RECQ-like helicases Sgs1 and BLM regulate R-loop–associated genome instability

PubMed Central

Chang, Emily Yun-Chia; Novoa, Carolina A.; Aristizabal, Maria J.; Coulombe, Yan; Segovia, Romulo; Shen, Yaoqing; Keong, Christelle; Tam, Annie S.; Jones, Steven J.M.; Masson, Jean-Yves; Kobor, Michael S.

2017-01-01

Sgs1, the orthologue of human Bloom’s syndrome helicase BLM, is a yeast DNA helicase functioning in DNA replication and repair. We show that SGS1 loss increases R-loop accumulation and sensitizes cells to transcription–replication collisions. Yeast lacking SGS1 accumulate R-loops and γ-H2A at sites of Sgs1 binding, replication pausing regions, and long genes. The mutation signature of sgs1Δ reveals copy number changes flanked by repetitive regions with high R-loop–forming potential. Analysis of BLM in Bloom’s syndrome fibroblasts or by depletion of BLM from human cancer cells confirms a role for Sgs1/BLM in suppressing R-loop–associated genome instability across species. In support of a potential direct effect, BLM is found physically proximal to DNA:RNA hybrids in human cells, and can efficiently unwind R-loops in vitro. Together, our data describe a conserved role for Sgs1/BLM in R-loop suppression and support an increasingly broad view of DNA repair and replication fork stabilizing proteins as modulators of R-loop–mediated genome instability. PMID:29042409

RECQ-like helicases Sgs1 and BLM regulate R-loop-associated genome instability.

PubMed

Chang, Emily Yun-Chia; Novoa, Carolina A; Aristizabal, Maria J; Coulombe, Yan; Segovia, Romulo; Chaturvedi, Richa; Shen, Yaoqing; Keong, Christelle; Tam, Annie S; Jones, Steven J M; Masson, Jean-Yves; Kobor, Michael S; Stirling, Peter C

2017-12-04

Sgs1, the orthologue of human Bloom's syndrome helicase BLM, is a yeast DNA helicase functioning in DNA replication and repair. We show that SGS1 loss increases R-loop accumulation and sensitizes cells to transcription-replication collisions. Yeast lacking SGS1 accumulate R-loops and γ-H2A at sites of Sgs1 binding, replication pausing regions, and long genes. The mutation signature of sgs1 Δ reveals copy number changes flanked by repetitive regions with high R-loop-forming potential. Analysis of BLM in Bloom's syndrome fibroblasts or by depletion of BLM from human cancer cells confirms a role for Sgs1/BLM in suppressing R-loop-associated genome instability across species. In support of a potential direct effect, BLM is found physically proximal to DNA:RNA hybrids in human cells, and can efficiently unwind R-loops in vitro. Together, our data describe a conserved role for Sgs1/BLM in R-loop suppression and support an increasingly broad view of DNA repair and replication fork stabilizing proteins as modulators of R-loop-mediated genome instability. © 2017 Chang et al.

Are chromosomal instabilities induced by exposure of cultured normal human cells to low- or high-LET radiation?

NASA Technical Reports Server (NTRS)

Dugan, Lawrence C.; Bedford, Joel S.

2003-01-01

Radiation-induced genomic instability has been proposed as a very early, if not an initiating, step in radiation carcinogenesis. Numerous studies have established the occurrence of radiation-induced chromosomal instability in various cells of both human and rodent origin. In many of these studies, however, the cells were not "normal" initially, and in many cases they involved tumor-derived cell lines. The phenomenon clearly would be of even greater interest if it were shown to occur generally in cells that are normal at the outset, rather than cells that may have been "selected" because of a pre-existing susceptibility to induced instability. As a test of the generality of the phenomenon, we studied low-passage normal diploid human fibroblasts (AG1521A) to determine whether they are susceptible to the induction of chromosomal instability in the progeny of surviving cells after exposure in G(0) to low- and high-LET radiation. Cytogenetic assays for instability were performed on both mixed populations of cells and clones of cells surviving exposure. We found no evidence for the induction of such instability as a result of radiation exposure, though we observed a senescence-related chromosomal instability in the progeny of both irradiated and unirradiated cell populations. Copyright 2003 by Radiation Research Society.

Effect of surface tension anisotropy on cellular morphologies

NASA Technical Reports Server (NTRS)

Mcfadden, G. B.; Coriell, S. R.; Sekerka, R. F.

1988-01-01

A three-dimensional weakly nonlinear analysis for conditions near the onset of instability at the crystal-melt interface was carried out to second order, taking into account the effects of latent heat generation and surface-tension anisotropy of the crystal-melt interface; particular consideration was given to the growth of a cubic crystal in the 001-, 011-, and 111-line directions. Numerical calculations by McFadden et al. (1987), performed for an aluminum-chromium alloy with the assumption of a linear temperature field and an isotropic surface tension, showed that only hexagonal nodes (and not hexagonal cells) occurred near the onset of instability. The results of the present analysis indicate that the nonlinear temperature field (which occurs when thermal conductivities of the crystal and the melt are different and/or the latent heat effects are not negligible) can modify this result and, for certain alloys and processing conditions, can cause the occurrence of hexagonal cells near the onset of instability.

