomarkers in everyday clinical practice remains conditional on the development of inexpensive bedside sequencing, targeted therapies, and the conduct of appropriate clinical trials, the promise of personalized treatment may be closer to realization than ever before.

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

PubMed

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

2017-10-01

In this review, we summarize and discuss the evidence regarding the interaction between air pollution, especially particulate matter (PM), and genomic instability. PM has been widely studied in the context of several diseases, and its role in lung carcinogenesis gained relevance due to an increase in cancer cases for which smoking does not seem to represent the main risk factor. According to epidemiological and toxicological evidence, PM acts as a carcinogenic factor in humans, inducing high rates of genomic alterations. Here, we discuss not only how PM is capable of inducing genomic instability during the carcinogenic process but also how our genetic background influences the response to the sources of damage. Copyright © 2017 Elsevier Ltd. All rights reserved.

Mixed Pierce-two-stream instability development in an extraction system of a negative ion source

DOE Office of Scientific and Technical Information (OSTI.GOV)

Barminova, H. Y., E-mail: barminova@mephi.ru; Chikhachev, A. S.

2016-02-15

Mixed Pierce-two-stream instability may occur in an extraction system of a negative ion source based on a volume-produced plasma. The reasons for instability development are discussed. Analytically the conditions of unstable beam propagation are determined. The instability threshold is shown to be increased compared with the pure Pierce instability. The influence of inclined perturbations on the instability behavior is investigated. The numerical calculations are performed in COMSOL Multiphysics. The simulation results confirm the existence of such a mixed instability appearance that develops due to both the electrons of the external circuit and the background positive ions.

Replication stress affects the fidelity of nucleosome-mediated epigenetic inheritance

PubMed Central

Li, Wenzhu; Yi, Jia; Agbu, Pamela; Zhou, Zheng; Kelley, Richard L.; Jia, Songtao

2017-01-01

The fidelity of epigenetic inheritance or, the precision by which epigenetic information is passed along, is an essential parameter for measuring the effectiveness of the process. How the precision of the process is achieved or modulated, however, remains largely elusive. We have performed quantitative measurement of epigenetic fidelity, using position effect variegation (PEV) in Schizosaccharomyces pombe as readout, to explore whether replication perturbation affects nucleosome-mediated epigenetic inheritance. We show that replication stresses, due to either hydroxyurea treatment or various forms of genetic lesions of the replication machinery, reduce the inheritance accuracy of CENP-A/Cnp1 nucleosome positioning within centromere. Mechanistically, we demonstrate that excessive formation of single-stranded DNA, a common molecular abnormality under these conditions, might have correlation with the reduction in fidelity of centromeric chromatin duplication. Furthermore, we show that replication stress broadly changes chromatin structure at various loci in the genome, such as telomere heterochromatin expanding and mating type locus heterochromatin spreading out of the boundaries. Interestingly, the levels of inheritable expanding at sub-telomeric heterochromatin regions are highly variable among independent cell populations. Finally, we show that HU treatment of the multi-cellular organisms C. elegans and D. melanogaster affects epigenetically programmed development and PEV, illustrating the evolutionary conservation of the phenomenon. Replication stress, in addition to its demonstrated role in genetic instability, promotes variable epigenetic instability throughout the epigenome. PMID:28749973

Male infertility: a risk factor for testicular cancer.

PubMed

Hotaling, James M; Walsh, Thomas J

2009-10-01

Male infertility lies at the crossroads of genetic determinants and environmental effects. Although the exact genetic mechanisms of male infertility are still unclear, this disorder is associated with a host of medical diseases, including testicular cancer. Testicular dysgenesis syndrome, the Hiwi protein and chromosome 12 aneuploidy, DNA mismatch repair, and Y-chromosome instability have been postulated as possible connections between male infertility and testicular germ cell tumor (TGCT). The advent of assisted reproductive technology has allowed men to bypass evaluation by a urologist with expertise in infertility at a time when semen quality seems to be decreasing in parallel with an increasing incidence of TGCT in industrialized nations. Advances in epigenetics, the sequencing of the human genome and maturation of large datasets from countries with centralized medical records are heralding a new era of genetic medicine in this field. The exquisite sensitivity of the germinal epithelium to changes in the external environment and the internal metabolic profile present an excellent opportunity to explore the interaction between infertility and TGCT. The elucidation of the pathways underlying this association will enable development of appropriate tests that will identify men susceptible to development of TGCT and other testicular pathologies.

Mechanisms and consequences of aneuploidy and chromosome instability in the aging brain.

PubMed

Andriani, Grasiella A; Vijg, Jan; Montagna, Cristina

2017-01-01

Aneuploidy and polyploidy are a form of Genomic Instability (GIN) known as Chromosomal Instability (CIN) characterized by sporadic abnormalities in chromosome copy numbers. Aneuploidy is commonly linked to pathological states. It is a hallmark of spontaneous abortions and birth defects and it is observed virtually in every human tumor, therefore being generally regarded as detrimental for the development or the maturation of tissues under physiological conditions. Polyploidy however, occurs as part of normal physiological processes during maturation and differentiation of some mammalian cell types. Surprisingly, high levels of aneuploidy are present in the brain, and their frequency increases with age suggesting that the brain is able to maintain its functionality in the presence of high levels of mosaic aneuploidy. Because somatic aneuploidy with age can reach exceptionally high levels, it is likely to have long-term adverse effects in this organ. We describe the mechanisms accountable for an abnormal DNA content with a particular emphasis on the CNS where cell division is limited. Next, we briefly summarize the types of GIN known to date and discuss how they interconnect with CIN. Lastly we highlight how several forms of CIN may contribute to genetic variation, tissue degeneration and disease in the CNS. Copyright © 2016. Published by Elsevier B.V.

Genes and Pathways Involved in Adult Onset Disorders Featuring Muscle Mitochondrial DNA Instability

PubMed Central

Ahmed, Naghia; Ronchi, Dario; Comi, Giacomo Pietro

2015-01-01

Replication and maintenance of mtDNA entirely relies on a set of proteins encoded by the nuclear genome, which include members of the core replicative machinery, proteins involved in the homeostasis of mitochondrial dNTPs pools or deputed to the control of mitochondrial dynamics and morphology. Mutations in their coding genes have been observed in familial and sporadic forms of pediatric and adult-onset clinical phenotypes featuring mtDNA instability. The list of defects involved in these disorders has recently expanded, including mutations in the exo-/endo-nuclease flap-processing proteins MGME1 and DNA2, supporting the notion that an enzymatic DNA repair system actively takes place in mitochondria. The results obtained in the last few years acknowledge the contribution of next-generation sequencing methods in the identification of new disease loci in small groups of patients and even single probands. Although heterogeneous, these genes can be conveniently classified according to the pathway to which they belong. The definition of the molecular and biochemical features of these pathways might be helpful for fundamental knowledge of these disorders, to accelerate genetic diagnosis of patients and the development of rational therapies. In this review, we discuss the molecular findings disclosed in adult patients with muscle pathology hallmarked by mtDNA instability. PMID:26251896

Increased microtubule assembly rates mediate chromosomal instability in colorectal cancer cells

PubMed Central

Ertych, Norman; Stolz, Ailine; Stenzinger, Albrecht; Weichert, Wilko; Kaulfuß, Silke; Burfeind, Peter; Aigner, Achim; Wordeman, Linda

2015-01-01

Chromosomal instability (CIN) is defined as the perpetual missegregation of whole chromosomes during mitosis and represents a hallmark of human cancer. However, the mechanisms causing CIN and its consequences on tumor growth are largely unknown. We identify an increase in microtubule plus end assembly rates as a fundamental trigger for CIN in CRC cells. This trigger is mediated by overexpression of the oncogene AURKA or by loss of the tumor suppressor gene CHK2, a genetic constitution found in 73% of human colorectal cancers. Increased microtubule assembly rates are associated with transient abnormalities in mitotic spindle geometry promoting the generation of lagging chromosomes and resulting in CIN. Reconstitution of proper microtubule assembly rates by chemical or genetic means suppresses CIN and thereby, unexpectedly, accelerates tumor growth in vitro and in vivo. Thus, we identify a fundamental mechanism triggering CIN in cancer cells and reveal its adverse consequence on tumor growth. PMID:24976383

Helicobacter pylori Update: Gastric Cancer, Reliable Therapy, and Possible Benefits

PubMed Central

Graham, David Y.

2015-01-01

Helicobacter pylori infection contributes to development of diverse gastric and extra-gastric diseases. The infection is necessary but not sufficient for development of gastric adenocarcinoma. Its eradication would eliminate a major worldwide cause of cancer death, so there is much interest in identifying how, if, and when this can be accomplished. There are several mechanisms by which H pylori contributes to development of gastric cancer. Gastric adenocarcinoma is one of many cancers associated with inflammation, which is induced by H pylori infection, yet the bacteria also cause genetic and epigenetic changes that lead to genetic instability in gastric epithelial cells. H pylori eradication reduces both. However, many factors must be considered in determining whether treating this bacterial infection will prevent cancer or only reduce its risk—these must be considered in designing reliable and effective eradication therapies. Furthermore, H pylori infection has been proposed to provide some benefits, such as reducing the risks of obesity or childhood asthma, although there are no convincing data to support the benefits of H pylori infections. PMID:25655557

Variability in Estrogen-Metabolizing Genes and Their Association with Genomic Instability in Untreated Breast Cancer Patients and Healthy Women

PubMed Central

Alves dos Santos, Raquel; Teixeira, Ana Cláudia; Mayorano, Mônica Beatriz; Carrara, Hélio Humberto Angotti; Moreira de Andrade, Jurandyr; Takahashi, Catarina Satie

2011-01-01

In the present study, we investigated the relationship between polymorphisms in the estrogen-metabolizing genes CYP17, CYP1B1, CYP1A1, and COMT and genomic instability in the peripheral blood lymphocytes of 62 BC patients and 62 controls considering that increased or prolonged exposure to estrogen can damage the DNA molecule and increase the genomic instability process in breast tissue. Our data demonstrated increased genomic instability in BC patients and that individuals with higher frequencies of MN exhibited higher risk to BC when belonging Val/Met genotype of the COMT gene. We also observed that CYP17 and CYP1A1 polymorphisms can modify the risk to BC depending on the menopause status. We can conclude that the genetic background in estrogen metabolism pathway can modulate chromosome damage in healthy controls and patients and thereby influence the risk to BC. These findings suggest the importance to ally biomarkers of susceptibility and effects to estimate risk groups. PMID:21716904

Nutrigenomics and nutrigenetics.

PubMed

Farhud, Dd; Zarif Yeganeh, M; Zarif Yeganeh, M

2010-01-01

The nutrients are able to interact with molecular mechanisms and modulate the physiological functions in the body. The Nutritional Genomics focuses on the interaction between bioactive food components and the genome, which includes Nutrigenetics and Nutrigenomics. The influence of nutrients on f genes expression is called Nutrigenomics, while the heterogeneous response of gene variants to nutrients, dietary components and developing nutraceticals is called Nutrigenetics. Genetic variation is known to affect food tolerances among human subpopulations and may also influence dietary requirements and raising the possibility of individualizing nutritional intake for optimal health and disease prevention on the basis of an individual's genome. Nutrigenomics provides a genetic understanding for how common dietary components affect the balance between health and disease by altering the expression and/or structure of an individual's genetic makeup. Nutrigenetics describes that the genetic profile have impact on the response of body to bioactive food components by influencing their absorption, metabolism, and site of action.In this way, considering different aspects of gene-nutrient interaction and designing appropriate diet for every specific genotype that optimize individual health, diagnosis and nutritional treatment of genome instability, we could prevent and control conversion of healthy phenotype to diseases.

Nutrigenomics and Nutrigenetics

PubMed Central

Farhud, DD; Zarif Yeganeh, M; Zarif Yeganeh, M

2010-01-01

The nutrients are able to interact with molecular mechanisms and modulate the physiological functions in the body. The Nutritional Genomics focuses on the interaction between bioactive food components and the genome, which includes Nutrigenetics and Nutrigenomics. The influence of nutrients on f genes expression is called Nutrigenomics, while the heterogeneous response of gene variants to nutrients, dietary components and developing nutraceticals is called Nutrigenetics. Genetic variation is known to affect food tolerances among human subpopulations and may also influence dietary requirements and raising the possibility of individualizing nutritional intake for optimal health and disease prevention on the basis of an individual’s genome. Nutrigenomics provides a genetic understanding for how common dietary components affect the balance between health and disease by altering the expression and/or structure of an individual’s genetic makeup. Nutrigenetics describes that the genetic profile have impact on the response of body to bioactive food components by influencing their absorption, metabolism, and site of action. In this way, considering different aspects of gene–nutrient interaction and designing appropriate diet for every specific genotype that optimize individual health, diagnosis and nutritional treatment of genome instability, we could prevent and control conversion of healthy phenotype to diseases. PMID:23113033

Relationship between nm23H1 genetic instability and clinical pathological characteristics in Chinese digestive system cancer patients.

PubMed

Yang, Yue-Qin; Wu, Liang; Chen, Jin-Xing; Sun, Jian-Zhong; Li, Meng; Li, Dong-Mei; Lu, Hai-Ying; Su, Zhi-Hong; Lin, Xin-Qiu; Li, Ji-Cheng

2008-09-28

To study the relationship between nm23H1 gene genetic instability and its clinical pathological characteristics in Chinese digestive system cancer patients. Polymerase chain reaction-single strand conformation polymorphism (PCR-SSCP) was used to analyze the microsatellite instability (MSI) and loss of heterozygosity (LOH). Immunohistochemistry was employed to detect the expression of nm23H1. The MSI was higher in TNM stage I + II than in stage III + IV of gastric, colonic and gallbladder carcinomas. The LOH was higher in TNM stage III + IV than in stage I + II of gastric, colonic and hepatocellular carcinomas. Lymphatic metastasis was also observed. The expression of nm23H1 protein was lower in TNM stage III + IV than in stage I + II of these tumors and in patients with lymphatic metastasis.The nm23H1 protein expression was higher in the LOH negative group than in the LOH positive group. MSI and LOH may independently control the biological behaviors of digestive system cancers. MSI could serve as an early biological marker of digestive system cancers. Enhanced expression of nm23H1 protein could efficiently inhibit cancer metastasis and improve its prognosis. LOH mostly appears in late digestive system cancer.

Chronic ankle instability: Current perspectives

PubMed Central

Al-Mohrej, Omar A.; Al-Kenani, Nader S.

2016-01-01

Ankle sprain is reported to be among the most common recurrent injuries. About 20% of acute ankle sprain patients develop chronic ankle instability. The failure of functional rehabilitation after acute ankle sprain leads to the development of chronic ankle instability. Differentiation between functional and anatomical ankle instability is very essential to guide the proper treatment. Stability testing by varus stress test and anterior drawer test should be carried out. Subtalar instability is an important pathology that is commonly by passed during the assessment of chronic ankle instability. Unlike acute ankle sprain, chronic ankle instability might require surgical intervention. The surgical and conservative management options can be very much developed by in-depth knowledge of the ankle anatomy, biomechanics, and pathology. Anatomical repair, augmentation by tendon, or both are the basic methods of surgical intervention. Arthroscopy is becoming more popular in the management of chronic ankle instability. PMID:27843798

The roles of muscle stem cells in muscle injury, atrophy and hypertrophy.

PubMed

Fukada, So-Ichiro

2018-05-01

Skeletal muscle is composed of multinuclear cells called myofibers. Muscular dystrophy (a genetic muscle disorder) induces instability in the cell membrane of myofibers and eventually causes myofibre damage. Non-genetic muscle disorders, including sarcopenia, diabetes, bedridden immobility and cancer cachexia, lead to atrophy of myofibres. In contrast, resistance training induces myofibre hypertrophy. Thus, myofibres exhibit a plasticity that is strongly affected by both intrinsic and extrinsic factors. There is no doubt that muscle stem cells (MuSCs, also known as muscle satellite cells) are indispensable for muscle repair/regeneration, but their contributions to atrophy and hypertrophy are still controversial. The present review focuses on the relevance of MuSCs to (i) muscle diseases and (ii) hypertrophy. Further, this review addresses fundamental questions about MuSCs to clarify the onset or progression of these diseases and which might lead to development of a MuSC-based therapy.

Etiological influences on the stability of autistic traits from childhood to early adulthood: evidence from a twin study.

PubMed

Taylor, Mark J; Gillberg, Christopher; Lichtenstein, Paul; Lundström, Sebastian

2017-01-01

Autism spectrum disorders (ASD) are persistent and lifelong conditions. Despite this, almost all twin studies focus on childhood. This twin study investigated the stability of autistic traits from childhood to early adulthood and explored the degree to which any stability could be explained by genetic or environmental factors. Parents of over 2500 twin pairs completed questionnaires assessing autistic traits when twins were aged either 9 or 12 years and again when twins were aged 18. Bivariate twin analysis assessed the degree of phenotypic and etiological stability in autistic traits across this period. Genetic overlap in autistic traits across development was also tested in individuals displaying a broad ASD phenotype, defined as scoring within the highest 5% of the sample. Autistic traits displayed moderate phenotypic stability ( r  = .39). The heritability of autistic traits was 76-77% in childhood and 60-62% in adulthood. A moderate degree of genetic influences on childhood autistic traits were carried across into adulthood (genetic correlation = .49). The majority (85%) of the stability in autistic traits was attributable to genetic factors. Genetic influences on autistic traits were moderately stable from childhood to early adulthood at the extremes (genetic correlation = .64). Broad autistic traits display moderate phenotypic and etiological stability from childhood to early adulthood. Genetic factors accounted for almost all phenotypic stability, although there was some phenotypic and etiological instability in autistic traits. Thus, autistic traits in adulthood are influenced by a combination of enduring and unique genetic factors.

Social management of laboratory rhesus macaques housed in large groups using a network approach: A review.

PubMed

McCowan, Brenda; Beisner, Brianne; Hannibal, Darcy

2017-12-07

Biomedical facilities across the nation and worldwide aim to develop cost-effective methods for the reproductive management of macaque breeding groups, typically by housing macaques in large, multi-male multi-female social groups that provide monkey subjects for research as well as appropriate socialization for their psychological well-being. One of the most difficult problems in managing socially housed macaques is their propensity for deleterious aggression. From a management perspective, deleterious aggression (as opposed to less intense aggression that serves to regulate social relationships) is undoubtedly the most problematic behavior observed in group-housed macaques, which can readily escalate to the degree that it causes social instability, increases serious physical trauma leading to group dissolution, and reduces psychological well-being. Thus for both welfare and other management reasons, aggression among rhesus macaques at primate centers and facilities needs to be addressed with a more proactive approach.Management strategies need to be instituted that maximize social housing while also reducing problematic social aggression due to instability using efficacious methods for detection and prevention in the most cost effective manner. Herein we review a new proactive approach using social network analysis to assess and predict deleterious aggression in macaque groups. We discovered three major pathways leading to instability, such as unusually high rates and severity of trauma and social relocations.These pathways are linked either directly or indirectly to network structure in rhesus macaque societies. We define these pathways according to the key intrinsic and extrinsic variables (e.g., demographic, genetic or social factors) that influence network and behavioral measures of stability (see Fig. 1). They are: (1) presence of natal males, (2) matrilineal genetic fragmentation, and (3) the power structure and conflict policing behavior supported by this power structure. We discuss how these three major pathways leading to greater understanding and predictability of deleterious aggression in macaque social groups. Copyright © 2017. Published by Elsevier B.V.

DOE Office of Scientific and Technical Information (OSTI.GOV)

Peltomaeki, Paeivi, E-mail: Paivi.Peltomaki@Helsinki.Fi

Cancer is traditionally viewed as a disease of abnormal cell proliferation controlled by a series of mutations. Mutations typically affect oncogenes or tumor suppressor genes thereby conferring growth advantage. Genomic instability facilitates mutation accumulation. Recent findings demonstrate that activation of oncogenes and inactivation of tumor suppressor genes, as well as genomic instability, can be achieved by epigenetic mechanisms as well. Unlike genetic mutations, epimutations do not change the base sequence of DNA and are potentially reversible. Similar to genetic mutations, epimutations are associated with specific patterns of gene expression that are heritable through cell divisions. Knudson's hypothesis postulates that inactivationmore » of tumor suppressor genes requires two hits, with the first hit occurring either in somatic cells (sporadic cancer) or in the germline (hereditary cancer) and the second one always being somatic. Studies on hereditary and sporadic forms of colorectal carcinoma have made it evident that, apart from genetic mutations, epimutations may serve as either hit or both. Furthermore, recent next-generation sequencing studies show that epigenetic genes, such as those encoding histone modifying enzymes and subunits for chromatin remodeling systems, are themselves frequent targets of somatic mutations in cancer and can act like tumor suppressor genes or oncogenes. This review discusses genetic vs. epigenetic origin of cancer, including cancer susceptibility, in light of recent discoveries. Situations in which mutations and epimutations occur to serve analogous purposes are highlighted.« less

PC3 (BTG2/TIS21) possible role in chromosome instability syndromes.

PubMed

Conti, Filippo; Ghigo, Eric

2013-07-01

Chromosome instability syndromes (CIS) are autosomal recessive genetic disorders associated with defects in cell cycle regulation following DNA damage. Although most of the proteins involved in these syndromes have been identified as part of the MRN complex, little is known about their physiological functions and their interactions with other molecules that might explain the wide clinical presentation found in CIS patients. Here we discuss several observations suggesting that PC3 (BTG2/TIS21) - a protein involved in G1-S checkpoint progression control - might play a role in these pathologies. Copyright © 2013 Elsevier Ltd. All rights reserved.

HTLV-I Tax Increases Genetic Instability by Inducing DNA Double Strand Breaks during DNA Replication and Switching Repair to NHEJ

PubMed Central

Baydoun, Hicham H.; Bai, Xue Tao; Shelton, Shary; Nicot, Christophe

2012-01-01

Background Appropriate responses to damaged DNA are indispensible for preserving genome stability and preventing cancer. Tumor viruses often target DNA repair machinery to achieve transformation. The Human T-cell leukemia virus type I (HTLV-I) is the only known transforming human retrovirus and the etiological agent of Adult T-cell Leukemia (ATLL). Although HTLV-I-transformed leukemic cells have numerous genetic lesions, the precise role of the viral tax gene in this process is not fully understood. Results Our results show a novel function of HTLV-I oncoprotein Tax as an inducer of genomic DNA double strand breaks (DDSB) during DNA replication. We also found that Tax acts as a potent inhibitor of homologous recombination (HR) DNA repair through the activation of the NF-kB pathway. These results were confirmed using HTLV-I molecular clones expressing Tax at physiological levels in a natural context. We further found that HTLV-I- and Tax-transformed cells are not more susceptible to DNA damaging agents and repair DNA lesions at a rate similar to that of normal cells. Finally, we demonstrated that during S phase, Tax-associated DDSB are preferentially repaired using the error-prone non-homologous end joining (NHEJ) pathway. Conclusions This study provides new insights in Tax effects on DNA repair and genome instability. Although it may not be self sufficient, the creation of DNA breaks and subsequent abnormal use of the non-conservative NHEJ DNA repair during the S phase in HTLV-I-infected Tax-expressing cells may cooperate with other factors to increase genetic and genome instability and favor transformation. PMID:22916124

Investigation on thermo-acoustic instability dynamic characteristics of hydrocarbon fuel flowing in scramjet cooling channel based on wavelet entropy method

NASA Astrophysics Data System (ADS)

Zan, Hao; Li, Haowei; Jiang, Yuguang; Wu, Meng; Zhou, Weixing; Bao, Wen

2018-06-01

As part of our efforts to find ways and means to further improve the regenerative cooling technology in scramjet, the experiments of thermo-acoustic instability dynamic characteristics of hydrocarbon fuel flowing have been conducted in horizontal circular tubes at different conditions. The experimental results indicate that there is a developing process from thermo-acoustic stability to instability. In order to have a deep understanding on the developing process of thermo-acoustic instability, the method of Multi-scale Shannon Wavelet Entropy (MSWE) based on Wavelet Transform Correlation Filter (WTCF) and Multi-Scale Shannon Entropy (MSE) is adopted in this paper. The results demonstrate that the developing process of thermo-acoustic instability from noise and weak signals is well detected by MSWE method and the differences among the stability, the developing process and the instability can be identified. These properties render the method particularly powerful for warning thermo-acoustic instability of hydrocarbon fuel flowing in scramjet cooling channels. The mass flow rate and the inlet pressure will make an influence on the developing process of the thermo-acoustic instability. The investigation on thermo-acoustic instability dynamic characteristics at supercritical pressure based on wavelet entropy method offers guidance on the control of scramjet fuel supply, which can secure stable fuel flowing in regenerative cooling system.

Clinicopathological and molecular stability and methylation analyses of gastric papillary adenocarcinoma.

PubMed

Uesugi, Noriyuki; Sugai, Tamotsu; Sugimoto, Ryo; Eizuka, Makoto; Fujita, Yasuko; Sato, Ayaka; Osakabe, Mitsumasa; Ishida, Kazuyuki; Koeda, Keisuke; Sasaki, Akira; Matsumoto, Takayuki

2017-10-01

The molecular alterations and pathological features of gastric papillary adenocarcinoma (GPA) remain unknown. We examined GPA samples and compared their molecular and pathological characteristics with those of gastric tubular adenocarcinoma (GTA). Additionally, we identified pathological and molecular features of GPA that vary with microsatellite stability. In the present study, samples from 63 GPA patients and 47 GTA patients were examined using a combination of polymerase chain reaction (PCR)-microsatellite assays and PCR-pyrosequencing in order to detect microsatellite instability (microsatellite instability, MSI; microsatellite stable, MSS), methylation status (low methylation, intermediate methylation and high methylation level), and chromosomal AI in multiple cancer-related loci. Additionally, the expression levels of TP53 and Her2 were evaluated using immunohistochemistry. GTA and GPA are statistically different in their frequency of pathological features, including mucinous, poorly differentiated and invasive micropapillary components. Clear genetic patterns differentiating GPA and GTA could not be identified with a hierarchical cluster analysis, but microsatellite stability was linked with TP53 and Her2 overexpression. Methylation status in GPA was also associated with the development of high microsatellite instability. However, no pathological differences were associated with microsatellite stability. We suggest that although molecular alterations in a subset of GPAs are closely associated with microsatellite stability, they play a minor role in GPA carcinogenesis. Copyright © 2017 Royal College of Pathologists of Australasia. Published by Elsevier B.V. All rights reserved.

Targeted therapy of multiple myeloma.

PubMed

Dolloff, Nathan G; Talamo, Giampaolo

2013-01-01

Multiple myeloma (MM) is a plasma cell malignancy and the second most common hematologic cancer. MM is characterized by the accumulation of malignant plasma cells within the bone marrow, and presents clinically with a broad range of symptoms, including hypercalcemia, renal insufficiency, anemia, and lytic bone lesions. MM is a heterogeneous disease associated with genomic instability, where patients may express multiple genetic abnormalities that affect several oncogenic pathways. Commonly detected genetic aberrations are translocations involving immunoglobulin heavy chain (IgH) switch regions (chromosome 14q32) and oncogenes such as c-maf [t(14:16)], cyclin D1 [t(11:14)], and FGFR3/MMSET [t(4:14)]. Advances in the basic understanding of MM and the development of novel agents, such as the immunomodulatory drugs (IMiDs) thalidomide and lenalidomide and the proteasome inhibitor bortezomib, have increased therapeutic response rates and prolonged patient survival. Despite these advances MM remains incurable in the majority of patients, and it is therefore critical to identify additional therapeutic strategies and targets for its treatment. In this chapter, we review the underlying genetic components of MM and discuss the results of recent clinical trials that demonstrate the effectiveness of targeted agents in the management of MM. In addition, we discuss experimental therapies that are currently in clinical development along with their molecular rationale in the treatment of MM.

In vitro short-term exposure to air pollution PM{sub 2.5-0.3} induced cell cycle alterations and genetic instability in a human lung cell coculture model

DOE Office of Scientific and Technical Information (OSTI.GOV)

Abbas, Imane; EA4492-UCEIV, Université du Littoral-Côte d’Opale, Dunkerque; Lebanese Atomic Energy Commission – CNRS, Beirut

Although its adverse health effects of air pollution particulate matter (PM2.5) are well-documented and often related to oxidative stress and pro-inflammatory response, recent evidence support the role of the remodeling of the airway epithelium involving the regulation of cell death processes. Hence, the overarching goals of the present study were to use an in vitro coculture model, based on human AM and L132 cells to study the possible alteration of TP53-RB gene signaling pathways (i.e. cell cycle phases, gene expression of TP53, BCL2, BAX, P21, CCND1, and RB, and protein concentrations of their active forms), and genetic instability (i.e. LOHmore » and/or MSI) in the PM{sub 2.5-0.3}-exposed coculture model. PM{sub 2.5-0.3} exposure of human AM from the coculture model induced marked cell cycle alterations after 24 h, as shown by increased numbers of L132 cells in subG1 and S+G2 cell cycle phases, indicating apoptosis and proliferation. Accordingly, activation of the TP53-RB gene signaling pathways after the coculture model exposure to PM{sub 2.5-0.3} was reported in the L132 cells. Exposure of human AM from the coculture model to PM{sub 2.5-0.3} resulted in MS alterations in 3p chromosome multiple critical regions in L132 cell population. Hence, in vitro short-term exposure of the coculture model to PM{sub 2.5-0.3} induced cell cycle alterations relying on the sequential occurrence of molecular abnormalities from TP53-RB gene signaling pathway activation and genetic instability. - Highlights: • Better knowledge on health adverse effects of air pollution PM{sub 2.5}. • Human alveolar macrophage and normal human epithelial lung cell coculture. • Molecular abnormalities from TP53-RB gene signaling pathway. • Loss of heterozygosity and microsatellite instability. • Pathologic changes in morphology and number of cells in relation to airway remodeling.« less

[Colorectal oncogenesis].

PubMed

Laurent-Puig, P; Agostini, J; Maley, K

2010-11-01

Recent progress in the field of molecular biology has allowed us to identify at least two different molecular mechanisms implicated in colorectal carcinogenesis (CRC): chromosomal instability (CIN) and genetic instability. Even though the two molecular mechanisms differ, their signalling pathways, implicated in malignant transformation of colonic epithelial cells, appear to be similar. The most frequent group of CRC, which represents 80% of sporadic CRC, is characterized by allelic losses on the short arm of chromosome 17 and 8 and on the long arm of chromosome 5, 18 and 22. These allelic losses are associated with mutations in TP53, APC, SMAD2 and SMAD4 genes. All of these alterations are grouped under the phenotype CIN. A genetic instability termed MSI (microsatellite instability), which results from a mismatch repair (MMR) deficiency, appears in 12-15% of CRC cases. The presence of MMR deficiency leads to the accumulation of mutations in genes controlling cell cycle and apoptosis (TGFBRII, BAX or CASPASE5). More recently, the existence of a third phenotype was suggested. The main alteration associated with this group of tumors is the hypermethylation of the promoter region of numerous genes, leading to their inactivation. An activating mutation of BRAF is frequently associated with this phenotype. As described above, CRC shows genetic heterogeneity, however the consequences in terms of signalling pathway alterations are similar. For example, the activation of Wnt signalling pathways can result from the inactivation of the APC gene in the CIN phenotype or from an activating mutation in the β-catenin gene in MSI tumors. The inactivation of TGFβ pathways is also present in both tumor types and is driven by SMAD4, and more rarely by a SMAD2 inactivating mutation in CIN tumors, or by the existence of a frame-shift mutation occurring in a polyG coding track of the TGFβ (transforming growth factor) receptor type II in MSI tumors. The RAS-MAP kinase pathway is activated by KRAS mutations in CIN tumors or by BRAF mutations in MSI tumors. The p53 pathway is inactivated by TP53 inactivation in CIN tumors or by BAX inactivating mutations in MSI tumors.

Screening for microsatellite instability target genes in colorectal cancers

PubMed Central

Vilkki, S; Launonen, V; Karhu, A; Sistonen, P; Vastrik, I; Aaltonen, L

2002-01-01

Background: Defects in the DNA repair system lead to genetic instability because replication errors are not corrected. This type of genetic instability is a key event in the malignant progression of HNPCC and a subset of sporadic colon cancers and mutation rates are particularly high at short repetitive sequences. Somatic deletions of coding mononucleotide repeats have been detected, for example, in the TGFßRII and BAX genes, and recently many novel target genes for microsatellite instability (MSI) have been proposed. Novel target genes are likely to be discovered in the future. More data should be created on background mutation rates in MSI tumours to evaluate mutation rates observed in the candidate target genes. Methods: Mutation rates in 14 neutral intronic repeats were evaluated in MSI tumours. Bioinformatic searches combined with keywords related to cancer and tumour suppressor or CRC related gene homology were used to find new candidate MSI target genes. By comparison of mutation frequencies observed in intronic mononucleotide repeats versus exonic coding repeats of potential MSI target genes, the significance of the exonic mutations was estimated. Results: As expected, the length of an intronic mononucleotide repeat correlated positively with the number of slippages for both G/C and A/T repeats (p=0.0020 and p=0.0012, respectively). BRCA1, CtBP1, and Rb1 associated CtIP and other candidates were found in a bioinformatic search combined with keywords related to cancer. Sequencing showed a significantly increased mutation rate in the exonic A9 repeat of CtIP (25/109=22.9%) as compared with similar intronic repeats (p≤0.001). Conclusions: We propose a new candidate MSI target gene CtIP to be evaluated in further studies. PMID:12414815

Molecular Diagnostics in Esophageal and Gastric Neoplasms: 2018 Update.

PubMed

Zulfiqar, Muhammad; Bluth, Martin H; Bhalla, Amarpreet

2018-06-01

Esophageal cancer (EC) is rapidly increasing in incidence in the United States. Genetic changes associated with the development of EC involve the p16, p53, and APC genes. Human epidermal growth factor 2 (HER-2) overexpression is seen in gastroesophageal junction carcinoma and a subset gastric carcinoma (GC). Interestingly, up to 50% cases of GC are related to Helicobacter pylori infection and up to 16% are related to EBV infection. Microsatellite instability is observed in up to 39% of GC and cell free nucleic acid analysis provides additional opportunities for diagnosis and prognosis of disease. Copyright © 2018 Elsevier Inc. All rights reserved.

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

PubMed

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

2010-11-01

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

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

PubMed

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.

A Dual Role for UVRAG in Maintaining Chromosomal Stability Independent of Autophagy

PubMed Central

Zhao, Zhen; Oh, Soohwan; Li, Dapeng; Ni, Duojiao; Pirooz, Sara Dolatshahi; Lee, Joo-Hyung; Yang, Shunhua; Lee, June-Yong; Ghozalli, Irene; Costanzo, Vincenzo; Stark, Jeremy M.; Liang, Chengyu

2012-01-01

SUMMARY Autophagy defects have been recently associated with chromosomal instability (CIN), a hallmark of human cancer. However, the functional specificity and mechanism of action of autophagy-related factors in genome stability remain elusive. Here we report that UVRAG, an autophagic tumor suppressor, plays a dual role in chromosomal stability, surprisingly independent of autophagy. We establish that UVRAG promotes DNA double-strand-breaks repair by directly binding and activating DNA-PK in non-homologous end-joining. Disruption of UVRAG increases genetic instability and sensitivity of cells to irradiation. Furthermore, UVRAG was found also localized at centrosomes and physically associated with CEP63, an integral component of centrosomes. Disruption of the association of UVRAG with centrosomes causes centrosome instability and aneuploidy. UVRAG thus represents an autophagy-related molecular factor that also has a convergent role in patrolling both the structural integrity and proper segregation of chromosomes, which may confer autophagy-independent tumor suppressor activity. PMID:22542840

Sites of instability in the human TCF3 (E2A) gene adopt G-quadruplex DNA structures in vitro

PubMed Central

Williams, Jonathan D.; Fleetwood, Sara; Berroyer, Alexandra; Kim, Nayun; Larson, Erik D.

2015-01-01

The formation of highly stable four-stranded DNA, called G-quadruplex (G4), promotes site-specific genome instability. G4 DNA structures fold from repetitive guanine sequences, and increasing experimental evidence connects G4 sequence motifs with specific gene rearrangements. The human transcription factor 3 (TCF3) gene (also termed E2A) is subject to genetic instability associated with severe disease, most notably a common translocation event t(1;19) associated with acute lymphoblastic leukemia. The sites of instability in TCF3 are not randomly distributed, but focused to certain sequences. We asked if G4 DNA formation could explain why TCF3 is prone to recombination and mutagenesis. Here we demonstrate that sequences surrounding the major t(1;19) break site and a region associated with copy number variations both contain G4 sequence motifs. The motifs identified readily adopt G4 DNA structures that are stable enough to interfere with DNA synthesis in physiological salt conditions in vitro. When introduced into the yeast genome, TCF3 G4 motifs promoted gross chromosomal rearrangements in a transcription-dependent manner. Our results provide a molecular rationale for the site-specific instability of human TCF3, suggesting that G4 DNA structures contribute to oncogenic DNA breaks and recombination. PMID:26029241

Accelerated Development of Cervical Spine Instabilities in Rheumatoid Arthritis: A Prospective Minimum 5-Year Cohort Study

PubMed Central

Yurube, Takashi; Sumi, Masatoshi; Nishida, Kotaro; Miyamoto, Hiroshi; Kohyama, Kozo; Matsubara, Tsukasa; Miura, Yasushi; Hirata, Hiroaki; Sugiyama, Daisuke; Doita, Minoru

2014-01-01

Objective To clarify the incidence and predictive risk factors of cervical spine instabilities which may induce compression myelopathy in patients with rheumatoid arthritis (RA). Methods Three types of cervical spine instability were radiographically categorized into “moderate” and “severe” based on atlantoaxial subluxation (AAS: atlantodental interval >3 mm versus ≥10 mm), vertical subluxation (VS: Ranawat value <13 mm versus ≤10 mm), and subaxial subluxation (SAS: irreducible translation ≥2 mm versus ≥4 mm or at multiple). 228 “definite” or “classical” RA patients (140 without instability and 88 with “moderate” instability) were prospectively followed for >5 years. The endpoint incidence of “severe” instabilities and predictors for “severe” instability were determined. Results Patients with baseline “moderate” instability, including all sub-groups (AAS+ [VS− SAS−], VS+ [SAS− AAS±], and SAS+ [AAS± VS±]), developed “severe” instabilities more frequently (33.3% with AAS+, 75.0% with VS+, and 42.9% with SAS+) than those initially without instability (12.9%; p<0.003, p<0.003, and p = 0.061, respectively). The incidence of cervical canal stenosis and/or basilar invagination was also higher in patients with initial instability (17.5% with AAS+, 37.5% with VS+, and 14.3% with SAS+) than in those without instability (7.1%; p = 0.028, p<0.003, and p = 0.427, respectively). Multivariable logistic regression analysis identified corticosteroid administration, Steinbrocker stage III or IV at baseline, mutilating changes at baseline, and the development of mutilans during the follow-up period correlated with the progression to “severe” instability (p<0.05). Conclusions This prospective cohort study demonstrates accelerated development of cervical spine involvement in RA patients with pre-existing instability—especially VS. Advanced peripheral erosiveness and concomitant corticosteroid treatment are indicators for poor prognosis of the cervical spine in RA. PMID:24558457

Evaluation of reliability on STR typing at leukemic patients used for forensic purposes.

PubMed

Filoglu, G; Bulbul, O; Rayimoglu, G; Yediay, F E; Zorlu, T; Ongoren, S; Altuncul, H

2014-06-01

Over the past decades, main advances in the field of molecular biology, coupled with benefits in genomic technologies, have led to detailed molecular investigations in the genetic diversity generated by researchers. Short tandem repeat (STR) loci are polymorphic loci found throughout all eukaryotic genome. DNA profiling identification, parental testing and kinship analysis by analysis of STR loci have been widely used in forensic sciences since 1993. Malignant tissues may sometimes be the source of biological material for forensic analysis, including identification of individuals or paternity testing. There are a number of studies on microsatellite instability in different types of tumors by comparing the STR profiles of malignant and healthy tissues on the same individuals. Defects in DNA repair pathways (non-repair or mis-repair) and metabolism lead to an accumulation of microsatellite alterations in genomic DNA of various cancer types that result genomic instabilities on forensic analyses. Common forms of genomic instability are loss of heterozygosity (LOH) and microsatellite instability (MSI). In this study, the applicability of autosomal STR markers, which are routinely used in forensic analysis, were investigated in order to detect genotypes in blood samples collected from leukemic patients to estimate the reliability of the results when malignant tissues are used as a source of forensic individual identification. Specimens were collected from 90 acute and 10 chronic leukemia volunteers with oral swabs as well as their paired peripheral blood samples from the Oncology Centre of the Department of Hematology at Istanbul University, during the years 2010-2011. Specimens were tested and compared with 16 somatic STR loci (CSFIPO, THO1, TPOX, vWA, D2S1338, D3S1358, D5S818, D7S820, D8S1179, D13S317, D16S539, D18S51, D19S433, D21S11 and FGA) widely used in forensic identification and kinship. Only two STR instabilities were encountered among 100 specimens. An MSI in the FGA loci and a LOH in the D2S1338 loci were determined in two individuals separately. Our results demonstrate that the use of the biological samples from leukemia patients in forensic identification and kinship testing is questionable, especially if known microsatellite instability is available. Genetic instabilities may alter the STR polymorphism, leading to potential errors on forensic identification of individuals. Therefore, typing of autosomal STRs from leukemia patients should be performed with both healthy and malignant tissue samples of individual as references.

The generation of meaningful information in molecular systems.

PubMed

Wills, Peter R

2016-03-13

The physico-chemical processes occurring inside cells are under the computational control of genetic (DNA) and epigenetic (internal structural) programming. The origin and evolution of genetic information (nucleic acid sequences) is reasonably well understood, but scant attention has been paid to the origin and evolution of the molecular biological interpreters that give phenotypic meaning to the sequence information that is quite faithfully replicated during cellular reproduction. The near universality and age of the mapping from nucleotide triplets to amino acids embedded in the functionality of the protein synthetic machinery speaks to the early development of a system of coding which is still extant in every living organism. We take the origin of genetic coding as a paradigm of the emergence of computation in natural systems, focusing on the requirement that the molecular components of an interpreter be synthesized autocatalytically. Within this context, it is seen that interpreters of increasing complexity are generated by series of transitions through stepped dynamic instabilities (non-equilibrium phase transitions). The early phylogeny of the amino acyl-tRNA synthetase enzymes is discussed in such terms, leading to the conclusion that the observed optimality of the genetic code is a natural outcome of the processes of self-organization that produced it. © 2016 The Author(s).

Photosynthetic limitation as a factor influencing yield in highbush blueberries (Vaccinium corymbosum) grown in a northern European environment.

PubMed

Petridis, Antonios; van der Kaay, Jeroen; Chrysanthou, Elina; McCallum, Susan; Graham, Julie; Hancock, Robert D

2018-05-25

Published evidence indicates that nearly 60% of blueberry-producing countries experience yield instability. Yield is a complex trait determined by genetic and environmental factors. Here, using physiological and biochemical approaches, we tested the hypothesis that yield instability results from year-to-year environmental variation that limits carbon assimilation, storage and partitioning. The data indicate that fruit development depends primarily on the daily production of non-structural carbohydrates by leaves, and there is no accumulation of a starch buffer to allow continuous ripening under conditions limiting for photosynthesis. Photosynthesis was saturated at moderate light irradiance and this was mainly due to stomatal and biochemical limitations. In a dynamic light environment, photosynthesis was further limited by slow stomatal response to increasing light. Finally, labelling with 13CO2 at specific stages of fruit development revealed a relatively even distribution of newly assimilated carbon between stems, roots and fruits, suggesting that the fruit is not a strong sink. We conclude that a significant component of yield variability results from limitations in photosynthetic efficiency that are compounded by an inability to accumulate starch reserves in blueberry storage tissues in a typical northern European environment. This work informs techniques for improving agronomic management and indicates key traits required for yield stability in such environments.

Photosynthetic limitation as a factor influencing yield in highbush blueberries (Vaccinium corymbosum) grown in a northern European environment

PubMed Central

van der Kaay, Jeroen; Chrysanthou, Elina; McCallum, Susan

2018-01-01

Abstract Published evidence indicates that nearly 60% of blueberry-producing countries experience yield instability. Yield is a complex trait determined by genetic and environmental factors. Here, using physiological and biochemical approaches, we tested the hypothesis that yield instability results from year-to-year environmental variation that limits carbon assimilation, storage and partitioning. The data indicate that fruit development depends primarily on the daily production of non-structural carbohydrates by leaves, and there is no accumulation of a starch buffer to allow continuous ripening under conditions limiting for photosynthesis. Photosynthesis was saturated at moderate light irradiance and this was mainly due to stomatal and biochemical limitations. In a dynamic light environment, photosynthesis was further limited by slow stomatal response to increasing light. Finally, labelling with 13CO2 at specific stages of fruit development revealed a relatively even distribution of newly assimilated carbon between stems, roots and fruits, suggesting that the fruit is not a strong sink. We conclude that a significant component of yield variability results from limitations in photosynthetic efficiency that are compounded by an inability to accumulate starch reserves in blueberry storage tissues in a typical northern European environment. This work informs techniques for improving agronomic management and indicates key traits required for yield stability in such environments. PMID:29590429

Two-year outcomes of open shoulder anterior capsular reconstruction for instability from severe capsular deficiency.

PubMed

Dewing, Christopher B; Horan, Marilee P; Millett, Peter J

2012-01-01

To document outcomes after anterior capsulolabral reconstruction for recurrent shoulder instability in 15 patients (20 shoulders) who have had multiple failed stabilizations or collagen disorders. Twenty shoulders with recurrent instability underwent revision stabilization with allograft reconstruction of anterior capsulolabral structures, which re-creates the labrum and capsular ligaments. The patients comprised 3 men and 12 women (mean age, 26 years [range, 18 to 38 years]) in whom multiple prior repairs failed and who had disability from continued pain and instability. Patients could choose to undergo either arthrodesis or salvage allograft reconstruction or to live with permanent disability. Of the patients, 5 had Ehlers-Danlos syndrome whereas 10 had hyperlaxity syndromes without genetic confirmation. Failure was defined as further instability surgery. Pain, shoulder function, instability (dislocations/subluxation), and American Shoulder and Elbow Surgeons scores were documented. At follow-up, 9 of 20 shoulders (45%) remained stable. Recurrent instability was reported in 5 shoulders (25%), but the patients chose not to undergo further surgery. In the 14 shoulders without further stabilization (nonfailures), the mean American Shoulder and Elbow Surgeons score increased 43 points at a mean of 3.8 years (range, 2 to 6 years) postoperatively (P < .05). Mean satisfaction with outcome in nonfailures was 7 of 10 points (range, 1 to 10). Six shoulders failed by progressing to instability surgery at a mean of 8.6 months (range, 2.8 to 24 months). In the 6 shoulders that failed, the mean number of prior surgeries was 8 (range, 3 to 15) compared with a mean of 4 prior surgeries (range, 1 to 16) for the 9 nonfailures. Treating patients in whom multiple stabilizations have failed remains challenging. In our series 9 shoulders (45%) remained completely stable at 3.8 years. Recurrent instability (3 reinjuries) requiring further stabilization occurred in 6 (30%). Subsequent treatment for non-instability reasons was performed in 3 (15%). Instability was reported but revision surgery was not performed in 5 (25%). In 8 nonfailures (64%), the patients were highly satisfied with their surgical outcomes. Our results support this salvage procedure as a viable alternative to arthrodesis in young patients with end-stage shoulder instability or collagen disorders. Level IV, therapeutic case series. Copyright © 2012 Arthroscopy Association of North America. Published by Elsevier Inc. All rights reserved.

High Frequency Adaptive Instability Suppression Controls in a Liquid-Fueled Combustor

NASA Technical Reports Server (NTRS)

Kopasakis, George

2003-01-01

This effort extends into high frequency (>500 Hz), an earlier developed adaptive control algorithm for the suppression of thermo-acoustic instabilities in a liquidfueled combustor. The earlier work covered the development of a controls algorithm for the suppression of a low frequency (280 Hz) combustion instability based on simulations, with no hardware testing involved. The work described here includes changes to the simulation and controller design necessary to control the high frequency instability, augmentations to the control algorithm to improve its performance, and finally hardware testing and results with an experimental combustor rig developed for the high frequency case. The Adaptive Sliding Phasor Averaged Control (ASPAC) algorithm modulates the fuel flow in the combustor with a control phase that continuously slides back and forth within the phase region that reduces the amplitude of the instability. The results demonstrate the power of the method - that it can identify and suppress the instability even when the instability amplitude is buried in the noise of the combustor pressure. The successful testing of the ASPAC approach helped complete an important NASA milestone to demonstrate advanced technologies for low-emission combustors.

Parkinsonism in fragile X-associated tremor/ataxia syndrome (FXTAS): revisited.

PubMed

Niu, Yu-Qiong; Yang, Jin-Chen; Hall, Deborah A; Leehey, Maureen A; Tassone, Flora; Olichney, John M; Hagerman, Randi J; Zhang, Lin

2014-04-01

Parkinsonian features have been used as a minor diagnostic criterion for fragile X-associated tremor/ataxia syndrome (FXTAS). However, prior studies have examined parkinsonism (defined as having bradykinesia with at least rest tremor or postural instability) mostly in premutation carriers without a diagnosis of FXTAS. The current study was intended to elaborate this important aspect of the FXTAS spectrum, and to quantify the relationships between parkinsonism, FXTAS clinical staging and genetic/molecular measures. Thirty eight (38) FXTAS patients and 10 age-matched normal controls underwent a detailed neurological examination that included all but one item (i.e. rigidity) of the motor section of the Unified Parkinson's Disease Rating Scale (UPDRS). The FXTAS patient group displayed substantially higher prevalence of parkinsonian features including body bradykinesia (57%) and rest tremor (26%), compared to the control group. Furthermore, parkinsonism was identified in 29% of FXTAS patients. Across all patients, body bradykinesia scores significantly correlated with FXTAS clinical stage, FMR1 mRNA level, and ataxic gait of cerebellar origin, while postural instability was associated with intention tremor. Parkinsonian features in FXTAS appear to be characterized as bradykinesia concurrent with cerebellar gait ataxia, postural instability accompanied by intention tremor, and frequent rest tremor, representing distinctive patterns that highlight the need for further clinical studies including genetic testing for the FMR1 premutation. The association between FMR1 mRNA level and bradykinesia implicates pathophysiological mechanisms which may link FMR1 mRNA toxicity, dopamine deficiency and parkinsonism in FXTAS. Copyright © 2014 Elsevier Ltd. All rights reserved.

Effects of camptothecin or TOP1 overexpression on genetic stability in Saccharomyces cerevisiae.

PubMed

Sloan, Roketa; Huang, Shar-Yin Naomi; Pommier, Yves; Jinks-Robertson, Sue

2017-11-01

Topoisomerase I (Top1) removes DNA torsional stress by nicking and resealing one strand of DNA, and is essential in higher eukaryotes. The enzyme is frequently overproduced in tumors and is the sole target of the chemotherapeutic drug camptothecin (CPT) and its clinical derivatives. CPT stabilizes the covalent Top1-DNA cleavage intermediate, which leads to toxic double-strand breaks (DSBs) when encountered by a replication fork. In the current study, we examined genetic instability associated with CPT treatment or with Top1 overexpression in the yeast Saccharomyces cerevisiae. Two types of instability were monitored: Top1-dependent deletions in haploid strains, which do not require processing into a DSB, and instability at the repetitive ribosomal DNA (rDNA) locus in diploid strains, which reflects DSB formation. Three 2-bp deletion hotspots were examined and mutations at each were elevated either when a wild-type strain was treated with CPT or when TOP1 was overexpressed, with the mutation frequency correlating with the level of TOP1 overexpression. Under both conditions, deletions at novel positions were enriched. rDNA stability was examined by measuring loss-of-heterozygosity and as was observed previously upon CPT treatment of a wild-type strain, Top1 overexpression destabilized rDNA. We conclude that too much, as well as too little of Top1 is detrimental to eukaryotic genomes, and that CPT has destabilizing effects that extend beyond those associated with DSB formation. Copyright © 2017 Elsevier B.V. All rights reserved.

Association between genomic instability and evolutionary chromosomal rearrangements in Neotropical Primates.

PubMed

Puntieri, Fiona; Andrioli, Nancy B; Nieves, Mariela

2018-06-14

During the last decades the mammalian genome has been proposed to have regions prone to breakage and reorganization concentrated in certain chromosomal bands that seem to correspond to evolutionary breakpoints. These bands are likely to be involved in chromosome fragility or instability. In Primates, some biomarkers of genetic damage may be associated with various degrees of genomic instability. Here, we investigated the usefulness of Sister Chromatid Exchange (SCE) as a biomarker of potential sites of frequent chromosome breakage and rearrangement in Alouatta caraya, Ateles chamek, Ateles paniscus and Cebus cay. These Neotropical species have particular genomic and chromosomal features allowing the analysis of genomic instability for comparative purposes. We determined the frequency of spontaneous induction of SCEs and assessed the relationship between these and structural rearrangements implicated in the evolution of the primates of interest. Overall, A. caraya and C. cay presented a low proportion of statistically significant unstable bands, suggesting fairly stable genomes and the existence of some kind of protection against endogenous damage. In contrast, Ateles showed a highly significant proportion of unstable bands; these were mainly found in the rearranged regions, which is consistent with the numerous genomic reorganizations that might have occurred during the evolution of this genus.

DNA damage in cells exhibiting radiation-induced genomic instability

DOE PAGES

Keszenman, Deborah J.; Kolodiuk, Lucia; Baulch, Janet E.

2015-02-22

Cells exhibiting radiation induced genomic instability exhibit varied spectra of genetic and chromosomal aberrations. Even so, oxidative stress remains a common theme in the initiation and/or perpetuation of this phenomenon. Isolated oxidatively modified bases, abasic sites, DNA single strand breaks and clustered DNA damage are induced in normal mammalian cultured cells and tissues due to endogenous reactive oxygen species generated during normal cellular metabolism in an aerobic environment. While sparse DNA damage may be easily repaired, clustered DNA damage may lead to persistent cytotoxic or mutagenic events that can lead to genomic instability. In this study, we tested the hypothesismore » that DNA damage signatures characterised by altered levels of endogenous, potentially mutagenic, types of DNA damage and chromosomal breakage are related to radiation-induced genomic instability and persistent oxidative stress phenotypes observed in the chromosomally unstable progeny of irradiated cells. The measurement of oxypurine, oxypyrimidine and abasic site endogenous DNA damage showed differences in non-double-strand breaks (DSB) clusters among the three of the four unstable clones evaluated as compared to genomically stable clones and the parental cell line. These three unstable clones also had increased levels of DSB clusters. The results of this study demonstrate that each unstable cell line has a unique spectrum of persistent damage and lead us to speculate that alterations in DNA damage signaling and repair may be related to the perpetuation of genomic instability.« less

Correlation of genetic variability with safety of mumps vaccine Urabe AM9 strain.