Strained hybrid perovskite thin films and their impact on the intrinsic stability of perovskite solar cells

PubMed Central

Zhao, Jingjing; Deng, Yehao; Wei, Haotong; Zheng, Xiaopeng; Yu, Zhenhua; Shao, Yuchuan; Shield, Jeffrey E.; Huang, Jinsong

2017-01-01

Organic-inorganic hybrid perovskite (OIHP) solar cells have achieved comparable efficiencies to those of commercial solar cells, although their instability hinders their commercialization. Although encapsulation techniques have been developed to protect OIHP solar cells from external stimuli such as moisture, oxygen, and ultraviolet light, understanding of the origin of the intrinsic instability of perovskite films is needed to improve their stability. We show that the OIHP films fabricated by existing methods are strained and that strain is caused by mismatched thermal expansion of perovskite films and substrates during the thermal annealing process. The polycrystalline films have compressive strain in the out-of-plane direction and in-plane tensile strain. The strain accelerates degradation of perovskite films under illumination, which can be explained by increased ion migration in strained OIHP films. This study points out an avenue to enhance the intrinsic stability of perovskite films and solar cells by reducing residual strain in perovskite films. PMID:29159287

Tumors Induce Complex DNA Damage in Distant Proliferative Tissues in Vivo | Center for Cancer Research

Cancer.gov

In radiation biology, a bystander effect occurs when cells not directly exposed to ionizing radiation show increased genomic instability and impaired viability due to the release of signaling molecules by the irradiated cells in their vicinity. Christophe Redon, Ph.D., and colleagues in CCR’s Laboratory of Molecular Pharmacology, decided to ask whether a tumor itself could

Cellular instability in rapid directional solidification - Bifurcation theory

NASA Technical Reports Server (NTRS)

Braun, R. J.; Davis, S. H.

1992-01-01

Merchant and Davis performed a linear stability analysis on a model for the directional solidification of a dilute binary alloy valid for all speeds. The analysis revealed that nonequilibrium segregation effects modify the Mullins and Sekerka cellular mode, whereas attachment kinetics has no effect on these cells. In this paper, the nonlinear stability of the steady cellular mode is analyzed. A Landau equation is obtained that determines the amplitude of the cells. The Landau coefficient here depends on both nonequilibrium segregation effects and attachment kinetics. This equation gives the ranges of parameters for subcritical bifurcation (jump transition) or supercritical bifurcation (smooth transition) to cells.

Does buckling instability of the pseudopodium limit how well an amoeba can climb?

PubMed

Ghosal, Sandip; Fukui, Yoshio

2011-02-21

The maximum force that a crawling cell can exert on a substrate is a quantity of interest in cell biomechanics. One way of quantifying this force is to allow the cell to crawl against a measurable and adjustable restraining force until the cell is no longer able to move in a direction opposite to the applied force. Fukui et al. (2000) reported on an experiment where amoeboid cells were imaged while they crawled against an artificial gravity field created by a centrifuge. An unexpected observation was that the net applied force on the amoeba did not seem to be the primary factor that limited its ability to climb. Instead, it appeared that the amoeba stalled when it was no longer able to support a pseudopodium against the applied gravity field. The high g-load bend the pseudopodium thereby preventing its attachment to the target point directly ahead of the cell. In this paper we further refine this idea by identifying the bending of the pseudopodium with the onset of elastic instability of a beam under its own weight. It is shown that the principal features of the experiment may be understood through this model and an estimate for the limiting g-load in reasonable accord with the experimental measurements is recovered. Copyright © 2010 Elsevier Ltd. All rights reserved.

Characterization of a novel epigenetic effect of ionizing radiation: the death-inducing effect

NASA Technical Reports Server (NTRS)

Nagar, Shruti; Smith, Leslie E.; Morgan, William F.

2003-01-01

The detrimental effects associated with exposure to ionizing radiation have long been thought to result from the direct targeting of the nucleus leading to DNA damage; however, the emergence of concepts such as radiation-induced genomic instability and bystander effects have challenged this dogma. After cellular exposure to ionizing radiation, we have isolated a number of clones of Chinese hamster-human hybrid GM10115 cells that demonstrate genomic instability as measured by chromosomal destabilization. These clones show dynamic and persistent generation of chromosomal rearrangements multiple generations after the original insult. We hypothesize that these unstable clones maintain this delayed instability phenotype by secreting factors into the culture medium. To test this hypothesis we transferred filtered medium from unstable cells to unirradiated GM10115 cells. No GM10115 cells were able to survive this medium. This phenomenon by which GM10115 cells die when cultured in medium from chromosomally unstable GM10115 clones is the death-inducing effect. Medium transfer experiments indicate that a factor or factors is/are secreted by unstable cells within 8 h of growth in fresh medium and result in cell killing within 24 h. These factors are stable at ambient temperature but do not survive heating or freezing, and are biologically active when diluted with fresh medium. We present the initial description and characterization of the death-inducing effect. This novel epigenetic effect of radiation has implications for radiation risk assessment and for health risks associated with radiation exposure.

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.

Immortal, telomerase-negative cell lines derived from a Li-Fraumeni syndrome patient exhibit telomere length variability and chromosomal and minisatellite instabilities.