PubMed

Amexis, G; Fineschi, N; Chumakov, K

2001-08-15

The Urabe AM9 strain of mumps vaccine live is known for its genetic instability and some vaccines derived from this strain were withdrawn from the market due to an excessive number of vaccine-associated parotitis and meningitis cases. To identify the molecular basis of this instability, we determined complete nucleotide sequences of several stocks of the Urabe strain used for vaccine production by different manufacturers and of two clinical isolates from cases of vaccine-associated meningitis. In contrast to previously published studies relating the Lys335 --> Glu mutation in the viral HN gene with neurovirulence of mumps virus, we could not confirm any association of this mutation with the safety of mumps vaccine. Each of the three vaccine stocks studied had its own characteristic profile of mutations that was identified by cDNA sequencing and quantitated by mutant analysis by PCR and restriction enzyme cleavage. Determination of the mutational profile of mumps vaccine lots could allow vaccine manufacturers to characterize seed viruses and monitor the consistency of vaccine production to prevent emergence of virulent revertants.

Aurora-A over-expression in high-grade PIN lesions and prostate cancer.

PubMed

Buschhorn, Holly McKlveen; Klein, Robert R; Chambers, Susan M; Hardy, Margaret C; Green, Sylvan; Bearss, David; Nagle, Raymond B

2005-09-01

Over-expression of Aurora-A (Aurora 2 kinase, STK-15), a protein found in centrosomes thought to be associated with genetic instability, has been previously documented in prostate cancer [Pihan et al.: Cancer Res 61(5):2212-2219, 2001]. It is unknown if this protein is also over-expressed in high-grade prostatic intraepithelial neoplasia (PIN) lesions. PIN lesions were examined for increased Aurora-A using immunohistochemical staining on archival paraffin embedded prostatectomy tissue. Aurora-A expression was scored using size, number, and staining intensity. Protein expression was examined and compared between stromal cells, normal glands, high-grade PIN lesions, and invasive cancer. Immunohistochemistry shows an increased expression of Aurora-A in 96% of high-grade PIN cases, and 98% in cancer lesions. Twenty-nine percent of cases of normal glands from cancerous prostates also showed increased Aurora-A expression. Over-expression of Aurora-A is present in some normal and the majority of high-grade PIN lesions indicating that this may be an early event that leads to the genetic instability seen in prostate carcinogenesis. Copyright 2005 Wiley-Liss, Inc.

Genetic instability of an oligomycin resistance mutation in yeast is associated with an amplification of a mitochondrial DNA segment.

PubMed Central

Ragnini, A; Fukuhara, H

1989-01-01

In the yeast Kluyveromyces lactis, mutations affecting mitochondrial functions are often highly unstable. In order to understand the basis of this genetic instability, we examined the case of an oligomycin resistant mutant. When the mutant was grown in the absence of the drug, the resistance was rapidly lost. This character showed a typical cytoplasmic inheritance. The unstable resistance was found to be associated with the presence of a repetitive DNA in which the repeating unit was a specific segment of the mitochondrial DNA. The amplified molecules were co-replicating with the wild type genome in the mutant cells. The spontaneous loss of the drug resistance was accompanied by the disappearance of the amplified DNA. The repetitive sequence came from a 405 base-pair segment immediately downstream of a cluster of two transfer RNA genes (threonyl 2 and glutamyl). Modified processing of these tRNAs was detected in the mutant. A possible mechanism by which these events could lead to drug resistance is discussed. Images PMID:2780315

Gravitational instability in isotropic MHD plasma waves

NASA Astrophysics Data System (ADS)

Cherkos, Alemayehu Mengesha

2018-04-01

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

Genetic features of metachronous esophageal cancer developed in Hodgkin's lymphoma or breast cancer long-term survivors: an exploratory study.

PubMed

Boldrin, Elisa; Rumiato, Enrica; Fassan, Matteo; Cappellesso, Rocco; Rugge, Massimo; Chiarion-Sileni, Vanna; Ruol, Alberto; Alfieri, Rita; Cagol, Matteo; Castoro, Carlo; Amadori, Alberto; Saggioro, Daniela

2015-01-01

Development of novel therapeutic drugs and regimens for cancer treatment has led to improvements in patient long-term survival. This success has, however, been accompanied by the increased occurrence of second primary cancers. Indeed, patients who received regional radiotherapy for Hodgkin's Lymphoma (HL) or breast cancer may develop, many years later, a solid metachronous tumor in the irradiated field. Despite extensive epidemiological studies, little information is available on the genetic changes involved in the pathogenesis of these solid therapy-related neoplasms. Using microsatellite markers located in 7 chromosomal regions frequently deleted in sporadic esophageal cancer, we investigated loss of heterozygosity (LOH) and microsatellite instability (MSI) in 46 paired (normal and tumor) samples. Twenty samples were of esophageal carcinoma developed in HL or breast cancer long-term survivors: 14 squamous cell carcinomas (ESCC) and 6 adenocarcinomas (EADC), while 26 samples, used as control, were of sporadic esophageal cancer (15 ESCC and 11 EADC). We found that, though the overall LOH frequency at the studied chromosomal regions was similar among metachronous and sporadic tumors, the latter exhibited a statistically different higher LOH frequency at 17q21.31 (p = 0.018). By stratifying for tumor histotype we observed that LOH at 3p24.1, 5q11.2 and 9p21.3 were more frequent in ESCC than in EADC suggesting a different role of the genetic determinants located nearby these regions in the development of the two esophageal cancer histotypes. Altogether, our results strengthen the genetic diversity among ESCC and EADC whether they occurred spontaneously or after therapeutic treatments. The presence of histotype-specific alterations in esophageal carcinoma arisen in HL or breast cancer long-term survivors suggests that their transformation process, though the putative different etiological origin, may retrace sporadic ESCC and EADC carcinogenesis.

[Sexual differences in a state systems of DNA structure maintenance and generation of reactive oxygen species in somatic cells of mice 101/H reparation-defective strain and manifestation of these differences after exposure to ionizing radiation].

PubMed

Mazurik, V K; Mikhaĭlov, V F; Ushenkova, L N; Raeva, N F

2004-01-01

To analyse a role of the factor of a genetic fundamentals of cells in formation of radiation-induced genome instability (RIGI) we investigated a condition of DNA pattern, content of superoxide anion-radical O2*- and a sum of reactive oxigen species (ROS) (O2*-, OH*, H2O2), and also catalase activity in bone marrow cells of male and female mice of 101/H strain in the norm and at once after chronic (10 day) exposure to 200 mGy gamma-radiation. Thus we based on conception about a significance of mechanisms of DNA repair and production of reactive oxygen species (ROS) in development of radiation-induced genome instability (RIGI), and also on the data on sex bound differences in efficiency of DNA repair in reply to impact of the genotoxic agents for male and female mice of 101/H strain. Sex connected differences in redox system of bone marrow cells were established. In males lower catalase activity was found in the norm, with considerable increase of the activity and the content of ROS after chronic irradiation with a low dose (200 mGy); at the same time a direct correlation between the ROS content and catalase activity occurred. In female, which have higher DNA repair potential, higher level of catalase activity was found in the norm, with reduction after irradiation and lower, than in male, level of O2*- content; no changes in the general ROS content, or direct correlation between the content of a superoxide anion-radical (O2*-) and the sum of ROS were observed. The detected differences between male and female the studied parameters in the norm and after irradiation indicate a connection of the studied characteristics and their changes with a sex, confirm the literature data about a significance of the factor of a genetic fundamentals of bioobject in formation of radiation-induced genome instability.

Spaceflight-induced genetic and epigenetic changes in the rice (Oryza sativa L.) genome are independent of each other.

PubMed

Ou, Xiufang; Long, Likun; Wu, Ying; Yu, Yingjie; Lin, Xiuyun; Qi, Xin; Liu, Bao

2010-07-01

An array of studies have reported that the spaceflight environment is mutagenic and may induce phenotypic and genetic changes in diverse organisms. We reported recently that in at least some plant species (e.g., rice) the spaceflight environment can be particularly potent in generating heritable epigenetic changes in the form of altered cytosine methylation patterns and activation of transposable elements. To further study the issue of spaceflight-induced genomic instability, and in particular to test whether the incurred genetic and epigenetic changes are connected or independent of each other, we performed the present study. We subjected seeds of the standard laboratory rice (Oryza sativa L.) cultivar Nipponbare to a spaceflight in the spaceship Long March 2 for 18 days. We then investigated the genetic and DNA methylation stabilities of 11 randomly selected plants germinated from the spaceflown seeds by using two kinds of DNA markers, amplified fragment length polymorphism (AFLP) and methylation sensitive amplified polymorphism (MSAP). For AFLP, by using 15 primer combinations, we assessed 460 genomic loci and found that the frequencies of genetic changes across the 11 plants ranged from 0.7% to 6.7% with an average frequency of 3.5%. For MSAP, by using 14 primer combinations, we assessed 467 loci and detected the occurrence of four major types of cytosine methylation alterations at the CCGG sites, namely CG or CNG hypomethylation and CG or CNG hypermethylation. Collectively, the frequencies of the two kinds of hypermethylation, CG (1.95%) and CNG (1.44%), are about two times higher than those of the two kinds of hypomethylation, CG (0.76%) and CNG (0.80%), though different plants showed variable frequencies for each type of alteration. Further analysis suggested that both the genetic and cytosine methylation changes manifested apparent mutational bias towards specific genomic regions, but the two kinds of instabilities are independent of each other based on correlation analysis.

Genetics of Progressive Supranuclear Palsy.

PubMed

Im, Sun Young; Kim, Young Eun; Kim, Yun Joong

2015-09-01

Progressive supranuclear palsy (PSP) is a neurodegenerative syndrome that is clinically characterized by progressive postural instability, supranuclear gaze palsy, parkinsonism and cognitive decline. Pathologically, diagnosis of PSP is based on characteristic features, such as neurofibrillary tangles, neutrophil threads, tau-positive astrocytes and their processes in basal ganglia and brainstem, and the accumulation of 4 repeat tau protein. PSP is generally recognized as a sporadic disorder; however, understanding of genetic background of PSP has been expanding rapidly. Here we review relevant publications to outline the genetics of PSP. Although only small number of familial PSP cases have been reported, the recognition of familial PSP has been increasing. In some familial cases of clinically probable PSP, PSP pathologies were confirmed based on NINDS neuropathological diagnostic criteria. Several mutations in MAPT, the gene that causes a form of familial frontotemporal lobar degeneration with tauopathy, have been identified in both sporadic and familial PSP cases. The H1 haplotype of MAPT is a risk haplotype for PSP, and within H1, a sub-haplotype (H1c) is associated with PSP. A recent genome-wide association study on autopsyproven PSP revealed additional PSP risk alleles in STX6 and EIF2AK3. Several heredodegenerative parkinsonian disorders are referred to as PSP-look-alikes because their clinical phenotype, but not their pathology, mimics PSP. Due to the fast development of genomics and bioinformatics, more genetic factors related to PSP are expected to be discovered. Undoubtedly, these studies will provide a better understanding of the pathogenesis of PSP and clues for developing therapeutic strategies.

Role of cytogenetic biomarkers in management of chronic kidney disease patients: A review.

PubMed

Khan, Zeba; Pandey, Manoj; Samartha, Ravindra M

2016-10-01

Chronic kidney disease (CKD) is much more common than people recognize, and habitually goes undetected and undiagnosed until the disease is well advanced or when their kidney functions is down to 25% of normal function. Genetic and non-genetic factors contribute to cause CKD. Non-genetic factors include hypertension, High level of DNA damage due to the production of reactive oxygen species and nucleic acid oxidation has been reported in CKD patients. Main genetic factor which causes CKD is diabetic nephropathy. A three- to nine-fold greater risk of End Stage Renal Disease (ESRD) is observed in individuals with a family history of ESRD. This greater risk have led researchers to search for genes linked to diabetic and other forms of nephropathy for the management of CKD. Multicenter consortia are currently recruiting large numbers of multiplex diabetic families with index cases having nephropathy for linkage and association analyses using various cytogenetic techniques. In addition, large-scale screening studies are underway, with the goals of better defining the overall prevalence of chronic kidney disease, as well as educating the population about risk factors for nephropathy, including family history. Cytogenetic biomarkers play an imperative role for the linkage study using G banding and detection of genomic instability in CKD patients. Classical and molecular cytogenetic tools with cytogenetic biomarkers provide remarkable findings in CKD patients. The aim of the present review is to draw outline of classical and molecular cytogenetic findings in CKD patients and their possible role in management to reduce genomic instability in CKD patients.

Family Structure Transitions and Child Development: Instability, Selection, and Population Heterogeneity.

PubMed

Lee, Dohoon; McLanahan, Sara

2015-08-01

A growing literature documents the importance of family instability for child wellbeing. In this article, we use longitudinal data from the Fragile Families and Child Wellbeing Study to examine the impacts of family instability on children's cognitive and socioemotional development in early and middle childhood. We extend existing research in several ways: (1) by distinguishing between the number and types of family structure changes; (2) by accounting for time-varying as well as time-constant confounding; and (3) by assessing racial/ethnic and gender differences in family instability effects. Our results indicate that family instability has a causal effect on children's development, but the effect depends on the type of change, the outcome assessed, and the population examined. Generally speaking, transitions out of a two-parent family are more negative for children's development than transitions into a two-parent family. The effect of family instability is stronger for children's socioemotional development than for their cognitive achievement. For socioemotional development, transitions out of a two-parent family are more negative for white children, whereas transitions into a two-parent family are more negative for Hispanic children. These findings suggest that future research should pay more attention to the type of family structure transition and to population heterogeneity.

Family Structure Transitions and Child Development: Instability, Selection, and Population Heterogeneity

PubMed Central

Lee, Dohoon; McLanahan, Sara

2016-01-01

A growing literature documents the importance of family instability for child wellbeing. In this article, we use longitudinal data from the Fragile Families and Child Wellbeing Study to examine the impacts of family instability on children’s cognitive and socioemotional development in early and middle childhood. We extend existing research in several ways: (1) by distinguishing between the number and types of family structure changes; (2) by accounting for time-varying as well as time-constant confounding; and (3) by assessing racial/ethnic and gender differences in family instability effects. Our results indicate that family instability has a causal effect on children’s development, but the effect depends on the type of change, the outcome assessed, and the population examined. Generally speaking, transitions out of a two-parent family are more negative for children’s development than transitions into a two-parent family. The effect of family instability is stronger for children’s socioemotional development than for their cognitive achievement. For socioemotional development, transitions out of a two-parent family are more negative for white children, whereas transitions into a two-parent family are more negative for Hispanic children. These findings suggest that future research should pay more attention to the type of family structure transition and to population heterogeneity. PMID:27293242

PRDM9 variation strongly influences recombination hot-spot activity and meiotic instability in humans.

PubMed

Berg, Ingrid L; Neumann, Rita; Lam, Kwan-Wood G; Sarbajna, Shriparna; Odenthal-Hesse, Linda; May, Celia A; Jeffreys, Alec J

2010-10-01

PRDM9 has recently been identified as a likely trans regulator of meiotic recombination hot spots in humans and mice. PRDM9 contains a zinc finger array that, in humans, can recognize a short sequence motif associated with hot spots, with binding to this motif possibly triggering hot-spot activity via chromatin remodeling. We now report that human genetic variation at the PRDM9 locus has a strong effect on sperm hot-spot activity, even at hot spots lacking the sequence motif. Subtle changes within the zinc finger array can create hot-spot nonactivating or enhancing variants and can even trigger the appearance of a new hot spot, suggesting that PRDM9 is a major global regulator of hot spots in humans. Variation at the PRDM9 locus also influences aspects of genome instability-specifically, a megabase-scale rearrangement underlying two genomic disorders as well as minisatellite instability-implicating PRDM9 as a risk factor for some pathological genome rearrangements.

Influence of nonlinear interactions on the development of instability in hydrodynamic wave systems

DOE Office of Scientific and Technical Information (OSTI.GOV)

Romanova, N. N.; Chkhetiani, O. G., E-mail: ochkheti@mx.iki.rssi.ru, E-mail: ochkheti@gmail.ru; Yakushkin, I. G.

2016-05-15

The problem of the development of shear instability in a three-layer medium simulating the flow of a stratified incompressible fluid is considered. The hydrodynamic equations are solved by expanding the Hamiltonian in a small parameter. The equations for three interacting waves, one of which is unstable, have been derived and solved numerically. The three-wave interaction is shown to stabilize the instability. Various regimes of the system’s dynamics, including the stochastic ones dependent on one of the invariants in the problem, can arise in this case. It is pointed out that the instability development scenario considered differs from the previously consideredmore » scenario of a different type, where the three-wave interaction does not stabilize the instability. The interaction of wave packets is considered briefly.« less

Radiation induces genomic instability and mammary ductal dysplasia in Atm heterozygous mice

NASA Technical Reports Server (NTRS)

Weil, M. M.; Kittrell, F. S.; Yu, Y.; McCarthy, M.; Zabriskie, R. C.; Ullrich, R. L.

2001-01-01

Ataxia-telangiectasia (AT) is a genetic syndrome resulting from the inheritance of two defective copies of the ATM gene that includes among its stigmata radiosensitivity and cancer susceptibility. Epidemiological studies have demonstrated that although women with a single defective copy of ATM (AT heterozygotes) appear clinically normal, they may never the less have an increased relative risk of developing breast cancer. Whether they are at increased risk for radiation-induced breast cancer from medical exposures to ionizing radiation is unknown. We have used a murine model of AT to investigate the effect of a single defective Atm allele, the murine homologue of ATM, on the susceptibility of mammary epithelial cells to radiation-induced transformation. Here we report that mammary epithelial cells from irradiated mice with one copy of Atm truncated in the PI-3 kinase domain were susceptible to radiation-induced genomic instability and generated a 10% incidence of dysplastic mammary ducts when transplanted into syngenic recipients, whereas cells from Atm(+/+) mice were stable and formed only normal ducts. Since radiation-induced ductal dysplasia is a precursor to mammary cancer, the results indicate that AT heterozygosity increases susceptibility to radiogenic breast cancer in this murine model system.

Single sperm analysis of the trinucleotide repeat in the Huntington`s disease gene

DOE Office of Scientific and Technical Information (OSTI.GOV)

Leeflang, E.P.; Zhang, L.; Hubert, R.

1994-09-01

Huntington`s disease (HD) is one of several genetic diseases caused by trinucleotide repeat expansion. The CAG repeat is very unstable, with size changes occurring in more than 80% of transmissions. The degree of instability of this repeat in the male germline can be determined by analysis of individual sperm cells. An easy and sensitive PCR assay has been developed to amplify this trinucleotide repeat region from single sperm using two rounds of PCR. As many as 90% of the single sperm show amplification for the HD repeat. The PCR product can be easily detected on an ethidium bromide-stained agarose gel.more » Single sperm samples from an HD patient with 18 and 49 repeats were studied. We observed size variations for the expanded alleles while the size of the normal allele in sperm is very consistent. We did not detect any significant bias in the amplification of normal alleles over the larger HD alleles. Our preliminary study supports the observation made by PCR of total sperm that instability of the HD trinucleotide repeat occurs in the germline. HD preimplantation diagnosis on single embryo blastomeres may also possible.« less

The effects of muscle hypotonia and weakness on balance: a study on Prader-Willi and Ehlers-Danlos syndrome patients.

PubMed

Galli, Manuela; Cimolin, Veronica; Vismara, Luca; Grugni, Graziano; Camerota, Filippo; Celletti, Claudia; Albertini, Giorgio; Rigoldi, Chiara; Capodaglio, Paolo

2011-01-01

Prader-Willi syndrome (PWS) and Ehlers-Danlos syndrome (EDS) are two different genetical disorders both characterized, among other features, by muscular hypotonia. Postural control seems to be impaired in both conditions. The aim of the present study was to quantitatively compare postural control in adult PWS and EDS using stabilometric platform to unveil possible common determinants of impaired balance. We enrolled 11 PWS and 21 EDS adult patients and 20 age-matched controls. They were instructed to maintain an upright standing position for 30s with open eyes (OEs) focusing on a 6 cm black circle positioned at a distance of 1.5m. Both PWS and EDS patients were characterized by higher RANGEML, RANGEAP and trajectory length of CoP values as compared to CG. No statistically differences were found between PWS and EDS in terms of any of these parameters. The results demonstrated that both PWS and EDS are characterized by a severe postural instability. Muscle hypotonia and weakness may account for reduced balance capacity. Quantitative characterization of instability is important to identify, develop and enhance rehabilitation interventions. Copyright © 2011 Elsevier Ltd. All rights reserved.

Distinct genetic profiles in colorectal tumors with or without the CpG island methylator phenotype

PubMed Central

Toyota, Minoru; Ohe-Toyota, Mutsumi; Ahuja, Nita; Issa, Jean-Pierre J.

2000-01-01

Colorectal cancers (CRCs) are characterized by multiple genetic (mutations) and epigenetic (CpG island methylation) alterations, but it is not known whether these evolve independently through stochastic processes. We have recently described a novel pathway termed CpG island methylator phenotype (CIMP) in CRC, which is characterized by the simultaneous methylation of multiple CpG islands, including several known genes, such as p16, hMLH1, and THBS1. We have now studied mutations in K-RAS, p53, DPC4, and TGFβRII in a panel of colorectal tumors with or without CIMP. We find that CIMP defines two groups of tumors with significantly different genetic lesions: frequent K-RAS mutations were found in CIMP+ CRCs (28/41, 68%) compared with CIMP− cases (14/47, 30%, P = 0.0005). By contrast, p53 mutations were found in 24% (10/41) of CIMP+ CRCs vs. 60% (30/46) of CIMP− cases (P = 0.002). Both of these differences were independent of microsatellite instability. These interactions between CIMP, K-RAS mutations, and p53 mutations were preserved in colorectal adenomas, suggesting that they occur early in carcinogenesis. The distinct combinations of epigenetic and genetic alterations in each group suggest that activation of oncogenes and inactivation of tumor suppressor genes is related to the underlying mechanism of generating molecular diversity in cancer, rather than simply accumulate stochastically during cancer development. PMID:10639144

Characterization and Simulation of the Thermoacoustic Instability Behavior of an Advanced, Low Emissions Combustor Prototype

NASA Technical Reports Server (NTRS)

DeLaat, John C.; Paxson, Daniel E.

2008-01-01

Extensive research is being done toward the development of ultra-low-emissions combustors for aircraft gas turbine engines. However, these combustors have an increased susceptibility to thermoacoustic instabilities. This type of instability was recently observed in an advanced, low emissions combustor prototype installed in a NASA Glenn Research Center test stand. The instability produces pressure oscillations that grow with increasing fuel/air ratio, preventing full power operation. The instability behavior makes the combustor a potentially useful test bed for research into active control methods for combustion instability suppression. The instability behavior was characterized by operating the combustor at various pressures, temperatures, and fuel and air flows representative of operation within an aircraft gas turbine engine. Trends in instability behavior versus operating condition have been identified and documented, and possible explanations for the trends provided. A simulation developed at NASA Glenn captures the observed instability behavior. The physics-based simulation includes the relevant physical features of the combustor and test rig, employs a Sectored 1-D approach, includes simplified reaction equations, and provides time-accurate results. A computationally efficient method is used for area transitions, which decreases run times and allows the simulation to be used for parametric studies, including control method investigations. Simulation results show that the simulation exhibits a self-starting, self-sustained combustion instability and also replicates the experimentally observed instability trends versus operating condition. Future plans are to use the simulation to investigate active control strategies to suppress combustion instabilities and then to experimentally demonstrate active instability suppression with the low emissions combustor prototype, enabling full power, stable operation.

Characterization and Simulation of Thermoacoustic Instability in a Low Emissions Combustor Prototype

NASA Technical Reports Server (NTRS)

DeLaat, John C.; Paxson, Daniel E.

2008-01-01

Extensive research is being done toward the development of ultra-low-emissions combustors for aircraft gas turbine engines. However, these combustors have an increased susceptibility to thermoacoustic instabilities. This type of instability was recently observed in an advanced, low emissions combustor prototype installed in a NASA Glenn Research Center test stand. The instability produces pressure oscillations that grow with increasing fuel/air ratio, preventing full power operation. The instability behavior makes the combustor a potentially useful test bed for research into active control methods for combustion instability suppression. The instability behavior was characterized by operating the combustor at various pressures, temperatures, and fuel and air flows representative of operation within an aircraft gas turbine engine. Trends in instability behavior vs. operating condition have been identified and documented. A simulation developed at NASA Glenn captures the observed instability behavior. The physics-based simulation includes the relevant physical features of the combustor and test rig, employs a Sectored 1-D approach, includes simplified reaction equations, and provides time-accurate results. A computationally efficient method is used for area transitions, which decreases run times and allows the simulation to be used for parametric studies, including control method investigations. Simulation results show that the simulation exhibits a self-starting, self-sustained combustion instability and also replicates the experimentally observed instability trends vs. operating condition. Future plans are to use the simulation to investigate active control strategies to suppress combustion instabilities and then to experimentally demonstrate active instability suppression with the low emissions combustor prototype, enabling full power, stable operation.

Darrieus-Landau instability of premixed flames enhanced by fuel droplets

NASA Astrophysics Data System (ADS)

Nicoli, Colette; Haldenwang, Pierre; Denet, Bruno

2017-07-01

Recent experiments on spray flames propagating in a Wilson cloud chamber have established that spray flames are much more sensitive to wrinkles or corrugations than single-phase flames. To propose certain elements of explanation, we numerically study the Darrieus-Landau (or hydrodynamic) instability (DL-instability) developing in premixtures that contain an array of fuel droplets. Two approaches are compared: numerical simulation starting from the general conservation laws in reactive media, and the numerical computation of Sivashinsky-type model equations for DL-instability. Both approaches provide us with results in deep agreement. It is first shown that the presence of droplets in fuel-air premixtures induces initial perturbations which are large enough to trigger the DL-instability. Second, the droplets are responsible for additional wrinkles when the DL-instability is developed. The latter wrinkles are of length scales shorter than those of the DL-instability, in such a way that the DL-unstable spray flames have a larger front surface and therefore propagate faster than the single-phase ones when subjected to the same instability.

Centrifugally Driven Rayleigh-Taylor Instability

NASA Astrophysics Data System (ADS)

Scase, Matthew; Hill, Richard

2017-11-01

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

[Genetically modified food--great unknown].

PubMed

Cichosz, G; Wiackowski, S K

2012-08-01

Genetically modified food (GMF) creates evident threat to consumers' health. In spite of assurances of biotechnologists, DNA of transgenic plants is instable, so, synthesis of foreign, allergenic proteins is possible. Due to high trypsin inhibitor content the GMF is digested much more slowly what, alike Bt toxin presence, increases probability of alimentary canal diseases. Next threats are bound to the presence of fitoestrogens and residues of Roundup pesticide, that can diminish reproductiveness; and even lead to cancerogenic transformation through disturbance of human hormonal metabolism. In spite of food producers and distributors assurances that food made of GMF raw materials is marked, de facto consumers have no choice. Moreover, along the food law products containing less than 0.9% of GMF protein are not included into genetically modified food.

Taylor instability in rhyolite lava flows

NASA Technical Reports Server (NTRS)

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

1989-01-01

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

The immune receptor Trem1 cooperates with diminished DNA damage response to induce preleukemic stem cell expansion.

PubMed

Du, W; Amarachintha, S; Wilson, A; Pang, Q

2017-02-01

Fanconi anemia (FA) is an inherited bone marrow failure syndrome with extremely high risk of leukemic transformation. Here we investigate the relationship between DNA damage response (DDR) and leukemogenesis using the Fanca knockout mouse model. We found that chronic exposure of the Fanca -/- hematopoietic stem cells to DNA crosslinking agent mitomycin C in vivo leads to diminished DDR, and the emergence/expansion of pre-leukemia stem cells (pre-LSCs). Surprisingly, although genetic correction of Fanca deficiency in the pre-LSCs restores DDR and reduces genomic instability, but fails to prevent pre-LSC expansion or delay leukemia development in irradiated recipients. Furthermore, we identified transcription program underlying dysregulated DDR and cell migration, myeloid proliferation, and immune response in the Fanca -/- pre-LSCs. Forced expression of the downregulated DNA repair genes, Rad51c or Trp53i13, in the Fanca -/- pre-LSCs partially rescues DDR but has no effect on leukemia, whereas shRNA knockdown of the upregulated immune receptor genes Trem1 or Pilrb improves leukemia-related survival, but not DDR or genomic instability. Furthermore, Trem1 cooperates with diminished DDR in vivo to promote Fanca -/- pre-LSC expansion and leukemia development. Our study implicates diminishing DDR as a root cause of FA leukemogenesis, which subsequently collaborates with other signaling pathways for leukemogenic transformation.

DNA repair and tumorigenesis: lessons from hereditary cancer syndromes.

PubMed

Heinen, Christopher D; Schmutte, Christoph; Fishel, Richard

2002-01-01

The discovery that alterations of the DNA mismatch repair system (MMR) were linked to the common human cancer susceptibility syndrome hereditary nonpolyposis colon cancer (HNPCC) resulted in the declaration of a third class of genes involved in tumor development. In addition to oncogenes and tumor suppressors, alterations of DNA repair genes involved in maintaining genomic stability were found to be a clear cause of tum the level of the single nucleotides or chromosomes. This observation suggested that the establishment of genomic instability, termed the Mutator Phenotype, was an important aspect of tumor development.(1,2) Since the initial identification of the human MutS homolog hMSH2 nearly a decade ago,(3,4) more links have been described between human cancers and genes involved in maintaining genomic stability. Work in recent years has revealed that DNA repair proteins may also function in signaling pathways that provoke cell cycle arrest and apoptosis. This review will focus on the genetic and biochemical functions of DNA repair genes linked to hereditary cancer predisposition characterized by genomic instability (Table 1). Interestingly, the protein products of these genes have been directly or indirectly linked to the DNA damage-induce cell cycle arrest and apoptosis. We conclude that a robust connection between DNA repair proteins and damage-induced apoptosis may be as important for tumorigenesis as their role in maintaining genome stability.

Upstream ionization instability associated with a current-free double layer.

PubMed

Aanesland, A; Charles, C; Lieberman, M A; Boswell, R W

2006-08-18

A low frequency instability has been observed using various electrostatic probes in a low-pressure expanding helicon plasma. The instability is associated with the presence of a current-free double layer (DL). The frequency of the instability increases linearly with the potential drop of the DL, and simultaneous measurements show their coexistence. A theory for an upstream ionization instability has been developed, which shows that electrons accelerated through the DL increase the ionization upstream and are responsible for the observed instability. The theory is in good agreement with the experimental results.

Breeding for sustainable production in a changing climate – understanding the physiological basis of genetic by environmental interactions

USDA-ARS?s Scientific Manuscript database

Abiotic stresses (drought, cold, heat, excess, water, salinity) result in loses in yield and quality of crops. In addition, these stresses limit the areas that can be cultivated because of yield instability and crop loss. Global warming models predict erratic weather patterns making the impact of th...

Fluctuating Asymmetry and General Intelligence: No Genetic or Phenotypic Association

ERIC Educational Resources Information Center

Johnson, Wendy; Segal, Nancy L.; Bouchard, Thomas J., Jr.

2008-01-01

Fluctuating asymmetry (FA) is the non-pathological left-right asymmetry of body traits that are usually left-right symmetrical, such as eye breadths and elbow to wrist lengths in humans, but which can be affected by developmental stressors. It is generally considered throughout biology to be an indicator of developmental instability and thus of…

Demonstration of Active Combustion Control

NASA Technical Reports Server (NTRS)

Lovett, Jeffrey A.; Teerlinck, Karen A.; Cohen, Jeffrey M.

2008-01-01

The primary objective of this effort was to demonstrate active control of combustion instabilities in a direct-injection gas turbine combustor that accurately simulates engine operating conditions and reproduces an engine-type instability. This report documents the second phase of a two-phase effort. The first phase involved the analysis of an instability observed in a developmental aeroengine and the design of a single-nozzle test rig to replicate that phenomenon. This was successfully completed in 2001 and is documented in the Phase I report. This second phase was directed toward demonstration of active control strategies to mitigate this instability and thereby demonstrate the viability of active control for aircraft engine combustors. This involved development of high-speed actuator technology, testing and analysis of how the actuation system was integrated with the combustion system, control algorithm development, and demonstration testing in the single-nozzle test rig. A 30 percent reduction in the amplitude of the high-frequency (570 Hz) instability was achieved using actuation systems and control algorithms developed within this effort. Even larger reductions were shown with a low-frequency (270 Hz) instability. This represents a unique achievement in the development and practical demonstration of active combustion control systems for gas turbine applications.

Development and Breakdown of Goertler Vortices in High Speed Boundary Layers

NASA Technical Reports Server (NTRS)

Li, Fei; Choudhari, Meelan; Chang, Chau-Lyan; Wu, Minwei; Greene, Ptrick T.

2010-01-01

The nonlinear development of G rtler instability over a concave surface gives rise to a highly distorted stationary flow in the boundary layer that has strong velocity gradients in both spanwise and wall-normal directions. This distorted flow is susceptible to strong, high frequency secondary instability that leads to the onset of transition. For high Mach number flows, the boundary layer is also subject to the second mode instability. The nonlinear development of G rtler vortices and the ensuing growth and breakdown of secondary instability, the G rtler vortex interactions with second mode instabilities as well as oblique second mode interactions are examined in the context of both internal and external hypersonic configurations using nonlinear parabolized stability equations, 2-D eigenvalue analysis and direct numerical simulation. For G rtler vortex development inside the Purdue Mach 6 Ludwieg tube wind tunnel, multiple families of unstable secondary eigenmodes are identified and their linear and nonlinear evolution is examined. The computation of secondary instability is continued past the onset of transition to elucidate the physical mechanisms underlying the laminar breakdown process. Nonlinear breakdown scenarios associated with transition over a Mach 6 compression cone configuration are also explored.

Mix and hydrodynamic instabilities on NIF

NASA Astrophysics Data System (ADS)

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.

Mix and hydrodynamic instabilities on NIF

DOE PAGES

Smalyuk, V. A.; Robey, H. F.; Casey, D. T.; ...

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. Here in the deceleration phase of implosions, several experimental platformsmore » 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.« less

Cost-Effectiveness Analysis of Different Genetic Testing Strategies for Lynch Syndrome in Taiwan.

PubMed

Chen, Ying-Erh; Kao, Sung-Shuo; Chung, Ren-Hua

2016-01-01

Patients with Lynch syndrome (LS) have a significantly increased risk of developing colorectal cancer (CRC) and other cancers. Genetic screening for LS among patients with newly diagnosed CRC aims to identify mutations in the disease-causing genes (i.e., the DNA mismatch repair genes) in the patients, to offer genetic testing for relatives of the patients with the mutations, and then to provide early prevention for the relatives with the mutations. Several genetic tests are available for LS, such as DNA sequencing for MMR genes and tumor testing using microsatellite instability and immunohistochemical analyses. Cost-effectiveness analyses of different genetic testing strategies for LS have been performed in several studies from different countries such as the US and Germany. However, a cost-effectiveness analysis for the testing has not yet been performed in Taiwan. In this study, we evaluated the cost-effectiveness of four genetic testing strategies for LS described in previous studies, while population-specific parameters, such as the mutation rates of the DNA mismatch repair genes and treatment costs for CRC in Taiwan, were used. The incremental cost-effectiveness ratios based on discounted life years gained due to genetic screening were calculated for the strategies relative to no screening and to the previous strategy. Using the World Health Organization standard, which was defined based on Taiwan's Gross Domestic Product per capita, the strategy based on immunohistochemistry as a genetic test followed by BRAF mutation testing was considered to be highly cost-effective relative to no screening. Our probabilistic sensitivity analysis results also suggest that the strategy has a probability of 0.939 of being cost-effective relative to no screening based on the commonly used threshold of $50,000 to determine cost-effectiveness. To the best of our knowledge, this is the first cost-effectiveness analysis for evaluating different genetic testing strategies for LS in Taiwan. The results will be informative for the government when considering offering screening for LS in patients newly diagnosed with CRC.

Genetic stability and instability of the cis-acting control element of the 5' untranslated region of the poliovirus RNA.

PubMed

Agol, V I

1993-01-01

The poliovirus genome exhibits tremendous plasticity, which is particularly evident when mutations diminishing the growth potential are introduced into the genome. An amazing variability can be observed even among the genomes derived from a single plaque. Not less amazing is the stability of the viral RNA sequences, which could be revealed, for example, upon the analysis of populations of a given viral strain separated by many cycles of reproduction in different laboratories but under standard conditions. This stability is obviously due to very strong selection for the "fit" phenotype. Implications of both the stability and instability of the poliovirus genome for the design, production and use of live poliovirus vaccines are briefly discussed.

DNA replication stress and cancer chemotherapy.

PubMed

Kitao, Hiroyuki; Iimori, Makoto; Kataoka, Yuki; Wakasa, Takeshi; Tokunaga, Eriko; Saeki, Hiroshi; Oki, Eiji; Maehara, Yoshihiko

2018-02-01

DNA replication is one of the fundamental biological processes in which dysregulation can cause genome instability. This instability is one of the hallmarks of cancer and confers genetic diversity during tumorigenesis. Numerous experimental and clinical studies have indicated that most tumors have experienced and overcome the stresses caused by the perturbation of DNA replication, which is also referred to as DNA replication stress (DRS). When we consider therapeutic approaches for tumors, it is important to exploit the differences in DRS between tumor and normal cells. In this review, we introduce the current understanding of DRS in tumors and discuss the underlying mechanism of cancer therapy from the aspect of DRS. © 2017 The Authors. Cancer Science published by John Wiley & Sons Australia, Ltd on behalf of Japanese Cancer Association.

A mobile threat to genome stability: The impact of non-LTR retrotransposons upon the human genome

PubMed Central

Konkel, Miriam K.; Batzer, Mark A.

2010-01-01

It is now commonly agreed that the human genome is not the stable entity originally presumed. Deletions, duplications, inversions, and insertions are common, and contribute significantly to genomic structural variations (SVs). Their collective impact generates much of the inter-individual genomic diversity observed among humans. Not only do these variations change the structure of the genome; they may also have functional implications, e.g. altered gene expression. Some SVs have been identified as the cause of genetic disorders, including cancer predisposition. Cancer cells are notorious for their genomic instability, and often show genomic rearrangements at the microscopic and submicroscopic level to which transposable elements (TEs) contribute. Here, we review the role of TEs in genome instability, with particular focus on non-LTR retrotransposons. Currently, three non-LTR retrotransposon families – long interspersed element 1 (L1), SVA (short interspersed element (SINE-R), variable number of tandem repeats (VNTR), and Alu), and Alu (a SINE) elements – mobilize in the human genome, and cause genomic instability through both insertion- and post-insertion-based mutagenesis. Due to the abundance and high sequence identity of TEs, they frequently mislead the homologous recombination repair pathway into non-allelic homologous recombination, causing deletions, duplications, and inversions. While less comprehensively studied, non-LTR retrotransposon insertions and TE-mediated rearrangements are probably more common in cancer cells than in healthy tissue. This may be at least partially attributed to the commonly seen global hypomethylation as well as general epigenetic dysfunction of cancer cells. Where possible, we provide examples that impact cancer predisposition and/or development. PMID:20307669

Bcr/Abl interferes with the Fanconi anemia/BRCA pathway: implications in the chromosomal instability of chronic myeloid leukemia cells.

PubMed

Valeri, Antonio; Alonso-Ferrero, Maria Eugenia; Río, Paula; Pujol, María Roser; Casado, José A; Pérez, Laura; Jacome, Ariana; Agirre, Xabier; Calasanz, Maria José; Hanenberg, Helmut; Surrallés, Jordi; Prosper, Felipe; Albella, Beatriz; Bueren, Juan A

2010-12-28

Chronic myeloid leukemia (CML) is a malignant clonal disorder of the hematopoietic system caused by the expression of the BCR/ABL fusion oncogene. Although it is well known that CML cells are genetically unstable, the mechanisms accounting for this genomic instability are still poorly understood. Because the Fanconi anemia (FA) pathway is believed to control several mechanisms of DNA repair, we investigated whether this pathway was disrupted in CML cells. Our data show that CML cells have a defective capacity to generate FANCD2 nuclear foci, either in dividing cells or after DNA damage. Similarly, human cord blood CD34(+) cells transduced with BCR/ABL retroviral vectors showed impaired FANCD2 foci formation, whereas FANCD2 monoubiquitination in these cells was unaffected. Soon after the transduction of CD34(+) cells with BCR/ABL retroviral vectors a high proportion of cells with supernumerary centrosomes was observed. Similarly, BCR/ABL induced a high proportion of chromosomal abnormalities, while mediated a cell survival advantage after exposure to DNA cross-linking agents. Significantly, both the impaired formation of FANCD2 nuclear foci, and also the predisposition of BCR/ABL cells to develop centrosomal and chromosomal aberrations were reverted by the ectopic expression of BRCA1. Taken together, our data show for the first time a disruption of the FA/BRCA pathway in BCR/ABL cells, suggesting that this defective pathway should play an important role in the genomic instability of CML by the co-occurrence of centrosomal amplification and DNA repair deficiencies.

Development and translational imaging of a TP53 porcine tumorigenesis model

PubMed Central

Sieren, Jessica C.; Meyerholz, David K.; Wang, Xiao-Jun; Davis, Bryan T.; Newell, John D.; Hammond, Emily; Rohret, Judy A.; Rohret, Frank A.; Struzynski, Jason T.; Goeken, J. Adam; Naumann, Paul W.; Leidinger, Mariah R.; Taghiyev, Agshin; Van Rheeden, Richard; Hagen, Jussara; Darbro, Benjamin W.; Quelle, Dawn E.; Rogers, Christopher S.

2014-01-01

Cancer is the second deadliest disease in the United States, necessitating improvements in tumor diagnosis and treatment. Current model systems of cancer are informative, but translating promising imaging approaches and therapies to clinical practice has been challenging. In particular, the lack of a large-animal model that accurately mimics human cancer has been a major barrier to the development of effective diagnostic tools along with surgical and therapeutic interventions. Here, we developed a genetically modified porcine model of cancer in which animals express a mutation in TP53 (which encodes p53) that is orthologous to one commonly found in humans (R175H in people, R167H in pigs). TP53R167H/R167H mutant pigs primarily developed lymphomas and osteogenic tumors, recapitulating the tumor types observed in mice and humans expressing orthologous TP53 mutant alleles. CT and MRI imaging data effectively detected developing tumors, which were validated by histopathological evaluation after necropsy. Molecular genetic analyses confirmed that these animals expressed the R167H mutant p53, and evaluation of tumors revealed characteristic chromosomal instability. Together, these results demonstrated that TP53R167H/R167H pigs represent a large-animal tumor model that replicates the human condition. Our data further suggest that this model will be uniquely suited for developing clinically relevant, noninvasive imaging approaches to facilitate earlier detection, diagnosis, and treatment of human cancers. PMID:25105366

Corrupting the DNA damage response: a critical role for Rad52 in tumor cell survival.

PubMed

Lieberman, Rachel; You, Ming

2017-07-15

The DNA damage response enables cells to survive, maintain genome integrity, and to safeguard the transmission of high-fidelity genetic information. Upon sensing DNA damage, cells respond by activating this multi-faceted DNA damage response leading to restoration of the cell, senescence, programmed cell death, or genomic instability if the cell survives without proper repair. However, unlike normal cells, cancer cells maintain a marked level of genomic instability. Because of this enhanced propensity to accumulate DNA damage, tumor cells rely on homologous recombination repair as a means of protection from the lethal effect of both spontaneous and therapy-induced double-strand breaks (DSBs) in DNA. Thus, modulation of DNA repair pathways have important consequences for genomic instability within tumor cell biology and viability maintenance under high genotoxic stress. Efforts are underway to manipulate specific components of the DNA damage response in order to selectively induce tumor cell death by augmenting genomic instability past a viable threshold. New evidence suggests that RAD52, a component of the homologous recombination pathway, is important for the maintenance of tumor genome integrity. This review highlights recent reports indicating that reducing homologous recombination through inhibition of RAD52 may represent an important focus for cancer therapy and the specific efforts that are already demonstrating potential.

[Cytomixis, its nature, significance and the cytological consequences].

PubMed

Kravets, E A

2012-01-01

Cytomixis is the widespread natural process of intercellular interaction which is characteristic for vegetative and generative tissues in both normal and pathological conditions. The origin significance and genetic control cytomixis still remain not completely clear. The popularity of view of the pathological nature of cytomixis based on its peculiar plants with genetic instability and impaired homeostasis. In the genetic control of cytomixis seem to be involved meiotic genes which are responsible for segregation and organization of chromosomes. Their activity is modified by environmental factors through signal transduction. It is assumed via cytomixis, from one side, the informational contact can be reached and meiosis and gametogenesis are synchronized, with another, increase of the genetic variety and level of the heterozygosis of microsporocytes. The activity of cytomixis varies over wide limits. The greatest influence on its activity have mutagenesis hybridization and polyploidy. In this context cytomixis can fulfill the function of cell selection which is activated by exceeding of the threshold level of the microsporocyte damages (or genetical disbalance).

A new classification system for shoulder instability.

PubMed

Kuhn, John E

2010-04-01

Glenohumeral joint instability is extremely common yet the definition and classification of instability remains unclear. In order to find the best ways to treat instability, the condition must be clearly defined and classified. This is particularly important so that treatment studies can be compared or combined, which can only be done if the patient population under study is the same. The purpose of this paper was to review the problems with historical methods of defining and classifying instability and to introduce the FEDS system of classifying instability, which was developed to have content validity and found to have high interobserver and intraobserver agreement.

Beam-plasma instability in inhomogeneous magnetic field and second order cyclotron resonance effects

NASA Astrophysics Data System (ADS)

Trakhtengerts, V. Y.; Hobara, Y.; Demekhov, A. G.; Hayakawa, M.

1999-03-01

A new analytical approach to cyclotron instability of electron beams with sharp gradients in velocity space (step-like distribution function) is developed taking into account magnetic field inhomogeneity and nonstationary behavior of the electron beam velocity. Under these conditions, the conventional hydrodynamic instability of such beams is drastically modified and second order resonance effects become important. It is shown that the optimal conditions for the instability occur for nonstationary quasimonochromatic wavelets whose frequency changes in time. The theory developed permits one to estimate the wave amplification and spatio-temporal characteristics of these wavelets.

On the shear instability in relativistic neutron stars

NASA Astrophysics Data System (ADS)

Corvino, Giovanni; Rezzolla, Luciano; Bernuzzi, Sebastiano; De Pietri, Roberto; Giacomazzo, Bruno

2010-06-01

We present new results on instabilities in rapidly and differentially rotating neutron stars. We model the stars in full general relativity and describe the stellar matter adopting a cold realistic equation of state based on the unified SLy prescription (Douchin and Haensel 2001 Astron. Astrophys. 380 151-67). We provide evidence that rapidly and differentially rotating stars that are below the expected threshold for the dynamical bar-mode instability, βc ≡ T/|W| ~= 0.25, do nevertheless develop a shear instability on a dynamical timescale and for a wide range of values of β. This class of instability, which has so far been found only for small values of β and with very small growth rates, is therefore more generic than previously found and potentially more effective in producing strong sources of gravitational waves. Overall, our findings support the phenomenological predictions made by Watts et al (2005 Astrophys. J. 618 L37) on the nature of the low-T/|W| instability as the manifestation of a shear instability in a region where the latter is possible only for small values of β. Furthermore, our results provide additional insight on shear instabilities and on the necessary conditions for their development.

Active Control of High Frequency Combustion Instability in Aircraft Gas-Turbine Engines

NASA Technical Reports Server (NTRS)

Corrigan, Bob (Technical Monitor); DeLaat, John C.; Chang, Clarence T.

2003-01-01

Active control of high-frequency (greater than 500 Hz) combustion instability has been demonstrated in the NASA single-nozzle combustor rig at United Technologies Research Center. The combustor rig emulates an actual engine instability and has many of the complexities of a real engine combustor (i.e. actual fuel nozzle and swirler, dilution cooling, etc.) In order to demonstrate control, a high-frequency fuel valve capable of modulating the fuel flow at up to 1kHz was developed. Characterization of the fuel delivery system was accomplished in a custom dynamic flow rig developed for that purpose. Two instability control methods, one model-based and one based on adaptive phase-shifting, were developed and evaluated against reduced order models and a Sectored-1-dimensional model of the combustor rig. Open-loop fuel modulation testing in the rig demonstrated sufficient fuel modulation authority to proceed with closed-loop testing. During closed-loop testing, both control methods were able to identify the instability from the background noise and were shown to reduce the pressure oscillations at the instability frequency by 30%. This is the first known successful demonstration of high-frequency combustion instability suppression in a realistic aero-engine environment. Future plans are to carry these technologies forward to demonstration on an advanced low-emission combustor.

Gravitational Instabilities in Circumstellar Disks

NASA Astrophysics Data System (ADS)

Kratter, Kaitlin; Lodato, Giuseppe

2016-09-01

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

Invertebrate population genetics across Earth's largest habitat: The deep-sea floor.

PubMed

Taylor, M L; Roterman, C N

2017-10-01

Despite the deep sea being the largest habitat on Earth, there are just 77 population genetic studies of invertebrates (115 species) inhabiting non-chemosynthetic ecosystems on the deep-sea floor (below 200 m depth). We review and synthesize the results of these papers. Studies reveal levels of genetic diversity comparable to shallow-water species. Generally, populations at similar depths were well connected over 100s-1,000s km, but studies that sampled across depth ranges reveal population structure at much smaller scales (100s-1,000s m) consistent with isolation by adaptation across environmental gradients, or the existence of physical barriers to connectivity with depth. Few studies were ocean-wide (under 4%), and 48% were Atlantic-focused. There is strong emphasis on megafauna and commercial species with research into meiofauna, "ecosystem engineers" and other ecologically important species lacking. Only nine papers account for ~50% of the planet's surface (depths below 3,500 m). Just two species were studied below 5,000 m, a quarter of Earth's seafloor. Most studies used single-locus mitochondrial genes revealing a common pattern of non-neutrality, consistent with demographic instability or selective sweeps; similar to deep-sea hydrothermal vent fauna. The absence of a clear difference between vent and non-vent could signify that demographic instability is common in the deep sea, or that selective sweeps render single-locus mitochondrial studies demographically uninformative. The number of population genetics studies to date is miniscule in relation to the size of the deep sea. The paucity of studies constrains meta-analyses where broad inferences about deep-sea ecology could be made. © 2017 The Authors. Molecular Ecology Published by John Wiley & Sons Ltd.

Numerical MHD study for plasmoid instability in uniform resistivity

NASA Astrophysics Data System (ADS)

Shimizu, Tohru; Kondoh, Koji; Zenitani, Seiji

2017-11-01

The plasmoid instability (PI) caused in uniform resistivity is numerically studied with a MHD numerical code of HLLD scheme. It is shown that the PI observed in numerical studies may often include numerical (non-physical) tearing instability caused by the numerical dissipations. By increasing the numerical resolutions, the numerical tearing instability gradually disappears and the physical tearing instability remains. Hence, the convergence of the numerical results is observed. Note that the reconnection rate observed in the numerical tearing instability can be higher than that of the physical tearing instability. On the other hand, regardless of the numerical and physical tearing instabilities, the tearing instability can be classified into symmetric and asymmetric tearing instability. The symmetric tearing instability tends to occur when the thinning of current sheet is stopped by the physical or numerical dissipations, often resulting in the drastic changes in plasmoid chain's structure and its activity. In this paper, by eliminating the numerical tearing instability, we could not specify the critical Lundquist number Sc beyond which PI is fully developed. It suggests that Sc does not exist, at least around S = 105.

DNA Damage and Genetic Instability as Harbingers of Prostate Cancer

DTIC Science & Technology

2013-01-01

incidence of prostate cancer as compared to placebo. Primary analysis of this trial indicated no statistically significant effect of selenium...Identification, isolation, staining, processing, and statistical analysis of slides for ERG and PTEN markers (aim 1) and interpretation of these results...participating in this study being conducted under Investigational New Drug #29829 from the Food and Drug Administration. STANDARD TREATMENT Patients

Resistive tearing instability in electron MHD: application to neutron star crusts

NASA Astrophysics Data System (ADS)

Gourgouliatos, Konstantinos N.; Hollerbach, Rainer

2016-12-01

We study a resistive tearing instability developing in a system evolving through the combined effect of Hall drift in the electron magnetohydrodynamic limit and Ohmic dissipation. We explore first the exponential growth of the instability in the linear case and we find the fastest growing mode, the corresponding eigenvalues and dispersion relation. The instability growth rate scales as γ ∝ B2/3σ-1/3, where B is the magnetic field and σ the electrical conductivity. We confirm the development of the tearing resistive instability in the fully non-linear case, in a plane-parallel configuration where the magnetic field polarity reverses, through simulations of systems initiating in Hall equilibrium with some superimposed perturbation. Following a transient phase, during which there is some minor rearrangement of the magnetic field, the perturbation grows exponentially. Once the instability is fully developed, the magnetic field forms the characteristic islands and X-type reconnection points, where Ohmic decay is enhanced. We discuss the implications of this instability for the local magnetic field evolution in neutron stars' crusts, proposing that it can contribute to heating near the surface of the star, as suggested by models of magnetar post-burst cooling. In particular, we find that a current sheet a few metres thick, covering as little as 1 per cent of the total surface, can provide 1042 erg in thermal energy within a few days. We briefly discuss applications of this instability in other systems where the Hall effect operates such as protoplanetary discs and space plasmas.

Heterogeneity of colon cancer: from bench to bedside

PubMed Central

Merlano, Marco C; Granetto, Cristina; Fea, Elena; Ricci, Vincenzo; Garrone, Ornella

2017-01-01

The large bowel shows biomolecular, anatomical and bacterial changes that proceed from the proximal to the distal tract. These changes account for the different behaviour of colon cancers arising from the diverse sides of the colon–rectum as well as for the sensitivity to the therapy, including immunotherapy. The gut microbiota plays an important role in the modulation of the immune response and differs between the right colon cancer and the left colorectal cancer. The qualitative and quantitative difference of the commensal bacteria between the right side and the left side induces epigenetic changes in the intestinal epithelial cells as well as in the resident immune population. The second player in the pathological homeostasis of colorectal cancer is the differences of the genetic features of cancer cells and the different effects that microsatellite instability, chromosomal instability and the CpG island methylator phenotype induce on the immunological organisation of the tumour microenvironment. The third player is the immunological composition of the tumour microenvironment, which changes under the influence of both genetic structures and gut microbiota. All these three players influence each other. This review describes these three aspects, highlights their interactions and discusses data from reported clinical trials. Click here to listen to the Podcast PMID:29209524

DNA Polymerases λ and β: The Double-Edged Swords of DNA Repair.

PubMed

Mentegari, Elisa; Kissova, Miroslava; Bavagnoli, Laura; Maga, Giovanni; Crespan, Emmanuele

2016-08-31

DNA is constantly exposed to both endogenous and exogenous damages. More than 10,000 DNA modifications are induced every day in each cell's genome. Maintenance of the integrity of the genome is accomplished by several DNA repair systems. The core enzymes for these pathways are the DNA polymerases. Out of 17 DNA polymerases present in a mammalian cell, at least 13 are specifically devoted to DNA repair and are often acting in different pathways. DNA polymerases β and λ are involved in base excision repair of modified DNA bases and translesion synthesis past DNA lesions. Polymerase λ also participates in non-homologous end joining of DNA double-strand breaks. However, recent data have revealed that, depending on their relative levels, the cell cycle phase, the ratio between deoxy- and ribo-nucleotide pools and the interaction with particular auxiliary proteins, the repair reactions carried out by these enzymes can be an important source of genetic instability, owing to repair mistakes. This review summarizes the most recent results on the ambivalent properties of these enzymes in limiting or promoting genetic instability in mammalian cells, as well as their potential use as targets for anticancer chemotherapy.