PubMed

Tsutsui, Takeki; Kumakura, Shin-Ichi; Tamura, Yukiko; Tsutsui, Takeo W; Sekiguchi, Mizuki; Higuchi, Tokihiro; Barrett, J Carl

2003-05-01

Five immortal cell lines derived from a Li-Fraumeni syndrome patient (MDAH 087) with a germline mutant p53 allele were characterized with respect to telomere length and genomic instability. The remaining wild-type p53 allele is lost in the cell lines. Telomerase activity was undetectable in all immortal cell lines. Five subclones of each cell line and five re-subclones of each of the subclones also showed undetectable telomerase activity. All five immortal cell lines exhibited variability in the mean length of terminal restriction fragments (TRFs). Subclones of each cell line, and re-subclones of the subclones also showed TRF variability, indicating that the variability is owing to clonal heterogeneity. Chromosome aberrations were observed at high frequencies in these cell lines including the subclones and re-subclones, and the principal types of aberrations were breaks, double minute chromosomes and dicentric chromosomes. In addition, minisatellite instability detected by DNA fingerprints was observed in the immortal cell lines. However, all of the cell lines were negative for microsatellite instability. As minisatellite sequences are considered recombinogenic in mammalian cells, these results suggest that recombination rates can be increased in these cell lines. Tumor-derived human cell lines, HT1080 cells and HeLa cells that also lack p53 function, exhibited little genomic instability involving chromosomal and minisatellite instabilities, indicating that chromosomal and minisatellite instabilities observed in the immortal cell lines lacking telomerase activity could not result from loss of p53 function.

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

PubMed

Baik, Jong Youn; Lee, Kelvin H

2017-05-01

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

Screening-Engineered Field-Effect Solar Cells

DTIC Science & Technology

2012-01-01

virtually any semiconductor, including the promising but hard-to- dope metal oxides, sulfides, and phosphides.3 Prototype SFPV devices have been...MIS interface. Unfortu- nately, MIS cells, though sporting impressive efficiencies,4−6 typically have short operating lifetimes due to surface state...instability at the MIS interface.7 Methods aimed at direct field- effect “ doping ” of semiconductors, in which the voltage is externally applied to a gate

Polyploidy can drive rapid adaptation in yeast

NASA Astrophysics Data System (ADS)

Selmecki, Anna M.; Maruvka, Yosef E.; Richmond, Phillip A.; Guillet, Marie; Shoresh, Noam; Sorenson, Amber L.; de, Subhajyoti; Kishony, Roy; Michor, Franziska; Dowell, Robin; Pellman, David

2015-03-01

Polyploidy is observed across the tree of life, yet its influence on evolution remains incompletely understood. Polyploidy, usually whole-genome duplication, is proposed to alter the rate of evolutionary adaptation. This could occur through complex effects on the frequency or fitness of beneficial mutations. For example, in diverse cell types and organisms, immediately after a whole-genome duplication, newly formed polyploids missegregate chromosomes and undergo genetic instability. The instability following whole-genome duplications is thought to provide adaptive mutations in microorganisms and can promote tumorigenesis in mammalian cells. Polyploidy may also affect adaptation independently of beneficial mutations through ploidy-specific changes in cell physiology. Here we perform in vitro evolution experiments to test directly whether polyploidy can accelerate evolutionary adaptation. Compared with haploids and diploids, tetraploids undergo significantly faster adaptation. Mathematical modelling suggests that rapid adaptation of tetraploids is driven by higher rates of beneficial mutations with stronger fitness effects, which is supported by whole-genome sequencing and phenotypic analyses of evolved clones. Chromosome aneuploidy, concerted chromosome loss, and point mutations all provide large fitness gains. We identify several mutations whose beneficial effects are manifest specifically in the tetraploid strains. Together, these results provide direct quantitative evidence that in some environments polyploidy can accelerate evolutionary adaptation.

Observation of astrophysical Weibel instability in counterstreaming laser-produced plasmas

NASA Astrophysics Data System (ADS)

Fox, W.; Fiksel, G.; Bhattacharjee, A.; Germaschewski, K.; Chang, P.-Y.; Hu, S. X.; Nilson, P. M.

2013-10-01

Astrophysical shocks are typically collisionless and require collective electromagnetic fields to couple the upstream and downstream plasmas. The Weibel instability has been proposed to be one of such collective mechanism. Here we present laboratory tests of this process through observations of the Weibel instability generated between two counterstreaming, supersonic plasma flows, generated on the OMEGA EP laser facility by irradiating of a pair of opposing parallel CH targets by UV laser pulses (0.351 μm, 1.8 kJ, 2 ns). The Weibel-generated electromagnetic fields were probed with an ultrafast proton beam, generated with a high-intensity laser pulse (1.053 μm, 800 J, 10 ps) focused to >1018 W/cm2 onto a thin Cu disk. Growth of a striated, transverse instability is observed at the midplane as the two plasmas interpenetrate, which is identified as the Weibel instability through agreement with analytic theory and particle-in-cell simulations. These laboratory observations directly demonstrate the existence of this astrophysical process, and pave the way for further detailed laboratory study of this instability and its consequences for particle energization and shock formation. This work was supported by DOE grant DE-SC0007168.

Electromagnetic Electron Cyclotron Instability in the Solar Wind

NASA Astrophysics Data System (ADS)

Lazar, M.; Yoon, P. H.; López, R. A.; Moya, P. S.

2018-01-01

The abundant reports on the existence of electromagnetic high-frequency fluctuations in space plasmas have increased the expectations that theoretical modeling may help understand their origins and implications (e.g., kinetic instabilities and dissipation). This paper presents an extended quasi-linear approach of the electromagnetic electron cyclotron instability in conditions typical for the solar wind, where the anisotropic electrons (T⊥>T∥) exhibit a dual distribution combining a bi-Maxwellian core and bi-Kappa halo. Involving both the core and halo populations, the instability is triggered by the cumulative effects of these components, mainly depending of their anisotropies. The instability is not very sensitive to the shape of halo distribution function conditioned in this case by the power index κ. This result seems to be a direct consequence of the low density of electron halo, which is assumed more dilute than the core component in conformity with the observations in the ecliptic. Quasi-linear time evolutions predicted by the theory are confirmed by the particle-in-cell simulations, which also suggest possible explanations for the inherent differences determined by theoretical constraints. These results provide premises for an advanced methodology to characterize, realistically, the electromagnetic electron cyclotron instability and its implication in the solar wind.