Active Combustion Control for Aircraft Gas-Turbine Engines-Experimental Results for an Advanced, Low-Emissions Combustor Prototype

NASA Technical Reports Server (NTRS)

DeLaat, John C.; Kopasakis, George; Saus, Joseph R.; Chang, Clarence T.; Wey, Changlie

2012-01-01

Lean combustion concepts for aircraft engine combustors are prone to combustion instabilities. Mitigation of instabilities is an enabling technology for these low-emissions combustors. NASA Glenn Research Center s prior activity has demonstrated active control to suppress a high-frequency combustion instability in a combustor rig designed to emulate an actual aircraft engine instability experience with a conventional, rich-front-end combustor. The current effort is developing further understanding of the problem specifically as applied to future lean-burning, very low-emissions combustors. A prototype advanced, low-emissions aircraft engine combustor with a combustion instability has been identified and previous work has characterized the dynamic behavior of that combustor prototype. The combustor exhibits thermoacoustic instabilities that are related to increasing fuel flow and that potentially prevent full-power operation. A simplified, non-linear oscillator model and a more physics-based sectored 1-D dynamic model have been developed to capture the combustor prototype s instability behavior. Utilizing these models, the NASA Adaptive Sliding Phasor Average Control (ASPAC) instability control method has been updated for the low-emissions combustor prototype. Active combustion instability suppression using the ASPAC control method has been demonstrated experimentally with this combustor prototype in a NASA combustion test cell operating at engine pressures, temperatures, and flows. A high-frequency fuel valve was utilized to perturb the combustor fuel flow. Successful instability suppression was shown using a dynamic pressure sensor in the combustor for controller feedback. Instability control was also shown with a pressure feedback sensor in the lower temperature region upstream of the combustor. It was also demonstrated that the controller can prevent the instability from occurring while combustor operation was transitioning from a stable, low-power condition to a normally unstable high-power condition, thus enabling the high-power condition.

Large Eddy Simulations of Transverse Combustion Instability in a Multi-Element Injector

DTIC Science & Technology

2016-07-27

plagued the development of liquid rocket engines and remains a large riskin the development and acquisition of new liquid rocket engines. Combustion...simulations to better understand the physics that can lead combustion instability in liquid rocket engines. Simulations of this type are able to...instabilities found in liquid rocket engines are transverse. The motivating of the experiment behind the current work is to subject the CVRC injector

A Genetically Informed Study of the Processes Underlying the Association Between Parental Marital Instability and Offspring Adjustment

PubMed Central

D’Onofrio, Brian M.; Turkheimer, Eric; Emery, Robert E.; Heath, Andrew C.; Madden, Pamela A.; Slutske, Wendy S.; Martin, Nicholas G.

2010-01-01

Parental divorce is associated with problematic offspring adjustment, but the relation may be due to shared genetic or environmental factors. One way to test for these confounds is to study offspring of twins discordant for divorce. The current analyses used this design to separate the mechanisms responsible for the association between parental divorce, experienced either before or after the age of 16, and offspring well-being. The results were consistent with a causal role of divorce in earlier initiation of sexual intercourse and emotional difficulties, in addition to a greater probability of educational problems, depressed mood, and suicidal ideation. In contrast, the increased risk for cohabitation and earlier initiation of drug use was explained by selection factors, including genetic confounds. PMID:16756440

Interplay between electric fields generated by reconnection and by secondary processes

NASA Astrophysics Data System (ADS)

Lapenta, G.; Innocenti, M. E.; Pucci, F.; Cazzola, E.; Berchem, J.; Newman, D. L.; El-Alaoui, M.; Walker, R. J.; Goldman, M. V.; Ergun, R.

2017-12-01

Reconnection regions are surrounded by several sources of free energy that push reconnection towards a turbulent regime: beams can drive streaming instabilities, currents can drive tearing like secondary instabilities, velocity and density shears can drive Kelvin-Helmholtz or Rayleigh-Taylor type of instabilities. The interaction between these instabilities can be very complex. For instance, from a kinetic point of view, instabilities resulting from shears are intermixed with drift-type instabilities, such as drift-kink, kink driven by relative species drift, lower hybrid modes of the electrostatic or electromagnetic type. In addition, the interaction with reconnection is two ways: reconnection causes the conditions for those instabilities to develop while the instabilities alter the progress of reconnection. Although MMS has observed features that can be associated with such instabilities: strong localized parallel electric fields (monopolar and bipolar), fluctuations in the drift range (lower hybrid, whistler), it has been difficult to determine which ones operate and how they differ depending on the symmetric and asymmetric reconnection configurations observed in the magnetotail and at the magnetopause, respectively. We present a comparison between the results of kinetic simulations obtained for typical magnetotail and the magnetopause configurations, using for each of them both analytical equilibria and results of global MHD simulations to initialize the iPIC3D simulations. By selecting what drivers (e.g. shear/no shear) are present, we can identify what instabilities develop and determine their effects on the progression of reconnection in the magnetotail and at the magnetopause. We focus especially on the role of drift waves and whistler instabilities, and discuss our results by comparing them with MMS observations.

Developmental Stability Covaries with Genome-Wide and Single-Locus Heterozygosity in House Sparrows

PubMed Central

Vangestel, Carl; Mergeay, Joachim; Dawson, Deborah A.; Vandomme, Viki; Lens, Luc

2011-01-01

Fluctuating asymmetry (FA), a measure of developmental instability, has been hypothesized to increase with genetic stress. Despite numerous studies providing empirical evidence for associations between FA and genome-wide properties such as multi-locus heterozygosity, support for single-locus effects remains scant. Here we test if, and to what extent, FA co-varies with single- and multilocus markers of genetic diversity in house sparrow (Passer domesticus) populations along an urban gradient. In line with theoretical expectations, FA was inversely correlated with genetic diversity estimated at genome level. However, this relationship was largely driven by variation at a single key locus. Contrary to our expectations, relationships between FA and genetic diversity were not stronger in individuals from urban populations that experience higher nutritional stress. We conclude that loss of genetic diversity adversely affects developmental stability in P. domesticus, and more generally, that the molecular basis of developmental stability may involve complex interactions between local and genome-wide effects. Further study on the relative effects of single-locus and genome-wide effects on the developmental stability of populations with different genetic properties is therefore needed. PMID:21747940

Is early-onset microsatellite and chromosomally stable colorectal cancer a hallmark of a genetic susceptibility syndrome?

PubMed

Kets, C M; van Krieken, J H J M; van Erp, P E J; Feuth, T; Jacobs, Y H A; Brunner, H G; Ligtenberg, M J L; Hoogerbrugge, N

2008-02-15

Most colorectal cancers show either microsatellite or chromosomal instability. A subset of colorectal cancers, especially those diagnosed at young age, is known to show neither of these forms of genetic instability and thus might have a distinct pathogenesis. Colorectal cancers diagnosed at young age are suggestive for hereditary predisposition. We investigate whether such early-onset microsatellite and chromosomally stable colorectal cancers are a hallmark of a genetic susceptibility syndrome. The ploidy status of microsatellite stable (familial) colorectal cancers of patients diagnosed before age 50 (n = 127) was analyzed in relation to the histopathological characteristics and family history. As a control the ploidy status of sporadic colorectal cancer, with normal staining of mismatch repair proteins, diagnosed at the age of 69 years or above (n = 70) was determined. A diploid DNA content was used as a marker for chromosomal stability. Within the group of patients with (familial) early onset microsatellite stable colorectal cancer the chromosomally stable tumors did not differ from chromosomally unstable tumors with respect to mean age at diagnosis, fulfillment of Amsterdam criteria or pathological characteristics. Segregation analysis did not reveal any family with microsatellite and chromosomally stable colorectal cancer in 2 relatives. The prevalence of microsatellite and chromosomally stable colorectal cancer was not significantly different for the early and late onset group (28 and 21%, respectively). We find no evidence that early-onset microsatellite and chromosomally stable colorectal cancer is a hallmark of a hereditary colorectal cancer syndrome. (c) 2007 Wiley-Liss, Inc.

Dependence of Early and Late Chromosomal Aberrations on Radiation Quality and Cell Types

NASA Technical Reports Server (NTRS)

Lu, Tao; Zhang, Ye; Krieger, Stephanie; Yeshitla, Samrawit; Goss, Rosalin; Bowler, Deborah; Kadhim, Munira; Wilson, Bobby; Rohde, Larry; Wu, Honglu

2017-01-01

Exposure to radiation induces different types of DNA damage, increases mutation and chromosome aberration rates, and increases cellular transformation in vitro and in vivo. The susceptibility of cells to radiation depends on genetic background and growth condition of cells, as well as types of radiation. Mammalian cells of different tissue types and with different genetic background are known to have different survival rate and different mutation rate after cytogenetic insults. Genomic instability, induced by various genetic, metabolic, and environmental factors including radiation, is the driving force of tumorigenesis. Accurate measurements of the relative biological effectiveness (RBE) is important for estimating radiation-related risks. To further understand genomic instability induced by charged particles and their RBE, we exposed human lymphocytes ex vivo, human fibroblast AG1522, human mammary epithelial cells (CH184B5F5/M10), and bone marrow cells isolated from CBA/CaH(CBA) and C57BL/6 (C57) mice to high energy protons and Fe ions. Normal human fibroblasts AG1522 have apparently normal DNA damage response and repair mechanisms, while mammary epithelial cells (M10) are deficient in the repair of DNA DSBs. Mouse strain CBA is radio-sensitive while C57 is radio-resistant. Metaphase chromosomes at different cell divisions after radiation exposure were collected and chromosome aberrations were analyzed as RBE for different cell lines exposed to different radiations at various time points up to one month post irradiation.

A Dual Role of Caspase-8 in Triggering and Sensing Proliferation-Associated DNA Damage, a Key Determinant of Liver Cancer Development.

PubMed

Boege, Yannick; Malehmir, Mohsen; Healy, Marc E; Bettermann, Kira; Lorentzen, Anna; Vucur, Mihael; Ahuja, Akshay K; Böhm, Friederike; Mertens, Joachim C; Shimizu, Yutaka; Frick, Lukas; Remouchamps, Caroline; Mutreja, Karun; Kähne, Thilo; Sundaravinayagam, Devakumar; Wolf, Monika J; Rehrauer, Hubert; Koppe, Christiane; Speicher, Tobias; Padrissa-Altés, Susagna; Maire, Renaud; Schattenberg, Jörn M; Jeong, Ju-Seong; Liu, Lei; Zwirner, Stefan; Boger, Regina; Hüser, Norbert; Davis, Roger J; Müllhaupt, Beat; Moch, Holger; Schulze-Bergkamen, Henning; Clavien, Pierre-Alain; Werner, Sabine; Borsig, Lubor; Luther, Sanjiv A; Jost, Philipp J; Weinlich, Ricardo; Unger, Kristian; Behrens, Axel; Hillert, Laura; Dillon, Christopher; Di Virgilio, Michela; Wallach, David; Dejardin, Emmanuel; Zender, Lars; Naumann, Michael; Walczak, Henning; Green, Douglas R; Lopes, Massimo; Lavrik, Inna; Luedde, Tom; Heikenwalder, Mathias; Weber, Achim

2017-09-11

Concomitant hepatocyte apoptosis and regeneration is a hallmark of chronic liver diseases (CLDs) predisposing to hepatocellular carcinoma (HCC). Here, we mechanistically link caspase-8-dependent apoptosis to HCC development via proliferation- and replication-associated DNA damage. Proliferation-associated replication stress, DNA damage, and genetic instability are detectable in CLDs before any neoplastic changes occur. Accumulated levels of hepatocyte apoptosis determine and predict subsequent hepatocarcinogenesis. Proliferation-associated DNA damage is sensed by a complex comprising caspase-8, FADD, c-FLIP, and a kinase-dependent function of RIPK1. This platform requires a non-apoptotic function of caspase-8, but no caspase-3 or caspase-8 cleavage. It may represent a DNA damage-sensing mechanism in hepatocytes that can act via JNK and subsequent phosphorylation of the histone variant H2AX. Copyright © 2017 The Authors. Published by Elsevier Inc. All rights reserved.

Genome health nutrigenomics and nutrigenetics--diagnosis and nutritional treatment of genome damage on an individual basis.

PubMed

Fenech, Michael

2008-04-01

The term nutrigenomics refers to the effect of diet on gene expression. The term nutrigenetics refers to the impact of inherited traits on the response to a specific dietary pattern, functional food or supplement on a specific health outcome. The specific fields of genome health nutrigenomics and genome health nutrigenetics are emerging as important new research areas because it is becoming increasingly evident that (a) risk for developmental and degenerative disease increases with DNA damage which in turn is dependent on nutritional status and (b) optimal concentration of micronutrients for prevention of genome damage is also dependent on genetic polymorphisms that alter function of genes involved directly or indirectly in uptake and metabolism of micronutrients required for DNA repair and DNA replication. Development of dietary patterns, functional foods and supplements that are designed to improve genome health maintenance in humans with specific genetic backgrounds may provide an important contribution to a new optimum health strategy based on the diagnosis and individualised nutritional treatment of genome instability i.e. Genome Health Clinics.

Development of Genetically Stable Escherichia coli Strains for Poly(3-Hydroxypropionate) Production

PubMed Central

Gao, Yongqiang; Liu, Changshui; Ding, Yamei; Sun, Chao; Zhang, Rubing; Xian, Mo; Zhao, Guang

2014-01-01

Poly(3-hydroxypropionate) (P3HP) is a biodegradable and biocompatible thermoplastic. In our previous study, a pathway for P3HP production was constructed in recombinant Esecherichia coli. Seven exogenous genes in P3HP synthesis pathway were carried by two plasmid vectors. However, the P3HP production was severely suppressed by strain instability due to plasmid loss. In this paper, two strategies, chromosomal gene integration and plasmid addiction system (PAS) based on amino acid anabolism, were applied to construct a genetically stable strain. Finally, a combination of those two methods resulted in the best results. The resultant strain carried a portion of P3HP synthesis genes on chromosome and the others on plasmid, and also brought a tyrosine-auxotrophy based PAS. In aerobic fed-batch fermentation, this strain produced 25.7 g/L P3HP from glycerol, about 2.5-time higher than the previous strain with two plasmids. To the best of our knowledge, this is the highest P3HP production from inexpensive carbon sources. PMID:24837211

Fluctuating asymmetry and psychometric intelligence.

PubMed Central

Furlow, F B; Armijo-Prewitt, T; Gangestad, S W; Thornhill, R

1997-01-01

Little is known about the genetic nature of human psychometric intelligence (IQ), but it is widely assumed that IQ's heritability is at loci for intelligence per se. We present evidence consistent with a hypothesis that interindividual IQ differences are partly due to heritable vulnerabilities to environmental sources of developmental stress, an indirect genetic mechanism for the heritability of IQ. Using fluctuating asymmetry (FA) of the body (the asymmetry resulting from errors in the development of normally symmetrical bilateral traits under stressful conditions), we estimated the relative developmental instability of 112 undergraduates and administered to them Cattell's culture fair intelligence test (CFIT). A subsequent replication on 128 students was performed. In both samples, FA correlated negatively and significantly with CFIT scores. We propose two non-mutually exclusive physiological explanations for this correlation. First, external body FA may correlate negatively with the developmental integrity of the brain. Second, individual energy budget allocations and/or low metabolic efficiency in high-FA individuals may lower IQ scores. We review the data on IQ in light of our findings and conclude that improving developmental quality may increase average IQ in future generations. PMID:9265189

Effect of polarization force on the Jeans instability in collisional dusty plasmas

NASA Astrophysics Data System (ADS)

A, ABBASI; M, R. RASHIDIAN VAZIRI

2018-03-01

The Jeans instability in collisional dusty plasmas has been analytically investigated by considering the polarization force effect. Instabilities due to dust-neutral and ion-neutral drags can occur in electrostatic waves of collisional dusty plasmas with self-gravitating particles. In this study, the effect of gravitational force on heavy dust particles is considered in tandem with both the polarization and electrostatic forces. The theoretical framework has been developed and the dispersion relation and instability growth rate have been derived, assuming the plane wave approximation. The derived instability growth rate shows that, in collisional dusty plasmas, the Jeans instability strongly depends on the magnitude of the polarization force.

[Chronic ankle instability in sports -- a review for sports physicians].

PubMed

Valderrabano, V; Leumann, A; Pagenstert, G; Frigg, A; Ebneter, L; Hintermann, B

2006-12-01

Chronic ankle instability represents a typical sports injury which can mostly be seen in basketball, soccer, orienteering and other high risk sports. 20 to 40 % of the acute ankle sprains develop into chronic ankle instability. From a sports orthopaedic point of view, chronic ankle instability can be subdivided into a lateral, medial or a combination of both so called rotational ankle instability. From a pathophysiological point of view, chronic ankle instability can be either mechanical with a structural ligament lesion or functional with loss of the neuromuscular control. For the sports physician, the chronic ankle instability is a difficult entity as the diagnosis is usually complex and the therapy usually surgical. This review on chronic ankle instability addresses pathomechanism, diagnostics, indications for conservative and surgical treatments, and possible long-term sequelae, as ligamentous osteoarthritis.

A role for chromosomal instability in the development of and selection for radioresistant cell variants

NASA Technical Reports Server (NTRS)

Limoli, C. L.; Corcoran, J. J.; Jordan, R.; Morgan, W. F.; Schwartz, J. L.

2001-01-01

Chromosome instability is a common occurrence in tumour cells. We examined the hypothesis that the elevated rate of mutation formation in unstable cells can lead to the development of clones of cells that are resistant to the cancer therapy. To test this hypothesis, we compared chromosome instability to radiation sensitivity in 30 independently isolated clones of GM10115 human-hamster hybrid cells. There was a broader distribution of radiosensitivity and a higher mean SF(2)in chromosomally unstable clones. Cytogenetic and DNA double-strand break rejoining assays suggest that sensitivity was a function of DNA repair efficiency. In the unstable population, the more radioresistant clones also had significantly lower plating efficiencies. These observations suggest that chromosome instability in GM10115 cells can lead to the development of cell variants that are more resistant to radiation. In addition, these results suggest that the process of chromosome breakage and recombination that accompanies chromosome instability might provide some selective pressure for more radioresistant variants. Copyright 2001 Cancer Research Campaign.

A Genome-Wide Association Study for Regulators of Micronucleus Formation in Mice.

PubMed

McIntyre, Rebecca E; Nicod, Jérôme; Robles-Espinoza, Carla Daniela; Maciejowski, John; Cai, Na; Hill, Jennifer; Verstraten, Ruth; Iyer, Vivek; Rust, Alistair G; Balmus, Gabriel; Mott, Richard; Flint, Jonathan; Adams, David J

2016-08-09

In mammals the regulation of genomic instability plays a key role in tumor suppression and also controls genome plasticity, which is important for recombination during the processes of immunity and meiosis. Most studies to identify regulators of genomic instability have been performed in cells in culture or in systems that report on gross rearrangements of the genome, yet subtle differences in the level of genomic instability can contribute to whole organism phenotypes such as tumor predisposition. Here we performed a genome-wide association study in a population of 1379 outbred Crl:CFW(SW)-US_P08 mice to dissect the genetic landscape of micronucleus formation, a biomarker of chromosomal breaks, whole chromosome loss, and extranuclear DNA. Variation in micronucleus levels is a complex trait with a genome-wide heritability of 53.1%. We identify seven loci influencing micronucleus formation (false discovery rate <5%), and define candidate genes at each locus. Intriguingly at several loci we find evidence for sexual dimorphism in micronucleus formation, with a locus on chromosome 11 being specific to males. Copyright © 2016 McIntyre et al.

The yeast Pif1 helicase prevents genomic instability caused by G-quadruplex-forming CEB1 sequences in vivo.

PubMed

Ribeyre, Cyril; Lopes, Judith; Boulé, Jean-Baptiste; Piazza, Aurèle; Guédin, Aurore; Zakian, Virginia A; Mergny, Jean-Louis; Nicolas, Alain

2009-05-01

In budding yeast, the Pif1 DNA helicase is involved in the maintenance of both nuclear and mitochondrial genomes, but its role in these processes is still poorly understood. Here, we provide evidence for a new Pif1 function by demonstrating that its absence promotes genetic instability of alleles of the G-rich human minisatellite CEB1 inserted in the Saccharomyces cerevisiae genome, but not of other tandem repeats. Inactivation of other DNA helicases, including Sgs1, had no effect on CEB1 stability. In vitro, we show that CEB1 repeats formed stable G-quadruplex (G4) secondary structures and the Pif1 protein unwinds these structures more efficiently than regular B-DNA. Finally, synthetic CEB1 arrays in which we mutated the potential G4-forming sequences were no longer destabilized in pif1Delta cells. Hence, we conclude that CEB1 instability in pif1Delta cells depends on the potential to form G-quadruplex structures, suggesting that Pif1 could play a role in the metabolism of G4-forming sequences.

Interfacial fluid instabilities and Kapitsa pendula.

PubMed

Krieger, Madison S

2017-07-01

The onset and development of instabilities is one of the central problems in fluid mechanics. Here we develop a connection between instabilities of free fluid interfaces and inverted pendula. When acted upon solely by the gravitational force, the inverted pendulum is unstable. This position can be stabilized by the Kapitsa phenomenon, in which high-frequency low-amplitude vertical vibrations of the base creates a fictitious force which opposes the gravitational force. By transforming the dynamical equations governing a fluid interface into an appropriate pendulum-type equation, we demonstrate how stability can be induced in fluid systems by properly tuned vibrations. We construct a "dictionary"-type relationship between various pendula and the classical Rayleigh-Taylor, Kelvin-Helmholtz, Rayleigh-Plateau and the self-gravitational instabilities. This makes several results in control theory and dynamical systems directly applicable to the study of tunable fluid instabilities, where the critical wavelength depends on the external forces or the instability is suppressed entirely. We suggest some applications and instances of the effect ranging in scale from microns to the radius of a galaxy.

Whole genome comparison of donor and cloned dogs

PubMed Central

Kim, Hak-Min; Cho, Yun Sung; Kim, Hyunmin; Jho, Sungwoong; Son, Bongjun; Choi, Joung Yoon; Kim, Sangsoo; Lee, Byeong Chun; Bhak, Jong; Jang, Goo

2013-01-01

Cloning is a process that produces genetically identical organisms. However, the genomic degree of genetic resemblance in clones needs to be determined. In this report, the genomes of a cloned dog and its donor were compared. Compared with a human monozygotic twin, the genome of the cloned dog showed little difference from the genome of the nuclear donor dog in terms of single nucleotide variations, chromosomal instability, and telomere lengths. These findings suggest that cloning by somatic cell nuclear transfer produced an almost identical genome. The whole genome sequence data of donor and cloned dogs can provide a resource for further investigations on epigenetic contributions in phenotypic differences. PMID:24141358

DNA Methylation and Methylation Polymorphism in Genetically Stable In vitro Regenerates of Jatropha curcas L. Using Methylation-Sensitive AFLP Markers.

PubMed

Rathore, Mangal S; Jha, Bhavanath

2016-03-01

The present investigation aimed to evaluate the degree and pattern of DNA methylation using methylation-sensitive AFLP (MS-AFLP) markers in genetically stable in vitro regenerates of Jatropha curcas L.. The genetically stable in vitro regenerates were raised through direct organogenesis via enhanced axillary shoot bud proliferation (Protocol-1) and in vitro-derived leaf regeneration (Protocol-2). Ten selective combinations of MS-AFLP primers produced 462 and 477 MS-AFLP bands in Protocol-1 (P-1) and Protocol-2 (P-2) regenerates, respectively. In P-1 regenerates, 15.8-31.17 % DNA was found methylated with an average of 25.24 %. In P-2 regenerates, 15.93-32.7 % DNA was found methylated with an average of 24.11 %. Using MS-AFLP in P-1 and P-2 regenerates, 11.52-25.53 % and 13.33-25.47 % polymorphism in methylated DNA was reported, respectively. Compared to the mother plant, P-1 regenerates showed hyper-methylation while P-2 showed hypo-methylation. The results clearly indicated alternation in degree and pattern of DNA methylation; hence, epigenetic instability in the genetically stable in vitro regenerates of J. curcas, developed so far using two different regeneration systems and explants of two different origins. The homologous nucleotide fragments in genomes of P-1 and P-2 regenerates showing methylation re-patterning might be involved in immediate adaptive responses and developmental processes through differential regulation of transcriptome under in vitro conditions.

CRISPR/Cas9: A Practical Approach in Date Palm Genome Editing

PubMed Central

Sattar, Muhammad N.; Iqbal, Zafar; Tahir, Muhammad N.; Shahid, Muhammad S.; Khurshid, Muhammad; Al-Khateeb, Abdullatif A.; Al-Khateeb, Suliman A.

2017-01-01

The genetic modifications through breeding of crop plants have long been used to improve the yield and quality. However, precise genome editing (GE) could be a very useful supplementary tool for improvement of crop plants by targeted genome modifications. Various GE techniques including ZFNs (zinc finger nucleases), TALENs (transcription activator-like effector nucleases), and most recently clustered regularly interspaced short palindromic repeats (CRISPR)/Cas9 (CRISPR-associated protein 9)-based approaches have been successfully employed for various crop plants including fruit trees. CRISPR/Cas9-based approaches hold great potential in GE due to their simplicity, competency, and versatility over other GE techniques. However, to the best of our knowledge no such genetic improvement has ever been developed in date palm—an important fruit crop in Oasis agriculture. The applications of CRISPR/Cas9 can be a challenging task in date palm GE due to its large and complex genome, high rate of heterozygosity and outcrossing, in vitro regeneration and screening of mutants, high frequency of single-nucleotide polymorphism in the genome and ultimately genetic instability. In this review, we addressed the potential application of CRISPR/Cas9-based approaches in date palm GE to improve the sustainable date palm production. The availability of the date palm whole genome sequence has made it feasible to use CRISPR/Cas9 GE approach for genetic improvement in this species. Moreover, the future prospects of GE application in date palm are also addressed in this review. PMID:28878801

Comprehensive high-resolution genomic profiling and cytogenetics of human chondrocyte cultures by GTG-banding, locus-specific FISH, SKY and SNP array.

PubMed

Wallenborn, M; Petters, O; Rudolf, D; Hantmann, H; Richter, M; Ahnert, P; Rohani, L; Smink, J J; Bulwin, G C; Krupp, W; Schulz, R M; Holland, H

2018-04-23

In the development of cell-based medicinal products, it is crucial to guarantee that the application of such an advanced therapy medicinal product (ATMP) is safe for the patients. The consensus of the European regulatory authorities is: "In conclusion, on the basis of the state of art, conventional karyotyping can be considered a valuable and useful technique to analyse chromosomal stability during preclinical studies". 408 chondrocyte samples (84 monolayers and 324 spheroids) from six patients were analysed using trypsin-Giemsa staining, spectral karyotyping and fluorescence in situ hybridisation, to evaluate the genetic stability of chondrocyte samples from non-clinical studies. Single nucleotide polymorphism (SNP) array analysis was performed on chondrocyte spheroids from five of the six donors. Applying this combination of techniques, the genetic analyses performed revealed no significant genetic instability until passage 3 in monolayer cells and interphase cells from spheroid cultures at different time points. Clonal occurrence of polyploid metaphases and endoreduplications were identified associated with prolonged cultivation time. Also, gonosomal losses were observed in chondrocyte spheroids, with increasing passage and duration of the differentiation phase. Interestingly, in one of the donors, chromosomal aberrations that are also described in extraskeletal myxoid chondrosarcoma were identified. The SNP array analysis exhibited chromosomal aberrations in two donors and copy neutral losses of heterozygosity regions in four donors. This study showed the necessity of combined genetic analyses at defined cultivation time points in quality studies within the field of cell therapy.

CRISPR/Cas9: A Practical Approach in Date Palm Genome Editing.

PubMed

Sattar, Muhammad N; Iqbal, Zafar; Tahir, Muhammad N; Shahid, Muhammad S; Khurshid, Muhammad; Al-Khateeb, Abdullatif A; Al-Khateeb, Suliman A

2017-01-01

The genetic modifications through breeding of crop plants have long been used to improve the yield and quality. However, precise genome editing (GE) could be a very useful supplementary tool for improvement of crop plants by targeted genome modifications. Various GE techniques including ZFNs (zinc finger nucleases), TALENs (transcription activator-like effector nucleases), and most recently clustered regularly interspaced short palindromic repeats (CRISPR)/Cas9 (CRISPR-associated protein 9)-based approaches have been successfully employed for various crop plants including fruit trees. CRISPR/Cas9-based approaches hold great potential in GE due to their simplicity, competency, and versatility over other GE techniques. However, to the best of our knowledge no such genetic improvement has ever been developed in date palm-an important fruit crop in Oasis agriculture. The applications of CRISPR/Cas9 can be a challenging task in date palm GE due to its large and complex genome, high rate of heterozygosity and outcrossing, in vitro regeneration and screening of mutants, high frequency of single-nucleotide polymorphism in the genome and ultimately genetic instability. In this review, we addressed the potential application of CRISPR/Cas9-based approaches in date palm GE to improve the sustainable date palm production. The availability of the date palm whole genome sequence has made it feasible to use CRISPR/Cas9 GE approach for genetic improvement in this species. Moreover, the future prospects of GE application in date palm are also addressed in this review.

SIMULATIONS OF THE KELVIN–HELMHOLTZ INSTABILITY DRIVEN BY CORONAL MASS EJECTIONS IN THE TURBULENT CORONA

DOE Office of Scientific and Technical Information (OSTI.GOV)

Gómez, Daniel O.; DeLuca, Edward E.; Mininni, Pablo D.

Recent high-resolution Atmospheric Imaging Assembly/Solar Dynamics Observatory images show evidence of the development of the Kelvin–Helmholtz (KH) instability, as coronal mass ejections (CMEs) expand in the ambient corona. A large-scale magnetic field mostly tangential to the interface is inferred, both on the CME and on the background sides. However, the magnetic field component along the shear flow is not strong enough to quench the instability. There is also observational evidence that the ambient corona is in a turbulent regime, and therefore the criteria for the development of the instability are a priori expected to differ from the laminar case. To studymore » the evolution of the KH instability with a turbulent background, we perform three-dimensional simulations of the incompressible magnetohydrodynamic equations. The instability is driven by a velocity profile tangential to the CME–corona interface, which we simulate through a hyperbolic tangent profile. The turbulent background is generated by the application of a stationary stirring force. We compute the instability growth rate for different values of the turbulence intensity, and find that the role of turbulence is to attenuate the growth. The fact that KH instability is observed sets an upper limit on the correlation length of the coronal background turbulence.« less

Nonlinear Development and Secondary Instability of Traveling Crossflow Vortices

NASA Technical Reports Server (NTRS)

Li, Fei; Choudhari, Meelan M.; Duan, Lian; Chang, Chau-Lyan

2014-01-01

Transition research under NASA's Aeronautical Sciences Project seeks to develop a validated set of variable fidelity prediction tools with known strengths and limitations, so as to enable "sufficiently" accurate transition prediction and practical transition control for future vehicle concepts. This paper builds upon prior effort targeting the laminar breakdown mechanisms associated with stationary crossflow instability over a swept-wing configuration relevant to subsonic aircraft with laminar flow technology. Specifically, transition via secondary instability of traveling crossflow modes is investigated as an alternate scenario for transition. Results show that, for the parameter range investigated herein, secondary instability of traveling crossflow modes becomes insignificant in relation to the secondary instability of the stationary modes when the relative initial amplitudes of the traveling crossflow instability are lower than those of the stationary modes by approximately two orders of magnitudes or more. Linear growth predictions based on the secondary instability theory are found to agree well with those based on PSE and DNS, with the most significant discrepancies being limited to spatial regions of relatively weak secondary growth, i.e., regions where the primary disturbance amplitudes are smaller in comparison to its peak amplitude. Nonlinear effects on secondary instability evolution is also investigated and found to be initially stabilizing, prior to breakdown.

Design and Management of Field Trials of Transgenic Cereals

NASA Astrophysics Data System (ADS)

Bedő, Zoltán; Rakszegi, Mariann; Láng, László

The development of gene transformation systems has allowed the introgression of alien genes into plant genomes, thus providing a mechanism for broadening the genetic resources available to plant breeders. The design and the management of field trials vary according to the purpose for which transgenic cereals are developed. Breeders study the phenotypic and genotypic stability of transgenic plants, monitor the increase in homozygosity of transgenic genotypes under field conditions, and develop backcross generations to transfer the introduced genes into secondary transgenic cereal genotypes. For practical purposes, they may also multiply seed of the transgenic lines to produce sufficient amounts of grain for the detailed analysis of trait(s) of interest, to determine the field performance of transgenic lines, and to compare them with the non-transformed parental genotypes. Prior to variety registration, the Distinctness, Uniformity and Stability (DUS) tests and Value for Cultivation and Use (VCU) experiments are carried out in field trials. Field testing includes specific requirements for transgenic cereals to assess potential environmental risks. The capacity of the pollen to survive, establish and disseminate in the field test environment, the potential for gene transfer, the effects of products expressed by the introduced sequences and phenotypic and genotypic instability that might cause deleterious effects must all be specifically monitored, as required by EU Directives 2003/701/EC (1) on the release of genetically modified higher plants in the environment.

Spontaneous and radiation-induced genomic instability in human cell lines differing in cellular TP53 status.

PubMed

Moore, Stephen R; Ritter, Linda E; Gibbons, Catherine F; Grosovsky, Andrew J

2005-10-01

Structural chromosomal rearrangements are commonly observed in tumor karyotypes and in radiation-induced genomic instability. Here we report the effects of TP53 deficiency on karyotypic stability before and after irradiation using related cells and clones differing in cellular TP53 status. The parental cell line, TK6, is a TP53 wild-type human B-lymphoblastoid line with a highly stable karyotype. In the two TK6 derivatives used here, TP53 has been inactivated by biochemical means (expression of HPV16 E6; TK6-5E) or genetic means (allelic inactivation; NH32). Biochemical inactivation of TP53 (TK6-5E) had little effect on the spontaneous karyotype, whereas allelic inactivation of TP53 (NH32) resulted in a modest increase in spontaneous karyotypic instability. After 2 Gy gamma irradiation, the number of unstable clones derived from TP53-deficient cells was significantly elevated compared to the TP53 wild-type counterpart. Extensively destabilized clones were common after irradiation in the set of clones derived from NH32 cells, and one was observed in the set of TK6-5E clones; however, they were never observed in TK6-derived clones. In two of the irradiated NH32 clones, whole chromosomes or chromosome bands were preferentially involved in alterations. These results suggest that genomic instability may differ both quantitatively and qualitatively as a consequence of altered TP53 expression. Some of the results showing repeated and preferential chromosome involvement in aberrations support a model in which instability may be driven by cis mechanisms.

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

PubMed

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.

Thermal effects in rapid directional solidification - Linear theory

NASA Technical Reports Server (NTRS)

Huntley, D. A.; Davis, S. H.

1993-01-01

We study the morphological instability of the planar solid/liquid interface for a unidirectionally-solidified dilute binary mixture. We use a model developed by Boettinger et al. (1985, 1986), Aziz (1982), and Jackson et al. (1980), which allows for nonequilibrium effects on the interface through velocity-dependent segregation and attachment kinetics. Two types of instabilities are found in the linear stability analysis: (1) a cellular instability, and (2) an oscillatory instability driven by disequilibrium effects. Merchant and Davis (1990) characterized these instabilities subject to the frozen-temperature approximation (FTA). The present work relaxes the FTA by including the effects of latent heat and the full temperature distribution. Thermal effects slightly postpone the onset of the cellular instability but dramatically postpone the onset of the oscillatory instability; however, the absolute-stability conditions, at which at high speed the cellular and oscillatory instabilities are suppressed, remain unchanged from the FTA.

An Adaptive Instability Suppression Controls Method for Aircraft Gas Turbine Engine Combustors

NASA Technical Reports Server (NTRS)

Kopasakis, George; DeLaat, John C.; Chang, Clarence T.

2008-01-01

An adaptive controls method for instability suppression in gas turbine engine combustors has been developed and successfully tested with a realistic aircraft engine combustor rig. This testing was part of a program that demonstrated, for the first time, successful active combustor instability control in an aircraft gas turbine engine-like environment. The controls method is called Adaptive Sliding Phasor Averaged Control. Testing of the control method has been conducted in an experimental rig with different configurations designed to simulate combustors with instabilities of about 530 and 315 Hz. Results demonstrate the effectiveness of this method in suppressing combustor instabilities. In addition, a dramatic improvement in suppression of the instability was achieved by focusing control on the second harmonic of the instability. This is believed to be due to a phenomena discovered and reported earlier, the so called Intra-Harmonic Coupling. These results may have implications for future research in combustor instability control.

Residential Instability, Family Support, and Parent-Child Relationships Among Ethnically Diverse Urban Families.

PubMed

Riina, Elizabeth M; Lippert, Adam; Brooks-Gunn, Jeanne

2016-08-01

From a social disorganization standpoint, neighborhood residential instability potentially brings negative consequences to parent-child relationship qualities, but family social support and racial/ethnic identity may modify this association. Using data (n = 3,116) from the Project on Human Development in Chicago Neighborhoods, this study examines associations between neighborhood residential instability and parent-child warmth and conflict, whether family social support moderates associations between residential instability and parent-child relationships, and variation by race/ethnicity. Multilevel models reveal that residential instability undermines parent-child relationship qualities, particularly for non-White individuals. Family support is a protective factor for families in less stable neighborhoods, and specifically buffers the association between neighborhood residential instability and reduced parent-child warmth. Among Hispanics, family support mitigates the association between residential instability and heightened parent-child conflict. Findings highlight residential instability as a detriment to parent-child relationships; families in unstable neighborhoods may benefit from family social support.

Hydrodynamic stability

NASA Astrophysics Data System (ADS)

Drazin, P. G.; Reid, W. H.

The book is written from the point of view intrinsic to fluid mechanics and applied mathematics. The analytical aspects of the theory are emphasized. However, it has also been tried, wherever possible, to relate the theory to experimental and numerical results. Mechanisms of instability are considered along with fundamental concepts of hydrodynamic stability, the Kelvin-Helmholtz instability, and the break-up of a liquid jet in air. Aspects of thermal instability are investigated, taking into account the equations of motion, the stability problem, general stability characteristics, particular stability characteristics, the cells, and experimental results. The inviscid theory and the viscous theory are examined in connection with a study of parallel shear flows. Centrifugal instability is discussed along with uniform asymptotic approximations, and problems of nonlinear stability. Attention is also given to baroclinic instability, the instability of the pinch, the development of linear instability in time and space, and the instability of unsteady flows.

Engine-Scale Combustor Rig Designed, Fabricated, and Tested for Combustion Instability Control Research

NASA Technical Reports Server (NTRS)

DeLaat, John C.; Breisacher, Kevin J.

2000-01-01

Low-emission combustor designs are prone to combustor instabilities. Because active control of these instabilities may allow future combustors to meet both stringent emissions and performance requirements, an experimental combustor rig was developed for investigating methods of actively suppressing combustion instabilities. The experimental rig has features similar to a real engine combustor and exhibits instabilities representative of those in aircraft gas turbine engines. Experimental testing in the spring of 1999 demonstrated that the rig can be tuned to closely represent an instability observed in engine tests. Future plans are to develop and demonstrate combustion instability control using this experimental combustor rig. The NASA Glenn Research Center at Lewis Field is leading the Combustion Instability Control program to investigate methods for actively suppressing combustion instabilities. Under this program, a single-nozzle, liquid-fueled research combustor rig was designed, fabricated, and tested. The rig has many of the complexities of a real engine combustor, including an actual fuel nozzle and swirler, dilution cooling, and an effusion-cooled liner. Prior to designing the experimental rig, a survey of aircraft engine combustion instability experience identified an instability observed in a prototype engine as a suitable candidate for replication. The frequency of the instability was 525 Hz, with an amplitude of approximately 1.5-psi peak-to-peak at a burner pressure of 200 psia. The single-nozzle experimental combustor rig was designed to preserve subcomponent lengths, cross sectional area distribution, flow distribution, pressure-drop distribution, temperature distribution, and other factors previously found to be determinants of burner acoustic frequencies, mode shapes, gain, and damping. Analytical models were used to predict the acoustic resonances of both the engine combustor and proposed experiment. The analysis confirmed that the test rig configuration and engine configuration had similar longitudinal acoustic characteristics, increasing the likelihood that the engine instability would be replicated in the rig. Parametric analytical studies were performed to understand the influence of geometry and condition variations and to establish a combustion test plan. Cold-flow experiments verified that the design values of area and flow distributions were obtained. Combustion test results established the existence of a longitudinal combustion instability in the 500-Hz range with a measured amplitude approximating that observed in the engine. Modifications to the rig configuration during testing also showed the potential for injector independence. The research combustor rig was developed in partnership with Pratt & Whitney of West Palm Beach, Florida, and United Technologies Research Center of East Hartford, Connecticut. Experimental testing of the combustor rig took place at United Technologies Research Center.

Deletion and reduced expression of the Fanconi anemia FANCA gene in sporadic acute myeloid leukemia.

PubMed

Tischkowitz, M D; Morgan, N V; Grimwade, D; Eddy, C; Ball, S; Vorechovsky, I; Langabeer, S; Stöger, R; Hodgson, S V; Mathew, C G

2004-03-01

Fanconi anemia (FA) is an autosomal recessive chromosomal instability disorder caused by mutations in one of seven known genes (FANCA,C,D2,E,F,G and BRCA2). Mutations in the FANCA gene are the most prevalent, accounting for two-thirds of FA cases. Affected individuals have greatly increased risks of acute myeloid leukemia (AML). This raises the question as to whether inherited or acquired mutations in FA genes might be involved in the development of sporadic AML. Quantitative fluorescent PCR was used to screen archival DNA from sporadic AML cases for FANCA deletions, which account for 40% of FANCA mutations in FA homozygotes. Four heterozygous deletions were found in 101 samples screened, which is 35-fold higher than the expected population frequency for germline FANCA deletions (P<0.0001). Sequencing FANCA in the AML samples with FANCA deletions did not detect mutations in the second allele and there was no evidence of epigenetic silencing by hypermethylation. However, real-time quantitative PCR analysis in these samples showed reduced expression of FANCA compared to nondeleted AML samples and to controls. These findings suggest that gene deletions and reduced expression of FANCA may be involved in the promotion of genetic instability in a subset of cases of sporadic AML.

A versatile microsatellite instability reporter system in human cells.

PubMed

Koole, Wouter; Schäfer, Henning S; Agami, Reuven; van Haaften, Gijs; Tijsterman, Marcel

2013-09-01

Here, we report the investigation of microsatellite instability (MSI) in human cells with a newly developed reporter system based on fluorescence. We composed a vector into which microsatellites of different lengths and nucleotide composition can be introduced between a functional copy of the fluorescent protein mCherry and an out-of-frame copy of EGFP; in vivo frameshifting will lead to EGFP expression, which can be quantified by fluorescence activated cell sorting (FACS). Via targeted recombineering, single copy reporters were introduced in HEK293 and MCF-7 cells. We found predominantly -1 and +1 base pair frameshifts, the levels of which are kept in tune by mismatch repair. We show that tract length and composition greatly influences MSI. In contrast, a tracts' potential to form a G-quadruplex structure, its strand orientation or its transcriptional status is not affecting MSI. We further validated the functionality of the reporter system for screening microsatellite mutagenicity of compounds and for identifying modifiers of MSI: using a retroviral miRNA expression library, we identified miR-21, which targets MSH2, as a miRNA that induces MSI when overexpressed. Our data also provide proof of principle for the strategy of combining fluorescent reporters with next-generation sequencing technology to identify genetic factors in specific pathways.

Parametric Instability Rates in Periodically Driven Band Systems

NASA Astrophysics Data System (ADS)

Lellouch, S.; Bukov, M.; Demler, E.; Goldman, N.

2017-04-01

In this work, we analyze the dynamical properties of periodically driven band models. Focusing on the case of Bose-Einstein condensates, and using a mean-field approach to treat interparticle collisions, we identify the origin of dynamical instabilities arising from the interplay between the external drive and interactions. We present a widely applicable generic numerical method to extract instability rates and link parametric instabilities to uncontrolled energy absorption at short times. Based on the existence of parametric resonances, we then develop an analytical approach within Bogoliubov theory, which quantitatively captures the instability rates of the system and provides an intuitive picture of the relevant physical processes, including an understanding of how transverse modes affect the formation of parametric instabilities. Importantly, our calculations demonstrate an agreement between the instability rates determined from numerical simulations and those predicted by theory. To determine the validity regime of the mean-field analysis, we compare the latter to the weakly coupled conserving approximation. The tools developed and the results obtained in this work are directly relevant to present-day ultracold-atom experiments based on shaken optical lattices and are expected to provide an insightful guidance in the quest for Floquet engineering.

History of shoulder instability surgery.

PubMed

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.

Loss of single immunoglobulin interlukin-1 receptor-related molecule leads to enhanced colonic polyposis in Apcmin mice

PubMed Central

Xiao, Hui; Yin, Weiguo; Khan, Mohammed A.; Gulen, Muhammet F.; Zhou, Hang; Sham, Ho Pan; Jacobson, Kevan; Vallance, Bruce A.; Li, Xiaoxia

2011-01-01

Background & Aims Commensal bacteria can activate signaling by the toll-like and interleukin-1 receptors (TLR and IL-1R) to mediate pathogenesis of inflammatory bowel diseases and colitis-associated cancer. We investigated the role of the single immunoglobulin IL-1 receptor-related (SIGIRR) molecule, a negative regulator of TLR and IL-1R signaling, as a tumor suppressor to determine whether SIGIRR controls cell cycle progression, genetic instability, and colon tumor initiation by modulating commensal TLR signaling in the gastrointestinal tract. Methods We analyzed Apcmin/+/Sigirr-/- mice for polyps, microadenomas, and anaphase bridge index. Commensal bacteria were depleted from mice with antibiotics. Akt, mTOR and β-catenin pathways were examined by immunoblotting and immunohistochemistry. Loss of heterozygosity (LOH) of Apc and expression of cytokines and proinflammatory mediators were measured by non-quantitative or quantitative PCR. Results Apcmin/+/Sigirr-/- mice had increased LOH of Apc and microadenoma formation, resulting in spontaneous colonic polyposis, compared with Apc min/+/Sigirr+/+ mice. The increased colonic tumorigenesis that occurred in the Apcmin/+/Sigirr-/- mice depended on the presence of commensal bacteria in the gastrointestinal tract. Cell proliferation and chromosomal instability increased in colon crypt cells of the Apcmin/+/Sigirr-/- mice. Akt, mTOR and their substrates were hyper-activated in colon epithelium of Apcmin/+/Sigirr-/- mice in response to TLR or IL-1R ligands. Inhibition of the mTOR pathway by rapamycin reduced formation of microadenomas and polyps in the Apcmin/+/Sigirr-/- mice. Conclusions SIGIRR acts as a tumor suppressor in the colon by inhibiting TLR-induced, mTOR-mediated cell cycle progression and genetic instability. PMID:20416302

Loss of single immunoglobulin interlukin-1 receptor-related molecule leads to enhanced colonic polyposis in Apc(min) mice.

PubMed

Xiao, Hui; Yin, Weiguo; Khan, Mohammed A; Gulen, Muhammet F; Zhou, Hang; Sham, Ho Pan; Jacobson, Kevan; Vallance, Bruce A; Li, Xiaoxia

2010-08-01

Commensal bacteria can activate signaling by the Toll-like and interleukin-1 receptors (TLR and IL-1R) to mediate pathogenesis of inflammatory bowel diseases and colitis-associated cancer. We investigated the role of the single immunoglobulin IL-1 receptor-related (SIGIRR) molecule, a negative regulator of TLR and IL-1R signaling, as a tumor suppressor to determine whether SIGIRR controls cell-cycle progression, genetic instability, and colon tumor initiation by modulating commensal TLR signaling in the gastrointestinal tract. We analyzed adenomatous polyposis coli (Apc)min/+/Sigirr-/- mice for polyps, microadenomas, and anaphase bridge index. Commensal bacteria were depleted from mice with antibiotics. Akt, mammalian target of rapamycin (mTOR), and beta-catenin pathways were examined by immunoblotting and immunohistochemistry. Loss of heterozygosity of Apc and expression of cytokines and proinflammatory mediators were measured by nonquantitative or quantitative polymerase chain reaction. Apcmin/+/Sigirr-/- mice had increased loss of heterozygosity of Apc and microadenoma formation, resulting in spontaneous colonic polyposis, compared with Apcmin/+/Sigirr+/+ mice. The increased colonic tumorigenesis that occurred in the Apcmin/+/Sigirr-/- mice depended on the presence of commensal bacteria in the gastrointestinal tract. Cell proliferation and chromosomal instability increased in colon crypt cells of the Apcmin/+/Sigirr-/- mice. Akt, mTOR, and their substrates were hyperactivated in colon epithelium of Apcmin/+/Sigirr-/- mice in response to TLR or IL-1R ligands. Inhibition of the mTOR pathway by rapamycin reduced formation of microadenomas and polyps in the Apcmin/+/Sigirr-/- mice. SIGIRR acts as a tumor suppressor in the colon by inhibiting TLR-induced, mTOR-mediated cell-cycle progression and genetic instability. Copyright (c) 2010 AGA Institute. Published by Elsevier Inc. All rights reserved.

A low-altitude mechanism for mesoscale dynamics, structure, and current filamentation in the discrete aurora

NASA Technical Reports Server (NTRS)

Keskinen, M. J.; Chaturvedi, P. K.; Ossakow, S. L.

1992-01-01

The 2D nonlinear evolution of the ionization-driven adiabatic auroral arc instability is studied. We find: (1) the adiabatic auroral arc instability can fully develop on time scales of tens to hundreds of seconds and on spatial scales of tens to hundreds of kilometers; (2) the evolution of this instability leads to nonlinear 'hook-shaped' conductivity structures: (3) this instability can lead to parallel current filamentation over a wide range of scale sizes; and (4) the k-spectra of the density, electric field, and parallel current develop into inverse power laws in agreement with satellite observations. Comparison with mesoscale auroral phenomenology and current filamentation structures is made.

Spatial Instability of the Linearly Polarized Plane Wave in a Cubic Crystal

NASA Astrophysics Data System (ADS)

Kuz'mina, M. S.; Khazanov, E. A.

2016-12-01

We study theoretically the development of a small-scale spatial instability of a plane wave in a cubic crystal with [111], [001] and [101] orientations. It is shown that in the [111] oriented crystals the instability develops at lower intensities than in the [001] and [101] oriented crystals. In the latter two crystals, the instability can significantly be suppressed by choosing the optimal radiation polarization. It is found that in the case of a small B integral, the method of temporal contrast enhancement of laser pulses by generating an orthogonal polarization achieves the largest efficiency with the [101] orientation, while the [001] orientation is more preferable for B > 3.

Intrastrand triplex DNA repeats in bacteria: a source of genomic instability

PubMed Central

Holder, Isabelle T.; Wagner, Stefanie; Xiong, Peiwen; Sinn, Malte; Frickey, Tancred; Meyer, Axel; Hartig, Jörg S.

2015-01-01

Repetitive nucleic acid sequences are often prone to form secondary structures distinct from B-DNA. Prominent examples of such structures are DNA triplexes. We observed that certain intrastrand triplex motifs are highly conserved and abundant in prokaryotic genomes. A systematic search of 5246 different prokaryotic plasmids and genomes for intrastrand triplex motifs was conducted and the results summarized in the ITxF database available online at http://bioinformatics.uni-konstanz.de/utils/ITxF/. Next we investigated biophysical and biochemical properties of a particular G/C-rich triplex motif (TM) that occurs in many copies in more than 260 bacterial genomes by CD and nuclear magnetic resonance spectroscopy as well as in vivo footprinting techniques. A characterization of putative properties and functions of these unusually frequent nucleic acid motifs demonstrated that the occurrence of the TM is associated with a high degree of genomic instability. TM-containing genomic loci are significantly more rearranged among closely related Escherichia coli strains compared to control sites. In addition, we found very high frequencies of TM motifs in certain Enterobacteria and Cyanobacteria that were previously described as genetically highly diverse. In conclusion we link intrastrand triplex motifs with the induction of genomic instability. We speculate that the observed instability might be an adaptive feature of these genomes that creates variation for natural selection to act upon. PMID:26450966

Gene amplification and microsatellite instability induced in tumorigenic human bronchial epithelial cells by alpha particles and heavy ions

NASA Technical Reports Server (NTRS)

Piao, C. Q.; Hei, T. K.; Hall, E. J. (Principal Investigator)

2001-01-01

Gene amplification and microsatellite alteration are useful markers of genomic instability in tumor and transformed cell lines. It has been suggested that genomic instability contributes to the progression of tumorigenesis by accumulating genetic changes. In this study, amplification of the carbamyl-P-synthetase, aspartate transcarbamylase, dihydro-orotase (CAD) gene in transformed and tumorigenic human bronchial epithelial (BEP2D) cells induced by either alpha particles or (56)Fe ions was assessed by measuring resistance to N-(phosphonacetyl)-l-aspartate (PALA). In addition, alterations of microsatellite loci located on chromosomes 3p and 18q were analyzed in a series of primary and secondary tumor cell lines generated in nude mice. The frequency of PALA-resistant colonies was 1-3 x 10(-3) in tumor cell lines, 5-8 x 10(-5) in transformed cells prior to inoculation into nude mice, and less than 10(-7) in control BEP2D cells. Microsatellite alterations were detected in all 11 tumor cell lines examined at the following loci: D18S34, D18S363, D18S877, D3S1038 and D3S1607. No significant difference in either PALA resistance or microsatellite instability was found in tumor cell lines that were induced by alpha particles compared to those induced by (56)Fe ions.

Absolute/convective secondary instabilities and the role of confinement in free shear layers

NASA Astrophysics Data System (ADS)

Arratia, Cristóbal; Mowlavi, Saviz; Gallaire, François

2018-05-01

We study the linear spatiotemporal stability of an infinite row of equal point vortices under symmetric confinement between parallel walls. These rows of vortices serve to model the secondary instability leading to the merging of consecutive (Kelvin-Helmholtz) vortices in free shear layers, allowing us to study how confinement limits the growth of shear layers through vortex pairings. Using a geometric construction akin to a Legendre transform on the dispersion relation, we compute the growth rate of the instability in different reference frames as a function of the frame velocity with respect to the vortices. This approach is verified and complemented with numerical computations of the linear impulse response, fully characterizing the absolute/convective nature of the instability. Similar to results by Healey on the primary instability of parallel tanh profiles [J. Fluid Mech. 623, 241 (2009), 10.1017/S0022112008005284], we observe a range of confinement in which absolute instability is promoted. For a parallel shear layer with prescribed confinement and mixing length, the threshold for absolute/convective instability of the secondary pairing instability depends on the separation distance between consecutive vortices, which is physically determined by the wavelength selected by the previous (primary or pairing) instability. In the presence of counterflow and moderate to weak confinement, small (large) wavelength of the vortex row leads to absolute (convective) instability. While absolute secondary instabilities in spatially developing flows have been previously related to an abrupt transition to a complex behavior, this secondary pairing instability regenerates the flow with an increased wavelength, eventually leading to a convectively unstable row of vortices. We argue that since the primary instability remains active for large wavelengths, a spatially developing shear layer can directly saturate on the wavelength of such a convectively unstable row, by-passing the smaller wavelengths of absolute secondary instability. This provides a wavelength selection mechanism, according to which the distance between consecutive vortices should be sufficiently large in comparison with the channel width in order for the row of vortices to persist. We argue that the proposed wavelength selection criteria can serve as a guideline for experimentally obtaining plane shear layers with counterflow, which has remained an experimental challenge.

A mobile threat to genome stability: The impact of non-LTR retrotransposons upon the human genome.

PubMed

Konkel, Miriam K; Batzer, Mark A

2010-08-01

It is now commonly agreed that the human genome is not the stable entity originally presumed. Deletions, duplications, inversions, and insertions are common, and contribute significantly to genomic structural variations (SVs). Their collective impact generates much of the inter-individual genomic diversity observed among humans. Not only do these variations change the structure of the genome; they may also have functional implications, e.g. altered gene expression. Some SVs have been identified as the cause of genetic disorders, including cancer predisposition. Cancer cells are notorious for their genomic instability, and often show genomic rearrangements at the microscopic and submicroscopic level to which transposable elements (TEs) contribute. Here, we review the role of TEs in genome instability, with particular focus on non-LTR retrotransposons. Currently, three non-LTR retrotransposon families - long interspersed element 1 (L1), SVA (short interspersed element (SINE-R), variable number of tandem repeats (VNTR), and Alu), and Alu (a SINE) elements - mobilize in the human genome, and cause genomic instability through both insertion- and post-insertion-based mutagenesis. Due to the abundance and high sequence identity of TEs, they frequently mislead the homologous recombination repair pathway into non-allelic homologous recombination, causing deletions, duplications, and inversions. While less comprehensively studied, non-LTR retrotransposon insertions and TE-mediated rearrangements are probably more common in cancer cells than in healthy tissue. This may be at least partially attributed to the commonly seen global hypomethylation as well as general epigenetic dysfunction of cancer cells. Where possible, we provide examples that impact cancer predisposition and/or development. Copyright © 2010 Elsevier Ltd. All rights reserved.

Myc, Aurora Kinase-A, and mutant p53R172H co-operate in a mouse model of metastatic skin carcinoma

PubMed Central

Torchia, Enrique C.; Caulin, Carlos; Acin, Sergio; Terzian, Tamara; Kubick, Bradley J.; Box, Neil F.; Roop, Dennis R.

2015-01-01

Clinical observations, as well as data obtained from the analysis of genetically engineered mouse models, firmly established the gain-of-function (GOF) properties of certain p53 mutations. However, little is known about the underlying mechanisms. We have used two independent microarray platforms to perform a comprehensive and global analysis of tumors arising in a model of metastatic skin cancer progression, which compares the consequences of a GOF p53R172H mutant vs. p53 deficiency. DNA profiling revealed a higher level of genomic instability in GOF vs. loss-of-function (LOF) p53 squamous cell carcinomas (SCCs). Moreover, GOF p53 SCCs showed preferential amplification of Myc with a corresponding increase in its expression and deregulation of Aurora Kinase-A. Fluorescent in situ hybridization confirmed amplification of Myc in primary GOF p53 SCCs and its retention in metastatic tumors. We also identified by RNA profiling distinct gene expression profiles in GOF p53 tumors, which included enriched integrin and Rho signaling, independent of tumor stage. Thus, the progression of GOF p53 papillomas to carcinoma was marked by the acquisition of epithelial to mesenchymal transition and metastatic signatures. In contrast, LOF p53 tumors showed enrichment of genes associated with cancer proliferation and chromosomal instability. Collectively, these observations suggest that genomic instability plays a prominent role in the early stages of GOF p53 tumor progression (i.e., papillomas), while it is implicated at a later stage in LOF p53 tumors (i.e., SCCs). This model will allow us to identify specific targets in mutant p53 SCCs, which may lead to the development of new therapeutic agents for the treatment of metastatic SCCs. PMID:21963848

Intracellular HMGB1 as a novel tumor suppressor of pancreatic cancer

PubMed Central

Kang, Rui; Xie, Yangchun; Zhang, Qiuhong; Hou, Wen; Jiang, Qingping; Zhu, Shan; Liu, Jinbao; Zeng, Dexing; Wang, Haichao; Bartlett, David L; Billiar, Timothy R; Zeh, Herbert J; Lotze, Michael T; Tang, Daolin

2017-01-01

Pancreatic ductal adenocarcinoma (PDAC) driven by oncogenic K-Ras remains among the most lethal human cancers despite recent advances in modern medicine. The pathogenesis of PDAC is partly attributable to intrinsic chromosome instability and extrinsic inflammation activation. However, the molecular link between these two events in pancreatic tumorigenesis has not yet been fully established. Here, we show that intracellular high mobility group box 1 (HMGB1) remarkably suppresses oncogenic K-Ras-driven pancreatic tumorigenesis by inhibiting chromosome instability-mediated pro-inflammatory nucleosome release. Conditional genetic ablation of either single or both alleles of HMGB1 in the pancreas renders mice extremely sensitive to oncogenic K-Ras-driven initiation of precursor lesions at birth, including pancreatic intraepithelial neoplasms, intraductal papillary mucinous neoplasms, and mucinous cystic neoplasms. Loss of HMGB1 in the pancreas is associated with oxidative DNA damage and chromosomal instability characterized by chromosome rearrangements and telomere abnormalities. These lead to inflammatory nucleosome release and propagate K-Ras-driven pancreatic tumorigenesis. Extracellular nucleosomes promote interleukin 6 (IL-6) secretion by infiltrating macrophages/neutrophils and enhance oncogenic K-Ras signaling activation in pancreatic lesions. Neutralizing antibodies to IL-6 or histone H3 or knockout of the receptor for advanced glycation end products all limit K-Ras signaling activation, prevent cancer development and metastasis/invasion, and prolong animal survival in Pdx1-Cre;K-RasG12D/+;Hmgb1−/− mice. Pharmacological inhibition of HMGB1 loss by glycyrrhizin limits oncogenic K-Ras-driven tumorigenesis in mice under inflammatory conditions. Diminished nuclear and total cellular expression of HMGB1 in PDAC patients correlates with poor overall survival, supporting intracellular HMGB1 as a novel tumor suppressor with prognostic and therapeutic relevance in PDAC. PMID:28374746

On the instability of a liquid sheet moving in vacuum

NASA Astrophysics Data System (ADS)

Sisoev, G. M.; Osiptsov, A. N.; Koroteev, A. A.

2018-03-01

A linear stability analysis of a non-isothermal liquid sheet moving in vacuum is studied taking into account the temperature dependencies of the liquid viscosity, thermal conductivity, and surface tension coefficients. It is found that there are two mechanisms of instability. The short-wave instability is caused by viscosity stratification across the sheet due to nonuniform temperature profiles developed downstream in the cooling sheet. The long-wave thermocapillary instability is caused by the temperature gradient along the sheet surfaces. Computed examples of steady flows and their instabilities demonstrated that the unstable short waves have much larger amplification factors.

Two-stream instability with time-dependent drift velocity

DOE PAGES

Qin, Hong; Davidson, Ronald C.

2014-06-26

The classical two-stream instability driven by a constant relative drift velocity between two plasma components is extended to the case with time-dependent drift velocity. A solution method is developed to rigorously define and calculate the instability growth rate for linear perturbations relative to the time-dependent unperturbed two-stream motions. The stability diagrams for the oscillating two-stream instability are presented over a large region of parameter space. It is shown that the growth rate for the classical two-stream instability can be significantly reduced by adding an oscillatory component to the relative drift velocity.

Lateral ankle instability: MR imaging of associated injuries and surgical treatment procedures.

PubMed

Alparslan, Leyla; Chiodo, Christopher P

2008-12-01

Chronic ankle instability has been defined as the development of recurrent ankle sprains and persistent symptoms after initial lateral ankle sprain. The diagnosis of ankle instability is usually established on the patient's history, physical examination, and radiographic assessment. Patients have signs of both functional and mechanical instability, and the repetitive, chronic nature of the injury may lead to intra-articular and periarticular pathologies. This article discusses the incidence, etiology, and magnetic resonance (MR) imaging of these pathologies, reviews the surgical treatment procedures for lateral ankle instability, and presents the postoperative MR imaging findings.

Experimental Replication of an Aeroengine Combustion Instability

NASA Technical Reports Server (NTRS)

Cohen, J. M.; Hibshman, J. R.; Proscia, W.; Rosfjord, T. J.; Wake, B. E.; McVey, J. B.; Lovett, J.; Ondas, M.; DeLaat, J.; Breisacher, K.

2000-01-01

Combustion instabilities in gas turbine engines are most frequently encountered during the late phases of engine development, at which point they are difficult and expensive to fix. The ability to replicate an engine-traceable combustion instability in a laboratory-scale experiment offers the opportunity to economically diagnose the problem (to determine the root cause), and to investigate solutions to the problem, such as active control. The development and validation of active combustion instability control requires that the causal dynamic processes be reproduced in experimental test facilities which can be used as a test bed for control system evaluation. This paper discusses the process through which a laboratory-scale experiment was designed to replicate an instability observed in a developmental engine. The scaling process used physically-based analyses to preserve the relevant geometric, acoustic and thermo-fluid features. The process increases the probability that results achieved in the single-nozzle experiment will be scalable to the engine.

The initial instability and finite-amplitude stability of alternate bars in straight channels

USGS Publications Warehouse

Nelson, J.M.

1990-01-01

The initial instability and fully developed stability of alternate bars in straight channels are investigated using linearized and nonlinear analyses. The fundamental instability leading to these features is identified through a linear stability analysis of the equations governing the flow and sediment transport fields. This instability is explained in terms of topographically induced steering of the flow and the associated pattern of erosion and deposition on the bed. While the linear theory is useful for examining the instability mechanism, this approach is shown to yield relatively little information about well-developed alternate bars and, specifically, the linear analysis is shown to yield poor predictions of the fully developed bar wavelength. A fully nonlinear approach is presented that permits computation of the evolution of these bed features from an initial perturbation to their fully developed morphology. This analysis indicates that there is typically substantial elongation of the bar wavelength during the evolution process, a result that is consistent with observations of bar development in flumes and natural channels. The nonlinear approach demonstrates that the eventual stability of these features is a result of the interplay between topographic steering effects, secondary flow production as a result of streamline curvature, and gravitationally induced modifications of sediment fluxes over a sloping bed. ?? 1990.

Long-wavelength instabilities in a system of interacting active particles

NASA Astrophysics Data System (ADS)

Fazli, Zahra; Najafi, Ali

2018-02-01

Based on a microscopic model, we develop a continuum description for a suspension of microscopic self-propelled particles. With this continuum description we study the role of long-range interactions in destabilizing macroscopic ordered phases that are developed by short-range interactions. Long-wavelength fluctuations can destabilize both isotropic and symmetry-broken polar phases in a suspension of dipolar particles. The instabilities in a suspension of pullers (pushers) arise from splay (bend) fluctuations. Such instabilities are not seen in a suspension of quadrupolar particles.

An enstrophy-based linear and nonlinear receptivity theory

NASA Astrophysics Data System (ADS)

Sengupta, Aditi; Suman, V. K.; Sengupta, Tapan K.; Bhaumik, Swagata

2018-05-01

In the present research, a new theory of instability based on enstrophy is presented for incompressible flows. Explaining instability through enstrophy is counter-intuitive, as it has been usually associated with dissipation for the Navier-Stokes equation (NSE). This developed theory is valid for both linear and nonlinear stages of disturbance growth. A previously developed nonlinear theory of incompressible flow instability based on total mechanical energy described in the work of Sengupta et al. ["Vortex-induced instability of an incompressible wall-bounded shear layer," J. Fluid Mech. 493, 277-286 (2003)] is used to compare with the present enstrophy based theory. The developed equations for disturbance enstrophy and disturbance mechanical energy are derived from NSE without any simplifying assumptions, as compared to other classical linear/nonlinear theories. The theory is tested for bypass transition caused by free stream convecting vortex over a zero pressure gradient boundary layer. We explain the creation of smaller scales in the flow by a cascade of enstrophy, which creates rotationality, in general inhomogeneous flows. Linear and nonlinear versions of the theory help explain the vortex-induced instability problem under consideration.

Instability in Parent-Child Coresidence and Adolescent Development in Urban South Africa.

PubMed

Marteleto, Letícia J; Cavanagh, Shannon; Prickett, Kate; Clark, Shelley

2016-03-01

There is widespread recognition of the importance of family stability for child development. South Africa presents an interesting context in which to study the consequences of family instability because of the traditionally fluid nature of household composition due to labor migration, child fostering, and non-marital fertility. More recently, the HIV pandemic has added another source of instability. Within South Africa, however, patterns of instability differ markedly across racial groups. We use the Cape Area Panel Study (CAPS) data to examine the implications of changes in parent-child coresidence for educational and sexual development of young South Africans. We show that changes in maternal and paternal coresidence have implications for the timing of sexual initiation for both black and coloured adolescents. Maternal and paternal transitions also lead to poorer educational outcomes for coloured adolescents, but parental disruptions are not significantly related to educational outcomes for blacks. These findings suggest that the implications of coresidential instability vary by race, reflecting racial differences with respect to cultural, social, and economic conditions. © 2016 The Population Council, Inc.

Flow morphologies after oblique shock acceelration of a cylindrical density interface

NASA Astrophysics Data System (ADS)

Wayne, Patrick; Simons, Dylan; Olmstead, Dell; Truman, C. Randall; Vorobieff, Peter; Kumar, Sanjay

2015-11-01

We present an experimental study of instabilities developing after an oblique shock interaction with a heavy gas column. The heavy gas in our experiments is sulfur hexafluoride infused with 11% acetone by mass. A misalignment of the pressure and density gradients results in three-dimensional vorticity deposition on the gaseous interface, dtriggering the onset of Richtmyer-Meshkov instability (RMI). Shortly thereafter, other instabilities develop along the interface, including a shear-driven instability that presents itself on the leading (with respect to the shock) and trailing edges of the column. This leads to the development of rows of co-rotating ``cat's eye'' vortices, characteristic of Kelvin-Helmholtz instability (KHI). Characteristics of the KHI, such as growth rate and wavelength, depend on several factors including the Mach number of the shock, the shock tube angle of inclination α (equal to the angle between the axis of the column and the plane of the shock), and the Atwood number. This work is supported by the US National Nuclear Security Agency (NNSA) via grant DE-NA0002913.

Catalytic Activity of a Binary Informational Macromolecule

NASA Technical Reports Server (NTRS)

Reader, John S.; Joyce, Gerald F.

2003-01-01

RNA molecules are thought to have played a prominent role in the early history of life on Earth based on their ability both to encode genetic information and to exhibit catalytic function. The modern genetic alphabet relies on two sets of complementary base pairs to store genetic information. However, due to the chemical instability of cytosine, which readily deaminates to uracil, a primitive genetic system composed of the bases A, U, G and C may have been difficult to establish. It has been suggested that the first genetic material instead contained only a single base-pairing unie'. Here we show that binary informational macromolecules, containing only two different nucleotide subunits, can act as catalysts. In vitro evolution was used to obtain ligase ribozymes composed of only 2,6-diaminopurine and uracil nucleotides, which catalyze the template-directed joining of two RNA molecules, one bearing a 5'-triphosphate and the other a 3'-hydroxyl. The active conformation of the fastest isolated ribozyme had a catalytic rate that was about 36,000-fold faster than the uncatalyzed rate of reaction. This ribozyme is specific for the formation of biologically relevant 3',5'-phosphodiester linkages.

Global insights into acetic acid resistance mechanisms and genetic stability of Acetobacter pasteurianus strains by comparative genomics

NASA Astrophysics Data System (ADS)

Wang, Bin; Shao, Yanchun; Chen, Tao; Chen, Wanping; Chen, Fusheng

2015-12-01

Acetobacter pasteurianus (Ap) CICC 20001 and CGMCC 1.41 are two acetic acid bacteria strains that, because of their strong abilities to produce and tolerate high concentrations of acetic acid, have been widely used to brew vinegar in China. To globally understand the fermentation characteristics, acid-tolerant mechanisms and genetic stabilities, their genomes were sequenced. Genomic comparisons with 9 other sequenced Ap strains revealed that their chromosomes were evolutionarily conserved, whereas the plasmids were unique compared with other Ap strains. Analysis of the acid-tolerant metabolic pathway at the genomic level indicated that the metabolism of some amino acids and the known mechanisms of acetic acid tolerance, might collaboratively contribute to acetic acid resistance in Ap strains. The balance of instability factors and stability factors in the genomes of Ap CICC 20001 and CGMCC 1.41 strains might be the basis for their genetic stability, consistent with their stable industrial performances. These observations provide important insights into the acid resistance mechanism and the genetic stability of Ap strains and lay a foundation for future genetic manipulation and engineering of these two strains.

Global insights into acetic acid resistance mechanisms and genetic stability of Acetobacter pasteurianus strains by comparative genomics.

PubMed

Wang, Bin; Shao, Yanchun; Chen, Tao; Chen, Wanping; Chen, Fusheng

2015-12-22

Acetobacter pasteurianus (Ap) CICC 20001 and CGMCC 1.41 are two acetic acid bacteria strains that, because of their strong abilities to produce and tolerate high concentrations of acetic acid, have been widely used to brew vinegar in China. To globally understand the fermentation characteristics, acid-tolerant mechanisms and genetic stabilities, their genomes were sequenced. Genomic comparisons with 9 other sequenced Ap strains revealed that their chromosomes were evolutionarily conserved, whereas the plasmids were unique compared with other Ap strains. Analysis of the acid-tolerant metabolic pathway at the genomic level indicated that the metabolism of some amino acids and the known mechanisms of acetic acid tolerance, might collaboratively contribute to acetic acid resistance in Ap strains. The balance of instability factors and stability factors in the genomes of Ap CICC 20001 and CGMCC 1.41 strains might be the basis for their genetic stability, consistent with their stable industrial performances. These observations provide important insights into the acid resistance mechanism and the genetic stability of Ap strains and lay a foundation for future genetic manipulation and engineering of these two strains.

Liquid propellant rocket combustion instability

NASA Technical Reports Server (NTRS)

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.

Genetic and clinical determinants of constitutional mismatch repair deficiency syndrome: report from the constitutional mismatch repair deficiency consortium.

PubMed

Bakry, Doua; Aronson, Melyssa; Durno, Carol; Rimawi, Hala; Farah, Roula; Alharbi, Qasim Kholaif; Alharbi, Musa; Shamvil, Ashraf; Ben-Shachar, Shay; Mistry, Matthew; Constantini, Shlomi; Dvir, Rina; Qaddoumi, Ibrahim; Gallinger, Steven; Lerner-Ellis, Jordan; Pollett, Aaron; Stephens, Derek; Kelies, Steve; Chao, Elizabeth; Malkin, David; Bouffet, Eric; Hawkins, Cynthia; Tabori, Uri

2014-03-01

Constitutional mismatch repair deficiency (CMMRD) is a devastating cancer predisposition syndrome for which data regarding clinical manifestations, molecular screening tools and management are limited. We established an international CMMRD consortium and collected comprehensive clinical and genetic data. Molecular diagnosis of tumour and germline biospecimens was performed. A surveillance protocol was developed and implemented. Overall, 22/23 (96%) of children with CMMRD developed 40 different tumours. While childhood CMMRD related tumours were observed in all families, Lynch related tumours in adults were observed in only 2/14 families (p=0.0007). All children with CMMRD had café-au-lait spots and 11/14 came from consanguineous families. Brain tumours were the most common cancers reported (48%) followed by gastrointestinal (32%) and haematological malignancies (15%). Importantly, 12 (30%) of these were low grade and resectable cancers. Tumour immunohistochemistry was 100% sensitive and specific in diagnosing mismatch repair (MMR) deficiency of the corresponding gene while microsatellite instability was neither sensitive nor specific as a diagnostic tool (p<0.0001). Furthermore, screening of normal tissue by immunohistochemistry correlated with genetic confirmation of CMMRD. The surveillance protocol detected 39 lesions which included asymptomatic malignant gliomas and gastrointestinal carcinomas. All tumours were amenable to complete resection and all patients undergoing surveillance are alive. CMMRD is a highly penetrant syndrome where family history of cancer may not be contributory. Screening tumours and normal tissues using immunohistochemistry for abnormal expression of MMR gene products may help in diagnosis and early implementation of surveillance for these children. Copyright © 2013 Elsevier Ltd. All rights reserved.

Genetic Biomarkers of Barrett's Esophagus Susceptibility and Progression to Dysplasia and Cancer: A Systematic Review and Meta-Analysis.

PubMed

Findlay, John M; Middleton, Mark R; Tomlinson, Ian

2016-01-01

Barrett's esophagus (BE) is a common and important precursor lesion of esophageal adenocarcinoma (EAC). A third of patients with BE are asymptomatic, and our ability to predict the risk of progression of metaplasia to dysplasia and EAC (and therefore guide management) is limited. There is an urgent need for clinically useful biomarkers of susceptibility to both BE and risk of subsequent progression. This study aims to systematically identify, review, and meta-analyze genetic biomarkers reported to predict both. A systematic review of the PubMed and EMBASE databases was performed in May 2014. Study and evidence quality were appraised using the revised American Society of Clinical Oncology guidelines, and modified Recommendations for Tumor Marker Scores. Meta-analysis was performed for all markers assessed by more than one study. A total of 251 full-text articles were reviewed; 52 were included. A total of 33 germline markers of susceptibility were identified (level of evidence II-III); 17 were included. Five somatic markers of progression were identified; meta-analysis demonstrated significant associations for chromosomal instability (level of evidence II). One somatic marker of progression/relapse following photodynamic therapy was identified. However, a number of failings of methodology and reporting were identified. This is the first systematic review and meta-analysis to evaluate genetic biomarkers of BE susceptibility and risk of progression. While a number of limitations of study quality temper the utility of those markers identified, some-in particular, those identified by genome-wide association studies, and chromosomal instability for progression-appear plausible, although robust validation is required.

Extensive genetic and DNA methylation variation contribute to heterosis in triploid loquat hybrids.

PubMed

Liu, Chao; Wang, Mingbo; Wang, Lingli; Guo, Qigao; Liang, Guolu

2018-04-24

We aim to overcome the unclear origin of the loquat and elucidate the heterosis mechanism of the triploid loquat. Here we investigated the genetic and epigenetic variations between the triploid plant and its parental lines using amplified fragment length polymorphism (AFLP) and methylation-sensitive amplified fragment length polymorphism (MSAP) analyses. We show that in addition to genetic variations, extensive DNA methylation variation occurred during the formation process of triploid loquat, with the triploid hybrid having increased DNA methylation compared to the parents. Furthermore, a correlation existed between genetic variation and DNA methylation remodeling, suggesting that genome instability may lead to DNA methylation variation or vice versa. Sequence analysis of the MSAP bands revealed that over 53% of them overlap with protein-coding genes, which may indicate a functional role of the differential DNA methylation in gene regulation and hence heterosis phenotypes. Consistent with this, the genetic and epigenetic alterations were associated closely to the heterosis phenotypes of triploid loquat, and this association varied for different traits. Our results suggested that the formation of triploid is accompanied by extensive genetic and DNA methylation variation, and these changes contribute to the heterosis phenotypes of the triploid loquats from the two cross lines.

Transcription as a Threat to Genome Integrity.

PubMed

Gaillard, Hélène; Aguilera, Andrés

2016-06-02

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

Genomic and epigenomic heterogeneity in molecular subtypes of gastric cancer.

PubMed

Lim, Byungho; Kim, Jong-Hwan; Kim, Mirang; Kim, Seon-Young

2016-01-21

Gastric cancer is a complex disease that is affected by multiple genetic and environmental factors. For the precise diagnosis and effective treatment of gastric cancer, the heterogeneity of the disease must be simplified; one way to achieve this is by dividing the disease into subgroups. Toward this effort, recent advances in high-throughput sequencing technology have revealed four molecular subtypes of gastric cancer, which are classified as Epstein-Barr virus-positive, microsatellite instability, genomically stable, and chromosomal instability subtypes. We anticipate that this molecular subtyping will help to extend our knowledge for basic research purposes and will be valuable for clinical use. Here, we review the genomic and epigenomic heterogeneity of the four molecular subtypes of gastric cancer. We also describe a mutational meta-analysis and a reanalysis of DNA methylation that were performed using previously reported gastric cancer datasets.

Chromosomal instability: A common feature and a therapeutic target of cancer.

PubMed

Tanaka, Kozo; Hirota, Toru

2016-08-01

Most cancer cells are aneuploid, containing abnormal numbers of chromosomes, mainly caused by elevated levels of chromosome missegregation, known as chromosomal instability (CIN). These well-recognized, but poorly understood, features of cancers have recently been studied extensively, unraveling causal relationships between CIN and cancer. Here we review recent findings regarding how CIN and aneuploidy occur, how they affect cellular functions, how cells respond to them, and their relevance to diseases, especially cancer. Aneuploid cells are under various kinds of stresses that result in reduced cellular fitness. Nevertheless, genetic heterogeneity derived from CIN allows the selection of cells better adapted to their environment, which supposedly facilitates generation and progression of cancer. We also discuss how we can exploit the properties of cancer cells exhibiting CIN for effective cancer therapy. Copyright © 2016 Elsevier B.V. All rights reserved.

Centrosome Defects, Genetic Instability and Breast Cancer Progression

DTIC Science & Technology

2006-08-01

midbody-ring localization of GFP-GAPCenA onfirmed the ring structure seen by immunofluores- ence microscopy and demonstrated that there were o antibody ...sec8 (upper panels). Graph shows sec8 levels, iodixanol density, and total protein. (C) Immunoprecipitation (IP) of Nud1-DBD (DBD antibody ) pulls down...immunoprecipi- tated endogenous centriolin from HeLa cell lysates with affinity-purified centriolin antibodies and showed that sec8 and sec5 coprecipitated

SnapShot: Fanconi anemia and associated proteins.

PubMed

Wang, Anderson T; Smogorzewska, Agata

2015-01-15

Fanconi anemia is a genetic disorder resulting from biallelic mutations in one of the 17 FANC genes. It is characterized by congenital abnormalities, bone marrow failure, and cancer predisposition. The underlying cause is genomic instability resulting from the deficiency in replication-dependent DNA interstrand crosslink repair pathway commonly referred to as the Fanconi anemia-BRCA pathway. This SnapShot presents the key factors involved. Copyright © 2015 Elsevier Inc. All rights reserved.

All y'all need to know 'bout retroelements in cancer.

PubMed

Belancio, Victoria P; Roy-Engel, Astrid M; Deininger, Prescott L

2010-08-01

Genetic instability is one of the principal hallmarks and causative factors in cancer. Human transposable elements (TE) have been reported to cause human diseases, including several types of cancer through insertional mutagenesis of genes critical for preventing or driving malignant transformation. In addition to retrotransposition-associated mutagenesis, TEs have been found to contribute even more genomic rearrangements through non-allelic homologous recombination. TEs also have the potential to generate a wide range of mutations derivation of which is difficult to directly trace to mobile elements, including double strand breaks that may trigger mutagenic genomic rearrangements. Genome-wide hypomethylation of TE promoters and significantly elevated TE expression in almost all human cancers often accompanied by the loss of critical DNA sensing and repair pathways suggests that the negative impact of mobile elements on genome stability should increase as human tumors evolve. The biological consequences of elevated retroelement expression, such as the rate of their amplification, in human cancers remain obscure, particularly, how this increase translates into disease-relevant mutations. This review is focused on the cellular mechanisms that control human TE-associated mutagenesis in cancer and summarizes the current understanding of TE contribution to genetic instability in human malignancies. Copyright © 2010 Elsevier Ltd. All rights reserved.

Overexpression of dominant negative PARP interferes with tumor formation of HeLa cells in nude mice: evidence for increased tumor cell apoptosis in vivo.

PubMed

Hans, M A; Müller, M; Meyer-Ficca, M; Bürkle, A; Küpper, J H

1999-11-25

Poly(ADP-ribose) polymerase (PARP4) catalyzes the formation of ADP-ribose polymers covalently attached to proteins by using NAD+ as substrate. PARP is strongly activated by DNA single- or double-strand breaks and is thought to be involved in cellular responses to DNA damage. We characterized a dominant negative PARP mutant, i.e. the DNA-binding domain of this enzyme, whose overexpression in cells leads to increased genetic instability following DNA damage. In order to study whether PARP activity is also implicated in the process of tumorigenesis, we generated stably transfected HeLa cell clones with constitutive overexpression of dominant negative PARP and investigated tumor formation of these clones in nude mice. We found that inhibition of PARP activity dramatically reduces tumor forming ability of HeLa cells. Moreover, we provide strong evidence that the observed reduction in tumor forming ability is due to increased tumor cell apoptosis in vivo. Viewed together, our data and those from other groups show that inhibition of PARP enzyme activity interferes with DNA base excision repair and leads to increased genetic instability and recombination but, on the other hand, can sensitize cells to apoptotic stimuli and by this mechanism may prevent tumor formation.

Rate-determining Step of Flap Endonuclease 1 (FEN1) Reflects a Kinetic Bias against Long Flaps and Trinucleotide Repeat Sequences.

PubMed

Tarantino, Mary E; Bilotti, Katharina; Huang, Ji; Delaney, Sarah

2015-08-21

Flap endonuclease 1 (FEN1) is a structure-specific nuclease responsible for removing 5'-flaps formed during Okazaki fragment maturation and long patch base excision repair. In this work, we use rapid quench flow techniques to examine the rates of 5'-flap removal on DNA substrates of varying length and sequence. Of particular interest are flaps containing trinucleotide repeats (TNR), which have been proposed to affect FEN1 activity and cause genetic instability. We report that FEN1 processes substrates containing flaps of 30 nucleotides or fewer at comparable single-turnover rates. However, for flaps longer than 30 nucleotides, FEN1 kinetically discriminates substrates based on flap length and flap sequence. In particular, FEN1 removes flaps containing TNR sequences at a rate slower than mixed sequence flaps of the same length. Furthermore, multiple-turnover kinetic analysis reveals that the rate-determining step of FEN1 switches as a function of flap length from product release to chemistry (or a step prior to chemistry). These results provide a kinetic perspective on the role of FEN1 in DNA replication and repair and contribute to our understanding of FEN1 in mediating genetic instability of TNR sequences. © 2015 by The American Society for Biochemistry and Molecular Biology, Inc.

Mitochondria damage checkpoint in apoptosis and genome stability.

PubMed

Singh, Keshav K

2004-11-01

Mitochondria perform multiple cellular functions including energy production, cell proliferation and apoptosis. Studies described in this paper suggest a role for mitochondria in maintaining genomic stability. Genomic stability appears to be dependent on mitochondrial functions involved in maintenance of proper intracellular redox status, ATP-dependent transcription, DNA replication, DNA repair and DNA recombination. To further elucidate the role of mitochondria in genomic stability, I propose a mitochondria damage checkpoint (mitocheckpoint) that monitors and responds to damaged mitochondria. Mitocheckpoint can coordinate and maintain proper balance between apoptotic and anti-apoptotic signals. When mitochondria are damaged, mitocheckpoint can be activated to help cells repair damaged mitochondria, to restore normal mitochondrial function and avoid production of mitochondria-defective cells. If mitochondria are severely damaged, mitocheckpoint may not be able to repair the damage and protect cells. Such an event triggers apoptosis. If damage to mitochondria is continuous or persistent such as damage to mitochondrial DNA resulting in mutations, mitocheckpoint may fail which can lead to genomic instability and increased cell survival in yeast. In human it can cause cancer. In support of this proposal we provide evidence that mitochondrial genetic defects in both yeast and mammalian systems lead to impaired DNA repair, increased genomic instability and increased cell survival. This study reveals molecular genetic mechanisms underlying a role for mitochondria in carcinogenesis in humans.

The origins and impact of primate segmental duplications.

PubMed

Marques-Bonet, Tomas; Girirajan, Santhosh; Eichler, Evan E

2009-10-01

Duplicated sequences are substrates for the emergence of new genes and are an important source of genetic instability associated with rare and common diseases. Analyses of primate genomes have shown an increase in the proportion of interspersed segmental duplications (SDs) within the genomes of humans and great apes. This contrasts with other mammalian genomes that seem to have their recently duplicated sequences organized in a tandem configuration. In this review, we focus on the mechanistic origin and impact of this difference with respect to evolution, genetic diversity and primate phenotype. Although many genomes will be sequenced in the future, resolution of this aspect of genomic architecture still requires high quality sequences and detailed analyses.

Altering Genomic Integrity: Heavy Metal Exposure Promotes Transposable Element-Mediated Damage.

PubMed

Morales, Maria E; Servant, Geraldine; Ade, Catherine; Roy-Engel, Astrid M

2015-07-01

Maintenance of genomic integrity is critical for cellular homeostasis and survival. The active transposable elements (TEs) composed primarily of three mobile element lineages LINE-1, Alu, and SVA comprise approximately 30% of the mass of the human genome. For the past 2 decades, studies have shown that TEs significantly contribute to genetic instability and that TE-caused damages are associated with genetic diseases and cancer. Different environmental exposures, including several heavy metals, influence how TEs interact with its host genome increasing their negative impact. This mini-review provides some basic knowledge on TEs, their contribution to disease, and an overview of the current knowledge on how heavy metals influence TE-mediated damage.

Adventures in hepatocarcinogenesis.

PubMed

Pitot, Henry C

2007-01-01

Neoplasia is a heritably altered, relatively autonomous growth of tissue. Hepatocarcinogenesis, the pathogenesis of neoplasia in liver, as modeled in the rat exhibits three distinct, quantifiable stages: initiation, promotion, and progression. Simple mutations and/or epigenetic alterations may result in the irreversible stage of initiation. The stage of promotion results from selective enhancement of cell replication and selective inhibition of cellular apoptosis of initiated cells dependent on the genetic and/or epigenetic alterations of the latter. The irreversible stage of progression results from initial karyotypic alterations that evolve into greater degrees of genomic instability. The initial genomic alteration in the transition from promotion to progression may involve primarily epigenetic mechanisms driven by epigenetic and genetic alterations fixed during the stage of promotion.

[Molecular basis of Fanconi's anemia].

PubMed

Digweed, M

1999-01-01

Fanconi anaemia (FA) is an autosomal recessive genetic disorder characterised clinically by progressive bone marrow failure, skeletal deformities and a predisposition to neoplasia. Patient cells manifest an extreme chromosomal instability and hypersensitivity to polyfunctional alkylating agents. It is assumed that the basic defect is related to the repair of DNA damage, in particular that of so-called DNA crosslinks. Currently there are eight complementation groups in FA (FA-A-FA-H) which indicates that at least eight independent genes can lead to FA. Three of these genes have been identified: FANCA, FANCC and FANCG. In this review, the molecular biology and genetics of FA are presented and possible functions of the FANC proteins are discussed.

Active damping of the e-p instability at the Los Alamos Proton Storage Ring

NASA Astrophysics Data System (ADS)

Macek, R. J.; Assadi, S.; Byrd, J. M.; Deibele, C. E.; Henderson, S. D.; Lee, S. Y.; McCrady, R. C.; Pivi, M. F. T.; Plum, M. A.; Walbridge, S. B.; Zaugg, T. J.

2007-12-01

A prototype of an analog, transverse (vertical) feedback system for active damping of the two-stream (e-p) instability has been developed and successfully tested at the Los Alamos Proton Storage Ring (PSR). This system was able to improve the instability threshold by approximately 30% (as measured by the change in RF buncher voltage at instability threshold). The feedback system configuration, setup procedures, and optimization of performance are described. Results of several experimental tests of system performance are presented including observations of instability threshold improvement and grow-damp experiments, which yield estimates of instability growth and damping rates. A major effort was undertaken to identify and study several factors limiting system performance. Evidence obtained from these tests suggests that performance of the prototype was limited by higher instability growth rates arising from beam leakage into the gap at lower RF buncher voltage and the onset of instability in the horizontal plane, which had no feedback.

Residential Instability, Family Support, and Parent–Child Relationships Among Ethnically Diverse Urban Families

PubMed Central

Riina, Elizabeth M.; Lippert, Adam; Brooks-Gunn, Jeanne

2016-01-01

From a social disorganization standpoint, neighborhood residential instability potentially brings negative consequences to parent–child relationship qualities, but family social support and racial/ethnic identity may modify this association. Using data (n = 3,116) from the Project on Human Development in Chicago Neighborhoods, this study examines associations between neighborhood residential instability and parent–child warmth and conflict, whether family social support moderates associations between residential instability and parent–child relationships, and variation by race/ethnicity. Multilevel models reveal that residential instability undermines parent–child relationship qualities, particularly for non-White individuals. Family support is a protective factor for families in less stable neighborhoods, and specifically buffers the association between neighborhood residential instability and reduced parent–child warmth. Among Hispanics, family support mitigates the association between residential instability and heightened parent–child conflict. Findings highlight residential instability as a detriment to parent–child relationships; families in unstable neighborhoods may benefit from family social support. PMID:27695136

Progress Toward Kelvin-Helmholtz instabilities in a High-Energy-Density Plasma on the Nike Laser

NASA Astrophysics Data System (ADS)

Harding, E. C.; Drake, R. P.; Aglitskiy, Y.; Dwarkadas, V. V.; Gillespie, R. S.; Grosskopf, M. J.; Huntington, C. M.; Gjeci, N.; Campbell, D. A.; Marion, D. C.

2007-11-01

In the realm of high-energy-density (HED) plasmas, there exist three primary hydrodynamic instabilities: Rayleigh-Taylor (RT), Richtmyer-Meshkov (RM), and Kelvin-Helmholtz (KH). Although the RT and the RM instabilities have been observed in the laboratory, no experiment to our knowledge has cleanly diagnosed the KH instability. While the RT instability results from the acceleration of a more dense fluid into a less dense fluid and the RM instability is due to shock deposited vorticity onto an interface, the KH instability is driven by a lifting force generated by velocity shear at a perturbed fluid interface. Understanding the KH instability mechanism in HED plasmas will provide essential insight into detailed RT-spike development, mass stripping, many astrophysical processes, as well as laying the groundwork for future transition to turbulence experiments. We present 2D simulations and data from our initial attempts to create a pure KH system using the Nike laser at the Naval Research Laboratory.

DOE Office of Scientific and Technical Information (OSTI.GOV)

Smalyuk, V. A.; Robey, H. F.; Casey, D. T.

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. Here in the deceleration phase of implosions, several experimental platformsmore » 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.« less

A new approach to the evolution of the blastic crisis from chronic myelocytic leukemia: dynamic interplay of cellular alterations and a changing microenvironment.

PubMed Central

Grossman, Z

1986-01-01

The mechanisms responsible for the massive hyperplasia and for the blastic crisis in chronic myelocytic leukemia are poorly understood. The most generally accepted hypothesis proposes that this progression is due to the development of genetic instability in the leukemic cells. In particular, the two phases of the disease are believed to reflect different, discrete genetic events. Such events remain undefined as yet, and the causal significance of observed genetic aberrations is not clear. An alternative hypothesis is presented here. It is assumed that the feedback interactions adjust the relative probabilities of maturation and replication of the 'committed' as well as the pluripotent cells, and further that mitotic cells at all stages possess considerable phenotypic adaptability; in particular their self-renewal capacity can vary in response to changes in the cellular composition of the tissue even within a conventionally defined compartment. On this basis, it is shown that chronic leukemia can arise and evolve into the blastic crisis from a progressive decline in a single clonal characteristic--inducibility to maturation. It is shown, with the help of mathematical considerations, how an initial hereditable event in an early hemopoietic cell can cause a disturbance of the tissue which feeds back onto the individual members of the clone, resulting in a cascade of dynamic changes which can lead to blast cell dominance. PMID:3458586

Genetic variation in DNA repair gene XRCC7 (G6721T) and susceptibility to breast cancer.

PubMed

Nasiri, Meysam; Saadat, Iraj; Omidvari, Shahpour; Saadat, Mostafa

2012-08-15

The human XRCC7 is a DNA double-strand break (DSBs) repair gene, involved in non-homologous end joining (NHEJ). It is speculated that DNA DSBs repair have an important role during development of breast cancer. The human XRCC7 is a NHEJ DSBs repair gene. Genetic variation G6721T of XRCC7 (rs7003908) is located in the intron 8 of the gene. This polymorphism may regulate splicing and cause mRNA instability. In the present study, we specifically investigated whether common G6721T genetic variant of XRCC7 was associated with an altered risk of breast cancer. The present study included 362 females with breast cancer. Age frequency-matched controls (362 persons) were randomly selected from the healthy female blood donors, according to the age distribution of the cases. Using RFLP-PCR based method, the polymorphism of XRCC7 was determined. The TG (OR=1.20, 95% CI: 0.83-1.74, P=0.320) and TT (OR=1.01, 95% CI: 0.67-1.53, P=0.933) genotypes had no significant effect on risk of breast cancer, in comparison with the GG genotype. Our present findings indicate that the TT and TG genotypes were not associated with an altered breast cancer risk. Copyright © 2012 Elsevier B.V. All rights reserved.

The molecular genetics of cervical carcinoma

PubMed Central

Lazo, P A

1999-01-01

In the pathogenesis of cervical carcinoma there are three major components, two of them related to the role of human papillomaviruses (HPV). First, the effect of viral E6 and E7 proteins. Second, the integration of viral DNA in chromosomal regions associated with well known tumour phenotypes. Some of these viral integrations occur recurrently at specific chromosomal locations, such as 8q24 and 12q15, both harbouring HPV18 and HPV16. And third, there are other recurrent genetic alterations not linked to HPV. Recurrent losses of heterozygosity (LOH) have been detected in chromosome regions 3p14–22, 4p16, 5p15, 6p21–22, 11q23, 17p13.3 without effect on p53, 18q12–22 and 19q13, all of them suggesting the alteration of putative tumour suppressor genes not yet identified. Recurrent amplification has been mapped to 3q+ arm, with the common region in 3q24–28 in 90% of invasive carcinomas. The mutator phenotype, microsatellite instability, plays a minor role and is detected in only 7% of cervical carcinomas. The development of cervical carcinoma requires the sequential occurrence and selection of several genetic alterations. The identification of the specific genes involved, and their correlation with specific tumour properties and stages could improve the understanding and perhaps the management of cervical carcinoma. © 1999 Cancer Research Campaign PMID:10471054

The molecular genetics of cervical carcinoma.

PubMed

Lazo, P A

1999-08-01

In the pathogenesis of cervical carcinoma there are three major components, two of them related to the role of human papillomaviruses (HPV). First, the effect of viral E6 and E7 proteins. Second, the integration of viral DNA in chromosomal regions associated with well known tumour phenotypes. Some of these viral integrations occur recurrently at specific chromosomal locations, such as 8q24 and 12q15, both harbouring HPV18 and HPV16. And third, there are other recurrent genetic alterations not linked to HPV. Recurrent losses of heterozygosity (LOH) have been detected in chromosome regions 3p14-22, 4p16, 5p15, 6p21-22, 11q23, 17p13.3 without effect on p53, 18q12-22 and 19q13, all of them suggesting the alteration of putative tumour suppressor genes not yet identified. Recurrent amplification has been mapped to 3q+ arm, with the common region in 3q24-28 in 90% of invasive carcinomas. The mutator phenotype, microsatellite instability, plays a minor role and is detected in only 7% of cervical carcinomas. The development of cervical carcinoma requires the sequential occurrence and selection of several genetic alterations. The identification of the specific genes involved, and their correlation with specific tumour properties and stages could improve the understanding and perhaps the management of cervical carcinoma.

Collective Temperature Anisotropy Instabilities in Intense Charged Particle Beams

NASA Astrophysics Data System (ADS)

Startsev, Edward

2006-10-01

Periodic focusing accelerators, transport systems and storage rings have a wide range of applications ranging from basic scientific research in high energy and nuclear physics, to applications such as ion-beam-driven high energy density physics and fusion, and spallation neutron sources. Of particular importance at the high beam currents and charge densities of practical interest, are the effects of the intense self fields produced by the beam space charge and current on determining the detailed equilibrium, stability and transport properties. Charged particle beams confined by external focusing fields represent an example of nonneutral plasma. A characteristic feature of such plasmas is the non-uniformity of the equilibrium density profiles and the nonlinearity of the self fields, which makes detailed analytical investigation very difficult. The development and application of advanced numerical tools such as eigenmode codes [1] and Monte-Carlo particle simulation methods [2] are often the only tractable approach to understand the underlying physics of different instabilities familiar in electrically neutral plasmas which may cause a degradation in beam quality. Two such instabilities are the electrostatic Harris instability [2] and the electromagnetic Weibel instability [1], both driven by a large temperature anisotropy which develops naturally in accelerators. The beam acceleration causes a large reduction in the longitudinal temperature and provides the free energy to drive collective temperature anisotropy instabilities. Such instabilities may lead to an increase in the longitudinal velocity spread, which will make focusing the beam difficult, and may impose a limit on the beam luminosity and the minimum spot size achievable in focusing experiments. This paper reviews recent advances in the theory and simulation of collective instabilities in intense charged particle beams caused by temperature anisotropy. We also describe new simulation tools that have been developed to study these instabilities. The results of the investigations that identify the instability growth rates, levels of saturations, and conditions for quiescent beam propagation will also be discussed. [1] E.A. Startsev and R.C. Davidson, Phys.Plasmas 10, 4829 (2003). [2] E.A. Startsev, R.C. Davidson and H. Qin, Phys.Rev. ST Accel. Beams 8,124201 (2005).

Magnetohydrodynamic Simulations of the Wiggle Instability in Spiral Galaxies

NASA Astrophysics Data System (ADS)

Tanaka, Minoru; Wada, Keiichi; Machida, Mami; Matsumoto, Ryoji; Miyaji, Shigeki

2005-09-01

We studied the stability of galactic spiral shocks through two dimensional global magnetohydrodynamic simulations. Recently, Wada & Koda (2003) showed, using global hydrodynamic simulations, that galactic gas flows behind a spiral shock becomes unstable against a perturbation parallel to the shock front and form spur-like density structures. They attributed the origin of this wiggle instability to the Kelvin-Helmholtz (K-H) instability triggered by the acceleration of the gas behind the shock. We carried out global simulations including galactic magnetic fields. The initial magnetic field is assumed to be either uniform or purely toroidal. We found that although the magnetic field reduces the growth rate of the K-H instability, wiggle instability develops even in galaxies with μG magnetic fields. We also present the results of local simulations to demonstrate the dependence of the growth rate of the instability with the wavelength. The interval of spurs is determined by the most unstable wavelength of the wiggle instability.

Progress toward Kelvin-Helmholtz instabilities in a High-Energy-Density Plasma on the Nike laser

NASA Astrophysics Data System (ADS)

Harding, E. C.; Drake, R. P.; Gillespie, R. S.; Grosskopf, M. J.; Huntington, C. M.; Aglitskiy, Y.; Weaver, J. L.; Velikovich, A. L.; Plewa, T.; Dwarkadas, V. V.

2008-04-01

In the realm of high-energy-density (HED) plasmas, there exist three primary hydrodynamic instabilities of concern: Rayleigh-Taylor (RT), Richtmyer-Meshkov (RM), and Kelvin-Helmholtz (KH). Although the RT and the RM instabilities have been readily observed and diagnosed in the laboratory, the KH instability remains relatively unexplored in HED plasmas. Unlike the RT and RM instabilities, the KH instability is driven by a lifting force generated by a strong velocity gradient in a stratified fluid. Understanding the KH instability mechanism in HED plasmas will provide essential insight into oblique shock systems, jets, mass stripping, and detailed RT-spike development. In addition, our KH experiment will help provide the groundwork for future transition to turbulence experiments. We present 2D FLASH simulations and experimental data from our initial attempts to create a pure KH system using the Nike laser at the Naval Research Laboratory.

Tertiary instability of zonal flows within the Wigner-Moyal formulation of drift turbulence

NASA Astrophysics Data System (ADS)

Zhu, Hongxuan; Ruiz, D. E.; Dodin, I. Y.

2017-10-01

The stability of zonal flows (ZFs) is analyzed within the generalized-Hasegawa-Mima model. The necessary and sufficient condition for a ZF instability, which is also known as the tertiary instability, is identified. The qualitative physics behind the tertiary instability is explained using the recently developed Wigner-Moyal formulation and the corresponding wave kinetic equation (WKE) in the geometrical-optics (GO) limit. By analyzing the drifton phase space trajectories, we find that the corrections proposed in Ref. to the WKE are critical for capturing the spatial scales characteristic for the tertiary instability. That said, we also find that this instability itself cannot be adequately described within a GO formulation in principle. Using the Wigner-Moyal equations, which capture diffraction, we analytically derive the tertiary-instability growth rate and compare it with numerical simulations. The research was sponsored by the U.S. Department of Energy.

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

NASA Astrophysics Data System (ADS)

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 occur in laboratory plasmas.

Shock tube Multiphase Experiments

NASA Astrophysics Data System (ADS)

Middlebrooks, John; Allen, Roy; Paudel, Manoj; Young, Calvin; Musick, Ben; McFarland, Jacob

2017-11-01

Shock driven multiphase instabilities (SDMI) are unique physical phenomena that have far-reaching practical applications in engineering and science. The instability is present in high energy explosions, scramjet combustors, and supernovae events. The SDMI arises when a multiphase interface is impulsively accelerated by the passage of a shockwave. It is similar in development to the Richtmyer-Meshkov (RM) instability however, particle-to-gas coupling is the driving mechanism of the SDMI. As particle effects such as lag and phase change become more prominent, the SDMI's development begins to significantly deviate from the RM instability. We have developed an experiment for studying the SDMI in our shock tube facility. In our experiments, a multiphase interface is created using a laminar jet and flowed into the shock tube where it is accelerated by the passage of a planar shockwave. The interface development is captured using CCD cameras synchronized with planar laser illumination. This talk will give an overview of new experiments conducted to examine the development of a shocked cylindrical multiphase interface. The effects of Atwood number, particle size, and a second acceleration (reshock) of the interface will be discussed.

Dynamic stability of electrodynamic maglev systems

DOE Office of Scientific and Technical Information (OSTI.GOV)

Cai, Y.; Chen, S.S.; Mulcahy, T.M.

1997-01-01

Because dynamic instabilities are not acceptable in any commercial maglev system, it is important to consider dynamic instability in the development of all maglev systems. This study considers the stability of maglev systems based on mathematical models and experimental data. Divergence and flutter are obtained for coupled vibration of a three-degree-of-freedom maglev vehicle on a guideway consisting of double L-shaped aluminum segments. The theory and analysis for motion-dependent magnetic-force-induced instability developed in this study provides basic stability characteristics and identifies future research needs for maglev systems.

Consensus in chronic ankle instability: aetiology, assessment, surgical indications and place for arthroscopy.

PubMed

Guillo, S; Bauer, T; Lee, J W; Takao, M; Kong, S W; Stone, J W; Mangone, P G; Molloy, A; Perera, A; Pearce, C J; Michels, F; Tourné, Y; Ghorbani, A; Calder, J

2013-12-01

Ankle sprains are the most common injuries sustained during sports activities. Most ankle sprains recover fully with non-operative treatment but 20-30% develop chronic ankle instability. Predicting which patients who sustain an ankle sprain will develop instability is difficult. This paper summarises a consensus on identifying which patients may require surgery, the optimal surgical intervention along with treatment of concomitant pathology given the evidence available today. It also discusses the role of arthroscopic treatment and the anatomical basis for individual procedures. Copyright © 2013. Published by Elsevier Masson SAS.

Single-cell sequencing reveals karyotype heterogeneity in murine and human malignancies.

PubMed

Bakker, Bjorn; Taudt, Aaron; Belderbos, Mirjam E; Porubsky, David; Spierings, Diana C J; de Jong, Tristan V; Halsema, Nancy; Kazemier, Hinke G; Hoekstra-Wakker, Karina; Bradley, Allan; de Bont, Eveline S J M; van den Berg, Anke; Guryev, Victor; Lansdorp, Peter M; Colomé-Tatché, Maria; Foijer, Floris

2016-05-31

Chromosome instability leads to aneuploidy, a state in which cells have abnormal numbers of chromosomes, and is found in two out of three cancers. In a chromosomal instable p53 deficient mouse model with accelerated lymphomagenesis, we previously observed whole chromosome copy number changes affecting all lymphoma cells. This suggests that chromosome instability is somehow suppressed in the aneuploid lymphomas or that selection for frequently lost/gained chromosomes out-competes the CIN-imposed mis-segregation. To distinguish between these explanations and to examine karyotype dynamics in chromosome instable lymphoma, we use a newly developed single-cell whole genome sequencing (scWGS) platform that provides a complete and unbiased overview of copy number variations (CNV) in individual cells. To analyse these scWGS data, we develop AneuFinder, which allows annotation of copy number changes in a fully automated fashion and quantification of CNV heterogeneity between cells. Single-cell sequencing and AneuFinder analysis reveals high levels of copy number heterogeneity in chromosome instability-driven murine T-cell lymphoma samples, indicating ongoing chromosome instability. Application of this technology to human B cell leukaemias reveals different levels of karyotype heterogeneity in these cancers. Our data show that even though aneuploid tumours select for particular and recurring chromosome combinations, single-cell analysis using AneuFinder reveals copy number heterogeneity. This suggests ongoing chromosome instability that other platforms fail to detect. As chromosome instability might drive tumour evolution, karyotype analysis using single-cell sequencing technology could become an essential tool for cancer treatment stratification.

Sedimentation from flocculated suspensions in the presence of settling-driven gravitational interface instabilities

NASA Astrophysics Data System (ADS)

Rouhnia, Mohamad; Strom, Kyle

2015-09-01

We experimentally examine sedimentation from a freshwater suspension of clay flocs overlying saltwater in the presence of gravitational instabilities. The study seeks to determine: (1) if flocculation hampers or alters interface instability formation; (2) how the removal rates of sediment from the buoyant layer compare to those predicted by individual floc settling; and (3) whether or not it is possible to develop a model for effective settling velocity. The experiments were conducted in a tank at isothermal conditions. All experiments were initially stably stratified but later developed instabilities near the interface that grew into downward convecting plumes of fluid and sediment. Throughout, we measured sediment concentration in the upper and lower layers, floc size, and plume descent rates. The data showed that flocculation modifies the mixture settling velocity, and therefore shifts the mode of interface instability from double-diffusive (what one would expect from unflocculated clay) to settling-driven leaking and Rayleigh-Taylor instability formation. Removal rates of sediment from the upper layer in the presence of these instabilities were on the same order of magnitude as those predicted by individual floc settling. However, removal rates were found to better correlate with the speed of the interface plumes. A simple force-balance model was found to be capable of reasonably describing plume velocity based on concentration in the buoyant layer. This relation, coupled with a critical Grashof number and geometry relations, allowed us to develop a model for the effective settling velocity of the mixture based solely on integral values of the upper layer.

Radiation-induced genomic instability

NASA Technical Reports Server (NTRS)

Kronenberg, A.

1994-01-01

Quantitative assessment of the heritable somatic effects of ionizing radiation exposures has relied upon the assumption that radiation-induced lesions were 'fixed' in the DNA prior to the first postirradiation mitosis. Lesion conversion was thought to occur during the initial round of DNA replication or as a consequence of error-prone enzymatic processing of lesions. The standard experimental protocols for the assessment of a variety of radiation-induced endpoints (cell death, specific locus mutations, neoplastic transformation and chromosome aberrations) evaluate these various endpoints at a single snapshot in time. In contrast with the aforementioned approaches, some studies have specifically assessed radiation effects as a function of time following exposure. Evidence has accumulated in support of the hypothesis that radiation exposure induces a persistent destabilization of the genome. This instability has been observed as a delayed expression of lethal mutations, as an enhanced rate of accumulation of non-lethal heritable alterations, and as a progressive intraclonal chromosomal heterogeneity. The genetic controls and biochemical mechanisms underlying radiation-induced genomic instability have not yet been delineated. The aim is to integrate the accumulated evidence that suggests that radiation exposure has a persistent effect on the stability of the mammalian genome.