Fully kinetic Biermann battery and associated generation of pressure anisotropy

NASA Astrophysics Data System (ADS)

Schoeffler, K. M.; Loureiro, N. F.; Silva, L. O.

2018-03-01

The dynamical evolution of a fully kinetic, collisionless system with imposed background density and temperature gradients is investigated analytically. The temperature gradient leads to the generation of temperature anisotropy, with the temperature along the gradient becoming larger than that in the direction perpendicular to it. This causes the system to become unstable to pressure anisotropy driven instabilities, dominantly to the electron Weibel instability. When both density and temperature gradients are present and nonparallel to each other, we obtain a Biermann-like linear-in-time magnetic field growth. Accompanying particle-in-cell numerical simulations are shown to confirm our analytical results.

Bacteria exploit a polymorphic instability of the flagellar filament to escape from traps.

PubMed

Kühn, Marco J; Schmidt, Felix K; Eckhardt, Bruno; Thormann, Kai M

2017-06-13

Many bacterial species swim by rotating single polar helical flagella. Depending on the direction of rotation, they can swim forward or backward and change directions to move along chemical gradients but also to navigate their obstructed natural environment in soils, sediments, or mucus. When they get stuck, they naturally try to back out, but they can also resort to a radically different flagellar mode, which we discovered here. Using high-speed microscopy, we monitored the swimming behavior of the monopolarly flagellated species Shewanella putrefaciens with fluorescently labeled flagellar filaments at an agarose-glass interface. We show that, when a cell gets stuck, the polar flagellar filament executes a polymorphic change into a spiral-like form that wraps around the cell body in a spiral-like fashion and enables the cell to escape by a screw-like backward motion. Microscopy and modeling suggest that this propagation mode is triggered by an instability of the flagellum under reversal of the rotation and the applied torque. The switch is reversible and bacteria that have escaped the trap can return to their normal swimming mode by another reversal of motor direction. The screw-type flagellar arrangement enables a unique mode of propagation and, given the large number of polarly flagellated bacteria, we expect it to be a common and widespread escape or motility mode in complex and structured environments.

Processing of double-R-loops in (CAG)·(CTG) and C9orf72 (GGGGCC)·(GGCCCC) repeats causes instability

PubMed Central

Reddy, Kaalak; Schmidt, Monika H.M.; Geist, Jaimie M.; Thakkar, Neha P.; Panigrahi, Gagan B.; Wang, Yuh-Hwa; Pearson, Christopher E.

2014-01-01

R-loops, transcriptionally-induced RNA:DNA hybrids, occurring at repeat tracts (CTG)n, (CAG)n, (CGG)n, (CCG)n and (GAA)n, are associated with diseases including myotonic dystrophy, Huntington's disease, fragile X and Friedreich's ataxia. Many of these repeats are bidirectionally transcribed, allowing for single- and double-R-loop configurations, where either or both DNA strands may be RNA-bound. R-loops can trigger repeat instability at (CTG)·(CAG) repeats, but the mechanism of this is unclear. We demonstrate R-loop-mediated instability through processing of R-loops by HeLa and human neuron-like cell extracts. Double-R-loops induced greater instability than single-R-loops. Pre-treatment with RNase H only partially suppressed instability, supporting a model in which R-loops directly generate instability by aberrant processing, or via slipped-DNA formation upon RNA removal and its subsequent aberrant processing. Slipped-DNAs were observed to form following removal of the RNA from R-loops. Since transcriptionally-induced R-loops can occur in the absence of DNA replication, R-loop processing may be a source of repeat instability in the brain. Double-R-loop formation and processing to instability was extended to the expanded C9orf72 (GGGGCC)·(GGCCCC) repeats, known to cause amyotrophic lateral sclerosis and frontotemporal dementia, providing the first suggestion through which these repeats may become unstable. These findings provide a mechanistic basis for R-loop-mediated instability at disease-associated repeats. PMID:25147206

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.

Functions of Replication Protein A as a Sensor of R Loops and a Regulator of RNaseH1

PubMed Central

Nguyen, Hai Dang; Yadav, Tribhuwan; Giri, Sumanprava; Saez, Borja; Graubert, Timothy A.; Zou, Lee

2017-01-01

R loop, a transcription intermediate containing RNA:DNA hybrids and displaced single-stranded DNA (ssDNA), has emerged as a major source of genomic instability. RNaseH1, which cleaves the RNA in RNA:DNA hybrids, plays an important role in R loop suppression. Here, we show that replication protein A (RPA), a ssDNA-binding protein, interacts with RNaseH1 and colocalizes with both RNaseH1 and R loops in cells. In vitro, purified RPA directly enhances the association of RNaseH1 with RNA:DNA hybrids and stimulates the activity of RNaseH1 on R loops. An RPA binding-defective RNaseH1 mutant is not efficiently stimulated by RPA in vitro, fails to accumulate at R loops in cells, and loses the ability to suppress R loops and associated genomic instability. Thus, in addition to sensing DNA damage and replication stress, RPA is a sensor of R loops and a regulator of RNaseH1, extending the versatile role of RPA in suppression of genomic instability. PMID:28257700

The firehose instability during multiple reconnection in the Earth's magnetotail

NASA Astrophysics Data System (ADS)

Alexandrova, Alexandra; Divin, Andrey; Retino, Alessandro; Deca, Jan; Catapano, Filomena; Cozzani, Giulia

2017-04-01

We found unique events in the Cluster spacecraft observations of the Earth's magnetotail which correspond to the case of multiple reconnection sites. The ion temperature anisotropy of more energized ions in the direction parallel to the magnetic field, rather than in the perpendicular direction, is observed in the region of dynamical interaction between two active X-lines. The magnetic field and plasma parameters associated with the anisotropy correspond to the firehose instability conditions. We discuss possible scenarios of development of the firehose instability in multiple reconnection by comparing the observations with numerical simulations. Conventional Particle-in-Cell simulations of 2D magnetic reconnection starting from Harris equilibria are performed using implicit PIC code iPIC3D [Markidis, 2010]. At earlier stages the evolution creates fronts which push the weakly magnetized current sheet plasma away from the X-line. Fronts accelerate and reflect particles, producing parallel ion beams and increasing parallel ion temperature ahead of the front. If multiple X-lines are present, then the counterstreaming ion beams appear inside the original current sheet between colliding reconnection jet fronts. For large enough parallel ion pressure anisotropy, the firehose-like mode is excited inside the original current sheet with a flapping-like appearance along the X GSM direction but not Y GSM (current) direction. One should note that our simulations do not include the Bz magnetic field component (normal to the current sheet), hence ion beams cannot escape into the lobes and the whole region between two colliding fronts is unstable to firehose-like instability. In the Earth's magnetotail such configuration likely occurs when two active X-lines are close enough to each other, similar to a few cases we found in the Cluster observations.

Particle-induced viscous fingering

NASA Astrophysics Data System (ADS)

Lee, Sungyon

2017-11-01

An inclusion of non-colloidal particles in a Newtonian liquid can fundamentally change the interfacial dynamics and even cause interfacial instabilities. In this talk, we report a particle-induced fingering instability when a mixture of particles and viscous oil is injected radially into a Hele-Shaw cell. Our experimental results show that the onset and characteristics of fingering are most directly affected by the particle volume fraction but also depend on the ratio of the particle diameter to gap size. In particular, the formation of a particle band is observed on the interface only when the particle diameter is comparable to the channel gap thickness. This work demonstrates the complex coupling between suspensions and fluid-fluid interfaces and has broad relevance in suspension processing, particle self-assembly, and oil recovery processes. The physical mechanism behind the instability and a quantitative model are also discussed.

Head Direction Cell Instability in the Anterior Dorsal Thalamus after Lesions of the Interpeduncular Nucleus

PubMed Central

Clark, Benjamin J.; Sarma, Asha; Taube, Jeffrey S.

2009-01-01

Previous research has identified a population of cells throughout the limbic system that discharge as a function of the animals head direction (HD). Altering normal motor cues can alter the HD cell responses and disrupt the updating of their preferred firing directions, thus suggesting that motor cues contribute to processing the HD signal. A pathway that conveys motor information may stem from the interpeduncular nucleus (IPN), a brain region that has reciprocal connections with HD cell circuitry. To test this hypothesis, we produced electrolytic or neurotoxic lesions of the IPN and recorded HD cells in the anterior dorsal thalamus (ADN) of rats. Direction-specific firing remained present in the ADN after lesions of the IPN, but measures of HD cell properties showed that cells had reduced peak firing rates, large directional firing ranges, and firing that predicted the animal’s future heading more than in intact controls. Furthermore, preferred firing directions were moderately less influenced by rotation of a salient visual landmark. Finally, the preferred directions of cells in lesioned rats exhibited large shifts when the animals foraged for scattered food-pellets in a darkened environment and when locomoting from a familiar environment to a novel one. We propose that the IPN contributes motor information about the animal’s movements to the HD cell circuitry. Further, these results suggest that the IPN plays a broad role in the discharge properties and stability of direction-specific activity in the HD cell circuit. PMID:19144850

On the numerical dispersion of electromagnetic particle-in-cell code: Finite grid instability

NASA Astrophysics Data System (ADS)

Meyers, M. D.; Huang, C.-K.; Zeng, Y.; Yi, S. A.; Albright, B. J.

2015-09-01

The Particle-In-Cell (PIC) method is widely used in relativistic particle beam and laser plasma modeling. However, the PIC method exhibits numerical instabilities that can render unphysical simulation results or even destroy the simulation. For electromagnetic relativistic beam and plasma modeling, the most relevant numerical instabilities are the finite grid instability and the numerical Cherenkov instability. We review the numerical dispersion relation of the Electromagnetic PIC model. We rigorously derive the faithful 3-D numerical dispersion relation of the PIC model, for a simple, direct current deposition scheme, which does not conserve electric charge exactly. We then specialize to the Yee FDTD scheme. In particular, we clarify the presence of alias modes in an eigenmode analysis of the PIC model, which combines both discrete and continuous variables. The manner in which the PIC model updates and samples the fields and distribution function, together with the temporal and spatial phase factors from solving Maxwell's equations on the Yee grid with the leapfrog scheme, is explicitly accounted for. Numerical solutions to the electrostatic-like modes in the 1-D dispersion relation for a cold drifting plasma are obtained for parameters of interest. In the succeeding analysis, we investigate how the finite grid instability arises from the interaction of the numerical modes admitted in the system and their aliases. The most significant interaction is due critically to the correct representation of the operators in the dispersion relation. We obtain a simple analytic expression for the peak growth rate due to this interaction, which is then verified by simulation. We demonstrate that our analysis is readily extendable to charge conserving models.