Electrophysiological predictors of sudden cardiac death on physical exercise test in young athletes

NASA Astrophysics Data System (ADS)

Balykova, L. A.; Kotlyarov, A. A.; Ivyanskiy, S. A.; Shirokova, A. A.; Miheeva, K. A.; Makarov, L. M.

2017-01-01

The problem of sudden death of young athletes continues to be actual. Among its reasons, primary electric myocardium diseases along with organic heart troubles (cardiomyopathies, cordites, anomalies of coronary arteries) take an important place. The most frequent variant of channelopathesis long QT syndrome (LQTS). Both inherited and acquired LQTS may be the reason of sudden cardiac death during physical activity and have to be revealed prior to sports admission. LQTS diagnostics in young athletes become problematic due to secondary exercise-related QT prolongation. Physical load test may reveal myocardium electric instability and enhance LQTS diagnostics accuracy without genetic testing. The aim was to study electrophysiological parameters of myocardium repolarization and reveal the signs of electrical instability as predictors of the life-threatening arrhythmias in young athletes during physical exercise test. In conclusion, electrophysiological myocardium parameters during physical exercise test noted to be markers of electrical myocardial instability and in combination with the other Schwartz criteria, was evidenced the inherited or acquired LQTS. QTc prolongation in athletes at the peak of exercise as well as in early recovery period were noted to be additional predictor life-threatening arrhythmias and sudden cardiac death in young athletes

[Genetic Mutation Accumulation and Clinical Outcome of Immune Checkpoint Blockade Therapy].

PubMed

Takahashi, Masanobu

2016-06-01

Immune checkpoint blockade therapy has recently attracted great attention in the area of oncology. In Japan, since 2014, an anti-PD-1 antibody nivolumab and anti-CTLA-4 antibody ipilimumab have been available for the treatment of patients with malignant melanoma, and nivolumab has been available for patients with non-small cell lung cancer. Clinical trials using these drugs and other immune checkpoint inhibitors are currently in progress worldwide. The immune checkpoint blockade therapy is a promising new cancer therapy; however, not all patients with cancer can benefit from this therapy. Recent evidence shows that markers reflecting the extent of genetic mutation accumulation, including mutation burden, non-synonymous mutation that produces neoantigen, and microsatellite instability, possibly serve as promising marker to predict who can benefit from the immune checkpoint blockade therapy. Here, I introduce the recent evidence and discuss the correlation between genetic mutation accumulation and clinical outcome of immune checkpoint blockade therapy.

Farley-Buneman Instability in the Solar Chromosphere

NASA Astrophysics Data System (ADS)

Gogoberidze, G.; Voitenko, Y.; Poedts, S.; Goossens, M.

2009-11-01

The Farley-Buneman instability (FBI) is studied in the partially ionized plasma of the solar chromosphere taking into account the finite magnetization of the ions and Coulomb collisions. We obtain the threshold value for the relative velocity between ions and electrons necessary for the instability to develop. It is shown that Coulomb collisions play a destabilizing role in the sense that they enable the instability even in the regions where the ion magnetization is larger than unity. By applying these results to chromospheric conditions, we show that the FBI cannot be responsible for the quasi-steady heating of the solar chromosphere. However, we do not exclude the instability development locally in the presence of strong cross-field currents and/or strong small-scale magnetic fields. In such cases, FBI should produce locally small-scale, ~0.1-3 m, density irregularities in the solar chromosphere. These irregularities can cause scintillations of radio waves with similar wave lengths and provide a tool for remote chromospheric sensing.

FARLEY-BUNEMAN INSTABILITY IN THE SOLAR CHROMOSPHERE

DOE Office of Scientific and Technical Information (OSTI.GOV)

Gogoberidze, G.; Voitenko, Y.; Poedts, S.

2009-11-20

The Farley-Buneman instability (FBI) is studied in the partially ionized plasma of the solar chromosphere taking into account the finite magnetization of the ions and Coulomb collisions. We obtain the threshold value for the relative velocity between ions and electrons necessary for the instability to develop. It is shown that Coulomb collisions play a destabilizing role in the sense that they enable the instability even in the regions where the ion magnetization is larger than unity. By applying these results to chromospheric conditions, we show that the FBI cannot be responsible for the quasi-steady heating of the solar chromosphere. However,more » we do not exclude the instability development locally in the presence of strong cross-field currents and/or strong small-scale magnetic fields. In such cases, FBI should produce locally small-scale, approx0.1-3 m, density irregularities in the solar chromosphere. These irregularities can cause scintillations of radio waves with similar wave lengths and provide a tool for remote chromospheric sensing.« less

Wing Wake Vortices and Temporal Vortex Pair Instabilities

NASA Astrophysics Data System (ADS)

Williamson, C. H. K.; Leweke, T.; Miller, G. D.

In this presentation we include selected results which have originated from vortex dynamics studies conducted at Cornell, in collaboration with IRPHE, Marseille. These studies concern, in particular, the spatial development of delta wing trailing vortices, and the temporal development of counter-rotating vortex pairs. There are, as might be expected, similarities in the instabilities of both of these basic flows, as shown in our laboratory-scale studies. In the case of the spatial development of vortex pairs in the wake of a delta wing, either in free flight or towed from an XY carriage system in a towing tank, we have found three distinct instability length scales as the trailing vortex pair travels downstream. The first (smallest-scale) instability is found immediately behind the delta wing, and this scales on the thickness of the two shear layers separating from the wing trailing edge. The second (short-wave) instability, at an intermediate distance downstream, scales on the primary vortex core dimensions. The third (long-wave) instability far downstream represents the classical "Crow" instability (Crow, 1970), scaling on the distance between the two primary vortices. By imposing disturbances on the delta wing incident velocity, we find that the long-wave instability is receptive to a range of wavelengths. Our experimental measurements of instability growth rates are compared with theoretical predictions, which are based on the theory of Widnall et al. (1971), and which require, as input, DPIV measurements of axial and circumferential velocity profiles. This represents the first time that theoretical and experimental growth rates have been compared, without the imposition of ad-hoc assumptions regarding the vorticity distribution. The agreement with theory appears to be good. The ease with which a Delta wing may be flown in free flight was demonstrated at the Symposium, using a giant polystyrene triangular wing, launched from the back of the auditorium, and ably caught by Professor Sid Leibovich, in whose honour the Symposium was held. In the case of the temporal growth of vortex pairs, formed by the closing of a pair of long flaps underwater, we find two principal instabilities; namely, a longwavelength Crow instability, and a short-wavelength "elliptic" instability. Comparisons between experiment and theory for the growth rates of the long-wave instability, over a range of perturbed wavelengths, appears to be very good. The vortex pair "pinches off", or reconnects, to form vortex rings in the manner assumed to occur in contrails behind jet aircraft. We discover a symmetry-breaking phase relationship for the short wave disturbances growing in the two vortices, which we 380 C.H.K. Williamson et al. show to be consistent with a kinematic matching condition between the two disturbances. Further results demonstrate that this instability is a manifestation of an elliptic instability, which is here identified for the first time in a real open flow. We therefore refer to this flow as a "cooperative elliptic" instability. The long-term evolution of the flow involves the inception of secondary miniscule vortex pairs, which are perpendicular to the primary vortex pair.

Long-wave instabilities of two interlaced helical vortices

NASA Astrophysics Data System (ADS)

Quaranta, H. U.; Brynjell-Rahkola, M.; Leweke, T.; Henningson, D. S.

2016-09-01

We present a comparison between experimental observations and theoretical predictions concerning long-wave displacement instabilities of the helical vortices in the wake of a two-bladed rotor. Experiments are performed with a small-scale rotor in a water channel, using a set-up that allows the individual triggering of various instability modes at different azimuthal wave numbers, leading to local or global pairing of successive vortex loops. The initial development of the instability and the measured growth rates are in good agreement with the predictions from linear stability theory, based on an approach where the helical vortex system is represented by filaments. At later times, local pairing develops into large-scale distortions of the vortices, whereas for global pairing the non-linear evolution returns the system almost to its initial geometry.

Charge-Induced Saffman-Taylor Instabilities in Toroidal Droplets

NASA Astrophysics Data System (ADS)

Fragkopoulos, A. A.; Aizenman, A.; Fernández-Nieves, A.

2017-06-01

We show that charged toroidal droplets can develop fingerlike structures as they expand due to Saffman-Taylor instabilities. While these are commonly observed in quasi-two-dimensional geometries when a fluid displaces another fluid of higher viscosity, we show that the toroidal confinement breaks the symmetry of the problem, effectively making it quasi-two-dimensional and enabling the instability to develop in this three-dimensional situation. We control the expansion speed of the torus with the imposed electric stress and show that fingers are observed provided the characteristic time scale associated with this instability is smaller than the characteristic time scale associated with Rayleigh-Plateau break-up. We confirm our interpretation of the results by showing that the number of fingers is consistent with expectations from linear stability analysis in radial Hele-Shaw cells.

Some observations of a sheared Rayleigh-Taylor/Benard instability

NASA Technical Reports Server (NTRS)

Humphrey, J. A. C.; Marcus, D. L.

1987-01-01

An account is provided of preliminary flow visualization observations made in an unstably stratified flow with shear superimposed. The structures observed appear to be the superposition of a Rayleigh-Taylor/Benard instability and a Kelvin-Helmholtz instability. Aside from its intrinsic fundamental value, the study of these structures is of special interest to theoreticians developing nonlinear stability calculation methodologies.

First Simulations of a Collisional Two-Stream Instability in the Chromosphere

NASA Astrophysics Data System (ADS)

Oppenheim, Meers; Dimant, Yakov; Madsen, Chad Allen; Fontenla, Juan

2014-06-01

Observations and modeling shows that immediately above the temperature minimum in the solar atmosphere, a steep rise from below 4,000 K to over 6,000K occurs. Recent papers show that a collisional two-stream plasma instability called the Farley-Buneman Instability can develop at the altitudes where this increase occurs. This instability may play an important role in transferring energy from turbulent neutral flows originating in the photosphere to the mid-chromosphere in the form of heat. Plasma turbulence resulting from this instability could account for some or most of this intense chromospheric heating. This paper presents a set of simulations showing the development and evolution of the Farley-Buneman Instability (FBI) applicable to the chromosphere. It compares these results with the better-understood ionospheric FBI. It examines the linear behavior and the dependence of growth rates for a range of altitudes and driving flows. It also presents the first study of FBI driven plasma nonlinearities and turbulence in the chromosphere. This research should help us evaluate the FBI as a mechanism to convert neutral flow and turbulence energy into electron thermal energy in the quiet Sun.

Effect of dust on tilted electrostatic resistive instability in a Hall thruster

NASA Astrophysics Data System (ADS)

Tyagi, Jasvendra; Singh, Sukhmander; Malik, Hitendra K.

2018-03-01

Effect of negatively charged dust on resistive instability corresponding to the electrostatic wave is investigated in a Hall thruster plasma when this purely azimuthal wave is tilted and strong axial component of wave vector is developed. Analytical calculations are done to obtain the relevant dispersion equation, which is solved numerically to investigate the growth rate of the instability. The magnitude of the growth rate in the plasma having dust particles is found to be much smaller than the case of pure plasma. However, the instability grows faster for the increasing dust density and the higher charge on the dust particles. The higher magnetic field is also found to support the instability.

Monoradiculopathy and secondary segmental instability caused by postoperative pars interarticularis fracture: a case report.

PubMed

Kaner, Tuncay; Tutkan, Ibrahim

2009-04-01

Instability can develop after lumbar spinal surgery. What is also known as secondary segmental instability is one of the important causes of failed back syndrome. In this paper, we described a 45-year-old female patient who was diagnosed with secondary segmental instability caused by left L3 pars interarticularis fracture after a high lumbar disc surgery and was subsequently treated with re-operation. We evaluated the clinical course, diagnosis, and treatment methods for secondary segmental instability caused by postoperative pars interarticularis fracture. Furthermore, we emphasized the importance of preserving the pars interarticularis during upper lumbar disc surgeries in order to avoid a potential stress fracture.

shock driven instability of a multi-phase particle-gas system

NASA Astrophysics Data System (ADS)

McFarland, Jacob; Black, Wolfgang; Dahal, Jeevan; Morgan, Brandon

2015-11-01

A computational study of a shock driven instability of a multiphse particle-gas system is presented. This instability can evolve in a similar fashion to the Richtmyer-Meshkov (RM) instability, but has addition parameters to be considered. Particle relaxation times, and density differences of the gas and particle-gas system can be adjusted to produce results which are different from the classical RM instability. We will show simulation results from the Ares code, developed at Lawrence Livermore National Laboratory, which uses a particle-in-cell approach to study the effects of the particle-gas system parameters. Mixing parameters will be presented to highlight the suppression of circulation and gas mixing by the particle phase.

Time-Domain Receiver Function Deconvolution using Genetic Algorithm

NASA Astrophysics Data System (ADS)

Moreira, L. P.

2017-12-01

Receiver Functions (RF) are well know method for crust modelling using passive seismological signals. Many different techniques were developed to calculate the RF traces, applying the deconvolution calculation to radial and vertical seismogram components. A popular method used a spectral division of both components, which requires human intervention to apply the Water Level procedure to avoid instabilities from division by small numbers. One of most used method is an iterative procedure to estimate the RF peaks and applying the convolution with vertical component seismogram, comparing the result with the radial component. This method is suitable for automatic processing, however several RF traces are invalid due to peak estimation failure.In this work it is proposed a deconvolution algorithm using Genetic Algorithm (GA) to estimate the RF peaks. This method is entirely processed in the time domain, avoiding the time-to-frequency calculations (and vice-versa), and totally suitable for automatic processing. Estimated peaks can be used to generate RF traces in a seismogram format for visualization. The RF trace quality is similar for high magnitude events, although there are less failures for RF calculation of smaller events, increasing the overall performance for high number of events per station.

Validation of an Adaptive Combustion Instability Control Method for Gas-Turbine Engines

NASA Technical Reports Server (NTRS)

Kopasakis, George; DeLaat, John C.; Chang, Clarence T.

2004-01-01

This paper describes ongoing testing of an adaptive control method to suppress high frequency thermo-acoustic instabilities like those found in lean-burning, low emission combustors that are being developed for future aircraft gas turbine engines. The method called Adaptive Sliding Phasor Averaged Control, was previously tested in an experimental rig designed to simulate a combustor with an instability of about 530 Hz. Results published earlier, and briefly presented here, demonstrated that this method was effective in suppressing the instability. Because this test rig did not exhibit a well pronounced instability, a question remained regarding the effectiveness of the control methodology when applied to a more coherent instability. To answer this question, a modified combustor rig was assembled at the NASA Glenn Research Center in Cleveland, Ohio. The modified rig exhibited a more coherent, higher amplitude instability, but at a lower frequency of about 315 Hz. Test results show that this control method successfully reduced the instability pressure of the lower frequency test rig. In addition, due to a certain phenomena discovered and reported earlier, the so called Intra-Harmonic Coupling, a dramatic suppression of the instability was achieved by focusing control on the second harmonic of the instability. These results and their implications are discussed, as well as a hypothesis describing the mechanism of intra-harmonic coupling.

Targeting Oxidative Stress and Aberrant Critical Period Plasticity in the Developmental Trajectory to Schizophrenia

PubMed Central

Do, Kim Q.; Cuenod, Michel; Hensch, Takao K.

2015-01-01

Schizophrenia is a neurodevelopmental disorder reflecting a convergence of genetic risk and early life stress. The slow progression to first psychotic episode represents both a window of vulnerability as well as opportunity for therapeutic intervention. Here, we consider recent neurobiological insight into the cellular and molecular components of developmental critical periods and their vulnerability to redox dysregulation. In particular, the consistent loss of parvalbumin-positive interneuron (PVI) function and their surrounding perineuronal nets (PNNs) as well as myelination in patient brains is consistent with a delayed or extended period of circuit instability. This linkage to critical period triggers (PVI) and brakes (PNN, myelin) implicates mistimed trajectories of brain development in mental illness. Strategically introduced antioxidant treatment or later reinforcement of molecular brakes may then offer a novel prophylactic psychiatry. PMID:26032508

Mendelian randomization with fine-mapped genetic data: Choosing from large numbers of correlated instrumental variables.

PubMed

Burgess, Stephen; Zuber, Verena; Valdes-Marquez, Elsa; Sun, Benjamin B; Hopewell, Jemma C

2017-12-01

Mendelian randomization uses genetic variants to make causal inferences about the effect of a risk factor on an outcome. With fine-mapped genetic data, there may be hundreds of genetic variants in a single gene region any of which could be used to assess this causal relationship. However, using too many genetic variants in the analysis can lead to spurious estimates and inflated Type 1 error rates. But if only a few genetic variants are used, then the majority of the data is ignored and estimates are highly sensitive to the particular choice of variants. We propose an approach based on summarized data only (genetic association and correlation estimates) that uses principal components analysis to form instruments. This approach has desirable theoretical properties: it takes the totality of data into account and does not suffer from numerical instabilities. It also has good properties in simulation studies: it is not particularly sensitive to varying the genetic variants included in the analysis or the genetic correlation matrix, and it does not have greatly inflated Type 1 error rates. Overall, the method gives estimates that are less precise than those from variable selection approaches (such as using a conditional analysis or pruning approach to select variants), but are more robust to seemingly arbitrary choices in the variable selection step. Methods are illustrated by an example using genetic associations with testosterone for 320 genetic variants to assess the effect of sex hormone related pathways on coronary artery disease risk, in which variable selection approaches give inconsistent inferences. © 2017 The Authors Genetic Epidemiology Published by Wiley Periodicals, Inc.

Molecular Mechanisms Underlying Genomic Instability in Brca-Deficient Cells

DTIC Science & Technology

2012-03-01

Fanconi anemia pathway for ICL repair. BRCA1 therefore has two separate roles in ICL repair that can be modulated by manipulating NHEJ, whereas FANCD2...repair pathway comprising at least 15 gene products. Mutation of any of these genes causes the human disease Fanconi anemia (FA), which is associated...genetic deficiency in components of the Fanconi anemia (FA) pathway (Wang, 2007). Cells from FA patients, or knockout mice with deficiencies in the FA

Centrosome Defects, Genetic Instability and Breast Cancer Progression

DTIC Science & Technology

2005-08-01

and is associated with cell cycle progression. Primary cilia loss is thought to be the cause of polycystic kidney disease, a condition in which kidney...polycyctin2 which is also implicated in polycystic kidney disease (Pazour, Baker et al. 2002; Pazour anrd Rosenbaum 2002; Pazour, San Agustin et al. 2002...1941-51. Pazour, G. J. (2004). "Intraflagellar transport and cilia-dependent renal disease: the ciliary hypothesis of polycystic kidney disease." J

Enhanced production of recombinant proteins with Corynebacterium glutamicum by deletion of insertion sequences (IS elements).

PubMed

Choi, Jae Woong; Yim, Sung Sun; Kim, Min Jeong; Jeong, Ki Jun

2015-12-29

In most bacteria, various jumping genetic elements including insertion sequences elements (IS elements) cause a variety of genetic rearrangements resulting in harmful effects such as genome and recombinant plasmid instability. The genetic stability of a plasmid in a host is critical for high-level production of recombinant proteins, and in this regard, the development of an IS element-free strain could be a useful strategy for the enhanced production of recombinant proteins. Corynebacterium glutamicum, which is a workhorse in the industrial-scale production of various biomolecules including recombinant proteins, also has several IS elements, and it is necessary to identify the critical IS elements and to develop IS element deleted strain. From the cultivation of C. glutamicum harboring a plasmid for green fluorescent protein (GFP) gene expression, non-fluorescent clones were isolated by FACS (fluorescent activated cell sorting). All the isolated clones had insertions of IS elements in the GFP coding region, and two major IS elements (ISCg1 and ISCg2 families) were identified. By co-cultivating cells harboring either the isolated IS element-inserted plasmid or intact plasmid, it was clearly confirmed that cells harboring the IS element-inserted plasmids became dominant during the cultivation due to their growth advantage over cells containing intact plasmids, which can cause a significant reduction in recombinant protein production during cultivation. To minimize the harmful effects of IS elements on the expression of heterologous genes in C. glutamicum, two IS element free C. glutamicum strains were developed in which each major IS element was deleted, and enhanced productivity in the engineered C. glutamicum strain was successfully demonstrated with three models: GFP, poly(3-hydroxybutyrate) [P(3HB)] and γ-aminobutyrate (GABA). Our findings clearly indicate that the hopping of IS elements could be detrimental to the production of recombinant proteins in C. glutamicum, emphasizing the importance of developing IS element free host strains.

Active Control of Combustor Instability Shown to Help Lower Emissions

NASA Technical Reports Server (NTRS)

DeLaat, John C.; Chang, Clarence T.

2002-01-01

In a quest to reduce the environmental impact of aerospace propulsion systems, extensive research is being done in the development of lean-burning (low fuel-to-air ratio) combustors that can reduce emissions throughout the mission cycle. However, these lean-burning combustors have an increased susceptibility to thermoacoustic instabilities, or high-pressure oscillations much like sound waves, that can cause severe high-frequency vibrations in the combustor. These pressure waves can fatigue the combustor components and even the downstream turbine blades. This can significantly decrease the safe operating life of the combustor and turbine. Thus, suppression of the thermoacoustic combustor instabilities is an enabling technology for lean, low-emissions combustors. Under the Aerospace Propulsion and Power Base Research and Technology Program, the NASA Glenn Research Center, in partnership with Pratt & Whitney and United Technologies Research Center, is developing technologies for the active control of combustion instabilities. With active combustion control, the fuel is pulsed to put pressure oscillations into the system. This cancels out the pressure oscillations being produced by the instabilities. Thus, the engine can have lower pollutant emissions and long life.The use of active combustion instability control to reduce thermo-acoustic-driven combustor pressure oscillations was demonstrated on a single-nozzle combustor rig at United Technologies. This rig has many of the complexities of a real engine combustor (i.e., an actual fuel nozzle and swirler, dilution cooling, etc.). Control was demonstrated through modeling, developing, and testing a fuel-delivery system able to the 280-Hz instability frequency. The preceding figure shows the capability of this system to provide high-frequency fuel modulations. Because of the high-shear contrarotating airflow in the fuel injector, there was some concern that the fuel pulses would be attenuated to the point where they would not be effective for control. Testing in the combustor rig showed that open-loop pulsing of the fuel was, in fact, able to effectively modulate the combustor pressure. To suppress the combustor pressure oscillations due to thermoacoustic instabilities, it is desirable to time the injection of the fuel so that it interferes with the instability. A closed-loop control scheme was developed that uses combustion pressure feedback and a phase-shifting controller to time the fuel-injection pulses. Some suppression of the pressure oscillations at the 280-Hz instability frequency was demonstrated (see the next figure). However, the overall peak-to- peak pressure oscillations in the combustor were only mildly reduced. Improvements to control hardware and control methods are being continued to gain improved closed-loop reduction of the pressure oscillations.pulse the fuel at

Elimination of Gravity Influence on Flame Propagation Via Enhancement of the Saffman-Taylor Instability

NASA Technical Reports Server (NTRS)

Aldredge, R. C.

2003-01-01

In this analytical work the influence of the Saffman-Taylor instability on flame propagation is formulated for computational investigation. Specifically, it is of interest to examine the influence of this instability as a potential means of eliminating the effect of gravitational acceleration on the development of thermoacoustic instability. Earlier experimental investigations of thermoacoustic instability employed tubes of large circular or annular cross-section, such that neither heat loss nor viscosity at the burner walls was of significant importance in influencing flame behavior. However, it has been demonstrated recently that flames propagating between closely spaced walls, may be subject to long-wavelength wrinkling associated with the Saffman-Taylor instability, known to be relevant when a less-viscous fluid pushes a more-viscous fluid through a porous medium or between two closely spaced walls.

Electromagnetic ion/ion cyclotron instability - Theory and simulations

NASA Technical Reports Server (NTRS)

Winske, D.; Omidi, N.

1992-01-01

Linear theory and 1D and 2D hybrid simulations are employed to study electromagnetic ion/ion cyclotron (EMIIC) instability driven by the relative streaming of two field-aligned ion beams. The characteristics of the instability are studied as a function of beam density, propagation angle, electron-ion temperature ratios, and ion beta. When the propagation angle is near 90 deg the EMIIC instability has the characteristics of an electrostatic instability, while at smaller angles electromagnetic effects play a significant role as does strong beam coupling. The 2D simulations point to a narrowing of the wave spectrum and accompanying coherent effects during the linear growth stage of development. The EMIIC instability is an important effect where ion beta is low such as in the plasma-sheet boundary layer and upstream of slow shocks in the magnetotail.

Plasma Instability Growth Rates in the F-Region Cusp Ionosphere

NASA Astrophysics Data System (ADS)

Moen, J. I.; Daabakk, Y.; Oksavik, K.; Clausen, L.; Bekkeng, T. A.; Abe, T.; Saito, Y.; Baddeley, L. J.; Lorentzen, D. A.; Sigernes, F.; Yeoman, T. K.

2014-12-01

There are at least two different micro-instability processes that applies to the F-region cusp/polar cap ionosphere. These are the Gradient Drift Instability (GDI) and the Kelvin Helmholtz Instability (KHI). Due to space weather effects on radio communication and satellite signals it is of practical interest to assess the relative importance of these two instability modes and to quantify their growth rates. The Investigation of Cusp Irregularities (ICI) rocket program has been developed to investigate these plasma instabilities and formation scintillation irregularities. High resolution measurements are critical to get realistic quantities on the growth rates. The results achieved so far demonstrates that cusp ionosphere precipitation can give rise to km scale plasma structures on which grow rates are down to a few tens of seconds compared to earlier measures of ten minutes based on ground observations. This has to do with the spatial resolution required for these measurements. Growth rates for the KHI instability is found to be of the same order, which is consistent with growth rates calculated from the EISCAT Svalbard Radar. I.e. both instability modes can be highly efficient in the cusp ionosphere.

DNA repair targeted therapy: the past or future of cancer treatment?

PubMed Central

Gavande, Navnath S.; VanderVere-Carozza, Pamela S.; Hinshaw, Hilary D.; Jalal, Shadia I.; Sears, Catherine R.; Pawelczak, Katherine S.; Turchi, John J.

2016-01-01

The repair of DNA damage is a complex process that relies on particular pathways to remedy specific types of damage to DNA. The range of insults to DNA includes small, modest changes in structure including mismatched bases and simple methylation events to oxidized bases, intra- and interstrand DNA crosslinks, DNA double strand breaks and protein-DNA adducts. Pathways required for the repair of these lesions include mismatch repair, base excision repair, nucleotide excision repair, and the homology directed repair/Fanconi anemia pathway. Each of these pathways contributes to genetic stability, and mutations in genes encoding proteins involved in these pathways have been demonstrated to promote genetic instability and cancer. In fact, it has been suggested all cancers display defects in DNA repair. It has also been demonstrated that the ability of cancer cells to repair therapeutically induced DNA damage impacts therapeutic efficacy. This has led to targeting DNA repair pathways and proteins to develop anti-cancer agents that will increase sensitivity to traditional chemotherapeutics. While initial studies languished and were plagued by a lack of specificity and a defined mechanism of action, more recent approaches to exploit synthetic lethal interaction and develop high affinity chemical inhibitors have proven considerably more effective. In this review we will highlight recent advances and discuss previous failures in targeting DNA repair to pave the way for future DNA repair targeted agents and their use in cancer therapy. PMID:26896565

Role of Macronutrients and Micronutrients in DNA Damage: Results From a Food Frequency Questionnaire.

PubMed

Ladeira, Carina; Carolino, Elisabete; Gomes, Manuel C; Brito, Miguel

2017-01-01

The links between diet and genomic instability have been under investigation for several decades, and evidence suggests a significant causal or preventive role for various dietary factors. This study investigates the influence of macronutrients (calories, protein, and glucides) and micronutrients, such as vitamins and minerals, as assessed by a food frequency questionnaire, on genotoxicity biomarkers measured by cytokinesis-blocked micronucleus assay and comet assay. The results found significant positive and negative correlations. Micronucleus frequency tends to increase with higher intake of caffeine, calcium, magnesium, zinc, and protein ( P < .05, Spearman correlation). Calorie and omega-6 intakes are negatively correlated with DNA damage measured by the comet assay. These results are somewhat controversial because some of the correlations found are contrary to dominant views in the literature; however, we suggest that unraveling the association between diet and genetic instability requires a much better understanding of the modulating role of macronutrients and micronutrients.

Regulated expression of the lncRNA TERRA and its impact on telomere biology.

PubMed

Oliva-Rico, Diego; Herrera, Luis A

2017-10-01

The telomere protects against genomic instability by minimizing the accelerated end resection of the genetic material, a phenomenon that results in severe chromosome instability that could favor the transformation of a cell by enabling the emergence of tumor-promoting mutations. Some mechanisms that avoid this fate, such as capping and loop formation, have been very well characterized; however, telomeric non-coding transcripts, such as long non-coding RNAs (lncRNAs), should also be considered in this context because they play roles in the organization of telomere dynamics, involving processes such as replication, degradation, extension, and heterochromatin stabilization. Although the mechanism through which the expression of telomeric transcripts regulates telomere dynamics is not yet clear, a non-coding RNA component opens the research options in telomere biology and the impact that it can have on telomere-associated diseases such as cancer. Copyright © 2017 The Authors. Published by Elsevier B.V. All rights reserved.

Electron Debye scale Kelvin-Helmholtz instability: Electrostatic particle-in-cell simulations

DOE Office of Scientific and Technical Information (OSTI.GOV)

Lee, Sang-Yun; Lee, Ensang, E-mail: eslee@khu.ac.kr; Kim, Khan-Hyuk

2015-12-15

In this paper, we investigated the electron Debye scale Kelvin-Helmholtz (KH) instability using two-dimensional electrostatic particle-in-cell simulations. We introduced a velocity shear layer with a thickness comparable to the electron Debye length and examined the generation of the KH instability. The KH instability occurs in a similar manner as observed in the KH instabilities in fluid or ion scales producing surface waves and rolled-up vortices. The strength and growth rate of the electron Debye scale KH instability is affected by the structure of the velocity shear layer. The strength depends on the magnitude of the velocity and the growth ratemore » on the velocity gradient of the shear layer. However, the development of the electron Debye scale KH instability is mainly determined by the electric field generated by charge separation. Significant mixing of electrons occurs across the shear layer, and a fraction of electrons can penetrate deeply into the opposite side fairly far from the vortices across the shear layer.« less

EXO1 is critical for embryogenesis and the DNA damage response in mice with a hypomorphic Nbs1 allele

PubMed Central

Rein, Katrin; Yanez, Diana A.; Terré, Berta; Palenzuela, Lluís; Aivio, Suvi; Wei, Kaichun; Edelmann, Winfried; Stark, Jeremy M.; Stracker, Travis H.

2015-01-01

The maintenance of genome stability is critical for the suppression of diverse human pathologies that include developmental disorders, premature aging, infertility and predisposition to cancer. The DNA damage response (DDR) orchestrates the appropriate cellular responses following the detection of lesions to prevent genomic instability. The MRE11 complex is a sensor of DNA double strand breaks (DSBs) and plays key roles in multiple aspects of the DDR, including DNA end resection that is critical for signaling and DNA repair. The MRE11 complex has been shown to function both upstream and in concert with the 5′-3′ exonuclease EXO1 in DNA resection, but it remains unclear to what extent EXO1 influences DSB responses independently of the MRE11 complex. Here we examine the genetic relationship of the MRE11 complex and EXO1 during mammalian development and in response to DNA damage. Deletion of Exo1 in mice expressing a hypomorphic allele of Nbs1 leads to severe developmental impairment, embryonic death and chromosomal instability. While EXO1 plays a minimal role in normal cells, its loss strongly influences DNA replication, DNA repair, checkpoint signaling and damage sensitivity in NBS1 hypomorphic cells. Collectively, our results establish a key role for EXO1 in modulating the severity of hypomorphic MRE11 complex mutations. PMID:26160886

Leaf fluctuating asymmetry, soil disturbance and plant stress: A multiple year comparison using two herbs, Ipomoea pandurata and Cnidoscolus stimulosus

USGS Publications Warehouse

Freeman, D.C.; Brown, M.L.; Duda, J.J.; Graraham, J.H.; Emlen, J.M.; Krzysik, A.J.; Balbach, H.; Kovacic, D.A.; Zak, J.C.

2005-01-01

We studied Cnidoscolus stimulosus and Ipomoea pandurata, two common herbs of the Fall Line Sandhills to assess their potential as ecosystem level stress indicators. We focused on plants because they are among the most persistent organisms in terrestrial ecosystems. We used developmental instability as an indicator of plant population stress. Developmental instability is usually measured as deviations from symmetry, in traits that normally develop symmetrically. Thus, symmetry represents an idealized a priori phenotype. Stress presumably causes perturbations during development that may exceed the capacity of the organism to buffer or correct, resulting in developmental instability, and hence deviations from this ideal. Soil disturbance imposed by different land use patterns at Fort Benning, Georgia provided a gradient of soil disturbance. In 2000-2002 we collected plants from nine different sites representing three levels of disturbance. In addition, in 2002 we collected microhabitat data in 1 m quadrats surrounding each plant whose developmental stability we also assessed. The developmental instability of both species was influenced by land use patterns, whether or not the sites had been previously burned, and microhabitat variables. Developmental instability increased with soil disturbance, burning in the prior year, and as the percentage of bare ground increased around the target individual. To some extent, favorable microhabitat conditions reduced developmental instability in sites with medium and high soil disturbance, whereas unfavorable conditions at low soil disturbance sites increased developmental instability. As an indicator of community level stress, developmental instability is best used in conjunction with other indices of environmental quality. ?? Published by Elsevier Ltd.

Mixing the Solar Wind Proton and Electron Scales: Effects of Electron Temperature Anisotropy on the Oblique Proton Firehose Instability

NASA Technical Reports Server (NTRS)

Maneva, Y.; Lazar, M.; Vinas, A.; Poedts, S.

2016-01-01

The double adiabatic expansion of the nearly collisionless solar wind plasma creates conditions for the firehose instability to develop and efficiently prevent the further increase of the plasma temperature in the direction parallel to the interplanetary magnetic field. The conditions imposed by the firehose instability have been extensively studied using idealized approaches that ignore the mutual effects of electrons and protons. Recently, more realistic approaches have been proposed that take into account the interplay between electrons and protons,? unveiling new regimes of the parallel oscillatory modes. However, for oblique wave propagation the instability develops distinct branches that grow much faster and may therefore be more efficient than the parallel firehose instability in constraining the temperature anisotropy of the plasma particles. This paper reports for the first time on the effects of electron plasma properties on the oblique proton firehose (PFH) instability and provides a comprehensive vision of the entire unstable wave-vector spectrum, unifying the proton and the smaller electron scales. The plasma ß and temperature anisotropy regimes considered here are specific for the solar wind and magnetospheric conditions, and enable the electrons and protons to interact via the excited electromagnetic fluctuations. For the selected parameters, simultaneous electron and PFH instabilities can be observed with a dispersion spectrum of the electron firehose (EFH) extending toward the proton scales. Growth rates of the PFH instability are markedly boosted by the anisotropic electrons, especially in the oblique direction where the EFH growth rates are orders of magnitude higher.

MIXING THE SOLAR WIND PROTON AND ELECTRON SCALES: EFFECTS OF ELECTRON TEMPERATURE ANISOTROPY ON THE OBLIQUE PROTON FIREHOSE INSTABILITY

DOE Office of Scientific and Technical Information (OSTI.GOV)

Maneva, Y.; Lazar, M.; Poedts, S.

2016-11-20

The double adiabatic expansion of the nearly collisionless solar wind plasma creates conditions for the firehose instability to develop and efficiently prevent the further increase of the plasma temperature in the direction parallel to the interplanetary magnetic field. The conditions imposed by the firehose instability have been extensively studied using idealized approaches that ignore the mutual effects of electrons and protons. Recently, more realistic approaches have been proposed that take into account the interplay between electrons and protons, unveiling new regimes of the parallel oscillatory modes. However, for oblique wave propagation the instability develops distinct branches that grow much fastermore » and may therefore be more efficient than the parallel firehose instability in constraining the temperature anisotropy of the plasma particles. This paper reports for the first time on the effects of electron plasma properties on the oblique proton firehose (PFH) instability and provides a comprehensive vision of the entire unstable wave-vector spectrum, unifying the proton and the smaller electron scales. The plasma β and temperature anisotropy regimes considered here are specific for the solar wind and magnetospheric conditions, and enable the electrons and protons to interact via the excited electromagnetic fluctuations. For the selected parameters, simultaneous electron and PFH instabilities can be observed with a dispersion spectrum of the electron firehose (EFH) extending toward the proton scales. Growth rates of the PFH instability are markedly boosted by the anisotropic electrons, especially in the oblique direction where the EFH growth rates are orders of magnitude higher.« less

Chromium genotoxicity: a double-edged sword

PubMed Central

Nickens, Kristen P.; Patierno, Steven R.; Ceryak, Susan

2010-01-01

Certain forms of hexavalent chromium [Cr(VI)] are known respiratory carcinogens that induce a broad spectrum of DNA damage. Cr(VI)-carcinogenesis may be initiated or promoted through several mechanistic processes including, the intracellular metabolic reduction of Cr(VI) producing chromium species capable of interacting with DNA to yield genotoxic and mutagenic effects, Cr(VI)-induced inflammatory/immunological responses, and alteration of survival signaling pathways. Cr(VI) enters the cell through nonspecific anion channels, and is metabolically reduced by agents including ascorbate, glutathione, and cysteine to Cr(V), Cr(IV), and Cr(III). Cr(III) has a weak membrane permeability capacity and is unable to cross the cell membrane, thereby trapping it within the cell where it can bind to DNA and produce genetic damage leading to genomic instability. Structural genetic lesions produced by the intracellular reduction of Cr(VI) include DNA adducts, DNA strand breaks, DNA-protein crosslinks, oxidized bases, abasic sites, and DNA inter- and intrastrand crosslinks. The damage induced by Cr(VI) can lead to dysfunctional DNA replication and transcription, aberrant cell cycle checkpoints, dysregulated DNA repair mechanisms, microsatelite instability, inflammatory responses, and the disruption of key regulatory gene networks responsible for the balance of cell survival and cell death, which may all play an important role in Cr(VI) carcinogenesis. Several lines of evidence have indicated that neoplastic progression is a result of consecutive genetic/epigenetic changes that provide cellular survival advantages, and ultimately lead to the conversion of normal human cells to malignant cancer cells. This review is based on studies that provide a glimpse into Cr(VI) carcinogenicity via mechanisms including Cr(VI)-induced death-resistance, the involvement of DNA repair mechanisms in survival after chromium exposure, and the activation of survival signaling cascades in response to Cr(VI) genotoxicity. PMID:20430016

Targetable genetic features of primary testicular and primary central nervous system lymphomas

PubMed Central

Chapuy, Bjoern; Roemer, Margaretha G. M.; Stewart, Chip; Tan, Yuxiang; Abo, Ryan P.; Zhang, Liye; Dunford, Andrew J.; Meredith, David M.; Thorner, Aaron R.; Jordanova, Ekaterina S.; Liu, Gang; Feuerhake, Friedrich; Ducar, Matthew D.; Illerhaus, Gerald; Gusenleitner, Daniel; Linden, Erica A.; Sun, Heather H.; Homer, Heather; Aono, Miyuki; Pinkus, Geraldine S.; Ligon, Azra H.; Ligon, Keith L.; Ferry, Judith A.; Freeman, Gordon J.; van Hummelen, Paul; Golub, Todd R.; Getz, Gad; Rodig, Scott J.; de Jong, Daphne; Monti, Stefano

2016-01-01

Primary central nervous system lymphomas (PCNSLs) and primary testicular lymphomas (PTLs) are extranodal large B-cell lymphomas (LBCLs) with inferior responses to current empiric treatment regimens. To identify targetable genetic features of PCNSL and PTL, we characterized their recurrent somatic mutations, chromosomal rearrangements, copy number alterations (CNAs), and associated driver genes, and compared these comprehensive genetic signatures to those of diffuse LBCL and primary mediastinal large B-cell lymphoma (PMBL). These studies identify unique combinations of genetic alterations in discrete LBCL subtypes and subtype-selective bases for targeted therapy. PCNSLs and PTLs frequently exhibit genomic instability, and near-uniform, often biallelic, CDKN2A loss with rare TP53 mutations. PCNSLs and PTLs also use multiple genetic mechanisms to target key genes and pathways and exhibit near-uniform oncogenic Toll-like receptor signaling as a result of MYD88 mutation and/or NFKBIZ amplification, frequent concurrent B-cell receptor pathway activation, and deregulation of BCL6. Of great interest, PCNSLs and PTLs also have frequent 9p24.1/PD-L1/PD-L2 CNAs and additional translocations of these loci, structural bases of immune evasion that are shared with PMBL. PMID:26702065

Borderline personality disorder traits and their relationship with dimensions of normative personality: a web-based cohort and twin study

PubMed Central

Kendler, K. S.; Myers, J.; Reichborn-Kjennerud, T.

2011-01-01

Objective To describe the structure of genetic and environmental risk factors for four dimensions of borderline personality disorder (BPD) and to understand the source of resemblance of these dimensions and normal personality. Method A web-based sample (n = 44,112 including 542 twin pairs) completed items from 4 scales of the Dimensional Assessment of Personality Pathology Basic Questionnaire and the Big Five Inventory. Results A one-factor common pathway model best fits the 4 BPD scales producing a highly heritable latent liability (heritability = 60%) and strong loadings on all 4 dimensions. Affective instability had the lowest trait-specific genetic loading, suggesting that it was a core feature of BPD. A complex pattern of genetic and environmental associations was found between the big five personality traits and BPD dimensions. The strongest genetic correlations with the BPD traits were generally seen for neuroticism (positive), followed by conscientiousness and agreeableness, both negative. Conclusion In the general population, these four BPD dimensions reflect one underlying highly heritable factor. The association between normative personality and dimensions of BPD is complex with high degrees of genetic correlation. PMID:21198457

Borderline personality disorder traits and their relationship with dimensions of normative personality: a web-based cohort and twin study.

PubMed

Kendler, K S; Myers, J; Reichborn-Kjennerud, T

2011-05-01

To describe the structure of genetic and environmental risk factors for four dimensions of borderline personality disorder (BPD) and to understand the source of resemblance of these dimensions and normal personality. A web-based sample (n = 44,112 including 542 twin pairs) completed items from 4 scales of the Dimensional Assessment of Personality Pathology Basic Questionnaire and the Big Five Inventory. A one-factor common pathway model best fits the 4 BPD scales producing a highly heritable latent liability (heritability = 60%) and strong loadings on all 4 dimensions. Affective instability had the lowest trait-specific genetic loading, suggesting that it was a core feature of BPD. A complex pattern of genetic and environmental associations was found between the big five personality traits and BPD dimensions. The strongest genetic correlations with the BPD traits were generally seen for neuroticism (positive), followed by conscientiousness and agreeableness, both negative. In the general population, these four BPD dimensions reflect one underlying highly heritable factor. The association between normative personality and dimensions of BPD is complex with high degrees of genetic correlation. © 2010 John Wiley & Sons A/S.

Global insights into acetic acid resistance mechanisms and genetic stability of Acetobacter pasteurianus strains by comparative genomics

PubMed Central

Wang, Bin; Shao, Yanchun; Chen, Tao; Chen, Wanping; Chen, Fusheng

2015-01-01

Acetobacter pasteurianus (Ap) CICC 20001 and CGMCC 1.41 are two acetic acid bacteria strains that, because of their strong abilities to produce and tolerate high concentrations of acetic acid, have been widely used to brew vinegar in China. To globally understand the fermentation characteristics, acid-tolerant mechanisms and genetic stabilities, their genomes were sequenced. Genomic comparisons with 9 other sequenced Ap strains revealed that their chromosomes were evolutionarily conserved, whereas the plasmids were unique compared with other Ap strains. Analysis of the acid-tolerant metabolic pathway at the genomic level indicated that the metabolism of some amino acids and the known mechanisms of acetic acid tolerance, might collaboratively contribute to acetic acid resistance in Ap strains. The balance of instability factors and stability factors in the genomes of Ap CICC 20001 and CGMCC 1.41 strains might be the basis for their genetic stability, consistent with their stable industrial performances. These observations provide important insights into the acid resistance mechanism and the genetic stability of Ap strains and lay a foundation for future genetic manipulation and engineering of these two strains. PMID:26691589

An Experimental Investigation of Incompressible Richtmyer-Meshkov Instability

NASA Technical Reports Server (NTRS)

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

2002-01-01

Richtmyer-Meshkov (RM) instability occurs when two different density fluids are impulsively accelerated in the direction normal to their nearly planar interface. The instability causes small perturbations on the interface to grow and eventually become a turbulent flow. It is closely related to Rayleigh-Taylor instability, which is the instability of a planar interface undergoing constant acceleration, such as caused by the suspension of a heavy fluid over a lighter one in the earth's gravitational field. Like the well-known Kelvin-Helmholtz instability, RM instability is a fundamental hydrodynamic instability which exhibits many of the nonlinear complexities that transform simple initial conditions into a complex turbulent flow. Furthermore, the simplicity of RM instability (in that it requires very few defining parameters), and the fact that it can be generated in a closed container, makes it an excellent test bed to study nonlinear stability theory as well as turbulent transport in a heterogeneous system. However, the fact that RM instability involves fluids of unequal densities which experience negligible gravitational force, except during the impulsive acceleration, requires RM instability experiments to be carried out under conditions of microgravity. This experimental study investigates the instability of an interface between incompressible, miscible liquids with an initial sinusoidal perturbation. The impulsive acceleration is generated by bouncing a rectangular tank containing two different density liquids off a retractable vertical spring. The initial perturbation is produced prior to release by oscillating the tank in the horizontal direction to produce a standing wave. The instability evolves in microgravity as the tank travels up and then down the vertical rails of a drop tower until hitting a shock absorber at the bottom. Planar Laser Induced Fluorescence (PLIF) is employed to visualize the flow. PLIF images are captured by a video camera that travels with the tank. Figure 1 is as sequence of images showing the development of the instability from the initial sinusoidal disturbance far into the nonlinear regime which is characterized by the appearance of mushroom structures resulting from the coalescence of baroclinic vorticity produced by the impulsive acceleration. At later times in this sequence the vortex cores are observed to become unstable showing the beginnings of the transition to turbulence in this flow. The amplitude of the growing disturbance after the impulsive acceleration is measured and found to agree well with theoretical predictions. The effects of Reynolds number (based on circulation) on the development of the vortices and the transition to turbulence are also determined.

Filamentation instability of a fast electron beam in a dielectric target.

PubMed

Debayle, A; Tikhonchuk, V T

2008-12-01

High-intensity laser-matter interaction is an efficient method for high-current relativistic electron beam production. At current densities exceeding a several kA microm{-2} , the beam propagation is maintained by an almost complete current neutralization by the target electrons. In such a geometry of two oppositely directed flows, beam instabilities can develop, depending on the target and the beam parameters. The present paper proposes an analytical description of the filamentation instability of an electron beam propagating through an insulator target. It is shown that the collisionless and resistive instabilities enter into competition with the ionization instability. This latter process is dominant in insulator targets where the field ionization by the fast beam provides free electrons for the neutralization current.

Effects of subsurface ocean dynamics on instability waves in the tropical Pacific

NASA Astrophysics Data System (ADS)

Lawrence, Sean P.; Allen, Myles R.; Anderson, David L. T.; Llewellyn-Jones, David T.

1998-08-01

Tropical instability waves in a primitive equation model of the tropical Pacific Ocean, forced with analyzed wind stresses updated daily, show unexpectedly close phase correspondence with observation through the latter half of 1992. This suggests that these waves are not pure instabilities developing from infinitesimal disturbances, but that their phases and phase speeds are at least partially determined by the wind stress forcing. To quantify and explain this observation, we perfomed several numerical experiments, which indicate that remotely forced Rossby waves can influence both the phase and phase speed of tropical instability waves. We suggest that a remote wind forcing determines the high model/observation phase correspondence of tropical instability waves through a relatively realistic simulation of equatorial Kelvin and Rossby wave activity.

Mismatch repair genes Mlh1 and Mlh3 modify CAG instability in Huntington's disease mice: genome-wide and candidate approaches.

PubMed

Pinto, Ricardo Mouro; Dragileva, Ella; Kirby, Andrew; Lloret, Alejandro; Lopez, Edith; St Claire, Jason; Panigrahi, Gagan B; Hou, Caixia; Holloway, Kim; Gillis, Tammy; Guide, Jolene R; Cohen, Paula E; Li, Guo-Min; Pearson, Christopher E; Daly, Mark J; Wheeler, Vanessa C

2013-10-01

The Huntington's disease gene (HTT) CAG repeat mutation undergoes somatic expansion that correlates with pathogenesis. Modifiers of somatic expansion may therefore provide routes for therapies targeting the underlying mutation, an approach that is likely applicable to other trinucleotide repeat diseases. Huntington's disease Hdh(Q111) mice exhibit higher levels of somatic HTT CAG expansion on a C57BL/6 genetic background (B6.Hdh(Q111) ) than on a 129 background (129.Hdh(Q111) ). Linkage mapping in (B6x129).Hdh(Q111) F2 intercross animals identified a single quantitative trait locus underlying the strain-specific difference in expansion in the striatum, implicating mismatch repair (MMR) gene Mlh1 as the most likely candidate modifier. Crossing B6.Hdh(Q111) mice onto an Mlh1 null background demonstrated that Mlh1 is essential for somatic CAG expansions and that it is an enhancer of nuclear huntingtin accumulation in striatal neurons. Hdh(Q111) somatic expansion was also abolished in mice deficient in the Mlh3 gene, implicating MutLγ (MLH1-MLH3) complex as a key driver of somatic expansion. Strikingly, Mlh1 and Mlh3 genes encoding MMR effector proteins were as critical to somatic expansion as Msh2 and Msh3 genes encoding DNA mismatch recognition complex MutSβ (MSH2-MSH3). The Mlh1 locus is highly polymorphic between B6 and 129 strains. While we were unable to detect any difference in base-base mismatch or short slipped-repeat repair activity between B6 and 129 MLH1 variants, repair efficiency was MLH1 dose-dependent. MLH1 mRNA and protein levels were significantly decreased in 129 mice compared to B6 mice, consistent with a dose-sensitive MLH1-dependent DNA repair mechanism underlying the somatic expansion difference between these strains. Together, these data identify Mlh1 and Mlh3 as novel critical genetic modifiers of HTT CAG instability, point to Mlh1 genetic variation as the likely source of the instability difference in B6 and 129 strains and suggest that MLH1 protein levels play an important role in driving of the efficiency of somatic expansions.

Mismatch Repair Genes Mlh1 and Mlh3 Modify CAG Instability in Huntington's Disease Mice: Genome-Wide and Candidate Approaches

PubMed Central

Pinto, Ricardo Mouro; Dragileva, Ella; Kirby, Andrew; Lloret, Alejandro; Lopez, Edith; St. Claire, Jason; Panigrahi, Gagan B.; Hou, Caixia; Holloway, Kim; Gillis, Tammy; Guide, Jolene R.; Cohen, Paula E.; Li, Guo-Min; Pearson, Christopher E.; Daly, Mark J.; Wheeler, Vanessa C.

2013-01-01

The Huntington's disease gene (HTT) CAG repeat mutation undergoes somatic expansion that correlates with pathogenesis. Modifiers of somatic expansion may therefore provide routes for therapies targeting the underlying mutation, an approach that is likely applicable to other trinucleotide repeat diseases. Huntington's disease HdhQ111 mice exhibit higher levels of somatic HTT CAG expansion on a C57BL/6 genetic background (B6.HdhQ111) than on a 129 background (129.HdhQ111). Linkage mapping in (B6x129).HdhQ111 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.HdhQ111 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. HdhQ111 somatic expansion was also abolished in mice deficient in the Mlh3 gene, implicating MutLγ (MLH1–MLH3) complex as a key driver of somatic expansion. Strikingly, Mlh1 and Mlh3 genes encoding MMR effector proteins were as critical to somatic expansion as Msh2 and Msh3 genes encoding DNA mismatch recognition complex MutSβ (MSH2–MSH3). The Mlh1 locus is highly polymorphic between B6 and 129 strains. While we were unable to detect any difference in base-base mismatch or short slipped-repeat repair activity between B6 and 129 MLH1 variants, repair efficiency was MLH1 dose-dependent. MLH1 mRNA and protein levels were significantly decreased in 129 mice compared to B6 mice, consistent with a dose-sensitive MLH1-dependent DNA repair mechanism underlying the somatic expansion difference between these strains. Together, these data identify Mlh1 and Mlh3 as novel critical genetic modifiers of HTT CAG instability, point to Mlh1 genetic variation as the likely source of the instability difference in B6 and 129 strains and suggest that MLH1 protein levels play an important role in driving of the efficiency of somatic expansions. PMID:24204323

DOE Office of Scientific and Technical Information (OSTI.GOV)

Niknam, A. R., E-mail: a-niknam@sbu.ac.ir; Rastbood, E.; Khorashadizadeh, S. M.

The dielectric permittivity tensor of a magnetoactive current-driven plasma is obtained by employing the kinetic theory based on the Vlasov equation and Lorentz transformation formulas with an emphasize on the q-nonextensive statistics. By deriving the q-generalized dispersion relation of the low frequency modes in this plasma system, the possibility and properties of filamentation and ion acoustic instabilities are then studied. It is shown that the occurrence and the growth rate of these instabilities depend strongly on the nonextensive parameters, external magnetic field strength, and drift velocity. It is observed that the growth rate of ion acoustic instability is affected bymore » the magnetic field strength much more than that of the filamentation instability in the low frequency range. The external magnetic field facilitates the development of the ion-acoustic instability. It is also shown that the filamentation is the dominant instability only for the high value of drift velocity.« less

Parametric Instability of Static Shafts-Disk System Using Finite Element Method

NASA Astrophysics Data System (ADS)

Wahab, A. M.; Rasid, Z. A.; Abu, A.

2017-10-01

Parametric instability condition is an important consideration in design process as it can cause failure in machine elements. In this study, parametric instability behaviour was studied for a simple shaft and disk system that was subjected to axial load under pinned-pinned boundary condition. The shaft was modelled based on the Nelson’s beam model, which considered translational and rotary inertias, transverse shear deformation and torsional effect. The Floquet’s method was used to estimate the solution for Mathieu equation. Finite element codes were developed using MATLAB to establish the instability chart. The effect of additional disk mass on the stability chart was investigated for pinned-pinned boundary conditions. Numerical results and illustrative examples are given. It is found that the additional disk mass decreases the instability region during static condition. The location of the disk as well has significant effect on the instability region of the shaft.

Anticipating Terrorist Safe Havens from Instability Induced Conflict

NASA Astrophysics Data System (ADS)

Shearer, Robert; Marvin, Brett

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

Hypothesis: solid tumours behave as systemic metabolic dictators.