On the numerical dispersion of electromagnetic particle-in-cell code: Finite grid instability

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

Meyers, M.D., E-mail: mdmeyers@physics.ucla.edu; Department of Physics and Astronomy, University of California Los Angeles, Los Angeles, CA 90095; Huang, C.-K., E-mail: huangck@lanl.gov

The Particle-In-Cell (PIC) method is widely used in relativistic particle beam and laser plasma modeling. However, the PIC method exhibits numerical instabilities that can render unphysical simulation results or even destroy the simulation. For electromagnetic relativistic beam and plasma modeling, the most relevant numerical instabilities are the finite grid instability and the numerical Cherenkov instability. We review the numerical dispersion relation of the Electromagnetic PIC model. We rigorously derive the faithful 3-D numerical dispersion relation of the PIC model, for a simple, direct current deposition scheme, which does not conserve electric charge exactly. We then specialize to the Yee FDTDmore » scheme. In particular, we clarify the presence of alias modes in an eigenmode analysis of the PIC model, which combines both discrete and continuous variables. The manner in which the PIC model updates and samples the fields and distribution function, together with the temporal and spatial phase factors from solving Maxwell's equations on the Yee grid with the leapfrog scheme, is explicitly accounted for. Numerical solutions to the electrostatic-like modes in the 1-D dispersion relation for a cold drifting plasma are obtained for parameters of interest. In the succeeding analysis, we investigate how the finite grid instability arises from the interaction of the numerical modes admitted in the system and their aliases. The most significant interaction is due critically to the correct representation of the operators in the dispersion relation. We obtain a simple analytic expression for the peak growth rate due to this interaction, which is then verified by simulation. We demonstrate that our analysis is readily extendable to charge conserving models.« less

Telomere dynamics, end-to-end fusions and telomerase activation during the human fibroblast immortalization process.

PubMed

Ducray, C; Pommier, J P; Martins, L; Boussin, F D; Sabatier, L

1999-07-22

Loss of telomeric repeats during cell proliferation could play a role in senescence. It has been generally assumed that activation of telomerase prevents further telomere shortening and is essential for cell immortalization. In this study, we performed a detailed cytogenetic and molecular characterization of four SV40 transformed human fibroblastic cell lines by regularly monitoring the size distribution of terminal restriction fragments, telomerase activity and the associated chromosomal instability throughout immortalization. The mean TRF lengths progressively decreased in pre-crisis cells during the lifespan of the cultures. At crisis, telomeres reached a critical size, different among the cell lines, contributing to the peak of dicentric chromosomes, which resulted mostly from telomeric associations. We observed a direct correlation between short telomere length at crisis and chromosomal instability. In two immortal cell lines, although telomerase was detected, mean telomere length still continued to decrease whereas the number of dicentric chromosomes associated was stabilized. Thus telomerase could protect specifically telomeres which have reached a critical size against end-to-end dicentrics, while long telomeres continue to decrease, although at a slower rate as before crisis. This suggests a balance between elongation by telomerase and telomere shortening, towards a stabilized 'optimal' length.

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

NASA Technical Reports Server (NTRS)

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

2001-01-01

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

Experimental viscous fingering in a tapered radial Hele-Shaw cell

NASA Astrophysics Data System (ADS)

Bongrand, Gregoire; Tsai, Peichun Amy; Complex Fludis Group Team

2017-11-01

The fluid-fluid displacement in porous media is a common process that finds direct applications in various fields, such as enhanced oil recovery and geological CO2 sequestration. In this work, we experimentally investigate the influence of converging cells on viscous fingering instabilities using a radially-tapered cell. For air displacing oil, in contrast to the classical Saffman-Taylor fingering, our results show that a converging gradient in a radial propagation can provide a stabilizing effect and hinder fingering. For a fixed gap gradient and thickness, with increasing injection rates we find a stable displacement under small flow rates, whereas unstable fingering occurs above a certain threshold. We further investigate this critical flow rate delineating the stable and unstable regimes for different gap gradients. These results reveal that the displacement efficiency not only depends on the fluid properties but also on the interfacial velocity and channel structure. The latter factors provide a useful and convenient control to either trigger or inhibit fingering instability. NSERC Discovery, Accelerator, and CRC programs.

Numerical Simulation of the Generation of Axisymmetric Mode Jet Screech Tones

NASA Technical Reports Server (NTRS)

Shen, Hao; Tam, Christopher K. W.

1998-01-01

An imperfectly expanded supersonic jet, invariably, radiates both broadband noise and discrete frequency sound called screech tones. Screech tones are known to be generated by a feedback loop driven by the large scale instability waves of the jet flow. Inside the jet plume is a quasi-periodic shock cell structure. The interaction of the instability waves and the shock cell structure, as the former propagates through the latter, is responsible for the generation of the tones. Presently, there are formulas that can predict the tone frequency fairly accurately. However, there is no known way to predict the screech tone intensity. In this work, the screech phenomenon of an axisymmetric jet at low supersonic Mach number is reproduced by numerical simulation. The computed mean velocity profiles and the shock cell pressure distribution of the jet are found to be in good agreement with experimental measurements. The same is true with the simulated screech frequency. Calculated screech tone intensity and directivity at selected jet Mach number are reported in this paper. The present results demonstrate that numerical simulation using computational aeroacoustics methods offers not only a reliable way to determine the screech tone intensity and directivity but also an opportunity to study the physics and detailed mechanisms of the phenomenon by an entirely new approach.

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.

Direct and indirect roles of RECQL4 in modulating base excision repair capacity

PubMed Central

Schurman, Shepherd H.; Hedayati, Mohammad; Wang, ZhengMing; Singh, Dharmendra K.; Speina, Elzbieta; Zhang, Yongqing; Becker, Kevin; Macris, Margaret; Sung, Patrick; Wilson, David M.; Croteau, Deborah L.; Bohr, Vilhelm A.

2009-01-01

RECQL4 is a human RecQ helicase which is mutated in approximately two-thirds of individuals with Rothmund–Thomson syndrome (RTS), a disease characterized at the cellular level by chromosomal instability. BLM and WRN are also human RecQ helicases, which are mutated in Bloom and Werner's syndrome, respectively, and associated with chromosomal instability as well as premature aging. Here we show that primary RTS and RECQL4 siRNA knockdown human fibroblasts accumulate more H2O2-induced DNA strand breaks than control cells, suggesting that RECQL4 may stimulate repair of H2O2-induced DNA damage. RTS primary fibroblasts also accumulate more XRCC1 foci than control cells in response to endogenous or induced oxidative stress and have a high basal level of endogenous formamidopyrimidines. In cells treated with H2O2, RECQL4 co-localizes with APE1, and FEN1, key participants in base excision repair. Biochemical experiments indicate that RECQL4 specifically stimulates the apurinic endonuclease activity of APE1, the DNA strand displacement activity of DNA polymerase β, and incision of a 1- or 10-nucleotide flap DNA substrate by Flap Endonuclease I. Additionally, RTS cells display an upregulation of BER pathway genes and fail to respond like normal cells to oxidative stress. The data herein support a model in which RECQL4 regulates both directly and indirectly base excision repair capacity. PMID:19567405

Investigating the anticipatory postural adjustment phase of gait initiation in different directions in chronic ankle instability patients.

PubMed

Ebrahimabadi, Zahra; Naimi, Sedigheh Sadat; Rahimi, Abbas; Sadeghi, Heydar; Hosseini, Seyed Majid; Baghban, Alireza Akbarzadeh; Arslan, Syed Asadullah

2018-01-01

The main objective of the present study was to analyze how supra spinal motor control mechanisms are altered in different directions during anticipatory postural phase of gait initiation in chronic ankle instability patients. It seems that supra spinal pathways modulate anticipatory postural adjustment phase of gait initiation. Yet, there is a dearth of research on the effect of chronic ankle instability on the anticipatory postural adjustment phase of gait initiation in different directions. A total of 20 chronic ankle instability participants and 20 healthy individuals initiated gait on a force plate in forward, 30° lateral, and 30° medial directions. According to the results of the present study, the peak lateral center of pressure shift decreased in forward direction compared to that in other directions in both groups. Also, it was found that the peak lateral center of pressure shift and the vertical center of mass velocity decreased significantly in chronic ankle instability patients, as compared with those of the healthy individuals. According to the results of the present study, it seems that chronic ankle instability patients modulate the anticipatory postural adjustment phase of gait initiation, compared with healthy control group, in order to maintain postural stability. These changes were observed in different directions, too. Copyright © 2017 Elsevier Ltd. All rights reserved.

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.

TP53-dependent chromosome instability is associated with transient reductions in telomere length in immortal telomerase-positive cell lines

NASA Technical Reports Server (NTRS)

Schwartz, J. L.; Jordan, R.; Liber, H.; Murnane, J. P.; Evans, H. H.

2001-01-01

Telomere shortening in telomerase-negative somatic cells leads to the activation of the TP53 protein and the elimination of potentially unstable cells. We examined the effect of TP53 gene expression on both telomere metabolism and chromosome stability in immortal, telomerase-positive cell lines. Telomere length, telomerase activity, and chromosome instability were measured in multiple clones isolated from three related human B-lymphoblast cell lines that vary in TP53 expression; TK6 cells express wild-type TP53, WTK1 cells overexpress a mutant form of TP53, and NH32 cells express no TP53 protein. Clonal variations in both telomere length and chromosome stability were observed, and shorter telomeres were associated with higher levels of chromosome instability. The shortest telomeres were found in WTK1- and NH32-derived cells, and these cells had 5- to 10-fold higher levels of chromosome instability. The primary marker of instability was the presence of dicentric chromosomes. Aneuploidy and other stable chromosome alterations were also found in clones showing high levels of dicentrics. Polyploidy was found only in WTK1-derived cells. Both telomere length and chromosome instability fluctuated in the different cell populations with time in culture, presumably as unstable cells and cells with short telomeres were eliminated from the growing population. Our results suggest that transient reductions in telomere lengths may be common in immortal cell lines and that these alterations in telomere metabolism can have a profound effect on chromosome stability. Copyright 2000 Wiley-Liss, Inc.

Understanding force-generating microtubule systems through in vitro reconstitution

PubMed Central

Kok, Maurits; Dogterom, Marileen

2016-01-01

ABSTRACT Microtubules switch between growing and shrinking states, a feature known as dynamic instability. The biochemical parameters underlying dynamic instability are modulated by a wide variety of microtubule-associated proteins that enable the strict control of microtubule dynamics in cells. The forces generated by controlled growth and shrinkage of microtubules drive a large range of processes, including organelle positioning, mitotic spindle assembly, and chromosome segregation. In the past decade, our understanding of microtubule dynamics and microtubule force generation has progressed significantly. Here, we review the microtubule-intrinsic process of dynamic instability, the effect of external factors on this process, and how the resulting forces act on various biological systems. Recently, reconstitution-based approaches have strongly benefited from extensive biochemical and biophysical characterization of individual components that are involved in regulating or transmitting microtubule-driven forces. We will focus on the current state of reconstituting increasingly complex biological systems and provide new directions for future developments. PMID:27715396

Ambient Oxygen Promotes Tumorigenesis

PubMed Central

Starost, Matthew F.; Lago, Cory U.; Lim, Philip K.; Sack, Michael N.; Kang, Ju-Gyeong; Wang, Ping-yuan; Hwang, Paul M.