PubMed

Lee, Yang-Ming; Chang, Wei-Chun; Ma, Wen-Lung

2016-06-01

Current knowledge regarding mechanisms of carcinogenesis in human beings centres around the accumulation of genetic instability, amplified cellular signalling, disturbed cellular energy metabolism and microenvironmental regulation governed by complicated cell-cell interactions. In this article, we provide an alternative view of cancer biology. We propose that cancer behaves as a systemic dictator that interacts with tissues throughout the body to control their metabolism and eventually homeostasis. The mechanism of development of this endocrine organ-like tumour (EOLT) tissue might be the driving force for cancer progression. Here, we review the literature that led to the development of this hypothesis. The EOLT phenotype can be defined as a tumour that alters systemic homeostasis. The literature indicates that the EOLT phenotype is present throughout cancer progression. The feedback mechanism that governs the interaction between tumours and various organs is unknown. We believe that investigating the mechanism of EOLT development may advance the current knowledge of regulation within the tumour macroenvironment and consequently lead to new diagnostic methods and therapy. © 2016 The Authors. Journal of Cellular and Molecular Medicine published by John Wiley & Sons Ltd and Foundation for Cellular and Molecular Medicine.

Collision-Driven Negative-Energy Waves and the Weibel Instability of a Relativistic Electron Beam in a Quasineutral Plasma

NASA Astrophysics Data System (ADS)

Karmakar, Anupam; Kumar, Naveen; Shvets, Gennady; Polomarov, Oleg; Pukhov, Alexander

2008-12-01

A new model describing the Weibel instability of a relativistic electron beam propagating through a resistive plasma is developed. For finite-temperature beams, a new class of negative-energy magnetosound waves is identified, whose growth due to collisional dissipation destabilizes the beam-plasma system even for high beam temperatures. We perform 2D and 3D particle-in-cell simulations and show that in 3D geometry the Weibel instability persists even for collisionless background plasma. The anomalous plasma resistivity in 3D is caused by the two-stream instability.

Aeroelastic instability in a jet plate interaction

NASA Astrophysics Data System (ADS)

Antoine, Maxime; Hémon, Pascal; de Langre, Emmanuel

2007-11-01

A flexible sheet subject to a normal impinging air jet can oscillate. We present a simple experiment that shows that added damping generated by the jet is responsible for this aeroelastic instability. The cases of planar jet and circular jet are studied. A model is presented to describe this instability and the results agree well with the experimental observations. The nozzle geometry is found to be a dominant parameter that drives the critical distance between the jet and the sheet, under which the instability develops. To cite this article: M. Antoine et al., C. R. Mecanique 335 (2007).

A classical instability of Reissner-Nordstrom solutions and the fate of magnetically charged black holes

NASA Technical Reports Server (NTRS)

Lee, Kimyeong; Nair, V. P.; Weinberg, Erick J.

1991-01-01

Working in the context of spontaneously broken gauge theories, we show that the magnetically charged Reissner-Nordstrom solution develops a classical instability if the horizon is sufficiently small. This instability has significant implications for the evolution of a magnetically charged black hole. In particular, it leads to the possibility that such a hole could evaporate completely, leaving in its place a nonsingular magnetic monopole.

Papaloizou-Pringle instability suppression by the magnetorotational instability in relativistic accretion discs

NASA Astrophysics Data System (ADS)

Bugli, M.; Guilet, J.; Müller, E.; Del Zanna, L.; Bucciantini, N.; Montero, P. J.

2018-03-01

Geometrically thick tori with constant specific angular momentum have been widely used in the last decades to construct numerical models of accretion flows on to black holes. Such discs are prone to a global non-axisymmetric hydrodynamic instability, known as Papaloizou-Pringle instability (PPI), which can redistribute angular momentum and also lead to an emission of gravitational waves. It is, however, not clear yet how the development of the PPI is affected by the presence of a magnetic field and by the concurrent development of the magnetorotational instability (MRI). We present a numerical analysis using three-dimensional GRMHD simulations of the interplay between the PPI and the MRI considering, for the first time, an analytical magnetized equilibrium solution as initial condition. In the purely hydrodynamic case, the PPI selects as expected the large-scale m = 1 azimuthal mode as the fastest growing and non-linearly dominant mode. However, when the torus is threaded by a weak toroidal magnetic field, the development of the MRI leads to the suppression of large-scale modes and redistributes power across smaller scales. If the system starts with a significantly excited m = 1 mode, the PPI can be dominant in a transient phase, before being ultimately quenched by the MRI. Such dynamics may well be important in compact star mergers and tidal disruption events.

Stabilizing effect of helical current drive on tearing modes

NASA Astrophysics Data System (ADS)

Yuan, Y.; Lu, X. Q.; Dong, J. Q.; Gong, X. Y.; Zhang, R. B.

2018-01-01

The effect of helical driven current on the m = 2/n = 1 tearing mode is studied numerically in a cylindrical geometry using the method of reduced magneto-hydro-dynamic simulation. The results show that the local persistent helical current drive from the beginning time can be applied to control the tearing modes, and will cause a rebound effect called flip instability when the driven current reaches a certain value. The current intensity threshold value for the occurrence of flip instability is about 0.00087I0. The method of controlling the development of tearing mode with comparative economy is given. If the local helical driven current is discontinuous, the magnetic island can be controlled within a certain range, and then, the tearing modes stop growing; thus, the flip instability can be avoided. We also find that the flip instability will become impatient with delay injection of the driven current because the high order harmonics have been developed in the original O-point. The tearing mode instability can be controlled by using the electron cyclotron current drive to reduce the gradient of the current intensity on the rational surfaces.

Causes of Combustion Instabilities with Passive and Active Methods of Control for practical application to Gas Turbine Engines

NASA Astrophysics Data System (ADS)

Cornwell, Michael D.

Combustion at high pressure in applications such as rocket engines and gas turbine engines commonly experience destructive combustion instabilities. These instabilities results from interactions between combustion heat release, fluid mechanics and acoustics. This research explores the significant affect of unstable fluid mechanics processes in augmenting unstable periodic combustion heat release. The frequency of the unstable heat release may shift to match one of the combustors natural acoustic frequencies which then can result in significant energy exchange from chemical to acoustic energy resulting in thermoacoustic instability. The mechanisms of the fluid mechanics in coupling combustion to acoustics are very broad with many varying mechanisms explained in detail in the first chapter. Significant effort is made in understanding these mechanisms in this research in order to find commonalities, useful for mitigating multiple instability mechanisms. The complexity of combustion instabilities makes mitigation of combustion instabilities very difficult as few mitigation methods have historically proven to be very effective for broad ranges of combustion instabilities. This research identifies turbulence intensity near the forward stagnation point and movement of the forward stagnation point as a common link in what would otherwise appear to be very different instabilities. The most common method of stabilization of both premixed and diffusion flame combustion is through the introduction of swirl. Reverse flow along the centerline is introduced to transport heat and chemically active combustion products back upstream to sustain combustion. This research develops methods to suppress the movement of the forward stagnation point without suppressing the development of the vortex breakdown process which is critical to the transport of heat and reactive species necessary for flame stabilization. These methods are useful in suppressing the local turbulence at the forward stagnation point, limiting dissipation of heat and reactive species significantly improving stability. Combustion hardware is developed and tested to demonstrate the stability principles developed as part of this research. In order to more completely understand combustion instability a very unique method of combustion was researched where there are no discrete points of combustion initiation such as the forward stagnation point typical in many combustion systems including swirl and jet wake stabilized combustion. This class of combustion which has empirical evidence of great stability and efficient combustion with low CO, NOx and UHC emissions is described as high oxidization temperature distributed combustion. This mechanism of combustion is shown to be stable largely because there are no stagnations points susceptible to fluid mechanic perturbations. The final topic of research is active combustion control by fuel modulation. This may be the only practical method of controlling most instabilities with a single technique. As there are many papers reporting active combustion control algorithms this research focused on the complexities of the physics of fuel modulation at frequencies up to 1000 Hz with proportionally controlled flow amplitude. This research into the physics of high speed fluid movement, oscillation mechanical mechanisms and electromagnetics are demonstrated by development and testing of a High Speed Latching Oscillator Valve.

Transcription as a source of genome instability

PubMed Central

Kim, Nayun; Jinks-Robertson, Sue

2012-01-01

Alterations in genome sequence and structure contribute to somatic disease, affect the fitness of subsequent generations and drive evolutionary processes. The critical roles of highly accurate replication and efficient repair in maintaining overall genome integrity are well known, but the more localized stability costs associated with transcribing DNA into RNA molecules are less appreciated. Here we review the diverse ways that the essential process of transcription alters the underlying DNA template and thereby modifies the genetic landscape. PMID:22330764

LINE dancing in the human genome: transposable elements and disease.

PubMed

Belancio, Victoria P; Deininger, Prescott L; Roy-Engel, Astrid M

2009-10-27

Transposable elements (TEs) have been consistently underestimated in their contribution to genetic instability and human disease. TEs can cause human disease by creating insertional mutations in genes, and also contributing to genetic instability through non-allelic homologous recombination and introduction of sequences that evolve into various cis-acting signals that alter gene expression. Other outcomes of TE activity, such as their potential to cause DNA double-strand breaks or to modulate the epigenetic state of chromosomes, are less fully characterized. The currently active human transposable elements are members of the non-LTR retroelement families, LINE-1, Alu (SINE), and SVA. The impact of germline insertional mutagenesis by TEs is well established, whereas the rate of post-insertional TE-mediated germline mutations and all forms of somatic mutations remain less well quantified. The number of human diseases discovered to be associated with non-allelic homologous recombination between TEs, and particularly between Alu elements, is growing at an unprecedented rate. Improvement in the technology for detection of such events, as well as the mounting interest in the research and medical communities in resolving the underlying causes of the human diseases with unknown etiology, explain this increase. Here, we focus on the most recent advances in understanding of the impact of the active human TEs on the stability of the human genome and its relevance to human disease.

Defective Cell Cycle Checkpoint Functions in Melanoma Are Associated with Altered Patterns of Gene Expression

PubMed Central

Kaufmann, William K.; Nevis, Kathleen R.; Qu, Pingping; Ibrahim, Joseph G.; Zhou, Tong; Zhou, Yingchun; Simpson, Dennis A.; Helms-Deaton, Jennifer; Cordeiro-Stone, Marila; Moore, Dominic T.; Thomas, Nancy E.; Hao, Honglin; Liu, Zhi; Shields, Janiel M.; Scott, Glynis A.; Sharpless, Norman E.

2009-01-01

Defects in DNA damage responses may underlie genetic instability and malignant progression in melanoma. Cultures of normal human melanocytes (NHMs) and melanoma lines were analyzed to determine whether global patterns of gene expression could predict the efficacy of DNA damage cell cycle checkpoints that arrest growth and suppress genetic instability. NHMs displayed effective G1 and G2 checkpoint responses to ionizing radiation-induced DNA damage. A majority of melanoma cell lines (11/16) displayed significant quantitative defects in one or both checkpoints. Melanomas with B-RAF mutations as a class displayed a significant defect in DNA damage G2 checkpoint function. In contrast the epithelial-like subtype of melanomas with wild-type N-RAS and B-RAF alleles displayed an effective G2 checkpoint but a significant defect in G1 checkpoint function. RNA expression profiling revealed that melanoma lines with defects in the DNA damage G1 checkpoint displayed reduced expression of p53 transcriptional targets, such as CDKN1A and DDB2, and enhanced expression of proliferation-associated genes, such as CDC7 and GEMININ. A Bayesian analysis tool was more accurate than significance analysis of microarrays for predicting checkpoint function using a leave-one-out method. The results suggest that defects in DNA damage checkpoints may be recognized in melanomas through analysis of gene expression. PMID:17597816

Fast instability caused by electron cloud in combined function magnets

DOE PAGES

Antipov, S. A.; Adamson, P.; Burov, A.; ...

2017-04-10

One of the factors which may limit the intensity in the Fermilab Recycler is a fast transverse instability. It develops within a hundred turns and, in certain conditions, may lead to a beam loss. The high rate of the instability suggest that its cause is electron cloud. Here, we studied the phenomena by observing the dynamics of stable and unstable beam, simulating numerically the build-up of the electron cloud, and developed an analytical model of an electron cloud driven instability with the electrons trapped in combined function di-poles. We also found that beam motion can be stabilized by a clearingmore » bunch, which confirms the electron cloud nature of the instability. The clearing suggest electron cloud trapping in Recycler combined function mag-nets. Numerical simulations show that up to 1% of the particles can be trapped by the magnetic field. Since the process of electron cloud build-up is exponential, once trapped this amount of electrons significantly increases the density of the cloud on the next revolution. Furthermore, in a Recycler combined function dipole this multi-turn accumulation allows the electron cloud reaching final intensities orders of magnitude greater than in a pure dipole. The estimated resulting instability growth rate of about 30 revolutions and the mode fre-quency of 0.4 MHz are consistent with experimental observations and agree with the simulation in the PEI code. The created instability model allows investigating the beam stability for the future intensity upgrades.« less

Fast instability caused by electron cloud in combined function magnets

DOE Office of Scientific and Technical Information (OSTI.GOV)

Antipov, S. A.; Adamson, P.; Burov, A.

One of the factors which may limit the intensity in the Fermilab Recycler is a fast transverse instability. It develops within a hundred turns and, in certain conditions, may lead to a beam loss. The high rate of the instability suggest that its cause is electron cloud. Here, we studied the phenomena by observing the dynamics of stable and unstable beam, simulating numerically the build-up of the electron cloud, and developed an analytical model of an electron cloud driven instability with the electrons trapped in combined function di-poles. We also found that beam motion can be stabilized by a clearingmore » bunch, which confirms the electron cloud nature of the instability. The clearing suggest electron cloud trapping in Recycler combined function mag-nets. Numerical simulations show that up to 1% of the particles can be trapped by the magnetic field. Since the process of electron cloud build-up is exponential, once trapped this amount of electrons significantly increases the density of the cloud on the next revolution. Furthermore, in a Recycler combined function dipole this multi-turn accumulation allows the electron cloud reaching final intensities orders of magnitude greater than in a pure dipole. The estimated resulting instability growth rate of about 30 revolutions and the mode fre-quency of 0.4 MHz are consistent with experimental observations and agree with the simulation in the PEI code. The created instability model allows investigating the beam stability for the future intensity upgrades.« less

DC dynamic pull-in instability of a dielectric elastomer balloon: an energy-based approach

NASA Astrophysics Data System (ADS)

Sharma, Atul Kumar; Arora, Nitesh; Joglekar, M. M.

2018-03-01

This paper reports an energy-based method for the dynamic pull-in instability analysis of a spherical dielectric elastomer (DE) balloon subjected to a quasi-statically applied inflation pressure and a Heaviside step voltage across the balloon wall. The proposed technique relies on establishing the energy balance at the point of maximum stretch in an oscillation cycle, followed by the imposition of an instability condition for extracting the threshold parameters. The material models of the Ogden family are employed for describing the hyperelasticity of the balloon. The accuracy of the critical dynamic pull-in parameters is established by examining the saddle-node bifurcation in the transient response of the balloon obtained by integrating numerically the equation of motion, derived using the Euler-Lagrange equation. The parametric study brings out the effect of inflation pressure on the onset of the pull-in instability in the DE balloon. A quantitative comparison between the static and dynamic pull-in parameters at four different levels of the inflation pressure is presented. The results indicate that the dynamic pull-in instability gets triggered at electric fields that are lower than those corresponding to the static instability. The results of the present investigation can find potential use in the design and development of the balloon actuators subjected to transient loading. The method developed is versatile and can be used in the dynamic instability analysis of other conservative systems of interest.

DC dynamic pull-in instability of a dielectric elastomer balloon: an energy-based approach.

PubMed

Sharma, Atul Kumar; Arora, Nitesh; Joglekar, M M

2018-03-01

This paper reports an energy-based method for the dynamic pull-in instability analysis of a spherical dielectric elastomer (DE) balloon subjected to a quasi-statically applied inflation pressure and a Heaviside step voltage across the balloon wall. The proposed technique relies on establishing the energy balance at the point of maximum stretch in an oscillation cycle, followed by the imposition of an instability condition for extracting the threshold parameters. The material models of the Ogden family are employed for describing the hyperelasticity of the balloon. The accuracy of the critical dynamic pull-in parameters is established by examining the saddle-node bifurcation in the transient response of the balloon obtained by integrating numerically the equation of motion, derived using the Euler-Lagrange equation. The parametric study brings out the effect of inflation pressure on the onset of the pull-in instability in the DE balloon. A quantitative comparison between the static and dynamic pull-in parameters at four different levels of the inflation pressure is presented. The results indicate that the dynamic pull-in instability gets triggered at electric fields that are lower than those corresponding to the static instability. The results of the present investigation can find potential use in the design and development of the balloon actuators subjected to transient loading. The method developed is versatile and can be used in the dynamic instability analysis of other conservative systems of interest.

Convective Electrokinetic Instability With Conductivity Gradients

NASA Astrophysics Data System (ADS)

Chen, Chuan-Hua; Lin, Hao; Lele, Sanjiva; Santiago, Juan

2003-11-01

Electrokinetic flow instability has been experimentally identified and quantified in a glass T-junction microchannel system with a cross section of 11 um x 155 um. In this system, buffers of different conductivities were electrokinetically driven into a common mixing channel by a DC electric field. A convective instability was observed with a threshold electric field of 0.45 kV/cm for a 10:1 conductivity ratio. A physical model has been developed which consists of a modified Ohmic model formulation for electrolyte solutions and the Navier-Stokes equations with an electric body force term. The model and experiments show that bulk charge accumulation in regions of conductivity gradients is the key mechanism of such instabilities. A linear stability analysis was performed in a convective framework, and Briggs-Bers criteria were applied to determine the nature of instability. The analysis shows the instability is governed by two key parameters: the ratio of molecular diffusion to electroviscous time scale which governs the onset of instability, and the ratio of electroviscous to electroosmotic velocity which governs whether the instability is convective or absolute. The model predicted critical electric field, growth rate, wavelength, and phase speed which were comparable to experimental data.

Experimental evidence of ion-induced instabilities in the NSLS-II storage ring

DOE PAGES

Cheng, Weixing; Li, Yongjun; Podobedov, Boris

2017-03-12

Fast ion instability has been identified as one of the most prominent instabilities in the recently constructed NSLS-II storage ring at Brookhaven National Laboratory. At a relatively low beam current (~ 25 mA) multi-bunch fills, ion-induced instabilities have already been observed during the early stages of machine commissioning. At present user operation with 250 mA in ~1000 bunches, the fast ion still remains the dominant instability, even after months of vacuum conditioning at high current. Ion-induced dipole motions of the electron beam have been suppressed using the transverse bunch-by-bunch (BxB) feedback system. However other adverse effects of this instability, suchmore » as the vertical beam size increase along the bunch train cannot be cured by the feedback system. Therefore, to achieve the NSLS-II design current of 500 mA while maintaining a small vertical beam emittance, it is important to further understand the fast ion instability and develop mitigation techniques. This paper reports on a series of ion-instability observations at various fill patterns and beam currents using start-of-art NSLS-II diagnostic tools.« less

Experimental evidence of ion-induced instabilities in the NSLS-II storage ring

DOE Office of Scientific and Technical Information (OSTI.GOV)

Cheng, Weixing; Li, Yongjun; Podobedov, Boris

Fast ion instability has been identified as one of the most prominent instabilities in the recently constructed NSLS-II storage ring at Brookhaven National Laboratory. At a relatively low beam current (~ 25 mA) multi-bunch fills, ion-induced instabilities have already been observed during the early stages of machine commissioning. At present user operation with 250 mA in ~1000 bunches, the fast ion still remains the dominant instability, even after months of vacuum conditioning at high current. Ion-induced dipole motions of the electron beam have been suppressed using the transverse bunch-by-bunch (BxB) feedback system. However other adverse effects of this instability, suchmore » as the vertical beam size increase along the bunch train cannot be cured by the feedback system. Therefore, to achieve the NSLS-II design current of 500 mA while maintaining a small vertical beam emittance, it is important to further understand the fast ion instability and develop mitigation techniques. This paper reports on a series of ion-instability observations at various fill patterns and beam currents using start-of-art NSLS-II diagnostic tools.« less

Hydrodynamic instabilities of flows involving melting in under-saturated porous media

NASA Astrophysics Data System (ADS)

Sajjadi, M.; Azaiez, J.

2016-03-01

The process of melting in partially saturated porous media is modeled for flow displacements prone to hydrodynamic instabilities due to adverse mobility ratios. The effects of the development of instabilities on the melting process are investigated through numerical simulations as well as analytical solution to unravel the physics of the flow. The effects of melting parameters, namely, the melting potential of the fluid, the rate of heat transfer to the frozen phase, and the saturation of the frozen material along with the parameters defining the viscous forces, i.e., the thermal and solutal log mobility ratios are examined. Results are presented for different scenarios and the enhancement or attenuation of instabilities are discussed based on the dominant physical mechanisms. Beside an extensive qualitative analysis, the performance of different displacement scenarios is compared with respect to the melt production and the extent of contribution of instability to the enhancement of melting. It is shown that the hydrodynamic instabilities tend in general to enhance melting but the rate of enhancement depends on the interplay between the instabilities and melting at the thermal front. A larger melting potential and a smaller saturation of the frozen material tend to increase the contribution of instability to melting.

Cell kinetics and genetic instabilities in differentiated type early gastric cancers with different mucin phenotype.

PubMed

Shibata, Naomi; Watari, Jiro; Fujiya, Mikihiro; Tanno, Satoshi; Saitoh, Yusuke; Kohgo, Yutaka

2003-01-01

To clarify the biological impact and molecular pathogenesis of cellular phenotype in differentiated-type gastric cancers (DGCs), we investigated cell kinetics and genetic instabilities in early stage of DGCs. A total of 43 early gastric cancers (EGCs) were studied. EGCs were divided into 3 phenotypic categories: gastric (G type, n = 11), ordinary (O type, n = 20), and complete intestinal (CI type, n = 12) based on the combination of HGM, ConA, MUC2, and CD10. Proliferative index (PI), apoptotic index (AI), and p53 overexpression were investigated by immunohistochemical staining with anti-Ki-67, the terminal deoxynucleotidyl transferase-mediated deoxyuridine triphosphate nick-end labeling method, and p53 antibody, respectively. Using a high-resolution fluorescent microsatellite analysis system, microsatellite instability (MSI) and loss of heterozygosity (LOH) were examined. Frameshift mutation analysis of transforming growth factor-beta type II receptor (TGF-betaRII) and bcl-2-associated X (BAX) in cancers with MSI was also performed. The mean AI/PI ratio values were 0.04 for G-type, 0.10 for O-type, and 0.13 for CI-type cancers--significantly lower in G type than in O and CI types (P = 0.02 and P = 0.001, respectively). No difference in the incidence of MSI and LOH was seen among the 3 cellular phenotypes. However, the major pattern of MSI, which showed drastic and widely dispersed changes and is related to an increased risk for cancer, was significantly higher in G and O types than in CI type (P <0.005). No frame shift mutations of TGF-betaRII or BAX were found in CI-type cancers. These results indicate that G-type cancers are likely to show more aggressive behaviors than CI-type cancers, and that O-type cancers show the intermediate characteristics of both types. However, the molecular pathogenesis of each phenotypic cancer is not associated with microsatellite alterations. Copyright 2003, Elsevier Science (USA). All rights reserved.

Self-organized kilometer-scale shoreline sand wave generation: Sensitivity to model and physical parameters

NASA Astrophysics Data System (ADS)

Idier, Déborah; Falqués, Albert; Rohmer, Jérémy; Arriaga, Jaime

2017-09-01

The instability mechanisms for self-organized kilometer-scale shoreline sand waves have been extensively explored by modeling. However, while the assumed bathymetric perturbation associated with the sand wave controls the feedback between morphology and waves, its effect on the instability onset has not been explored. In addition, no systematic investigation of the effect of the physical parameters has been done yet. Using a linear stability model, we investigate the effect of wave conditions, cross-shore profile, closure depth, and two perturbation shapes (P1: cross-shore bathymetric profile shift, and P2: bed level perturbation linearly decreasing offshore). For a P1 perturbation, no instability occurs below an absolute critical angle θc0≈ 40-50°. For a P2 perturbation, there is no absolute critical angle: sand waves can develop also for low-angle waves. In fact, the bathymetric perturbation shape plays a key role in low-angle wave instability: such instability only develops if the curvature of the depth contours offshore the breaking zone is larger than the shoreline one. This can occur for the P2 perturbation but not for P1. The analysis of bathymetric data suggests that both curvature configurations could exist in nature. For both perturbation types, large wave angle, small wave period, and large closure depth strongly favor instability. The cross-shore profile has almost no effect with a P1 perturbation, whereas large surf zone slope and gently sloping shoreface strongly enhance instability under low-angle waves for a P2 perturbation. Finally, predictive statistical models are set up to identify sites prone to exhibit either a critical angle close to θc0 or low-angle wave instability.

Electromechanical instability in soft materials: Theory, experiments and applications

NASA Astrophysics Data System (ADS)

Suo, Zhigang

2013-03-01

Subject to a voltage, a membrane of a dielectric elastomer reduces thickness and expands area, possibly straining over 100%. The phenomenon is being developed as transducers for broad applications, including soft robots, adaptive optics, Braille displays, and electric generators. The behavior of dielectric elastomers is closely tied to electromechanical instability. This instability may limit the performance of devices, and may also be used to achieve giant actuation strains. This talk reviews the theory of dielectric elastomers, coupling large deformation and electric potential. The theory is developed within the framework of continuum mechanics and thermodynamics. The theory attempts to answer commonly asked questions. How do mechanics and electrostatics work together to generate large deformation? How efficiently can a material convert energy from one form to another? How do molecular processes affect macroscopic behavior? The theory is used to describe electromechanical instability, and is related to recent experiments.

Contribution to study of interfaces instabilities in plane, cylindrical and spherical geometry

NASA Astrophysics Data System (ADS)

Toque, Nathalie

1996-12-01

This thesis proposes several experiments of hydrodynamical instabilities which are studied, numerically and theoretically. The experiments are in plane and cylindrical geometry. Their X-ray radiographies show the evolution of an interface between two solid media crossed by a detonation wave. These materials are initially solid. They become liquide under shock wave or stay between two phases, solid and liquid. The numerical study aims at simulating with the codes EAD and Ouranos, the interfaces instabilities which appear in the experiments. The experimental radiographies and the numerical pictures are in quite good agreement. The theoretical study suggests to modelise a spatio-temporal part of the experiments to obtain the quantitative development of perturbations at the interfaces and in the flows. The models are linear and in plane, cylindrical and spherical geometry. They preceed the inoming study of transition between linear and non linear development of instabilities in multifluids flows crossed by shock waves.

Exact Solutions for Nonlinear Development of a Kelvin-Helmholtz Instability for the Counterflow of Superfluid and Normal Components of Helium II.

PubMed

Lushnikov, Pavel M; Zubarev, Nikolay M

2018-05-18

Relative motion of the normal and superfluid components of helium II results in the quantum Kelvin-Helmholtz instability (KHI) at their common free surface. We found the integrability and exact growing solutions for the nonlinear stage of the development of that instability. Contrary to the usual KHI of the interface between two classical fluids, the dynamics of a helium II free surface allows reduction to the Laplace growth equation, which has an infinite number of exact solutions, including the generic formation of sharp cusps at the free surface in a finite time.

Exact Solutions for Nonlinear Development of a Kelvin-Helmholtz Instability for the Counterflow of Superfluid and Normal Components of Helium II

NASA Astrophysics Data System (ADS)

Lushnikov, Pavel M.; Zubarev, Nikolay M.

2018-05-01

Relative motion of the normal and superfluid components of helium II results in the quantum Kelvin-Helmholtz instability (KHI) at their common free surface. We found the integrability and exact growing solutions for the nonlinear stage of the development of that instability. Contrary to the usual KHI of the interface between two classical fluids, the dynamics of a helium II free surface allows reduction to the Laplace growth equation, which has an infinite number of exact solutions, including the generic formation of sharp cusps at the free surface in a finite time.

Development and Application of Plasma Actuators for Active Control of High-Speed and High Reynolds Number Flows

NASA Technical Reports Server (NTRS)

Sammy, Mo

2010-01-01

Active flow control is often used to manipulate flow instabilities to achieve a desired goal (e.g. prevent separation, enhance mixing, reduce noise, etc.). Instability frequencies normally scale with flow velocity scale and inversely with flow length scale (U/l). In a laboratory setting for such flow experiments, U is high, but l is low, resulting in high instability frequency. In addition, high momentum and high background noise & turbulence in the flow necessitate high amplitude actuation. Developing a high amplitude and high frequency actuator is a major challenge. Ironically, these requirements ease up in application (but other issues arise).

Genomic instability--an evolving hallmark of cancer.

PubMed

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

2010-03-01

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

Theoretical Studies of Low Frequency Instabilities in the Ionosphere. Final Report

DOE Office of Scientific and Technical Information (OSTI.GOV)

Dimant, Y. S.

2003-08-20

The objective of the current project is to provide a theoretical basis for better understanding of numerous radar and rocket observations of density irregularities and related effects in the lower equatorial and high-latitude ionospheres. The research focused on: (1) continuing efforts to develop a theory of nonlinear saturation of the Farley-Buneman instability; (2) revision of the kinetic theory of electron-thermal instability at low altitudes; (3) studying the effects of strong anomalous electron heating in the high-latitude electrojet; (4) analytical and numerical studies of the combined Farley-Bunemadion-thermal instabilities in the E-region ionosphere; (5) studying the effect of dust charging in Polarmore » Mesospheric Clouds. Revision of the kinetic theory of electron thermal instability at low altitudes.« less

Waves on the surface of the Orion molecular cloud.

PubMed

Berné, Olivier; Marcelino, Núria; Cernicharo, José

2010-08-19

Massive stars influence their parental molecular cloud, and it has long been suspected that the development of hydrodynamical instabilities can compress or fragment the cloud. Identifying such instabilities has proved difficult. It has been suggested that elongated structures (such as the 'pillars of creation') and other shapes arise because of instabilities, but alternative explanations are available. One key signature of an instability is a wave-like structure in the gas, which has hitherto not been seen. Here we report the presence of 'waves' at the surface of the Orion molecular cloud near where massive stars are forming. The waves seem to be a Kelvin-Helmholtz instability that arises during the expansion of the nebula as gas heated and ionized by massive stars is blown over pre-existing molecular gas.

Assessment of genetic stability and instability of tissue culture-propagated plantlets of Aloe vera L. by RAPD and ISSR markers.

PubMed

Rathore, Mangal Singh; Chikara, J; Mastan, Shaik G; Rahman, H; Anand, K G V; Shekhawat, N S

2011-11-01

Efficient plantlet regeneration with and without intermediate callus phase was achieved for a selected genotype of Aloe vera L. which is sweet in test and used as a vegetable and source of food. Random amplified polymorphic DNA (RAPD) and inter simple sequence repeats (ISSR) marker assays were employed to evaluate genetic stability of plantlets and validate the most reliable method for true-to-type propagation of sweet aloe, among two regeneration systems developed so far. Despite phenotypic similarities in plantlets produced through both regeneration systems, the differences in genomic constituents of plantlets produced through intermediate callus phase using soft base of inflorescence have been effectively distinguished by RAPD and ISSR markers. No polymorphism was observed in regenerants produced following direct regeneration of axillary buds, whereas 80% and 73.3% of polymorphism were observed in RAPD and ISSR, respectively, in the regenerants produced indirectly from base of the inflorescence axis via an intermediate callus phase. Overall, 86.6% of variations were observed in the plantlets produced via an intermediate callus phase. The occurrence of genetic polymorphism is associated with choice of explants and method used for plantlet regeneration. This confirms that clonal propagation of sweet aloe using axillary shoot buds can be used for commercial exploitation of the selected genotype where a high degree of fidelity is an essential prerequisite. On the other hand, a high degree of variations were observed in plantlets obtained through indirect regeneration and thus cannot be used for the mass multiplication of the genotype; however, it can be used for crop improvement through induction of somaclonal variations and genetic manipulations.

Looking at the stability of life-support microorganisms in space : the MELGEN activity highlights the cyanobacterium Arthrospira sp. PCC8005

NASA Astrophysics Data System (ADS)

Morin, Nicolas

The MELGEN activity (MELiSSA Genetic Stability Study) mainly covers the molecular aspects of the regenerative life-support system MELiSSA (Micro-Ecological Life Support System Alternative) of the European Space Agency (ESA). The general objective of MELGEN is to establish and validate methods and the related hardware in order to detect genetic instability and microbial contaminants in the MELISSA compartments. This includes (1) a genetic description of the MELISSA strains, (2) studies of microbial behavior and genetic stability in bioreactors and (3) the detection of chemical, genetical and biological contamination and their effect on microbial metabolism. Selected as oxygen producer and complementary food source, the cyanobacterium Arthrospira sp. PCC8005 plays a major role within the MELiSSA loop. As the genomic information on this organism was insufficient, sequencing of its genome was proposed at the French National Sequencing Center, Genoscope, as a joint effort between ESA and different laboratories. So far, a preliminary assembly of 16 contigs representing circa 6.3 million basepairs was obtained. Even though the finishing of the genome is on its way, automatic annotation of the contigs has already been performed on the MaGe annotation platform, and curation of the sequence is currently being carried out, with a special focus on biosynthesis pathways, photosynthesis, and maintenance processes of the cell. According to the index of repetitiveness described by Haubold and Wiehe (2006), we discovered that the genome of Arthrospira sp. is among the 50 most repeated bacterial genomes sequenced to date. Thanks to the sequencing project, we have identified and catalogued mobile genetics elements (MGEs) dispersed throughout the unique chromosome of this cyanobacterium. They represent a quite large proportion of the genome, as genes identified as putative transposases are indeed found in circa 5 Results : We currently have a first draft of the complete genome of Arthrospira sp. PCC 8005, fully annotated. This genomic information opens the gates to a better understanding of the biology of this cyanobacterium and will be a key to the development of appropriate derivatives that provide enhanced performances (e.g. radiation resistance, genetic stability, photosynthesis and nutritive properties).

Dynamics Evolution Investigation of Mack Mode Instability in a Hypersonic Boundary Layer by Bicoherence Spectrum Analysis

NASA Astrophysics Data System (ADS)

Han, Jian; Jiang, Nan

2012-07-01

The instability of a hypersonic boundary layer on a cone is investigated by bicoherence spectrum analysis. The experiment is conducted at Mach number 6 in a hypersonic wind tunnel. The time series signals of instantaneous fluctuating surface-thermal-flux are measured by Pt-thin-film thermocouple temperature sensors mounted at 28 stations on the cone surface along streamwise direction to investigate the development of the unstable disturbances. The bicoherence spectrum analysis based on wavelet transform is employed to investigate the nonlinear interactions of the instability of Mack modes in hypersonic laminar boundary layer transition. The results show that wavelet bicoherence is a powerful tool in studying the unstable mode nonlinear interaction of hypersonic laminar-turbulent transition. The first mode instability gives rise to frequency shifts to higher unstable modes at the early stage of hypersonic laminar-turbulent transition. The modulations subsequently lead to the second mode instability occurrence. The second mode instability governs the last stage of instability and final breakdown to turbulence with multi-scale disturbances growth.

Energy dynamics in a simulation of LAPD turbulence

NASA Astrophysics Data System (ADS)

Friedman, B.; Carter, T. A.; Umansky, M. V.; Schaffner, D.; Dudson, B.

2012-10-01

Energy dynamics calculations in a 3D fluid simulation of drift wave turbulence in the linear Large Plasma Device [W. Gekelman et al., Rev. Sci. Instrum. 62, 2875 (1991)] illuminate processes that drive and dissipate the turbulence. These calculations reveal that a nonlinear instability dominates the injection of energy into the turbulence by overtaking the linear drift wave instability that dominates when fluctuations about the equilibrium are small. The nonlinear instability drives flute-like (k∥=0) density fluctuations using free energy from the background density gradient. Through nonlinear axial wavenumber transfer to k∥≠0 fluctuations, the nonlinear instability accesses the adiabatic response, which provides the requisite energy transfer channel from density to potential fluctuations as well as the phase shift that causes instability. The turbulence characteristics in the simulations agree remarkably well with experiment. When the nonlinear instability is artificially removed from the system through suppressing k∥=0 modes, the turbulence develops a coherent frequency spectrum which is inconsistent with experimental data. This indicates the importance of the nonlinear instability in producing experimentally consistent turbulence.

Conservation laws in baroclinic inertial-symmetric instabilities

NASA Astrophysics Data System (ADS)

Grisouard, Nicolas; Fox, Morgan B.; Nijjer, Japinder

2017-04-01

Submesoscale oceanic density fronts are structures in geostrophic and hydrostatic balance, but are more prone to instabilities than mesoscale flows. As a consequence, they are believed to play a large role in air-sea exchanges, near-surface turbulence and dissipation of kinetic energy of geostrophically and hydrostatically balanced flows. We will present two-dimensional (x, z) Boussinesq numerical experiments of submesoscale baroclinic fronts on the f-plane. Instabilities of the mixed inertial and symmetric types (the actual name varies across the literature) develop, with the absence of along-front variations prohibiting geostrophic baroclinic instabilities. Two new salient facts emerge. First, contrary to pure inertial and/or pure symmetric instability, the potential energy budget is affected, the mixed instability extracting significant available potential energy from the front and dissipating it locally. Second, in the submesoscale regime, the growth rate of this mixed instability is sufficiently large that significant radiation of near-inertial internal waves occurs. Although energetically small compared to e.g. local dissipation within the front, this process might be a significant source of near-inertial energy in the ocean.

A classical instability of Reissner-Nordstrom solutions and the fate of magnetically charged black holes

NASA Technical Reports Server (NTRS)

Lee, Kimyeong; Nair, V. P.; Weinberg, Erick J.

1992-01-01

Working in the context of spontaneously broken gauge theories, it is shown that the magnetically charged Reissner-Nordstrom solution develops a classical instability if the horizon is sufficiently small. This instability has significant implications for the evolution of a magnetically charged black hole. In particular, it leads to the possibility that such a hole could evaporate completely, leaving in its place a nonsingular magnetic monopole.

Threshold of transverse mode coupling instability with arbitrary space charge

DOE Office of Scientific and Technical Information (OSTI.GOV)

Balbekov, V.

The threshold of the transverse mode coupling instability is calculated in framework of the square well model at arbitrary value of space charge tune shift. A new method of calculation is developed beyond the traditional expansion technique. The square, resistive, and exponential wakes are investigated. It is shown that the instability threshold goes up indefinitely when the tune shift increases. Finally, a comparison with conventional case of the parabolic potential well is performed.

Threshold of transverse mode coupling instability with arbitrary space charge

DOE PAGES

Balbekov, V.

2017-11-30

The threshold of the transverse mode coupling instability is calculated in framework of the square well model at arbitrary value of space charge tune shift. A new method of calculation is developed beyond the traditional expansion technique. The square, resistive, and exponential wakes are investigated. It is shown that the instability threshold goes up indefinitely when the tune shift increases. Finally, a comparison with conventional case of the parabolic potential well is performed.

A comparison between metaheuristics as strategies for minimizing cyclic instability in Ambient Intelligence.

PubMed

Romero, Leoncio A; Zamudio, Victor; Baltazar, Rosario; Mezura, Efren; Sotelo, Marco; Callaghan, Vic

2012-01-01

In this paper we present a comparison between six novel approaches to the fundamental problem of cyclic instability in Ambient Intelligence. These approaches are based on different optimization algorithms, Particle Swarm Optimization (PSO), Bee Swarm Optimization (BSO), micro Particle Swarm Optimization (μ-PSO), Artificial Immune System (AIS), Genetic Algorithm (GA) and Mutual Information Maximization for Input Clustering (MIMIC). In order to be able to use these algorithms, we introduced the concept of Average Cumulative Oscillation (ACO), which enabled us to measure the average behavior of the system. This approach has the advantage that it does not need to analyze the topological properties of the system, in particular the loops, which can be computationally expensive. In order to test these algorithms we used the well-known discrete system called the Game of Life for 9, 25, 49 and 289 agents. It was found that PSO and μ-PSO have the best performance in terms of the number of agents locked. These results were confirmed using the Wilcoxon Signed Rank Test. This novel and successful approach is very promising and can be used to remove instabilities in real scenarios with a large number of agents (including nomadic agents) and complex interactions and dependencies among them.

A Comparison between Metaheuristics as Strategies for Minimizing Cyclic Instability in Ambient Intelligence

PubMed Central

Romero, Leoncio A.; Zamudio, Victor; Baltazar, Rosario; Mezura, Efren; Sotelo, Marco; Callaghan, Vic

2012-01-01

In this paper we present a comparison between six novel approaches to the fundamental problem of cyclic instability in Ambient Intelligence. These approaches are based on different optimization algorithms, Particle Swarm Optimization (PSO), Bee Swarm Optimization (BSO), micro Particle Swarm Optimization (μ-PSO), Artificial Immune System (AIS), Genetic Algorithm (GA) and Mutual Information Maximization for Input Clustering (MIMIC). In order to be able to use these algorithms, we introduced the concept of Average Cumulative Oscillation (ACO), which enabled us to measure the average behavior of the system. This approach has the advantage that it does not need to analyze the topological properties of the system, in particular the loops, which can be computationally expensive. In order to test these algorithms we used the well-known discrete system called the Game of Life for 9, 25, 49 and 289 agents. It was found that PSO and μ-PSO have the best performance in terms of the number of agents locked. These results were confirmed using the Wilcoxon Signed Rank Test. This novel and successful approach is very promising and can be used to remove instabilities in real scenarios with a large number of agents (including nomadic agents) and complex interactions and dependencies among them. PMID:23112643

Analyses of Injection-Coupled Combustion Instability from J-2X Gas Generator Development

NASA Technical Reports Server (NTRS)

Hulka, James R.; Kenny, R. Jeremy; Protz, Chris; Casiano, Matthew

2011-01-01

During development of the gas generator for the liquid oxygen/liquid hydrogen propellant J-2X rocket engine, combustion instabilities were observed near the frequency of the first longitudinal acoustic mode of the hot gas combustion chamber duct. These instabilities were similar to intermediate-frequency or buzz-type instabilities as described in historical programs, except for several aspects: 1) the frequencies were low, in the realm of chug; 2) at times the instability oscillation amplitudes were quite large, with peak-to-peak amplitudes exceeding 50% of the mean chamber pressure along with the appearance of harmonics; 3) the chamber excitation was related to but not exactly at the first longitudinal combustion chamber acoustic mode; and 4) the injector provided mass flow rate oscillations induced by capacitance and inertance effects in the injector rather than by organ pipe resonances of the coaxial oxidizer posts. This type of combustion instability is referred to as "injection coupling" because one critical driving source of the instability is mass flow rate oscillations from the injector. However, the type of injection coupling observed here is different than observed in previous instances of buzz instability with coaxial injectors, because of the lower frequencies and lack of influence from the oxidizer post organ pipe resonances. Test data and preliminary analyses of the initial combustion instabilities were presented in several papers at the 5th Liquid Propulsion Subcommittee meeting. Since that time, additional hot-fire tests with several new hardware configurations have been conducted, and additional analyses have been completed. The analytical models described in previous papers have been updated to include the influences of new geometrical configurations, including a different oxidizer injector manifold configuration and a branch pipe in the hot gas duct that supplies gaseous helium during the start transient to pre-spin the turbine. In addition, the analysis methodology has been revisited to evaluate the potential influence of a combustion response as well as an injection response.

Numerical methods for large eddy simulation of acoustic combustion instabilities

NASA Astrophysics Data System (ADS)

Wall, Clifton T.

Acoustic combustion instabilities occur when interaction between the combustion process and acoustic modes in a combustor results in periodic oscillations in pressure, velocity, and heat release. If sufficiently large in amplitude, these instabilities can cause operational difficulties or the failure of combustor hardware. In many situations, the dominant instability is the result of the interaction between a low frequency acoustic mode of the combustor and the large scale hydrodynamics. Large eddy simulation (LES), therefore, is a promising tool for the prediction of these instabilities, since both the low frequency acoustic modes and the large scale hydrodynamics are well resolved in LES. Problems with the tractability of such simulations arise, however, due to the difficulty of solving the compressible Navier-Stokes equations efficiently at low Mach number and due to the large number of acoustic periods that are often required for such instabilities to reach limit cycles. An implicit numerical method for the solution of the compressible Navier-Stokes equations has been developed which avoids the acoustic CFL restriction, allowing for significant efficiency gains at low Mach number, while still resolving the low frequency acoustic modes of interest. In the limit of a uniform grid the numerical method causes no artificial damping of acoustic waves. New, non-reflecting boundary conditions have also been developed for use with the characteristic-based approach of Poinsot and Lele (1992). The new boundary conditions are implemented in a manner which allows for significant reduction of the computational domain of an LES by eliminating the need to perform LES in regions where one-dimensional acoustics significantly affect the instability but details of the hydrodynamics do not. These new numerical techniques have been demonstrated in an LES of an experimental combustor. The new techniques are shown to be an efficient means of performing LES of acoustic combustion instabilities and are shown to accurately predict the occurrence and frequency of the dominant mode of the instability observed in the experiment.

Recurrent Shoulder Instability in a Young, Active, Military Population and Its Professional Implications.

PubMed

Flint, James H; Pickett, Adam; Owens, Brett D; Svoboda, Steven J; Peck, Karen Y; Cameron, Kenneth L; Biery, John; Giuliani, Jeffrey; Rue, John-Paul

Shoulder instability is a topic of significant interest within the sports medicine literature, particularly regarding recurrence rates and the ideal treatment indications and techniques. Little has been published specifically addressing the occupational implications of symptomatic recurrent shoulder instability. Previous arthroscopic repair will continue to be a significant predisposing factor for recurrent instability in a young, active population, and that recurrent instability may have a negative effect on college graduation and postgraduate occupational selection. Case series. Level 4. We conducted a retrospective review of approved medical waivers for surgical treatment of anterior shoulder dislocation or instability prior to matriculation at the US Military Academy or the US Naval Academy for the graduating classes of 2010 to 2013. Statistical analysis was performed to determine the incidence and risk factors for recurrence and to determine the impact on graduation rate and occupation selection. Fifty-nine patients were evaluated; 34% developed recurrent anterior instability. Patients with previous arthroscopic repair had a significantly higher incidence of recurrence (38%, P = 0.044). Recurrent shoulder instability did not significantly affect graduation rates or self-selected occupation ( P ≥ 0.05). There is a significant rate of recurrent shoulder instability after primary surgical repair, particularly among young, active individuals. In addition, arthroscopic repair resulted in a significantly higher recurrence rate compared with open repair in our population. Surgical repair for shoulder instability should not necessarily preclude young individuals from pursuing (or being considered for) occupations that may place them at greater risk of recurrence. The risk of recurrent instability is greater than the rate typically described, which may suggest that some subpopulations are at greater risk than others. A unique data point regarding instability is the effect on occupation selection.

Microscopic theory of traffic-flow instability governing traffic breakdown at highway bottlenecks: Growing wave of increase in speed in synchronized flow.

PubMed

Kerner, Boris S

2015-12-01

We have revealed a growing local speed wave of increase in speed that can randomly occur in synchronized flow (S) at a highway bottleneck. The development of such a traffic flow instability leads to free flow (F) at the bottleneck; therefore, we call this instability an S→F instability. Whereas the S→F instability leads to a local increase in speed (growing acceleration wave), in contrast, the classical traffic flow instability introduced in the 1950s-1960s and incorporated later in a huge number of traffic flow models leads to a growing wave of a local decrease in speed (growing deceleration wave). We have found that the S→F instability can occur only if there is a finite time delay in driver overacceleration. The initial speed disturbance of increase in speed (called "speed peak") that initiates the S→F instability occurs usually at the downstream front of synchronized flow at the bottleneck. There can be many speed peaks with random amplitudes that occur randomly over time. It has been found that the S→F instability exhibits a nucleation nature: Only when a speed peak amplitude is large enough can the S→F instability occur; in contrast, speed peaks of smaller amplitudes cause dissolving speed waves of a local increase in speed (dissolving acceleration waves) in synchronized flow. We have found that the S→F instability governs traffic breakdown-a phase transition from free flow to synchronized flow (F→S transition) at the bottleneck: The nucleation nature of the S→F instability explains the metastability of free flow with respect to an F→S transition at the bottleneck.

Microscopic theory of traffic-flow instability governing traffic breakdown at highway bottlenecks: Growing wave of increase in speed in synchronized flow

NASA Astrophysics Data System (ADS)

Kerner, Boris S.

2015-12-01

We have revealed a growing local speed wave of increase in speed that can randomly occur in synchronized flow (S) at a highway bottleneck. The development of such a traffic flow instability leads to free flow (F) at the bottleneck; therefore, we call this instability an S →F instability. Whereas the S →F instability leads to a local increase in speed (growing acceleration wave), in contrast, the classical traffic flow instability introduced in the 1950s-1960s and incorporated later in a huge number of traffic flow models leads to a growing wave of a local decrease in speed (growing deceleration wave). We have found that the S →F instability can occur only if there is a finite time delay in driver overacceleration. The initial speed disturbance of increase in speed (called "speed peak") that initiates the S →F instability occurs usually at the downstream front of synchronized flow at the bottleneck. There can be many speed peaks with random amplitudes that occur randomly over time. It has been found that the S →F instability exhibits a nucleation nature: Only when a speed peak amplitude is large enough can the S →F instability occur; in contrast, speed peaks of smaller amplitudes cause dissolving speed waves of a local increase in speed (dissolving acceleration waves) in synchronized flow. We have found that the S →F instability governs traffic breakdown—a phase transition from free flow to synchronized flow (F →S transition) at the bottleneck: The nucleation nature of the S →F instability explains the metastability of free flow with respect to an F →S transition at the bottleneck.

Ion heating, burnout of the high-frequency field, and ion sound generation under the development of a modulation instability of an intense Langmuir wave in a plasma

NASA Astrophysics Data System (ADS)

Kirichok, A. V.; Kuklin, V. M.; Pryimak, A. V.; Zagorodny, A. G.

2015-09-01

The development of one-dimensional parametric instabilities of intense long plasma waves is considered in terms of the so-called hybrid models, with electrons being treated as a fluid and ions being regarded as particles. The analysis is performed for both cases when the average plasma field energy is lower (Zakharov's hybrid model—ZHM) or greater (Silin's hybrid model—SHM) than the plasma thermal energy. The efficiency of energy transfer to ions and to ion perturbations under the development of the instability is considered for various values of electron-to-ion mass ratios. The energy of low-frequency oscillations (ion-sound waves) is found to be much lower than the final ion kinetic energy. We also discuss the influence of the changes in the damping rate of the high-frequency (HF) field on the instability development. The decrease of the absorption of the HF field inhibits the HF field burnout within plasma density cavities and gives rise to the broadening of the HF spectrum. At the same time, the ion velocity distribution tends to the normal distribution in both ZHM and SHM.

Ion heating, burnout of the high-frequency field, and ion sound generation under the development of a modulation instability of an intense Langmuir wave in a plasma

DOE Office of Scientific and Technical Information (OSTI.GOV)

Kirichok, A. V., E-mail: sandyrcs@gmail.com; Kuklin, V. M.; Pryimak, A. V.

The development of one-dimensional parametric instabilities of intense long plasma waves is considered in terms of the so-called hybrid models, with electrons being treated as a fluid and ions being regarded as particles. The analysis is performed for both cases when the average plasma field energy is lower (Zakharov's hybrid model—ZHM) or greater (Silin's hybrid model—SHM) than the plasma thermal energy. The efficiency of energy transfer to ions and to ion perturbations under the development of the instability is considered for various values of electron-to-ion mass ratios. The energy of low-frequency oscillations (ion-sound waves) is found to be much lowermore » than the final ion kinetic energy. We also discuss the influence of the changes in the damping rate of the high-frequency (HF) field on the instability development. The decrease of the absorption of the HF field inhibits the HF field burnout within plasma density cavities and gives rise to the broadening of the HF spectrum. At the same time, the ion velocity distribution tends to the normal distribution in both ZHM and SHM.« less

Hereditary nonpolyposis colorectal cancer: Review of clinical, molecular genetics, and counseling aspects

DOE Office of Scientific and Technical Information (OSTI.GOV)

Bellacosa, A.; Genuardi, M.; Anti, M.

Lynch syndrome, or hereditary nonpolyposis colon cancer (HNPCC), is an autosomal dominant disease accounting for approximately 1-5% of all colorectal cancer cases. Due to the lack of pathognomonic morphological or biomolecular markers, HNPCC has traditionally posed unique problems to clinicians and geneticists alike, both in terms of diagnosis and clinical management. Recently, novel insight into the pathogenesis of this syndrome has been provided by the identification of its molecular basis. In HNPCC families, germline mutations in any of four genes encoding proteins of a specialized DNA repair system, the mismatch repair, predispose to cancer development. Mutations in mismatch repair genesmore » lead to an overall increase of the mutation rate and are associated with a phenotype of length instability of microsatellite loci. The present report summarizes the clinicopathological aspects of HNPCC and reviews the most recent molecular and biochemical findings. 115 refs., 2 figs., 3 tabs.« less

[Epidemiology, risk factors and molecular pathogenesis of primary liver cancer].

PubMed

Hagymási, Krisztina; Tulassay, Zsolt

2008-03-23

Primary liver cancer is the fifth most common cancer worldwide. Hepatocellular carcinoma accounts for 85-90% of primary liver cancers. Distribution of hepatocellular carcinoma shows variations among geographic regions and ethnic groups. Males have higher liver cancer rates than females. Hepatocellular carcinoma occurs within an established background of chronic liver disease and cirrhosis (70-90%). Major causes (80%) of hepatocellular carcinoma are hepatitis B, C virus infection, and aflatoxin exposition. Its development is a multistep process. We have a growing understanding on the molecular pathogenesis. Genetic and epigenetic changes activate oncogenes, inhibit tumorsuppressor genes, which result in autonomous cell proliferation. The chromosomal instability caused by telomere dysfunction, the growth-retrained environment and the alterations of the micro- and macroenvironment help the expansion of the malignant cells. Understanding the molecular mechanisms could improve the screening of patients with chronic liver disease, or cirrhosis, and the prevention as well as treatment of hepatocellular carcinoma.

Prediction of high frequency combustion instability in liquid propellant rocket engines

NASA Technical Reports Server (NTRS)

Kim, Y. M.; Chen, C. P.; Ziebarth, J. P.; Chen, Y. S.

1992-01-01

The present use of a numerical model developed for the prediction of high-frequency combustion stabilities in liquid propellant rocket engines focuses on (1) the overall behavior of nonlinear combustion instabilities (2) the effects of acoustic oscillations on the fuel-droplet vaporization and combustion process in stable and unstable engine operating conditions, oscillating flowfields, and liquid-fuel trajectories during combustion instability, and (3) the effects of such design parameters as inlet boundary conditions, initial spray conditions, and baffle length. The numerical model has yielded predictions of the tangential-mode combustion instability; baffle length and droplet size variations are noted to have significant effects on engine stability.

Studies of fluid instabilities in flows of lava and debris

NASA Technical Reports Server (NTRS)

Fink, Jonathan H.

1987-01-01

At least two instabilities have been identified and utilized in lava flow studies: surface folding and gravity instability. Both lead to the development of regularly spaced structures on the surfaces of lava flows. The geometry of surface folds have been used to estimate the rheology of lava flows on other planets. One investigation's analysis assumed that lava flows have a temperature-dependent Newtonian rheology, and that the lava's viscosity decreased exponentially inward from the upper surface. The author reviews studies by other investigators on the analysis of surface folding, the analysis of Taylor instability in lava flows, and the effect of surface folding on debris flows.

Modeling of two-phase flow instabilities during startup transients utilizing RAMONA-4B methodology

DOE Office of Scientific and Technical Information (OSTI.GOV)

Paniagua, J.; Rohatgi, U.S.; Prasad, V.

1996-10-01

RAMONA-4B code is currently under development for simulating thermal hydraulic instabilities that can occur in Boiling Water Reactors (BWRs) and the Simplified Boiling Water Reactor (SBWR). As one of the missions of RAMONA-4B is to simulate SBWR startup transients, where geysering or condensation-induced instability may be encountered, the code needs to be assessed for this application. This paper outlines the results of the assessments of the current version of RAMONA-4B and the modifications necessary for simulating the geysering or condensation-induced instability. The test selected for assessment are the geysering tests performed by Prof Aritomi (1993).

Residential Instability Among Low-Income Families: A Concept Analysis.

PubMed

Cotton, Brandi Parker; Schwartz-Barcott, Donna

2016-04-01

Residential instability is relatively common among low-income families and is associated with a host of negative outcomes, especially for children and adolescents. Psychiatric nurses, especially those in the advanced practice role, observe the consequences of residential instability within the clinical setting. Yet, to-date, the concept is somewhat vague and its essential meaning and definition remain unclear. The aim of this paper is to develop a definition of residential instability using Wilson's method of concept analysis. An overview of historical perspectives is included. The paper concludes with recommendations for future research and application within clinical practice. Copyright © 2015 Elsevier Inc. All rights reserved.

Numerical studies of edge localized instabilities in tokamaks

NASA Astrophysics Data System (ADS)

Wilson, H. R.; Snyder, P. B.; Huysmans, G. T. A.; Miller, R. L.

2002-04-01

A new computational tool, edge localized instabilities in tokamaks equilibria (ELITE), has been developed to help our understanding of short wavelength instabilities close to the edge of tokamak plasmas. Such instabilities may be responsible for the edge localized modes observed in high confinement H-mode regimes, which are a serious concern for next step tokamaks because of the high transient power loads which they can impose on divertor target plates. ELITE uses physical insight gained from analytic studies of peeling and ballooning modes to provide an efficient way of calculating the edge ideal magnetohydrodynamic stability properties of tokamaks. This paper describes the theoretical formalism which forms the basis for the code.

Feedback control of plasma instabilities with charged particle beams and study of plasma turbulence

NASA Technical Reports Server (NTRS)

Tham, Philip Kin-Wah

1994-01-01

A new non-perturbing technique for feedback control of plasma instabilities has been developed in the Columbia Linear Machine (CLM). The feedback control scheme involves the injection of a feedback modulated ion beam as a remote suppressor. The ion beam was obtained from a compact ion beam source which was developed for this purpose. A Langmuir probe was used as the feedback sensor. The feedback controller consisted of a phase-shifter and amplifiers. This technique was demonstrated by stabilizing various plasma instabilities to the background noise level, like the trapped particle instability, the ExB instability and the ion-temperature-gradient (ITG) driven instability. An important feature of this scheme is that the injected ion beam is non-perturbing to the plasma equilibrium parameters. The robustness of this feedback stabilization scheme was also investigated. The principal result is that the scheme is fairly robust, tolerating about 100% variation about the nominal parameter values. Next, this scheme is extended to the unsolved general problem of controlling multimode plasma instabilities simultaneously with a single sensor-suppressor pair. A single sensor-suppressor pair of feedback probes is desirable to reduce the perturbation caused by the probes. Two plasma instabilities the ExB and the ITG modes, were simultaneously stabilized. A simple 'state' feedback type method was used where more state information was generated from the single sensor Langmuir probe by appropriate signal processing, in this case, by differentiation. This proof-of-principle experiment demonstrated for the first time that by designing a more sophisticated electronic feedback controller, many plasma instabilities may be simultaneously controlled. Simple theoretical models showed generally good agreement with the feedback experimental results. On a parallel research front, a better understanding of the saturated state of a plasma instability was sought partly with the help of feedback. A plasma instability is usually observed in its saturated state and appears as a single feature in the frequency spectrum with a single azimuthal and parallel wavenumbers. The physics of the non-zero spectral width was investigated in detail because the finite spectral width can cause "turbulent" transport. One aspect of the "turbulence" was investigated by obtaining the scaling of the linear growth rate of the instabilities with the fluctuation levels. The linear growth rates were measured with the established gated feedback technique. The research showed that the ExB instability evolves into a quasi-coherent state when the fluctuation level is high. The coherent aspects were studied with a bispectral analysis. Moreover, the single spectral feature was discovered to be actually composed of a few radial harmonics. The radial harmonics play a role in the nonlinear saturation of the instability via three-wave coupling.

Cultural diversity, economic development and societal instability.

PubMed

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.

Cultural diversity, economic development and societal instability

USGS Publications Warehouse

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

2007-01-01

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

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

PubMed

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 mutation accumulation to address mechanisms underlying genome instability during replicative aging.

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

PubMed

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

Data on the genotoxic and mutagenic effects of occupational exposure to the most frequently used volatile anesthetics are limited and controversial. The current study is the first to evaluate genomic instability, cell death and proliferative index in exfoliated buccal cells (EBC) from anesthesiologists. We also evaluated DNA damage and determined the concentrations of the anesthetic gases most commonly used in operating rooms. This study was conducted on physicians who were allocated into two groups: the exposed group, which consisted of anesthesiologists who had been exposed to waste anesthetic gases (isoflurane, sevoflurane, desflurane and nitrous oxide - N 2 O) for at least two years; and the control group, which consisted of non-exposed physicians matched for age, sex and lifestyle with the exposed group. Venous blood and EBC samples were collected from all participants. Basal DNA damage was evaluated in lymphocytes by the comet assay, whereas the buccal micronucleus (MN) cytome (BMCyt) assay was applied to evaluate genotoxic and cytotoxic effects. The concentrations of N 2 O and anesthetics were measured via a portable infrared spectrophotometer. The average concentration of waste gases was greater than 5 parts per million (ppm) for all of the halogenated anesthetics and was more than 170ppm for N 2 O, expressed as a time-weighted average. There was no significant difference between the groups in relation to lymphocyte DNA damage. The exposed group had higher frequencies of MN, karyorrhexis and pyknosis, and a lower frequency of basal cells compared with the control group. In conclusion, exposure to modern waste anesthetic gases did not induce systemic DNA damage, but it did result in genomic instability, cytotoxicity and proliferative changes, which were detected in the EBC of anesthesiologists. Thus, these professionals can be considered at risk for developing genetic alterations resulting from occupational exposure to these gases, suggesting the need to minimize this exposure. Copyright © 2016 Elsevier B.V. All rights reserved.

The Case for Adopting the "Species Complex" Nomenclature for the Etiologic Agents of Cryptococcosis.

PubMed

Kwon-Chung, Kyung J; Bennett, John E; Wickes, Brian L; Meyer, Wieland; Cuomo, Christina A; Wollenburg, Kurt R; Bicanic, Tihana A; Castañeda, Elizabeth; Chang, Yun C; Chen, Jianghan; Cogliati, Massimo; Dromer, Françoise; Ellis, David; Filler, Scott G; Fisher, Matthew C; Harrison, Thomas S; Holland, Steven M; Kohno, Shigeru; Kronstad, James W; Lazera, Marcia; Levitz, Stuart M; Lionakis, Michail S; May, Robin C; Ngamskulrongroj, Popchai; Pappas, Peter G; Perfect, John R; Rickerts, Volker; Sorrell, Tania C; Walsh, Thomas J; Williamson, Peter R; Xu, Jianping; Zelazny, Adrian M; Casadevall, Arturo

2017-01-01

Cryptococcosis is a potentially lethal disease of humans/animals caused by Cryptococcus neoformans and Cryptococcus gattii . Distinction between the two species is based on phenotypic and genotypic characteristics. Recently, it was proposed that C. neoformans be divided into two species and C. gattii into five species based on a phylogenetic analysis of 115 isolates. While this proposal adds to the knowledge about the genetic diversity and population structure of cryptococcosis agents, the published genotypes of 2,606 strains have already revealed more genetic diversity than is encompassed by seven species. Naming every clade as a separate species at this juncture will lead to continuing nomenclatural instability. In the absence of biological differences between clades and no consensus about how DNA sequence alone can delineate a species, we recommend using " Cryptococcus neoformans species complex" and " C. gattii species complex" as a practical intermediate step, rather than creating more species. This strategy recognizes genetic diversity without creating confusion.

Defects in Mitochondrial DNA Replication and Human Disease

PubMed Central

Copeland, William C.

2011-01-01

Mitochondrial DNA (mtDNA) is replicated by the DNA polymerase γ in concert with accessory proteins such as the mitochondrial DNA helicase, single stranded DNA binding protein, topoisomerase, and initiating factors. Nucleotide precursors for mtDNA replication arise from the mitochondrial salvage pathway originating from transport of nucleosides, or alternatively from cytoplasmic reduction of ribonucleotides. Defects in mtDNA replication or nucleotide metabolism can cause mitochondrial genetic diseases due to mtDNA deletions, point mutations, or depletion which ultimately cause loss of oxidative phosphorylation. These genetic diseases include mtDNA depletion syndromes (MDS) such as Alpers or early infantile hepatocerebral syndromes, and mtDNA deletion disorders, such as progressive external ophthalmoplegia (PEO), ataxia-neuropathy, or mitochondrial neurogastrointestinal encephalomyopathy (MNGIE). This review focuses on our current knowledge of genetic defects of mtDNA replication (POLG, POLG2, C10orf2) and nucleotide metabolism (TYMP, TK2, DGOUK, and RRM2B) that cause instability of mtDNA and mitochondrial disease. PMID:22176657

Editorial overview: Molecular and genetic bases of disease: the double life of DNA.

PubMed

McMurray, Cynthia T; Vijg, Jan

2014-06-01

This issue of Current Opinions focuses on the dual role of DNA in life and death. In ancient Roman religion and myth, Janus is the god who looks both to the past and to the future. He guides the beginnings of life, its progression from one condition to another, and he foresees distant events. The analogy to DNA could not be stronger. Closely interacting with the environment, our basic genetics provides the origin of life, guides the quality of health with age, predicts disease, and ultimately foresees our end. A shared and deep interest with the origin of life has long prompted our desire to define aging, and, ultimately, to understand whether it can be reversed. In this special issue, the authors collectively review concepts of normative aging, DNA instability, DNA repair, the genetic contribution of age and diet to disease, and how the basic molecular transactions of DNA guide both the transitions to life as well as the transitions to death. Published by Elsevier Ltd.

The Genetic Basis of Natural Variation in Caenorhabditis elegans Telomere Length.

PubMed

Cook, Daniel E; Zdraljevic, Stefan; Tanny, Robyn E; Seo, Beomseok; Riccardi, David D; Noble, Luke M; Rockman, Matthew V; Alkema, Mark J; Braendle, Christian; Kammenga, Jan E; Wang, John; Kruglyak, Leonid; Félix, Marie-Anne; Lee, Junho; Andersen, Erik C

2016-09-01

Telomeres are involved in the maintenance of chromosomes and the prevention of genome instability. Despite this central importance, significant variation in telomere length has been observed in a variety of organisms. The genetic determinants of telomere-length variation and their effects on organismal fitness are largely unexplored. Here, we describe natural variation in telomere length across the Caenorhabditis elegans species. We identify a large-effect variant that contributes to differences in telomere length. The variant alters the conserved oligonucleotide/oligosaccharide-binding fold of protection of telomeres 2 (POT-2), a homolog of a human telomere-capping shelterin complex subunit. Mutations within this domain likely reduce the ability of POT-2 to bind telomeric DNA, thereby increasing telomere length. We find that telomere-length variation does not correlate with offspring production or longevity in C. elegans wild isolates, suggesting that naturally long telomeres play a limited role in modifying fitness phenotypes in C. elegans. Copyright © 2016 by the Genetics Society of America.

A rare human syndrome provides genetic evidence that WNT signaling is required for reprogramming of fibroblasts to induced pluripotent stem cells

PubMed Central

Ross, Jason; Busch, Julia; Mintz, Ellen; Ng, Damian; Stanley, Alexandra; Brafman, David; Sutton, V. Reid; Van den Veyver, Ignatia; Willert, Karl

2015-01-01

SUMMARY WNT signaling promotes the reprogramming of somatic cells to an induced pluripotent state. We provide genetic evidence that WNT signaling is a requisite step during the induction of pluripotency. Fibroblasts from individuals with Focal Dermal Hypoplasia (FDH), a rare genetic syndrome caused by mutations in the essential WNT processing enzyme PORCN, fail to reprogram using standard methods. This blockade in reprogramming is overcome by ectopic WNT signaling and by PORCN overexpression, thus demonstrating that WNT signaling is essential for reprogramming. The rescue of reprogramming is critically dependent on the level of WNT signaling: steady baseline activation of the WNT pathway yields karyotypically normal iPS cells, whereas daily stimulation with Wnt3a produces FDH-iPS cells with severely abnormal karyotypes. Therefore, although WNT signaling is required for cellular reprogramming, inappropriate activation of WNT signaling induces chromosomal instability, highlighting the precarious nature of ectopic WNT activation, and its tight relationship with oncogenic transformation. PMID:25464842

Psychodynamic therapy from the perspective of self-organization. a concept of change and a methodological approach for empirical examination.

PubMed

Gumz, Antje; Geyer, Michael; Brähler, Elmar

2014-01-01

Observations from therapeutic practice and a series of empirical findings, for example, those on discontinuous change in psychotherapeutic processes, suggest modelling the therapeutic process as a self-organizing system with stable and critical instable phases and abrupt transitions. Here, a concept of psychotherapeutic change is presented that applies self-organization theory to psychodynamic principles. The authors explain the observations and considerations that form the basis of the concept and present some connections with existing findings and concepts. On the basis of this model, they generated two hypotheses regarding the co-occurrence of instability and discontinuous change and the degree of synchrony between the therapist and patient. A study design to test these hypotheses was developed and applied to a single case (psychodynamic therapy). After each session, patient and therapist rated their interaction. A measure of instability was calculated across the resulting time series. Sequences of destabilization were observed. On the basis of points of extreme instability, the process was divided into phases. Local instability maxima were accompanied by significant discontinuous change. Destabilization was highly synchronous in therapist and patient ratings. The authors discussed the concept and the methodological procedure. The approach enables the operationalization of crises and to empirically assess the significance of critical phases and developments within the therapeutic relationship. We present a concept of change that applies self-organization theory to psychodynamic therapy. We empirically tested the hypotheses formulated in the concept based on an extract of 125 long-term psychodynamic therapy sessions. We continuously monitored the therapeutic interaction and calculated a measure of the instability of the assessments. We identified several sequences of stable and unstable episodes. Episodes of high instability were accompanied by discontinuous change. On the basis of these episodes of high instability, we divided the process into four phases. Mean values of variables differed across these phases. Destabilization proved to be highly synchronous in therapist and patient ratings. The approach allows to empirically assess critical phases and developments within the therapeutic relationship. Copyright © 2013 John Wiley & Sons, Ltd.

Aequorin fusion proteins as bioluminescent tracers for competitive immunoassays

NASA Astrophysics Data System (ADS)

Mirasoli, Mara; Michelini, Elisa; Deo, Sapna K.; Dikici, Emre; Roda, Aldo; Daunert, Sylvia

2004-06-01

The use of bio- and chemiluminescence for the development of quantitative binding assays offers undoubted advantages over other detection systems, such as spectrophotometry, fluorescence, or radioactivity. Indeed, bio- and chemiluminescence detection provides similar, or even better, sensitivity and detectability than radioisotopes, while avoiding the problems of health hazards, waste disposal, and instability associated with the use of radioisotopes. Among bioluminescent labels, the calcium-activated photoprotein aequorin, originally isolated from Aequorea victoria and today available as a recombinant product, is characterized by very high detectability, down to attomole levels. It has been used as a bioluminescent label for developing a variety of highly sensitive immunoassays, using various analyte-aequorin conjugation strategies. When the analyte is a protein or a peptide, genetic engineering techniques can be used to produce protein fusions where the analyte is in-frame fused with aequorin, thus producing homogeneous one-to-one conjugation products, available in virtually unlimited amount. Various assays were developed using this strategy: a short review of the most interesting applications is presented, as well as the cloning, purification and initial characterization of an endothelin-1-aequorin conjugate suitable for developing a competitive immunoassay for endothelin-1, a potent vasoconstrictor peptide, involved in hypertension.

Functional Analysis of Interactions Between 53BP1, BRCA1 and p53

DTIC Science & Technology

2004-07-01

deficiency synergize in tumorigenesis. Furthermore, the loss of a single 53BP1 allele enhances the susceptibility to cancer in the absence of p53. 14...specific antibodies against these sites and showed that at least two of them (S25 and S29) are phosphorylated in vivo by ATM, the kinase mutated in cancer ...characterized by chromosomal aberrations, genetic instability and cancer predisposition. +HU 153BP1 Fig. 5: Lack of 53BP1 prevents the efficient accumulation

Genetic Instability of Breast Cancer Cells Induced by Aberrant Expression of hMpS1

DTIC Science & Technology

2004-09-01

and function of the mitotic spindle is dependent on the MpS1 protein kinase. The components of mitotic spindle checkpoints were first identified in...yeast and their homologs of higher organisms were then identified and characterized. These include Bubl, Bub2, Bub3, Madl, Mad2, Mad3 and MpS1 . MpS 1...spindle checkpoint and centrosome duplication (1-6). Although several recent reports demonstrated that vertebrate MpS1 proteins regulate the spindle

Study of Pure Proteins, Nucleic Acids and Their Complexes from Halobacteria of the Dead Sea: RNA Polymerase-DNA Interaction.

DTIC Science & Technology

1987-09-21

objectives of our program are to isolate and characterize a fully active DNA dependent RNA polymerase from the extremely halophilic archaebacteria of the genus...operons in II. Marismortui. The halobacteriaceae are extreme halophiles . They require 3.5 M NaCI for optimal growth an(l no growth is observed below 2...was difficutlt to perform due to the extreme genetic instability in this strain (6). In contrast, the genoine of the extreme halophilic and prototrophic

Detection of occult high graded microsatellite instabilities in MMR gene mutation negative HNPCC tumors by addition of complementary marker analysis.

PubMed

Schiemann, U; Müller-Koch, Y; Gross, M; Glas, J; Baretton, G; Muders, M; Mussack, T; Holinski-Feder, E

2005-01-28

Hereditary non-polyposis colorectal cancer (HNPCC) is an autosomal dominant tumor syndrome predisposing to predominantly colorectal and endometrial cancer. In 90% of the cases, molecular analyses reveal microsatellite instabilities due to germline mutations in DNA mismatch repair (MMR) genes, mainly MLH1, MSH2, among these tumors. Tumors from 40 HNPCC index patients (31 Amsterdam positive, 9 Bethesda positive; 21 females, 19 males; mean age 48.0 +/- 13.2 years) were examined. In contrast to the classical constellation, their tumors revealed only a microsatellite stable (MSS, n=31)--or low instable (MSI-L, n=9)--tumor phenotype following the international reference panel of 5 microsatellites. No MLH1 and MSH2 mutations were detectable. Complementary microsatellites (BAT40, D10S197, D13S153, D18S58, MYCL1) were investigated by PCR and fragment analysis to find other instabilities which might hint to the MIN-pathway of the tumors. Due to ten microsatellites in total tumors were now reclassified in 4 MSI-H (10%), 24 MSI-L (60%) and 12 in MSS (30%) phenotypes. The mean age of onset for CRCs was the lowest in the MSI-H group with 45.7 +/- 9.6 years (vs. 48.7 +/- 14.3 and 49.0 +/- 12.9 years in MSI-L and MSS group). MSI-H-and MSI-L tumors were often localized in the proximal colon (50 and 52%), whereas MSS tumors were preferentially localized in the distal colon (77%). - Complementary microsatellites help to subdive "non-classical" HNPCC in subgroups with different clinical appearance. It allows to detect occult MSI-H tumors with up to 10% and to confirm MSS tumors who seem to have a similar biological behaviour like sporadic CRC. Maybe that this genetic reclassification influence the decision of whether to offer patients chemotherapy or not, since it is known that patients with instable tumors do not benefit from chemotherapy as well as patients with microsatellite stable tumors.

Energetic particle instabilities in fusion plasmas

NASA Astrophysics Data System (ADS)

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.

Cosmological Signature of the Standard Model Higgs Vacuum Instability: Primordial Black Holes as Dark Matter

NASA Astrophysics Data System (ADS)

Espinosa, J. R.; Racco, D.; Riotto, A.

2018-03-01

For the current central values of the Higgs boson and top quark masses, the standard model Higgs potential develops an instability at a scale of the order of 1 011 GeV . We show that a cosmological signature of such instability could be dark matter in the form of primordial black holes seeded by Higgs fluctuations during inflation. The existence of dark matter might not require physics beyond the standard model.

Are pulsars spun up or down by SASI spiral modes?

NASA Astrophysics Data System (ADS)

Kazeroni, Rémi; Guilet, Jérôme; Foglizzo, Thierry

2017-10-01

Pulsars may either be spun up or down by hydrodynamic instabilities during the supernova explosion of massive stars. Besides rapidly rotating cases related to bipolar explosions, stellar rotation may affect the explosion of massive stars in the more common situations where the centrifugal force is minor. Using 2D simulations of a simplified set-up in cylindrical geometry, we examine the impact of rotation on the standing accretion shock instability (SASI) and the corotation instability, also known as low-T/|W|. The influence of rotation on the saturation amplitude of these instabilities depends on the specific angular momentum in the accretion flow and the ratio of the shock to the neutron star radii. The spiral mode of SASI becomes more vigorous with faster rotation only if this ratio is large enough. A corotation instability develops at large rotation rates and impacts the dynamics more dramatically, leading to a strong one-armed spiral wave. Non-axisymmetric instabilities are able to redistribute angular momentum radially and affect the pulsar spin at birth. A systematic study of the relationship between the core rotation period of the progenitor and the initial pulsar spin is performed. Stellar rotation rates for which pulsars are spun up or down by SASI are estimated. Rapidly spinning progenitors are modestly spun down by spiral modes, less than ˜30 per cent, when a corotation instability develops. Given the observational constraints on pulsar spin periods at birth, this suggests that rapid rotation might not play a significant hydrodynamic role in most core-collapse supernovae.

Greenscreen Teaching: Institutional Instability and Classroom Innovation

ERIC Educational Resources Information Center

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…

Observation of single-mode, Kelvin-Helmholtz instability in a supersonic flow

DOE PAGES

Wan, W. C.; Malamud, Guy; Shimony, A.; ...

2015-10-01

This manuscript reports the first observations of the Kelvin-Helmholtz instability evolving from well-characterized seed perturbations in a steady, supersonic flow. The Kelvin-Helmholtz instability occurs when two fluids move parallel to one another at different velocities, and contributes to an intermixing of fluids and transition to turbulence. It is ubiquitous in nature and engineering, including terrestrial systems such as cloud formations, astrophysical systems such as supernovae, and laboratory systems such as fusion experiments. In a supersonic flow, the growth rate of the instability is inhibited due to effects of compressibility. These effects are still not fully understood, and hold the motivationmore » for the current work. The data presented here were obtained by developing a novel experimental platform capable of sustaining a steady shockwave over a precision-machined interface for unprecedented durations. The chosen interface was a well-characterized, single-mode sine wave, allowing us to document the evolution of individual vortices at high resolution. Understanding the behavior of individual vortices is the first of two fundamental steps towards developing a comprehensive model for the Kelvin-Helmholtz instability in a compressible flow. The results of this experiment were well reproduced with 2D hydrodynamic simulations. The platform has been extended to additional experiments, which study the evolution of different hydrodynamic instabilities in steady, supersonic flows.« less

Observation of single-mode, Kelvin-Helmholtz instability in a supersonic flow

DOE Office of Scientific and Technical Information (OSTI.GOV)

Wan, W. C.; Malamud, Guy; Shimony, A.

This manuscript reports the first observations of the Kelvin-Helmholtz instability evolving from well-characterized seed perturbations in a steady, supersonic flow. The Kelvin-Helmholtz instability occurs when two fluids move parallel to one another at different velocities, and contributes to an intermixing of fluids and transition to turbulence. It is ubiquitous in nature and engineering, including terrestrial systems such as cloud formations, astrophysical systems such as supernovae, and laboratory systems such as fusion experiments. In a supersonic flow, the growth rate of the instability is inhibited due to effects of compressibility. These effects are still not fully understood, and hold the motivationmore » for the current work. The data presented here were obtained by developing a novel experimental platform capable of sustaining a steady shockwave over a precision-machined interface for unprecedented durations. The chosen interface was a well-characterized, single-mode sine wave, allowing us to document the evolution of individual vortices at high resolution. Understanding the behavior of individual vortices is the first of two fundamental steps towards developing a comprehensive model for the Kelvin-Helmholtz instability in a compressible flow. The results of this experiment were well reproduced with 2D hydrodynamic simulations. The platform has been extended to additional experiments, which study the evolution of different hydrodynamic instabilities in steady, supersonic flows.« less

Association between hMLH1 hypermethylation and JC virus (JCV) infection in human colorectal cancer (CRC).

PubMed

Vilkin, Alex; Niv, Yaron

2011-04-01

Incorporation of viral DNA may interfere with the normal sequence of human DNA bases on the genetic level or cause secondary epigenetic changes such as gene promoter methylation or histone acetylation. Colorectal cancer (CRC) is the second leading cause of cancer mortality in the USA. Chromosomal instability (CIN) was established as the key mechanism in cancer development. Later, it was found that CRC results not only from the progressive accumulation of genetic alterations but also from epigenetic changes. JC virus (JCV) is a candidate etiologic factor in sporadic CRC. It may act by stabilizing β-catenin, facilitating its entrance to the cell nucleus, initialing proliferation and cancer development. Diploid CRC cell lines transfected with JCV-containing plasmids developed CIN. This result provides direct experimental evidence for the ability of JCV T-Ag to induce CIN in the genome of colonic epithelial cells. The association of CRC hMLH1 methylation and tumor positivity for JCV was recently documented. JC virus T-Ag DNA sequences were found in 77% of CRCs and are associated with promoter methylation of multiple genes. hMLH1 was methylated in 25 out of 80 CRC patients positive for T-Ag (31%) in comparison with only one out of 11 T-Ag negative cases (9%). Thus, JCV can mediate both CIN and aberrant methylation in CRC. Like other viruses, chronic infection with JCV may induce CRC by different mechanisms which should be further investigated. Thus, gene promoter methylation induced by JCV may be an important process in CRC and the polyp-carcinoma sequence.

Paclitaxel stimulates chromosomal fusion and instability in cells with dysfunctional telomeres: Implication in multinucleation and chemosensitization

DOE Office of Scientific and Technical Information (OSTI.GOV)

Park, Jeong-Eun; Woo, Seon Rang; Department of Biochemistry, College of Medicine, Korea University, Seoul 136-705

Research highlights: {yields} Paclitaxel serves as a stimulator of chromosomal fusion in cells in which telomeres are dysfunctional. {yields} Typical fusions involve p-arms, but paclitaxel-induced fusions occur between both q- and p-arms. {yields} Paclitaxel-stimulated fusions in cells in which telomeres are dysfunctional evoke prolonged G2/M cell cycle arrest and delay multinucleation. {yields} Upon telomere erosion, paclitaxel promotes chromosomal instability and subsequent apoptosis. {yields} Chromosomal fusion enhances paclitaxel chemosensitivity under telomere dysfunction. -- Abstract: The anticancer effect of paclitaxel is attributable principally to irreversible promotion of microtubule stabilization and is hampered upon development of chemoresistance by tumor cells. Telomere shortening, andmore » eventual telomere erosion, evoke chromosomal instability, resulting in particular cellular responses. Using telomerase-deficient cells derived from mTREC-/-p53-/- mice, here we show that, upon telomere erosion, paclitaxel propagates chromosomal instability by stimulating chromosomal end-to-end fusions and delaying the development of multinucleation. The end-to-end fusions involve both the p- and q-arms in cells in which telomeres are dysfunctional. Paclitaxel-induced chromosomal fusions were accompanied by prolonged G2/M cell cycle arrest, delayed multinucleation, and apoptosis. Telomere dysfunctional cells with mutlinucleation eventually underwent apoptosis. Thus, as telomere erosion proceeds, paclitaxel stimulates chromosomal fusion and instability, and both apoptosis and chemosensitization eventually develop.« less

Finite-temperature mechanical instability in disordered lattices.

PubMed

Zhang, Leyou; Mao, Xiaoming

2016-02-01

Mechanical instability takes different forms in various ordered and disordered systems and little is known about how thermal fluctuations affect different classes of mechanical instabilities. We develop an analytic theory involving renormalization of rigidity and coherent potential approximation that can be used to understand finite-temperature mechanical stabilities in various disordered systems. We use this theory to study two disordered lattices: a randomly diluted triangular lattice and a randomly braced square lattice. These two lattices belong to two different universality classes as they approach mechanical instability at T=0. We show that thermal fluctuations stabilize both lattices. In particular, the triangular lattice displays a critical regime in which the shear modulus scales as G∼T(1/2), whereas the square lattice shows G∼T(2/3). We discuss generic scaling laws for finite-T mechanical instabilities and relate them to experimental systems.

Kelvin-Helmholtz instability of the Dirac fluid of charge carriers on graphene

NASA Astrophysics Data System (ADS)

Coelho, Rodrigo C. V.; Mendoza, Miller; Doria, Mauro M.; Herrmann, Hans J.

2017-11-01

We provide numerical evidence that a Kelvin-Helmholtz instability occurs in the Dirac fluid of electrons in graphene and can be detected in current experiments. This instability appears for electrons in the viscous regime passing though a micrometer-scale obstacle and affects measurements on the time scale of nanoseconds. A possible realization with a needle-shaped obstacle is proposed to produce and detect this instability by measuring the electric potential difference between contact points located before and after the obstacle. We also show that, for our setup, the Kelvin-Helmholtz instability leads to the formation of whirlpools similar to the ones reported in Bandurin et al. [Science 351, 1055 (2016), 10.1126/science.aad0201]. To perform the simulations, we develop a lattice Boltzmann method able to recover the full dissipation in a fluid of massless particles.

DOE Office of Scientific and Technical Information (OSTI.GOV)

Awe, T. J., E-mail: tjawe@sandia.gov; Jennings, C. A.; McBride, R. D.

Recent experiments at the Sandia National Laboratories Z Facility have, for the first time, studied the implosion dynamics of magnetized liner inertial fusion (MagLIF) style liners that were pre-imposed with a uniform axial magnetic field. As reported [T. J. Awe et al., Phys. Rev. Lett. 111, 235005 (2013)] when premagnetized with a 7 or 10 T axial field, these liners developed 3D-helix-like hydrodynamic instabilities; such instabilities starkly contrast with the azimuthally correlated magneto-Rayleigh-Taylor (MRT) instabilities that have been consistently observed in many earlier non-premagnetized experiments. The helical structure persisted throughout the implosion, even though the azimuthal drive field greatly exceeded themore » expected axial field at the liner's outer wall for all but the earliest stages of the experiment. Whether this modified instability structure has practical importance for magneto-inertial fusion concepts depends primarily on whether the modified instability structure is more stable than standard azimuthally correlated MRT instabilities. In this manuscript, we discuss the evolution of the helix-like instability observed on premagnetized liners. While a first principles explanation of this observation remains elusive, recent 3D simulations suggest that if a small amplitude helical perturbation can be seeded on the liner's outer surface, no further influence from the axial field is required for the instability to grow.« less

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

PubMed Central

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.

2015-01-01

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. PMID:25869442

In vivo and in vitro studies support that a new splicing isoform of OLR1 gene is protective against acute myocardial infarction.

PubMed

Mango, Ruggiero; Biocca, Silvia; del Vecchio, Francesca; Clementi, Fabrizio; Sangiuolo, Federica; Amati, Francesca; Filareto, Antonio; Grelli, Sandro; Spitalieri, Paola; Filesi, Ilaria; Favalli, Cartesio; Lauro, Renato; Mehta, Jawahar L; Romeo, Francesco; Novelli, Giuseppe

2005-07-22

Lectin-like oxidized low-density lipoprotein receptor-1 (LOX-1), encoded by the OLR1 gene, is a scavenger receptor that plays a fundamental role in the pathogenesis of atherosclerosis. LOX-1 activation is associated with apoptosis of endothelial cells, smooth muscle cells (SMCs), and macrophages. This process is an important underlying mechanism that contributes to plaque instability and subsequent development of acute coronary syndromes. Independent association genetic studies have implicated OLR1 gene variants in myocardial infarction (MI) susceptibility. Because single nucleotide polymorphisms (SNPs) linked to MI are located in intronic sequences of the gene, it remains unclear as to how they determine their biological effects. Using quantitative real-time PCR and minigene approach, we show that intronic SNPs, linked to MI, regulate the expression of a new functional splicing isoform of the OLR1 gene, LOXIN, which lacks exon 5. Macrophages from subjects carrying the "non-risk" disease haplotype at OLR1 gene have an increased expression of LOXIN at mRNA and protein level, which results in a significant reduction of apoptosis in response to oxLDL. Expression of LOXIN in different cell types results in loss of surface staining, indicating that truncation of the C-terminal portion of the protein has a profound effect on its cellular trafficking. Furthermore, the proapoptotic effect of LOX-1 receptor in cell culture is specifically rescued by the coexpression of LOXIN in a dose-dependent manner. The demonstration that increasing levels of LOXIN protect cells from LOX-1 induced apoptosis sets a groundwork for developing therapeutic approaches for prevention of plaque instability.

The clinical and molecular genetic features of idiopathic infantile periodic alternating nystagmus

PubMed Central

Thomas, Mervyn G.; Crosier, Moira; Lindsay, Susan; Kumar, Anil; Thomas, Shery; Araki, Masasuke; Talbot, Chris J.; McLean, Rebecca J.; Surendran, Mylvaganam; Taylor, Katie; Leroy, Bart P.; Moore, Anthony T.; Hunter, David G.; Hertle, Richard W.; Tarpey, Patrick; Langmann, Andrea; Lindner, Susanne; Brandner, Martina

2011-01-01

Periodic alternating nystagmus consists of involuntary oscillations of the eyes with cyclical changes of nystagmus direction. It can occur during infancy (e.g. idiopathic infantile periodic alternating nystagmus) or later in life. Acquired forms are often associated with cerebellar dysfunction arising due to instability of the optokinetic-vestibular systems. Idiopathic infantile periodic alternating nystagmus can be familial or occur in isolation; however, very little is known about the clinical characteristics, genetic aetiology and neural substrates involved. Five loci (NYS1-5) have been identified for idiopathic infantile nystagmus; three are autosomal (NYS2, NYS3 and NYS4) and two are X-chromosomal (NYS1 and NYS5). We previously identified the FRMD7 gene on chromosome Xq26 (NYS1 locus); mutations of FRMD7 are causative of idiopathic infantile nystagmus influencing neuronal outgrowth and development. It is unclear whether the periodic alternating nystagmus phenotype is linked to NYS1, NYS5 (Xp11.4-p11.3) or a separate locus. From a cohort of 31 X-linked families and 14 singletons (70 patients) with idiopathic infantile nystagmus we identified 10 families and one singleton (21 patients) with periodic alternating nystagmus of which we describe clinical phenotype, genetic aetiology and neural substrates involved. Periodic alternating nystagmus was not detected clinically but only on eye movement recordings. The cycle duration varied from 90 to 280 s. Optokinetic reflex was not detectable horizontally. Mutations of the FRMD7 gene were found in all 10 families and the singleton (including three novel mutations). Periodic alternating nystagmus was predominantly associated with missense mutations within the FERM domain. There was significant sibship clustering of the phenotype although in some families not all affected members had periodic alternating nystagmus. In situ hybridization studies during mid-late human embryonic stages in normal tissue showed restricted FRMD7 expression in neuronal tissue with strong hybridization signals within the afferent arms of the vestibulo-ocular reflex consisting of the otic vesicle, cranial nerve VIII and vestibular ganglia. Similarly within the afferent arm of the optokinetic reflex we showed expression in the developing neural retina and ventricular zone of the optic stalk. Strong FRMD7 expression was seen in rhombomeres 1 to 4, which give rise to the cerebellum and the common integrator site for both these reflexes (vestibular nuclei). Based on the expression and phenotypic data, we hypothesize that periodic alternating nystagmus arises from instability of the optokinetic-vestibular systems. This study shows for the first time that mutations in FRMD7 can cause idiopathic infantile periodic alternating nystagmus and may affect neuronal circuits that have been implicated in acquired forms. PMID:21303855

Spontaneous Symmetry Breaking in Supernova Neutrinos

NASA Astrophysics Data System (ADS)

Raffelt, Georg G.

2015-08-01

Some recent developments in supernova neutrino physics are introduced where spontaneous symmetry breaking is a common theme. The physics of self-induced flavor conversion has acquired a new complication in that a new class of instabilities breaks axial symmetry of a neutrino stream, the multi-azimuth angle (MAA) instability. A completely different new phenomenon, discovered in the first realistic three-dimensional (3D) simulations, is the Lepton-Emission Self-sustained Asymmetry (LESA) during the accretion phase. Here, a neutrino-hydrodynamical instability breaks global spherical symmetry in that the lepton-number flux (νe minus ν‾e) develops a stable dipole pattern such that the lepton flux is almost exclusively emitted in one hemisphere.

Mutation scanning in a single and a stacked genetically modified (GM) event by real-time PCR and high resolution melting (HRM) analysis.

PubMed

Ben Ali, Sina-Elisabeth; Madi, Zita Erika; Hochegger, Rupert; Quist, David; Prewein, Bernhard; Haslberger, Alexander G; Brandes, Christian

2014-10-31

Genetic mutations must be avoided during the production and use of seeds. In the European Union (EU), Directive 2001/18/EC requires any DNA construct introduced via transformation to be stable. Establishing genetic stability is critical for the approval of genetically modified organisms (GMOs). In this study, genetic stability of two GMOs was examined using high resolution melting (HRM) analysis and real-time polymerase chain reaction (PCR) employing Scorpion primers for amplification. The genetic variability of the transgenic insert and that of the flanking regions in a single oilseed rape variety (GT73) and a stacked maize (MON88017×MON810) was studied. The GT73 and the 5' region of MON810 showed no instabilities in the examined regions. However; two out of 100 analyzed samples carried a heterozygous point mutation in the 3' region of MON810 in the stacked variety. These results were verified by direct sequencing of the amplified PCR products as well as by sequencing of cloned PCR fragments. The occurrence of the mutation suggests that the 5' region is more suitable than the 3' region for the quantification of MON810. The identification of the single nucleotide polymorphism (SNP) in a stacked event is in contrast to the results of earlier studies of the same MON810 region in a single event where no DNA polymorphism was found.

The evolutionary stability of cross-sex, cross-trait genetic covariances.

PubMed

Gosden, Thomas P; Chenoweth, Stephen F

2014-06-01

Although knowledge of the selective agents behind the evolution of sexual dimorphism has advanced considerably in recent years, we still lack a clear understanding of the evolutionary durability of cross-sex genetic covariances that often constrain its evolution. We tested the relative stability of cross-sex genetic covariances for a suite of homologous contact pheromones of the fruit fly Drosophila serrata, along a latitudinal gradient where these traits have diverged in mean. Using a Bayesian framework, which allowed us to account for uncertainty in all parameter estimates, we compared divergence in the total amount and orientation of genetic variance across populations, finding divergence in orientation but not total variance. We then statistically compared orientation divergence of within-sex (G) to cross-sex (B) covariance matrices. In line with a previous theoretical prediction, we find that the cross-sex covariance matrix, B, is more variable than either within-sex G matrix. Decomposition of B matrices into their symmetrical and nonsymmetrical components revealed that instability is linked to the degree of asymmetry. We also find that the degree of asymmetry correlates with latitude suggesting a role for spatially varying natural selection in shaping genetic constraints on the evolution of sexual dimorphism. © 2014 The Author(s). Evolution © 2014 The Society for the Study of Evolution.

Impact of 226C>T MSH2 gene mutation on cancer phenotypes in two HNPCC-associated highly-consanguineous families from Kuwait: emphasis on premarital genetic testing.

PubMed

Marafie, Makia J; Al-Awadi, Sadiqa; Al-Mosawi, Fatemah; Elshafey, Alaa; Al-Ali, Waleed; Al-Mulla, Fahd

2009-01-01

Lynch syndrome or hereditary nonpolyposis colorectal cancer (HNPCC) is one of the commonest cancer susceptibility syndromes. It is characterized by early onset colon cancer and a variety of extracolonic tumours. Germline mutations in the DNA mismatch repair genes (MLH1, MSH2, MSH6, PMS1, and PMS2) are responsible for this disorder. Identifying an affected individual depends on the tumour histopathology, family history that fulfils the Amsterdam and/or Bethesda criteria, tumour immunohistochemistry, microsatellite instability, and finally molecular analysis of an affected member. It is a laborious, time consuming and expensive procedure, which needs the effort of a multi-disciplinary team. However, once the diagnosis is established and germline defect is identified, other high risk pre-symptomatic carriers could be offered intensive surveillance and management as a preventive measure against cancer development. Here, we present two large highly consanguineous HNPCC-families from Kuwait in whom a founder MSH2 mutation was identified. The relationship between this mutation and cancer expressivity in two large consanguineous families harbouring other genetic defects is discussed. Moreover, we shed light on the challenges pertaining to diagnosis, screening, premarital counselling of couples and prenatal diagnosis of offspring with biallelic MSH2 gene mutation.

Biallelic inactivation of REV7 is associated with Fanconi anemia.

PubMed

Bluteau, Dominique; Masliah-Planchon, Julien; Clairmont, Connor; Rousseau, Alix; Ceccaldi, Raphael; Dubois d'Enghien, Catherine; Bluteau, Olivier; Cuccuini, Wendy; Gachet, Stéphanie; Peffault de Latour, Régis; Leblanc, Thierry; Socié, Gérard; Baruchel, André; Stoppa-Lyonnet, Dominique; D'Andrea, Alan D; Soulier, Jean

2016-09-01

Fanconi anemia (FA) is a recessive genetic disease characterized by congenital abnormalities, chromosome instability, progressive bone marrow failure (BMF), and a strong predisposition to cancer. Twenty FA genes have been identified, and the FANC proteins they encode cooperate in a common pathway that regulates DNA crosslink repair and replication fork stability. We identified a child with severe BMF who harbored biallelic inactivating mutations of the translesion DNA synthesis (TLS) gene REV7 (also known as MAD2L2), which encodes the mutant REV7 protein REV7-V85E. Patient-derived cells demonstrated an extended FA phenotype, which included increased chromosome breaks and G2/M accumulation upon exposure to DNA crosslinking agents, γH2AX and 53BP1 foci accumulation, and enhanced p53/p21 activation relative to cells derived from healthy patients. Expression of WT REV7 restored normal cellular and functional phenotypes in the patient's cells, and CRISPR/Cas9 inactivation of REV7 in a non-FA human cell line produced an FA phenotype. Finally, silencing Rev7 in primary hematopoietic cells impaired progenitor function, suggesting that the DNA repair defect underlies the development of BMF in FA. Taken together, our genetic and functional analyses identified REV7 as a previously undescribed FA gene, which we term FANCV.

Biallelic inactivation of REV7 is associated with Fanconi anemia

PubMed Central

Masliah-Planchon, Julien; Clairmont, Connor; Rousseau, Alix; Ceccaldi, Raphael; Dubois d’Enghien, Catherine; Bluteau, Olivier; Cuccuini, Wendy; Gachet, Stéphanie; Peffault de Latour, Régis; Leblanc, Thierry; Socié, Gérard; Baruchel, André; Stoppa-Lyonnet, Dominique; D’Andrea, Alan D.

2016-01-01

Fanconi anemia (FA) is a recessive genetic disease characterized by congenital abnormalities, chromosome instability, progressive bone marrow failure (BMF), and a strong predisposition to cancer. Twenty FA genes have been identified, and the FANC proteins they encode cooperate in a common pathway that regulates DNA crosslink repair and replication fork stability. We identified a child with severe BMF who harbored biallelic inactivating mutations of the translesion DNA synthesis (TLS) gene REV7 (also known as MAD2L2), which encodes the mutant REV7 protein REV7-V85E. Patient-derived cells demonstrated an extended FA phenotype, which included increased chromosome breaks and G2/M accumulation upon exposure to DNA crosslinking agents, γH2AX and 53BP1 foci accumulation, and enhanced p53/p21 activation relative to cells derived from healthy patients. Expression of WT REV7 restored normal cellular and functional phenotypes in the patient’s cells, and CRISPR/Cas9 inactivation of REV7 in a non-FA human cell line produced an FA phenotype. Finally, silencing Rev7 in primary hematopoietic cells impaired progenitor function, suggesting that the DNA repair defect underlies the development of BMF in FA. Taken together, our genetic and functional analyses identified REV7 as a previously undescribed FA gene, which we term FANCV. PMID:27500492

Physical biology of human brain development.

PubMed

Budday, Silvia; Steinmann, Paul; Kuhl, Ellen

2015-01-01

Neurodevelopment is a complex, dynamic process that involves a precisely orchestrated sequence of genetic, environmental, biochemical, and physical events. Developmental biology and genetics have shaped our understanding of the molecular and cellular mechanisms during neurodevelopment. Recent studies suggest that physical forces play a central role in translating these cellular mechanisms into the complex surface morphology of the human brain. However, the precise impact of neuronal differentiation, migration, and connection on the physical forces during cortical folding remains unknown. Here we review the cellular mechanisms of neurodevelopment with a view toward surface morphogenesis, pattern selection, and evolution of shape. We revisit cortical folding as the instability problem of constrained differential growth in a multi-layered system. To identify the contributing factors of differential growth, we map out the timeline of neurodevelopment in humans and highlight the cellular events associated with extreme radial and tangential expansion. We demonstrate how computational modeling of differential growth can bridge the scales-from phenomena on the cellular level toward form and function on the organ level-to make quantitative, personalized predictions. Physics-based models can quantify cortical stresses, identify critical folding conditions, rationalize pattern selection, and predict gyral wavelengths and gyrification indices. We illustrate that physical forces can explain cortical malformations as emergent properties of developmental disorders. Combining biology and physics holds promise to advance our understanding of human brain development and enable early diagnostics of cortical malformations with the ultimate goal to improve treatment of neurodevelopmental disorders including epilepsy, autism spectrum disorders, and schizophrenia.

Predictors of respiratory instability in neonates undergoing patient ductus arteriosus ligation after the introduction of targeted milrinone treatment.

PubMed

Ting, Joseph Y; Resende, Maura; More, Kiran; Nicholls, Donna; Weisz, Dany E; El-Khuffash, Afif; Jain, Amish; McNamara, Patrick J

2016-08-01

The postoperative course of preterm babies undergoing surgical closure of a patent ductus arteriosus (PDA) is often complicated by postligation cardiac syndrome (PLCS). Despite targeted milrinone prophylaxis, some infants continue to experience postoperative respiratory deterioration. Our objective is to describe the immediate postoperative course and identify risk factors for respiratory instability when preterm infants undergoing PDA ligation are managed with targeted milrinone treatment. A retrospective review of a cohort of infants undergoing PDA ligation between January, 2010 and August, 2013 was conducted. All infants had a targeted neonatal echocardiogram performed 1 hour after surgery. Infants received prophylactic milrinone treatment if the left ventricular output was <200 mL/kg/min. The primary outcome measure was the development of respiratory instability within 24 hours of surgery. Multivariable logistic regression was performed to identify predictors of respiratory instability. Eighty-six infants with a median gestational age of 25 weeks (interquartile range [IQR], 24-26) and a birth weight of 740 g (IQR, 640-853) were included in this study. Forty-nine (57.0%) received milrinone prophylaxis. There were 44 (51.2%) infants who developed oxygenation or ventilation failure, and 7 (8.1%) neonates developed PLCS. Infants with longer isovolumic relaxation time (IVRT ≥30 milliseconds) were more likely to develop either oxygenation or ventilation failure. Although the incidence of PLCS has declined after the introduction of targeted milrinone prophylaxis, many preterm infants continue to develop respiratory instability after surgical ligation. In this population, diastolic dysfunction manifested by prolonged IVRT could be associated with an adverse postoperative respiratory course. Copyright © 2016 The American Association for Thoracic Surgery. Published by Elsevier Inc. All rights reserved.

Handbook of structural stability part VI : strength of stiffened curved plates and shells

NASA Technical Reports Server (NTRS)

Becker, Herbert

1958-01-01

A comprehensive review of failure of stiffened curved plates and shells is presented. Panel instability in stiffened curved plates and general instability of stiffened cylinders are discussed. The loadings considered for the plates are axial, shear, and the combination of the two. For the cylinders, bending, external pressure, torsion, transverse shear, and combinations of these loads are considered. When possible, test data and theory were correlated. General instability in stiffened cylinders was investigated. For bending and torsion loads, test data and theory were correlated. For external pressure several existing theories were compared. As a result of this investigation a unified theoretical approach to analysis of general instability in stiffened cylinders was developed. (author)

SHEET PLASMA DEVICE

DOEpatents

Henderson, O.A.

1962-07-17

An ion-electron plasma heating apparatus of the pinch tube class was developed wherein a plasma is formed by an intense arc discharge through a gas and is radially constricted by the magnetic field of the discharge. To avoid kink and interchange instabilities which can disrupt a conventional arc shortiy after it is formed, the apparatus is a pinch tube with a flat configuration for forming a sheet of plasma between two conductive plates disposed parallel and adjacent to the plasma sheet. Kink instabilities are suppressed by image currents induced in the conductive plates while the interchange instabilities are neutrally stable because of the flat plasma configuration wherein such instabilities may occur but do not dynamically increase in amplitude. (AEC)

Health coverage instability for mothers in working families.

PubMed

Anderson, Steven G; Eamon, Mary Keegan

2004-07-01

Using data from the National Longitudinal Survey of Youth, the authors examined the health insurance coverage stability of 1,667 women in working families over a three-year period (1995-1997). Findings revealed that coverage instability is common. Nearly one-half of low-income women experienced health coverage instability over the three-year study period, and low-income women with poor education, single marital status, low work hours, and frequent job changes were at even greater risk of coverage instability. The findings also imply that women affected by recent welfare reforms are likely to experience widespread health coverage problems. The implications for health care policy development, social work administration, and social work practice are discussed.

Beam instabilities in hadron synchrotrons

DOE PAGES

Metral, E.; T. Argyropoulos; Bartosik, H.; ...

2016-04-01

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. Furthermore, the aim of this paper is to review the main mechanisms, discussing in particular the recent developments of beam instability theories and simulations.

Cosmological Signature of the Standard Model Higgs Vacuum Instability: Primordial Black Holes as Dark Matter.

PubMed

Espinosa, J R; Racco, D; Riotto, A

2018-03-23

For the current central values of the Higgs boson and top quark masses, the standard model Higgs potential develops an instability at a scale of the order of 10^{11}  GeV. We show that a cosmological signature of such instability could be dark matter in the form of primordial black holes seeded by Higgs fluctuations during inflation. The existence of dark matter might not require physics beyond the standard model.

Classroom Demonstrations Of Atmosphere-ocean Dynamics: Baroclinic Instability

NASA Astrophysics Data System (ADS)

Aurnou, Jonathan; Nadiga, B. T.

2008-09-01

Here we will present simple hands-on experimental demonstrations that show how baroclinic instabilities develop in rotating fluid dynamical systems. Such instabilities are found in the Earth's oceans and atmosphere as well as in the atmospheres and oceans of planetary bodies throughout the solar system and beyond. Our inexpensive experimental apparatus consists of a vinyl-record player, a wide shallow pan, and a weighted, dyed block of ice. Most directly, these demonstrations can be used to explain winter-time atmospheric weather patterns observed in Earth's mid-latitudes.

Collective Effects in a Diffraction Limited Storage Ring

DOE Office of Scientific and Technical Information (OSTI.GOV)

Nagaoka, Ryutaro; Bane, Karl L.F.

Our paper gives an overview of collective effects that are likely to appear and possibly limit the performance in a diffraction-limited storage ring (DLSR) that stores a high-intensity ultra-low-emittance beam. Beam instabilities and other intensity-dependent effects that may significantly impact the machine performance are covered. The latter include beam-induced machine heating, Touschek scattering, intra-beam scattering, as well as incoherent tune shifts. The general trend that the efforts to achieve ultra-low emittance result in increasing the machine coupling impedance and the beam sensitivity to instability is reviewed. The nature of coupling impedance in a DLSR is described, followed by a seriesmore » of potentially dangerous beam instabilities driven by the former, such as resistive-wall, TMCI (transverse mode coupling instability), head-tail and microwave instabilities. Additionally, beam-ion and CSR (coherent synchrotron radiation) instabilities are also treated. Means to fight against collective effects such as lengthening of the bunch with passive harmonic cavities and bunch-by-bunch transverse feedback are introduced. Numerical codes developed and used to evaluate the machine coupling impedance, as well as to simulate beam instability using the former as inputs are described.« less

Simultaneous use of camera and probe diagnostics to unambiguously identify and study the dynamics of multiple underlying instabilities during the route to plasma turbulence.

PubMed

Thakur, S C; Brandt, C; Light, A; Cui, L; Gosselin, J J; Tynan, G R

2014-11-01

We use multiple-tip Langmuir probes and fast imaging to unambiguously identify and study the dynamics of underlying instabilities during the controlled route to fully-developed plasma turbulence in a linear magnetized helicon plasma device. Langmuir probes measure radial profiles of electron temperature, plasma density and potential; from which we compute linear growth rates of instabilities, cross-phase between density and potential fluctuations, Reynold's stress, particle flux, vorticity, time-delay estimated velocity, etc. Fast imaging complements the 1D probe measurements by providing temporally and spatially resolved 2D details of plasma structures associated with the instabilities. We find that three radially separated plasma instabilities exist simultaneously. Density gradient driven resistive drift waves propagating in the electron diamagnetic drift direction separate the plasma into an edge region dominated by strong, velocity shear driven Kelvin-Helmholtz instabilities and a central core region which shows coherent Rayleigh-Taylor modes propagating in the ion diamagnetic drift direction. The simultaneous, complementary use of both probes and camera was crucial to identify the instabilities and understand the details of the very rich plasma dynamics.

Collective Effects in a Diffraction Limited Storage Ring

DOE PAGES

Nagaoka, Ryutaro; Bane, Karl L.F.

2015-10-20

Our paper gives an overview of collective effects that are likely to appear and possibly limit the performance in a diffraction-limited storage ring (DLSR) that stores a high-intensity ultra-low-emittance beam. Beam instabilities and other intensity-dependent effects that may significantly impact the machine performance are covered. The latter include beam-induced machine heating, Touschek scattering, intra-beam scattering, as well as incoherent tune shifts. The general trend that the efforts to achieve ultra-low emittance result in increasing the machine coupling impedance and the beam sensitivity to instability is reviewed. The nature of coupling impedance in a DLSR is described, followed by a seriesmore » of potentially dangerous beam instabilities driven by the former, such as resistive-wall, TMCI (transverse mode coupling instability), head-tail and microwave instabilities. Additionally, beam-ion and CSR (coherent synchrotron radiation) instabilities are also treated. Means to fight against collective effects such as lengthening of the bunch with passive harmonic cavities and bunch-by-bunch transverse feedback are introduced. Numerical codes developed and used to evaluate the machine coupling impedance, as well as to simulate beam instability using the former as inputs are described.« less

EXO1 is critical for embryogenesis and the DNA damage response in mice with a hypomorphic Nbs1 allele.

PubMed

Rein, Katrin; Yanez, Diana A; Terré, Berta; Palenzuela, Lluís; Aivio, Suvi; Wei, Kaichun; Edelmann, Winfried; Stark, Jeremy M; Stracker, Travis H

2015-09-03

The maintenance of genome stability is critical for the suppression of diverse human pathologies that include developmental disorders, premature aging, infertility and predisposition to cancer. The DNA damage response (DDR) orchestrates the appropriate cellular responses following the detection of lesions to prevent genomic instability. The MRE11 complex is a sensor of DNA double strand breaks (DSBs) and plays key roles in multiple aspects of the DDR, including DNA end resection that is critical for signaling and DNA repair. The MRE11 complex has been shown to function both upstream and in concert with the 5'-3' exonuclease EXO1 in DNA resection, but it remains unclear to what extent EXO1 influences DSB responses independently of the MRE11 complex. Here we examine the genetic relationship of the MRE11 complex and EXO1 during mammalian development and in response to DNA damage. Deletion of Exo1 in mice expressing a hypomorphic allele of Nbs1 leads to severe developmental impairment, embryonic death and chromosomal instability. While EXO1 plays a minimal role in normal cells, its loss strongly influences DNA replication, DNA repair, checkpoint signaling and damage sensitivity in NBS1 hypomorphic cells. Collectively, our results establish a key role for EXO1 in modulating the severity of hypomorphic MRE11 complex mutations. © The Author(s) 2015. Published by Oxford University Press on behalf of Nucleic Acids Research.

Family Turbulence and Child Internalizing and Externalizing Behaviors: Moderation of Effects by Race.

PubMed

Womack, Sean R; Taraban, Lindsay; Shaw, Daniel S; Wilson, Melvin N; Dishion, Thomas J

2018-06-19

This study examined the impact of residential instability and family structure transitions on the development of internalizing and externalizing problems from age 2 through 10.5. Child's race was examined as a moderator. Caregiver reports of internalizing and externalizing behaviors were obtained on 665 children at ages 5 and 10.5. Early-childhood residential and family structure transitions predicted elevated internalizing and externalizing problems at ages 5 and 10.5, but only for Caucasian children. These findings suggest that residential and family structure instability during early childhood independently contribute to children's later emotional and behavioral development, but vary as a function of the child's race. Community organizations (e.g., Women, Infant, and Children) can connect turbulent families with resources to attenuate effects of residential and family structure instability. © 2018 Society for Research in Child Development.

The characterization of socio-political instability, development and sustainability with Fisher information

EPA Science Inventory

In an effort to evaluate socio-political instability, we studied the relationship between dynamic order, socio-political upheavals and sustainability in nation states. Estimating the degree of dynamic order inherent in the socio-political regime of various countries throughout th...

Cultural Diversity, Economic Development and Societal Instability

PubMed Central

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

2007-01-01

Background Social scientists have suggested that cultural diversity in a nation leads to societal instability. However, societal instability may be affected not only by within-nation or α diversity, but also diversity between a nation and its neighbours or β diversity. It is also necessary to distinguish different domains of diversity, namely linguistic, ethnic and religious, and to distinguish between the direct effects of diversity on societal instability, and effects that are mediated by economic conditions. Methodology/Principal Findings We assembled a large cross-national dataset with information on α and β 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 α 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 β diversity, the higher the linguistic diversity among nations in a region, the less stable the nation. But, religious β diversity has the opposite effect, reducing instability, particularly in the presence of high linguistic diversity. Conclusions Within-nation linguistic diversity is associated with reduced economic performance, which, in turn, increases societal instability. Nations which differ linguistically from their neighbors are also less stable. However, religious diversity between neighboring nations has the opposite effect, decreasing societal instability. PMID:17895970

The TP53 dependence of radiation-induced chromosome instability in human lymphoblastoid cells

NASA Technical Reports Server (NTRS)

Schwartz, Jeffrey L.; Jordan, Robert; Evans, Helen H.; Lenarczyk, Marek; Liber, Howard

2003-01-01

The dose and TP53 dependence for the induction of chromosome instability were examined in cells of three human lymphoblastoid cell lines derived from WIL2 cells: TK6, a TP53-normal cell line, NH32, a TP53-knockout created from TK6, and WTK1, a WIL2-derived cell line that spontaneously developed a TP53 mutation. Cells of each cell line were exposed to (137)Cs gamma rays, and then surviving clones were isolated and expanded in culture for approximately 35 generations before the frequency and characteristics of the instability were analyzed. The presence of dicentric chromosomes, formed by end-to-end fusions, served as a marker of chromosomal instability. Unexposed TK6 cells had low levels of chromosomal instability (0.002 +/- 0.001 dicentrics/cell). Exposure of TK6 cells to doses as low as 5 cGy gamma rays increased chromosome instability levels nearly 10-fold to 0.019 +/- 0.008 dicentrics/cell. There was no further increase in instability levels beyond 5 cGy. In contrast to TK6 cells, unexposed cultures of WTK1 and NH32 cells had much higher levels of chromosome instability of 0.034 +/- 0.007 and 0.041 +/- 0.009, respectively, but showed little if any effect of radiation on levels of chromosome instability. The results suggest that radiation exposure alters the normal TP53-dependent cell cycle checkpoint controls that recognize alterations in telomere structure and activate apoptosis.

Hydrodynamic Model of Spatio-Temporal Evolution of Two-Plasmon Decay

DOE Office of Scientific and Technical Information (OSTI.GOV)

Dimitrijevic, D. R.; Maluckov, A. A.

A hydrodynamic model of two-plasmon decay in a homogeneous plasma slab near the quarter-critical density is constructed in order to gain better insight into the spatio-temporal evolution of the daughter electron plasma waves in plasma in the course of the instability. The influence of laser and plasma parameters on the evolution of the amplitudes of the participating waves is discussed. The secondary coupling of two daughter electron plasma waves with an ion-acoustic wave is assumed to be the principal mechanism of saturation of the instability. The impact of the inherently nonresonant nature of this secondary coupling on the development ofmore » TPD is investigated and it is shown to significantly influence the electron plasma wave dynamics. Its inclusion leads to nonuniformity of the spatial profile of the instability and causes the burst-like pattern of the instability development, which should result in the burst-like hot-electron production in homogeneous plasma.« less

The prediction of nonlinear three dimensional combustion instability in liquid rockets with conventional nozzles

NASA Technical Reports Server (NTRS)

Powell, E. A.; Zinn, B. T.

1973-01-01

An analytical technique is developed to solve nonlinear three-dimensional, transverse and axial combustion instability problems associated with liquid-propellant rocket motors. The Method of Weighted Residuals is used to determine the nonlinear stability characteristics of a cylindrical combustor with uniform injection of propellants at one end and a conventional DeLaval nozzle at the other end. Crocco's pressure sensitive time-lag model is used to describe the unsteady combustion process. The developed model predicts the transient behavior and nonlinear wave shapes as well as limit-cycle amplitudes and frequencies typical of unstable motor operation. The limit-cycle amplitude increases with increasing sensitivity of the combustion process to pressure oscillations. For transverse instabilities, calculated pressure waveforms exhibit sharp peaks and shallow minima, and the frequency of oscillation is within a few percent of the pure acoustic mode frequency. For axial instabilities, the theory predicts a steep-fronted wave moving back and forth along the combustor.

Actomyosin drives cancer cell nuclear dysmorphia and threatens genome stability.

PubMed

Takaki, Tohru; Montagner, Marco; Serres, Murielle P; Le Berre, Maël; Russell, Matt; Collinson, Lucy; Szuhai, Karoly; Howell, Michael; Boulton, Simon J; Sahai, Erik; Petronczki, Mark

2017-07-24

Altered nuclear shape is a defining feature of cancer cells. The mechanisms underlying nuclear dysmorphia in cancer remain poorly understood. Here we identify PPP1R12A and PPP1CB, two subunits of the myosin phosphatase complex that antagonizes actomyosin contractility, as proteins safeguarding nuclear integrity. Loss of PPP1R12A or PPP1CB causes nuclear fragmentation, nuclear envelope rupture, nuclear compartment breakdown and genome instability. Pharmacological or genetic inhibition of actomyosin contractility restores nuclear architecture and genome integrity in cells lacking PPP1R12A or PPP1CB. We detect actin filaments at nuclear envelope rupture sites and define the Rho-ROCK pathway as the driver of nuclear damage. Lamin A protects nuclei from the impact of actomyosin activity. Blocking contractility increases nuclear circularity in cultured cancer cells and suppresses deformations of xenograft nuclei in vivo. We conclude that actomyosin contractility is a major determinant of nuclear shape and that unrestrained contractility causes nuclear dysmorphia, nuclear envelope rupture and genome instability.

Loss of centrioles causes chromosomal instability in vertebrate somatic cells.

PubMed

Sir, Joo-Hee; Pütz, Monika; Daly, Owen; Morrison, Ciaran G; Dunning, Mark; Kilmartin, John V; Gergely, Fanni

2013-12-09

Most animal cells contain a centrosome, which comprises a pair of centrioles surrounded by an ordered pericentriolar matrix (PCM). Although the role of this organelle in organizing the mitotic spindle poles is well established, its precise contribution to cell division and cell survival remains a subject of debate. By genetically ablating key components of centriole biogenesis in chicken DT40 B cells, we generated multiple cell lines that lack centrioles. PCM components accumulated in acentriolar microtubule (MT)-organizing centers but failed to adopt a higher-order structure, as shown by three-dimensional structured illumination microscopy. Cells without centrioles exhibited both a delay in bipolar spindle assembly and a high rate of chromosomal instability. Collectively, our results expose a vital role for centrosomes in establishing a mitotic spindle geometry that facilitates correct kinetochore-MT attachments. We propose that centrosomes are essential in organisms in which rapid segregation of a large number of chromosomes needs to be attained with fidelity.

Computational model for chromosomal instabilty

NASA Astrophysics Data System (ADS)

Zapperi, Stefano; Bertalan, Zsolt; Budrikis, Zoe; La Porta, Caterina

2015-03-01

Faithful segregation of genetic material during cell division requires alignment of the chromosomes between the spindle poles and attachment of their kinetochores to each of the poles. Failure of these complex dynamical processes leads to chromosomal instability (CIN), a characteristic feature of several diseases including cancer. While a multitude of biological factors regulating chromosome congression and bi-orientation have been identified, it is still unclear how they are integrated into a coherent picture. Here we address this issue by a three dimensional computational model of motor-driven chromosome congression and bi-orientation. Our model reveals that successful cell division requires control of the total number of microtubules: if this number is too small bi-orientation fails, while if it is too large not all the chromosomes are able to congress. The optimal number of microtubules predicted by our model compares well with early observations in mammalian cell spindles. Our results shed new light on the origin of several pathological conditions related to chromosomal instability.

Instability of Helios-deficient Tregs is associated with conversion to a T-effector phenotype and enhanced antitumor immunity.

PubMed

Nakagawa, Hidetoshi; Sido, Jessica M; Reyes, Edwin E; Kiers, Valerie; Cantor, Harvey; Kim, Hye-Jung

2016-05-31

Expression of the transcription factor Helios by Tregs ensures stable expression of a suppressive and anergic phenotype in the face of intense inflammatory responses, whereas Helios-deficient Tregs display diminished lineage stability, reduced FoxP3 expression, and production of proinflammatory cytokines. Here we report that selective Helios deficiency within CD4 Tregs leads to enhanced antitumor immunity through induction of an unstable phenotype and conversion of intratumoral Tregs into T effector cells within the tumor microenvironment. Induction of an unstable Treg phenotype is associated with enhanced production of proinflammatory cytokines by tumor-infiltrating but not systemic Tregs and significantly delayed tumor growth. Ab-dependent engagement of Treg surface receptors that result in Helios down-regulation also promotes conversion of intratumoral but not systemic Tregs into T effector cells and leads to enhanced antitumor immunity. These findings suggest that selective instability and conversion of intratumoral CD4 Tregs through genetic or Ab-based targeting of Helios may represent an effective approach to immunotherapy.

A genetic network that suppresses genome rearrangements in Saccharomyces cerevisiae and contains defects in cancers

PubMed Central

Putnam, Christopher D.; Srivatsan, Anjana; Nene, Rahul V.; Martinez, Sandra L.; Clotfelter, Sarah P.; Bell, Sara N.; Somach, Steven B.; E.S. de Souza, Jorge; Fonseca, André F.; de Souza, Sandro J.; Kolodner, Richard D.

2016-01-01

Gross chromosomal rearrangements (GCRs) play an important role in human diseases, including cancer. The identity of all Genome Instability Suppressing (GIS) genes is not currently known. Here multiple Saccharomyces cerevisiae GCR assays and query mutations were crossed into arrays of mutants to identify progeny with increased GCR rates. One hundred eighty two GIS genes were identified that suppressed GCR formation. Another 438 cooperatively acting GIS genes were identified that were not GIS genes, but suppressed the increased genome instability caused by individual query mutations. Analysis of TCGA data using the human genes predicted to act in GIS pathways revealed that a minimum of 93% of ovarian and 66% of colorectal cancer cases had defects affecting one or more predicted GIS gene. These defects included loss-of-function mutations, copy-number changes associated with reduced expression, and silencing. In contrast, acute myeloid leukaemia cases did not appear to have defects affecting the predicted GIS genes. PMID:27071721

Zim17/Tim15 links mitochondrial iron-sulfur cluster biosynthesis to nuclear genome stability.

PubMed

Díaz de la Loza, María Del Carmen; Gallardo, Mercedes; García-Rubio, María Luisa; Izquierdo, Alicia; Herrero, Enrique; Aguilera, Andrés; Wellinger, Ralf Erik

2011-08-01

Genomic instability is related to a wide-range of human diseases. Here, we show that mitochondrial iron-sulfur cluster biosynthesis is important for the maintenance of nuclear genome stability in Saccharomyces cerevisiae. Cells lacking the mitochondrial chaperone Zim17 (Tim15/Hep1), a component of the iron-sulfur biosynthesis machinery, have limited respiration activity, mimic the metabolic response to iron starvation and suffer a dramatic increase in nuclear genome recombination. Increased oxidative damage or deficient DNA repair do not account for the observed genomic hyperrecombination. Impaired cell-cycle progression and genetic interactions of ZIM17 with components of the RFC-like complex involved in mitotic checkpoints indicate that replicative stress causes hyperrecombination in zim17Δ mutants. Furthermore, nuclear accumulation of pre-ribosomal particles in zim17Δ mutants reinforces the importance of iron-sulfur clusters in normal ribosome biosynthesis. We propose that compromised ribosome biosynthesis and cell-cycle progression are interconnected, together contributing to replicative stress and nuclear genome instability in zim17Δ mutants.

Role of Macronutrients and Micronutrients in DNA Damage: Results From a Food Frequency Questionnaire

PubMed Central

Ladeira, Carina; Carolino, Elisabete; Gomes, Manuel C; Brito, Miguel

2017-01-01

The links between diet and genomic instability have been under investigation for several decades, and evidence suggests a significant causal or preventive role for various dietary factors. This study investigates the influence of macronutrients (calories, protein, and glucides) and micronutrients, such as vitamins and minerals, as assessed by a food frequency questionnaire, on genotoxicity biomarkers measured by cytokinesis-blocked micronucleus assay and comet assay. The results found significant positive and negative correlations. Micronucleus frequency tends to increase with higher intake of caffeine, calcium, magnesium, zinc, and protein (P < .05, Spearman correlation). Calorie and omega-6 intakes are negatively correlated with DNA damage measured by the comet assay. These results are somewhat controversial because some of the correlations found are contrary to dominant views in the literature; however, we suggest that unraveling the association between diet and genetic instability requires a much better understanding of the modulating role of macronutrients and micronutrients. PMID:28469462

Actomyosin drives cancer cell nuclear dysmorphia and threatens genome stability

PubMed Central

Takaki, Tohru; Montagner, Marco; Serres, Murielle P.; Le Berre, Maël; Russell, Matt; Collinson, Lucy; Szuhai, Karoly; Howell, Michael; Boulton, Simon J.; Sahai, Erik; Petronczki, Mark

2017-01-01

Altered nuclear shape is a defining feature of cancer cells. The mechanisms underlying nuclear dysmorphia in cancer remain poorly understood. Here we identify PPP1R12A and PPP1CB, two subunits of the myosin phosphatase complex that antagonizes actomyosin contractility, as proteins safeguarding nuclear integrity. Loss of PPP1R12A or PPP1CB causes nuclear fragmentation, nuclear envelope rupture, nuclear compartment breakdown and genome instability. Pharmacological or genetic inhibition of actomyosin contractility restores nuclear architecture and genome integrity in cells lacking PPP1R12A or PPP1CB. We detect actin filaments at nuclear envelope rupture sites and define the Rho-ROCK pathway as the driver of nuclear damage. Lamin A protects nuclei from the impact of actomyosin activity. Blocking contractility increases nuclear circularity in cultured cancer cells and suppresses deformations of xenograft nuclei in vivo. We conclude that actomyosin contractility is a major determinant of nuclear shape and that unrestrained contractility causes nuclear dysmorphia, nuclear envelope rupture and genome instability. PMID:28737169

Recent Insights into the Control of Human Papillomavirus (HPV) Genome Stability, Loss, and Degradation.

PubMed

Fisher, Chris

2015-01-01

Most human papillomavirus (HPV) antiviral strategies have focused upon inhibiting viral DNA replication, but it is increasingly apparent that viral DNA levels can be chemically controlled by approaches that promote its instability. HPVs and other DNA viruses have a tenuous relationship with their hosts. They must replicate and hide from the DNA damage response (DDR) and innate immune systems, which serve to protect cells from foreign or "non-self" DNA, and yet they draft these same systems to support their life cycles. DNA binding antiviral agents promoting massive viral DNA instability and elimination are reviewed. Mechanistic studies of these agents have identified genetic antiviral enhancers and repressors, antiviral sensitizers, and host cell elements that protect and stabilize HPV genomes. Viral DNA degradation appears to be an important means of controlling HPV DNA levels in some cases, but the underlying mechanisms remain poorly understood. These findings may prove useful not only for understanding viral DNA persistence but also in devising future antiviral strategies.

Assessment of anterior shoulder instability by CT arthrography.

PubMed

Yang, S O; Cho, K J; Kim, M J; Ro, I W

1987-09-01

Computed tomography (CT) immediately after double-contrast shoulder arthrography was taken in twenty-two young male patients with anterior shoulder instability including recurrent dislocation and subluxation. This recently developed technique called CT arthrography can provide significant information about patients with glenohumeral instability which is difficult to obtain by conventional arthrography. Information about glenoid labrum pathology is useful for proper management of the shoulder with instability. Lesions identified in this study include anterior labral defects (attenuation, tear, displacement), anterior capsular distension and/or detachment, Hill-Sachs lesion, anterior glenoid rim compression fracture, and fracture of scapula. This article describes the method used in CT arthrography of the glenohumeral joint, reviews the normal cross-sectional anatomy, and emphasizes the importance of the application of CT arthrography in the shoulder disorder with instability. CT arthrography of the glenohumeral joint is easy to perform, is accurate, and has lower radiation dose than arthrotomography.

A technique to remove the tensile instability in weakly compressible SPH

NASA Astrophysics Data System (ADS)

Xu, Xiaoyang; Yu, Peng

2018-01-01

When smoothed particle hydrodynamics (SPH) is directly applied for the numerical simulations of transient viscoelastic free surface flows, a numerical problem called tensile instability arises. In this paper, we develop an optimized particle shifting technique to remove the tensile instability in SPH. The basic equations governing free surface flow of an Oldroyd-B fluid are considered, and approximated by an improved SPH scheme. This includes the implementations of the correction of kernel gradient and the introduction of Rusanov flux into the continuity equation. To verify the effectiveness of the optimized particle shifting technique in removing the tensile instability, the impacting drop, the injection molding of a C-shaped cavity, and the extrudate swell, are conducted. The numerical results obtained are compared with those simulated by other numerical methods. A comparison among different numerical techniques (e.g., the artificial stress) to remove the tensile instability is further performed. All numerical results agree well with the available data.

Helicopters: The Platform of Choice for Defense and Development

DTIC Science & Technology

2013-04-25

FID effort by facilitating the IDAD tasks of balanced development, security, neutralization, and mobilization. In order to prevent instability...security, neutralization, and mobilization. In order to prevent instability inside a Host Nation (HN), it is important to build cohesive IDAD and...derived from the H -53 (arguably the oldest, biggest, and most cost-prohibitive platform of this type) compared to STOL-capable 4-9 passenger fixed wing

Dioecy in Amborella trichopoda: evidence for genetically based sex determination and its consequences for inferences of the breeding system in early angiosperms.

PubMed

Anger, Nicolas; Fogliani, Bruno; Scutt, Charles P; Gâteblé, Gildas

2017-03-01

This work aimed to gain insight into the breeding system at the base of living angiosperms through both character state reconstructions and the study of sex ratios and phenotypes in the likely sister to all other living angiosperms, Amborella trichopoda . Sex phenotypes were mapped onto a phylogeny of basally diverging angiosperms using maximum parsimony. In parallel, sex ratios and phenotypes were studied over two consecutive flowering seasons in an ex situ population of A. trichopoda , while the sex ratio of an in situ population was also assessed. Parsimony analyses failed to resolve the breeding system present at the base of living angiosperms, but indicated the importance of A. trichopoda for the future elucidation of this question. The ex situ A. trichopoda population studied showed a primary sex ratio close to 1:1, though sex ratio bias was found in the in situ population studied. Instances of sexual instability were quantified in both populations. Sex ratio data support the presence of genetic sex determination in A. trichopoda , whose further elucidation may guide inferences on the breeding system at the base of living angiosperms. Sexual instability in A. trichopoda suggests the operation of epigenetic mechanisms, and the evolution of dioecy via a gynodioecious intermediate. © The Author 2017. Published by Oxford University Press on behalf of the Annals of Botany Company. All rights reserved. For Permissions, please email: journals.permissions@oup.com

Differing patterns of genetic instability in mice deficient in the mismatch repair genes Pms2, Mlh1, Msh2, Msh3 and Msh6.

PubMed

Hegan, Denise Campisi; Narayanan, Latha; Jirik, Frank R; Edelmann, Winfried; Liskay, R Michael; Glazer, Peter M

2006-12-01

Defects in genes associated with DNA mismatch repair (MMR) have been linked to hereditary colon cancer. Because the MMR pathway includes multiple factors with both overlapping and divergent functions, we sought to compare the impact of deficiencies in each of several MMR genes on genetic instability using a collection of knock-out mouse models. We investigated mutation frequencies and patterns in MMR-deficient mice using two transgenic reporter genes, supFG1 and cII, in the context of mice deficient for Pms2, Mlh1, Msh2, Msh3 or Msh6 or both Msh2 and Msh3 or both Msh3 and Msh6. We found that the mean mutation frequencies of all of the MMR-deficient mice were significantly higher than the mean mutation frequencies of wild-type mice. Mlh1-deficient mice and Msh2-deficient mice had the highest mutation frequencies in a comparison of the single nullizygous mice. Of all the mice studied, mice nullizygous for both Msh2 and Msh3 and those nullizygous for both Msh3 and Msh6 displayed the greatest overall increases in mutation frequencies compared with wild-type mice. Sequence analysis of the mutated reporter genes revealed significant differences between the individual groups of MMR-deficient mice. Taken together, our results further characterize the functions of the MMR factors in mutation avoidance and provide in vivo correlation to biochemical models of the MMR pathway.

Housing Mobility and Cognitive Development: Change in Verbal and Nonverbal Abilities

PubMed Central

Fowler, Patrick J.; McGrath, Lauren M.; Henry, David B.; Schoeny, Michael; Chavira, Dina; Taylor, Jeremy J.; Day, Orin

2015-01-01

This study investigates the influence of housing instability on verbal and nonverbal cognitive development among at-risk children and adolescents involved in the child welfare system. Frequent residential changes threaten child mental health, especially among low-income families. Little is known regarding disruptions to cognitive growth, specifically the impact on verbal and nonverbal abilities. The study tests whether developmental timing of housing mobility affects cognitive development beyond individual and family risks. A nationally representative study of families (n = 2,442) susceptible to housing and family instability tracked children and adolescents aged four to 14 years (M = 8.95 years) over 36 months following investigation by the child welfare system. Youth completed standardized cognitive assessments while caregivers reported on behavior problems and family risk at three time points. Latent growth models examined change in cognitive abilities over time. Housing mobility in the 12 months prior to baseline predicts lower verbal cognitive abilities that improve marginally. Similar effects emerge for all age groups; however, frequent moves in infancy diminish the influence of subsequent housing mobility on verbal tasks. Housing instability threatened cognitive development beyond child maltreatment, family changes, poverty, and other risks. Findings inform emerging research on environmental influences on neurocognitive development, as well as identify targets for early intervention. Systematic assessment of family housing problems, including through the child welfare system, provides opportunities for coordinated responses to prevent instability and cognitive threats. PMID:26184055

Disease-associated repeat instability and mismatch repair.

PubMed

Schmidt, Monika H M; Pearson, Christopher E

2016-02-01

Expanded tandem repeat sequences in DNA are associated with at least 40 human genetic neurological, neurodegenerative, and neuromuscular diseases. Repeat expansion can occur during parent-to-offspring transmission, and arise at variable rates in specific tissues throughout the life of an affected individual. Since the ongoing somatic repeat expansions can affect disease age-of-onset, severity, and progression, targeting somatic expansion holds potential as a therapeutic target. Thus, understanding the factors that regulate this mutation is crucial. DNA repair, in particular mismatch repair (MMR), is the major driving force of disease-associated repeat expansions. In contrast to its anti-mutagenic roles, mammalian MMR curiously drives the expansion mutations of disease-associated (CAG)·(CTG) repeats. Recent advances have broadened our knowledge of both the MMR proteins involved in disease repeat expansions, including: MSH2, MSH3, MSH6, MLH1, PMS2, and MLH3, as well as the types of repeats affected by MMR, now including: (CAG)·(CTG), (CGG)·(CCG), and (GAA)·(TTC) repeats. Mutagenic slipped-DNA structures have been detected in patient tissues, and the size of the slip-out and their junction conformation can determine the involvement of MMR. Furthermore, the formation of other unusual DNA and R-loop structures is proposed to play a key role in MMR-mediated instability. A complex correlation is emerging between tissues showing varying amounts of repeat instability and MMR expression levels. Notably, naturally occurring polymorphic variants of DNA repair genes can have dramatic effects upon the levels of repeat instability, which may explain the variation in disease age-of-onset, progression and severity. An increasing grasp of these factors holds prognostic and therapeutic potential. Copyright © 2015 Elsevier B.V. All rights reserved.

Dosage Mutator Genes in Saccharomyces cerevisiae: A Novel Mutator Mode-of-Action of the Mph1 DNA Helicase.

PubMed

Ang, J Sidney; Duffy, Supipi; Segovia, Romulo; Stirling, Peter C; Hieter, Philip

2016-11-01

Mutations that cause genome instability are considered important predisposing events that contribute to initiation and progression of cancer. Genome instability arises either due to defects in genes that cause an increased mutation rate (mutator phenotype), or defects in genes that cause chromosome instability (CIN). To extend the catalog of genome instability genes, we systematically explored the effects of gene overexpression on mutation rate, using a forward-mutation screen in budding yeast. We screened ∼5100 plasmids, each overexpressing a unique single gene, and characterized the five strongest mutators, MPH1 (mutator phenotype 1), RRM3, UBP12, PIF1, and DNA2 We show that, for MPH1, the yeast homolog of Fanconi Anemia complementation group M (FANCM), the overexpression mutator phenotype is distinct from that of mph1Δ. Moreover, while four of our top hits encode DNA helicases, the overexpression of 48 other DNA helicases did not cause a mutator phenotype, suggesting this is not a general property of helicases. For Mph1 overexpression, helicase activity was not required for the mutator phenotype; in contrast Mph1 DEAH-box function was required for hypermutation. Mutagenesis by MPH1 overexpression was independent of translesion synthesis (TLS), but was suppressed by overexpression of RAD27, a conserved flap endonuclease. We propose that binding of DNA flap structures by excess Mph1 may block Rad27 action, creating a mutator phenotype that phenocopies rad27Δ. We believe this represents a novel mutator mode-of-action and opens up new prospects to understand how upregulation of DNA repair proteins may contribute to mutagenesis. Copyright © 2016 by the Genetics Society of America.

Microscale electrokinetic transport and stability

NASA Astrophysics Data System (ADS)

Chen, Chuan-Hua

Electrokinetics is a leading mechanism for transport and separation of biochemical samples in microdevices due to its favorable scaling at small scales. However, electrokinetic systems can become highly unstable, and this instability adversely affects key processes such as sample stacking and electrophoretic separation. This dissertation deals with two major topics: a novel planar micropump exploiting the favorable scaling of electroosmosis at the microscale, and a fundamental study of electrokinetic flow instabilities induced by electrical conductivity gradients. Electroosmotic micropumps use field-induced ion drag to drive liquids and achieve high pressures in a compact design with no moving parts. An analytical model applicable to planar, etched-structure micropumps was developed to guide the geometrical design and working fluid selection. Standard microlithography and wet etching techniques were used to fabricate a pump 1 mm long along the flow direction and 0.9 mum by 38 mm in cross section. The pump produced a maximum pressure of 0.33 atm and a maximum flow rate of 15 mul/min at 1 kV applied potential with deionized water as working fluid. The pump performance agreed well with the theoretical model. Electrokinetic flow instabilities occur under high electric field in the presence of electrical conductivity gradients. In a microfluidic T-junction 11 mum by 155 mum in cross section, aqueous electrolytes of 10:1 conductivity ratio were electrokinetically driven into a common mixing channel. Convectively unstable waves were observed at 0.5 kV/cm, and upstream propagating waves at 1.5 kV/cm. A physical model for this instability has been developed. A linear stability analysis of the governing equations in the thin-layer limit predicts both qualitative trends and quantitative features that agree well with experimental data. Briggs-Bers criteria were applied to select physically unstable modes and determine the nature of instability. Conductivity gradients and bulk charge accumulation are a crucial factor in the instability. The role of electroosmotic flow is mainly as a convecting medium. The instability is governed by two key controlling parameters: the ratio of dynamic to dissipative forces which determines the onset of instability, and the ratio of electroviscous to electroosmotic velocities which governs the convective versus absolute nature of instability.

Evidence of Active MHD Instability in EULAG-MHD Simulations of Solar Convection

NASA Astrophysics Data System (ADS)

Lawson, Nicolas; Strugarek, Antoine; Charbonneau, Paul

2015-11-01

We investigate the possible development of magnetohydrodynamical instabilities in the EULAG-MHD “millennium simulation” of Passos & Charbonneau. This simulation sustains a large-scale magnetic cycle characterized by solar-like polarity reversals taking place on a regular multidecadal cadence, and in which zonally oriented bands of strong magnetic fields accumulate below the convective layers, in response to turbulent pumping from above in successive magnetic half-cycles. Key aspects of this simulation include low numerical dissipation and a strongly sub-adiabatic fluid layer underlying the convectively unstable layers corresponding to the modeled solar convection zone. These properties are conducive to the growth and development of two-dimensional instabilities that are otherwise suppressed by stronger dissipation. We find evidence for the action of a non-axisymmetric magnetoshear instability operating in the upper portions of the stably stratified fluid layers. We also investigate the possibility that the Tayler instability may be contributing to the destabilization of the large-scale axisymmetric magnetic component at high latitudes. On the basis of our analyses, we propose a global dynamo scenario whereby the magnetic cycle is driven primarily by turbulent dynamo action in the convecting layers, but MHD instabilities accelerate the dissipation of the magnetic field pumped down into the overshoot and stable layers, thus perhaps significantly influencing the magnetic cycle period. Support for this scenario is found in the distinct global dynamo behaviors observed in an otherwise identical EULAG-MHD simulations, using a different degree of sub-adiabaticity in the stable fluid layers underlying the convection zone.

Nonlinear structures and anomalous transport in partially magnetized E×B plasmas

DOE PAGES

Janhunen, Salomon; Smolyakov, Andrei; Chapurin, Oleksandr; ...

2017-12-29

Nonlinear dynamics of the electron-cyclotron instability driven by the electron E x B current in a crossed electric and magnetic field is studied. In the nonlinear regime, the instability proceeds by developing a large amplitude coherent wave driven by the energy input from the fundamental cyclotron resonance. Further evolution shows the formation of the long wavelength envelope akin to the modulational instability. Simultaneously, the ion density shows the development of a high-k content responsible for wave focusing and sharp peaks on the periodic cnoidal wave structure. Here, it is shown that the anomalous electron transport (along the direction of themore » applied electric field) is dominated by the long wavelength part of the turbulent spectrum.« less

Buoyancy-driven instabilities around miscible A+B→C reaction fronts: a general classification.

PubMed

Trevelyan, P M J; Almarcha, C; De Wit, A

2015-02-01

Upon contact between miscible solutions of reactants A and B along a horizontal interface in the gravity field, various buoyancy-driven instabilities can develop when an A+B→C reaction takes place and the density varies with the concentrations of the various chemicals. To classify the possible convective instability scenarios, we analyze the spatial dependence of the large time asymptotic density profiles as a function of the key parameters of the problem, which are the ratios of diffusion coefficients and of solutal expansion coefficients of species A, B, and C. We find that 62 different density profiles can develop in the reactive problem, whereas only 6 of them can be obtained in the nonreactive one.

Simulation of the development and interaction of instabilities in a relativistic electron beam under variation of the beam wall thickness

DOE Office of Scientific and Technical Information (OSTI.GOV)

Badarin, A. A.; Kurkin, S. A.; Koronovskii, A. A.

The development and interaction of Bursian and diocotron instabilities in an annular relativistic electron beam propagating in a cylindrical drift chamber are investigated analytically and numerically as functions of the beam wall thickness and the magnitude of the external uniform magnetic field. It is found that the interaction of instabilities results in the formation of a virtual cathode with a complicated rotating helical structure and several reflection regions (electron bunches) in the azimuthal direction. It is shown that the number of electron bunches in the azimuthal direction increases with decreasing beam wall thickness and depends in a complicated manner onmore » the magnitude of the external magnetic field.« less

CHPA, a Cysteine- and Histidine-Rich-Domain-Containing Protein, Contributes to Maintenance of the Diploid State in Aspergillus nidulans

PubMed Central

Sadanandom, Ari; Findlay, Kim; Doonan, John H.; Schulze-Lefert, Paul; Shirasu, Ken

2004-01-01

The alternation of eukaryotic life cycles between haploid and diploid phases is crucial for maintaining genetic diversity. In some organisms, the growth and development of haploid and diploid phases are nearly identical, and one might suppose that all genes required for one phase are likely to be critical for the other phase. Here, we show that targeted disruption of the chpA (cysteine- and histidine-rich-domain- [CHORD]-containing protein A) gene in haploid Aspergillus nidulans strains gives rise to chpA knockout haploids and heterozygous diploids but no chpA knockout diploids. A. nidulans chpA heterozygous diploids showed impaired conidiophore development and reduced conidiation. Deletion of chpA from diploid A. nidulans resulted in genome instability and reversion to a haploid state. Thus, our data suggest a vital role for chpA in maintenance of the diploid phase in A. nidulans. Furthermore, the human chpA homolog, Chp-1, was able to complement haploinsufficiency in A. nidulans chpA heterozygotes, suggesting that the function of CHORD-containing proteins is highly conserved in eukaryotes. PMID:15302831

Serrated pathway in colorectal carcinogenesis

PubMed Central

Yamane, Letícia; Scapulatempo-Neto, Cristovam; Reis, Rui Manuel; Guimarães, Denise Peixoto

2014-01-01

Serrated adenocarcinoma is a recently described subset of colorectal cancer (CRC), which account for about 10% of all CRCs and follows an alternative pathway in which serrated polyps replace the traditional adenoma as the precursor lesion to CRC. Serrated polyps form a heterogeneous group of colorectal lesions that includes hyperplastic polyps (HPs), sessile serrated adenoma (SSA), traditional serrated adenoma (TSA) and mixed polyps. HPs are the most common serrated polyp followed by SSA and TSA. This distinct histogenesis is believed to have a major influence in prevention strategies, patient prognosis and therapeutic impact. Genetically, serrated polyps exhibited also a distinct pattern, with KRAS and BRAF having an important contribution to its development. Two other molecular changes that have been implicated in the serrated pathway include microsatellite instability and the CpG island methylator phenotype. In the present review we will address the current knowledge of serrated polyps, clinical pathological features and will update the most recent findings of its molecular pathways. The understanding of their biology and malignancy potential is imperative to implement a surveillance approach in order to prevent colorectal cancer development. PMID:24627599

Investigation of the relevant kinetic processes in the initial stage of a double-arcing instability in oxygen plasmas

NASA Astrophysics Data System (ADS)

Mancinelli, B.; Prevosto, L.; Chamorro, J. C.; Minotti, F. O.; Kelly, H.

2018-05-01

A numerical investigation of the kinetic processes in the initial (nanosecond range) stage of the double-arcing instability was developed. The plasma-sheath boundary region of an oxygen-operated cutting torch was considered. The energy balance and chemistry processes in the discharge were described. It is shown that the double-arcing instability is a sudden transition from a diffuse (glow-like) discharge to a constricted (arc-like) discharge in the plasma-sheath boundary region arising from a field-emission instability. A critical electric field value of ˜107 V/m was found at the cathodic part of the nozzle wall under the conditions considered. The field-emission instability drives in turn a fast electronic-to-translational energy relaxation mechanism, giving rise to a very fast gas heating rate of at least ˜109 K/s, mainly due to reactions of preliminary dissociation of oxygen molecules via the highly excited electronic state O2(B3Σu-) populated by electron impact. It is expected that this fast oxygen heating rate further stimulates the discharge contraction through the thermal instability mechanism.

A Review of LOX/Kerosene Combustion Instability in American and Russian Combustion Devices in Application to Next-Generation Launch Technology

NASA Technical Reports Server (NTRS)

Rocker, Marvin; Nesman, Tomas E.; Hulka, James R.; Dougherty, N. Sam

2003-01-01

The Next-Generation Launch Technology (NGLT) project was introduced with its objectives. To meet the objectives, NASA has directed aerospace industry to perform advances and risk reduction of relevant technologies, including propulsion. Originally, the propulsion industry focused on producing both LOWLH2 and LOWkerosene flight engine technology demonstrators. These flight engine technology demonstrators were briefly reviewed. NASA recently redirected this focus to Lowkerosene only. Discussion of LOWkerosene combustion devices was and is prefaced by grave concerns about combustion instability. These concerns have prompted a review of LOWkerosene combustion instability in American and Russian combustion devices. In the review of the Russian propulsion industry's experience in eliminating LOWkerosene combustion instabilities, the history of principal Russian rocket scientists and their role in the development of LOXkerosene combustion devices is presented. The innovative methods implemented by the Russians of eliminations combustion instabilities in LOXkerosene combustion devices were reviewed. The successful elimination of these combustion instabilities has resulted in two generations of Russian-produced, high-performance LOWkerosene combustion devices.

Active control: an investigation method for combustion instabilities

NASA Astrophysics Data System (ADS)

Poinsot, T.; Yip, B.; Veynante, D.; Trouvé, A.; Samaniego, J. M.; Candel, S.

1992-07-01

Closed-loop active control methods and their application to combustion instabilities are discussed. In these methods the instability development is impeded with a feedback control loop: the signal provided by a sensor monitoring the flame or pressure oscillations is processed and sent back to actuators mounted on the combustor or on the feeding system. Different active control systems tested on a non-premixed multiple-flame turbulent combustor are described. These systems can suppress all unstable plane modes of oscillation (i.e. low frequency modes). The active instability control (AIC) also constitutes an original and powerful technique for studies of mechanisms leading to instability or resulting from the instability. Two basic applications of this kind are described. In the first case the flame is initially controlled with AIC, the feedback loop is then switched off and the growth of the instability is analysed through high speed Schlieren cinematography and simultaneous sound pressure and reaction rate measurements. Three phases are identified during th growth of the oscillations: (1) a linear phase where acoustic waves induce a flapping motion of the flame sheets without interaction between sheets, (2) a modulation phase, where flame sheets interact randomly and (3) a nonlinear phase where the flame sheets are broken and a limit cycle is reached. In the second case we investigate different types of flame extinctions associated with combustion instability. It is shown that pressure oscillations may lead to partial or total extinctions. Extinctions occur in various forms but usually follow a rapid growth of pressure oscillations. The flame is extinguished during the modulation phase observed in the initiation experiments. In these studies devoted to transient instability phenomena, the control system constitutes a unique investigation tool because it is difficult to obtain the same information by other means. Implications for modelling and prediction of combustion instabilities are discussed.

An in vitro recombination-based reverse genetic system for rapid mutagenesis of structural genes of the Japanese encephalitis virus.

PubMed

Du, Ruikun; Wang, Manli; Hu, Zhihong; Wang, Hualin; Deng, Fei

2015-10-01

Japanese encephalitis virus (JEV) is one of the most common pathogens of severe viral encephalitis, which is a severe threat to human health. Despite instability of the JEV genome in bacteria, many strategies have been developed to establish molecular clone systems of JEV, providing convenient tools for studying the virus life cycle and virus-host interactions. In this study, we adapted an In-Fusion enzyme-based in vitro recombination method to construct a reverse genetic system of JEV, thereby providing a rapid approach to introduce mutations into the structural genes. A truncated genome without the structural genes was constructed as the backbone, and the complementary segment containing the structural genes was recombined in vitro, which was then transfected directly into virus-permissive cells. The progeny of the infectious virus was successfully detected in the supernatant of the transfected cells, and showed an identical phenotype to its parental virus. To provide a proof-of-principle, the 12 conserved cysteine residues in the envelope (E) protein of JEV were respectively mutated using this approach, and all mutations resulted in a complete failure to generate infectious virus. However, a leucine-tophenylanine mutation at amino acid 107 of the E protein did not interfere with the production of the infectious virus. These results suggested that all 12 cysteines in the E protein are essential for the JEV life cycle. In summary, a novel reverse genetic system of JEV was established for rapidly introducing mutations into structural genes, which will serve as a useful tool for functional studies.

Annals of morphology. Atavisms: phylogenetic Lazarus?

PubMed

Zanni, Ginevra; Opitz, John M

2013-11-01

Dedication: with highest respect and affection to Prof. Giovanni Neri on the eve of his official administrative retirement as Chair of the Institute of Medical Genetics of the Università Cattolica of Rome for leadership in medical genetics and medical science and friendship for decades. The concept "atavism," reversion, throwback, Rückschlag remains an epistemological challenge in biology; unwise or implausible over-interpretation of a given structure as such has led some to almost total skepticism as to its existence. Originating in botany in the 18th century it became applied to zoology (and humans) with increasing frequency over the last two centuries such that the very concept became widely discredited. Presently, atavisms have acquired a new life and reconsideration given certain reasonable criteria, including: Homology of structure of the postulated atavism to that of ancestral fossils or collateral species with plausible soft tissue reconstructions taking into account relationships of parts, obvious sites of origin and insertion of muscles, vascular channels, etc. Most parsimonious, plausible phylogenetic assumptions. Evident rudimentary or vestigial anatomical state in prior generations or in morphogenesis of a given organism. Developmental instability in prior generations, that is, some closely related species facultatively with or without the trait. Genetic identity or phylogenomic similarity inferred in ancestors and corroborated in more or less closely related species. Fluctuating asymmetry may be the basis for the striking evolutionary diversification and common atavisms in limbs; however, strong selection and developmental constraints would make atavisms in, for example, cardiac or CNS development less likely. Thus, purported atavisms must be examined critically in light of the above criteria. © 2013 Wiley Periodicals, Inc.

Molecular Diagnostics in Colorectal Carcinoma: Advances and Applications for 2018.

PubMed

Bhalla, Amarpreet; Zulfiqar, Muhammad; Bluth, Martin H

2018-06-01

The molecular pathogenesis and classification of colorectal carcinoma are based on the traditional adenomaecarcinoma sequence, serrated polyp pathway, and microsatellite instability (MSI). The genetic basis for hereditary nonpolyposis colorectal cancer is the detection of mutations in the MLH1, MSH2, MSH6, PMS2, and EPCAM genes. Genetic testing for Lynch syndrome includes MSI testing, methylator phenotype testing, BRAF mutation testing, and molecular testing for germline mutations in MMR genes. Molecular makers with predictive and prognostic implications include quantitative multigene reverse transcriptase polymerase chain reaction assay and KRAS and BRAF mutation analysis. Mismatch repair-deficient tumors have higher rates of programmed death-ligand 1 expression. Cell-free DNA analysis in fluids are proving beneficial for diagnosis and prognosis in these disease states towards effective patient management. Copyright © 2018 Elsevier Inc. All rights reserved.

[Epstein-Barr virus associated gastric carcinoma: the genetic alteration and the expression of CD44 variant].

PubMed

Chong, J M; Fukayama, M

1997-02-01

Epstein-Barr virus (EBV), a ubiquitous human herpes virus, was recently identified in 2-16% of gastric carcinomas. EBV-encoded small RNA was found in nearly all of the carcinoma cells even at the intramucosal stage. EBV in EBV associated gastric carcinoma (EBVaGC) is monoclonal based on Southern blot hybridization using probes adjacent to the unique terminal repeat of EBV-DNA. Furthermore, the genetic pathway of this carcinogenesis is different of EBVaGC: deletion of 5q and/or 17p and microsatellite instability are extremely rare in EBVaGC, in contrast to their high frequency in EBV-negative carcinomas. We also examined the relationship between the expression of CD44 variants and EBVaGC, and found the expression of CD44 variants was significantly correlated with EBV-etiology.

Discovery of an ultra-short linear antibacterial tetrapeptide with anti-MRSA activity from a structure-activity relationship study.

PubMed

Lau, Qiu Ying; Ng, Fui Mee; Cheong, Jin Wei Darryl; Yap, Yi Yong Alvin; Tan, Yoke Yan Fion; Jureen, Roland; Hill, Jeffrey; Chia, Cheng San Brian

2015-11-13

The overuse and misuse of antibiotics has resulted in the emergence of drug-resistant pathogenic bacteria, including meticillin-resistant Staphylococcus aureus (MRSA), the primary pathogen responsible for human skin and soft-tissue infections. Antibacterial peptides are known to kill bacteria by rapidly disrupting their membranes and are deemed plausible alternatives to conventional antibiotics. One advantage of their membrane-targeting mode of action is that bacteria are unlikely to develop resistance as changing their cell membrane structure and morphology would likely involve extensive genetic mutations. However, major concerns in using peptides as antibacterial drugs include their instability towards plasma proteases, toxicity towards human cells due to their membrane-targeting mode of action and high manufacturing cost. These concerns can be mitigated by developing peptides as topical agents, by the judicial selection of amino acids and developing very short peptides respectively. In this preliminary report, we reveal a linear, non-hemolytic tetrapeptide with rapid bactericidal activity against MRSA developed from a structure-activity relationship study based on the antimicrobial hexapeptide WRWRWR-NH2. Our finding opens promising avenues for the development of ultra-short antibacterials to treat multidrug-resistant MRSA skin and soft tissue infections. Copyright © 2015 Elsevier Masson SAS. All rights reserved.

The inactive X chromosome is epigenetically unstable and transcriptionally labile in breast cancer.

PubMed

Chaligné, Ronan; Popova, Tatiana; Mendoza-Parra, Marco-Antonio; Saleem, Mohamed-Ashick M; Gentien, David; Ban, Kristen; Piolot, Tristan; Leroy, Olivier; Mariani, Odette; Gronemeyer, Hinrich; Vincent-Salomon, Anne; Stern, Marc-Henri; Heard, Edith

2015-04-01

Disappearance of the Barr body is considered a hallmark of cancer, although whether this corresponds to genetic loss or to epigenetic instability and transcriptional reactivation is unclear. Here we show that breast tumors and cell lines frequently display major epigenetic instability of the inactive X chromosome, with highly abnormal 3D nuclear organization and global perturbations of heterochromatin, including gain of euchromatic marks and aberrant distributions of repressive marks such as H3K27me3 and promoter DNA methylation. Genome-wide profiling of chromatin and transcription reveal modified epigenomic landscapes in cancer cells and a significant degree of aberrant gene activity from the inactive X chromosome, including several genes involved in cancer promotion. We demonstrate that many of these genes are aberrantly reactivated in primary breast tumors, and we further demonstrate that epigenetic instability of the inactive X can lead to perturbed dosage of X-linked factors. Taken together, our study provides the first integrated analysis of the inactive X chromosome in the context of breast cancer and establishes that epigenetic erosion of the inactive X can lead to the disappearance of the Barr body in breast cancer cells. This work offers new insights and opens up the possibility of exploiting the inactive X chromosome as an epigenetic biomarker at the molecular and cytological levels in cancer. © 2015 Chaligné et al.; Published by Cold Spring Harbor Laboratory Press.

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

PubMed

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

2016-08-01

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

Alternative DNA structure formation in the mutagenic human c-MYC promoter

PubMed Central

del Mundo, Imee Marie A.; Zewail-Foote, Maha; Kerwin, Sean M.

2017-01-01

Abstract Mutation ‘hotspot’ regions in the genome are susceptible to genetic instability, implicating them in diseases. These hotspots are not random and often co-localize with DNA sequences potentially capable of adopting alternative DNA structures (non-B DNA, e.g. H-DNA and G4-DNA), which have been identified as endogenous sources of genomic instability. There are regions that contain overlapping sequences that may form more than one non-B DNA structure. The extent to which one structure impacts the formation/stability of another, within the sequence, is not fully understood. To address this issue, we investigated the folding preferences of oligonucleotides from a chromosomal breakpoint hotspot in the human c-MYC oncogene containing both potential G4-forming and H-DNA-forming elements. We characterized the structures formed in the presence of G4-DNA-stabilizing K+ ions or H-DNA-stabilizing Mg2+ ions using multiple techniques. We found that under conditions favorable for H-DNA formation, a stable intramolecular triplex DNA structure predominated; whereas, under K+-rich, G4-DNA-forming conditions, a plurality of unfolded and folded species were present. Thus, within a limited region containing sequences with the potential to adopt multiple structures, only one structure predominates under a given condition. The predominance of H-DNA implicates this structure in the instability associated with the human c-MYC oncogene. PMID:28334873

The formation and dissipation of electrostatic shock waves: the role of ion–ion acoustic instabilities

NASA Astrophysics Data System (ADS)

Zhang, Wen-shuai; Cai, Hong-bo; Zhu, Shao-ping

2018-05-01

The role of ion–ion acoustic instabilities in the formation and dissipation of collisionless electrostatic shock waves driven by counter-streaming supersonic plasma flows has been investigated via two-dimensional particle-in-cell simulations. The nonlinear evolution of unstable waves and ion velocity distributions has been analyzed in detail. It is found that for electrostatic shocks driven by moderate-velocity flows, longitudinal and oblique ion–ion acoustic instabilities can be excited in the downstream and upstream regions, which lead to thermalization of the transmitted and reflected ions, respectively. For high-velocity flows, oblique ion–ion acoustic instabilities can develop in the overlap layer during the shock formation process and impede the shock formation.

Innovative Adaptive Control Method Demonstrated for Active Suppression of Instabilities in Engine Combustors

NASA Technical Reports Server (NTRS)

Kopasakis, George

2005-01-01

This year, an improved adaptive-feedback control method was demonstrated that suppresses thermoacoustic instabilities in a liquid-fueled combustor of a type used in aircraft engines. Extensive research has been done to develop lean-burning (low fuel-to-air ratio) combustors that can reduce emissions throughout the mission cycle to reduce the environmental impact of aerospace propulsion systems. However, these lean-burning combustors are susceptible to thermoacoustic instabilities (high-frequency pressure waves), which can fatigue combustor components and even downstream turbine blades. This can significantly decrease the safe operating life of the combustor and turbine. Thus, suppressing the thermoacoustic combustor instabilities is an enabling technology for meeting the low-emission goals of the NASA Ultra-Efficient Engine Technology (UEET) Project.

Family Instability and Exposure to Violence in the Early Life Course.

PubMed

Cavanagh, Shannon E; Stritzel, Haley; Smith, Chelsea; Crosnoe, Robert

2017-10-11

Family instability has been linked with a host of outcomes across the early life course. This study extends this literature by connecting instability with violence in the community by examining the associations among family structure, family structure change, and secondary exposure to violence during adolescence across diverse segments of the population. Using longitudinal data from the Project on Human Development in Chicago Neighborhoods study, we found that living with a single parent and experiencing family structure changes were associated with secondary exposure to violence. Multiple group models suggest that partner change translated into more exposure for boys than girls. Findings also suggest that family instability may lead to more secondary exposure to violence for African American youth. © 2017 Society for Research on Adolescence.

DOE Office of Scientific and Technical Information (OSTI.GOV)

Hirano, Shin'ichi; Nishi, Sakine; Kobayashi, Tsutomu, E-mail: s.hirano@rikkyo.ac.jp, E-mail: sakine@rikkyo.ac.jp, E-mail: tsutomu@rikkyo.ac.jp

We study the stability of a recently proposed model of scalar-field matter called mimetic dark matter or imperfect dark matter. It has been known that mimetic matter with higher derivative terms suffers from gradient instabilities in scalar perturbations. To seek for an instability-free extension of imperfect dark matter, we develop an effective theory of cosmological perturbations subject to the constraint on the scalar field's kinetic term. This is done by using the unifying framework of general scalar-tensor theories based on the ADM formalism. We demonstrate that it is indeed possible to construct a model of imperfect dark matter which ismore » free from ghost and gradient instabilities. As a side remark, we also show that mimetic F (R) theory is plagued with the Ostrogradsky instability.« less

Study of coherent synchrotron radiation effects by means of a new simulation code based on the non-linear extension of the operator splitting method

NASA Astrophysics Data System (ADS)

Dattoli, G.; Migliorati, M.; Schiavi, A.

2007-05-01

The coherent synchrotron radiation (CSR) is one of the main problems limiting the performance of high-intensity electron accelerators. The complexity of the physical mechanisms underlying the onset of instabilities due to CSR demands for accurate descriptions, capable of including the large number of features of an actual accelerating device. A code devoted to the analysis of these types of problems should be fast and reliable, conditions that are usually hardly achieved at the same time. In the past, codes based on Lie algebraic techniques have been very efficient to treat transport problems in accelerators. The extension of these methods to the non-linear case is ideally suited to treat CSR instability problems. We report on the development of a numerical code, based on the solution of the Vlasov equation, with the inclusion of non-linear contribution due to wake field effects. The proposed solution method exploits an algebraic technique that uses the exponential operators. We show that the integration procedure is capable of reproducing the onset of instability and the effects associated with bunching mechanisms leading to the growth of the instability itself. In addition, considerations on the threshold of the instability are also developed.

Cryogenic High-Pressure Shear-Coaxial Jets Exposed to Transverse Acoustic Forcing

DTIC Science & Technology

2011-12-13

formation. Detailed studies on the development and growth of natural instabilities in a single circular jet6 or a single circular jet with coflow7...reveal two of the most significant natural modes of instability: the axisymmetric and the first azimuthal or helical modes. These modes have comparable... natural as well as externally imposed flow conditions such as pressure or velocity perturbations, affecting their development, may be used to assess