2011-01-01

Oxygen serves as an essential factor for oxidative stress, and it has been shown to be a mutagen in bacteria. While it is well established that ambient oxygen can also cause genomic instability in cultured mammalian cells, its effect on de novo tumorigenesis at the organismal level is unclear. Herein, by decreasing ambient oxygen exposure, we report a ∼50% increase in the median tumor-free survival time of p53−/− mice. In the thymus, reducing oxygen exposure decreased the levels of oxidative DNA damage and RAG recombinase, both of which are known to promote lymphomagenesis in p53−/− mice. Oxygen is further shown to be associated with genomic instability in two additional cancer models involving the APC tumor suppressor gene and chemical carcinogenesis. Together, these observations represent the first report directly testing the effect of ambient oxygen on de novo tumorigenesis and provide important physiologic evidence demonstrating its critical role in increasing genomic instability in vivo. PMID:21589870

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

Conditional fast expression and function of multimeric TRPV5 channels using Shield-1.

PubMed

Schoeber, Joost P H; van de Graaf, Stan F J; Lee, Kyu Pil; Wittgen, Hanneke G M; Hoenderop, Joost G J; Bindels, René J M

2009-01-01

A recently described novel controllable method to regulate protein expression is based on a mutated FK506-binding protein-12 (mtFKBP) that is unstable and rapidly degraded in mammalian cells. This instability can be conferred to other proteins directly fused to mtFKBP. Binding of a synthetic cell-permeant ligand (Shield-1) to mtFKBP reverses the instability, allowing conditional expression of mtFKBP-fused proteins. We adapted this strategy to study multimeric plasma membrane proteins using the ion channel TRPV5 as model protein. mtFKBP-TRPV5 forms functional ion channels and its expression can be controlled in a time- and dose-dependent fashion using Shield-1. Moreover, in the presence of Shield-1, mtFKBP-TRPV5 formed heteromultimeric channels with untagged TRPV5, which were codegraded upon washout of Shield-1, providing a strategy to study multimeric plasma membrane protein complexes without the need to destabilize all individual subunits.

Tumors Induce Complex DNA Damage in Distant Proliferative Tissues in Vivo | Center for Cancer Research

Cancer.gov

In radiation biology, a bystander effect occurs when cells not directly exposed to ionizing radiation show increased genomic instability and impaired viability due to the release of signaling molecules by the irradiated cells in their vicinity. Christophe Redon, Ph.D., and colleagues in CCR’s Laboratory of Molecular Pharmacology, decided to ask whether a tumor itself could exhibit a similar effect. Their results were recently published in the Proceedings of the National Academy of Sciences.

Wave Turning and Flow Angle in the E-Region Ionosphere

NASA Astrophysics Data System (ADS)

Young, M.; Oppenheim, M. M.; Dimant, Y. S.

2016-12-01

This work presents results of particle-in-cell (PIC) simulations of Farley-Buneman (FB) turbulence at various altitudes in the high-latitude E-region ionosphere. In that region, the FB instability regularly produces meter-scale plasma irregularities. VHF radars observe coherent echoes via Bragg scatter from wave fronts parallel or anti-parallel to the radar line of sight (LoS) but do not necessarily measure the mean direction of wave propagation. Haldoupis (1984) conducted a study of diffuse radar aurora and found that the spectral width of back-scattered power depends critically on the angle between the radar LoS and the true flow direction, called the flow angle. Knowledge of the flow angle will allow researchers to better interpret observations of coherent back-scatter. Experiments designed to observe meter-scale irregularities in the E-region ionosphere created by the FB instability typically assume that the predominant flow direction is the E×B direction. However, linear theory of Dimant and Oppenheim (2004) showed that FB waves should turn away from E×B and particle-in-cell simulations by Oppenheim and Dimant (2013) support the theory. The present study comprises a quantitative analysis of the dependence of back-scattered power, flow velocity, and spectral width as functions of the flow angle. It also demonstrates that the mean direction of meter-scale wave propagation may differ from the E×B direction by tens of degrees. The analysis includes 2-D and 3-D simulations at a range of altitudes in the auroral ionosphere. Comparison between 2-D and 3-D simulations illustrates the relative importance to the irregularity spectrum of a small but finite component in the direction parallel to B. Previous work has shown this small parallel component to be important to turbulent electron heating and nonlinear transport.

Development and Characterization of a High Throughput Screen to investigate the delayed Effects of Radiations Commonly Encountered in Space

NASA Astrophysics Data System (ADS)

Morgan, W. F.

Astronauts based on the space station or on long-term space missions will be exposed to high Z radiations in the cosmic environment In order to evaluate the potentially deleterious effects of exposure to radiations commonly encountered in space we have developed and characterized a high throughput assay to detect mutation deletion events and or hyperrecombination in the progeny of exposed cells This assay is based on a plasmid vector containing a green fluorescence protein reporter construct We have shown that after stable transfection of the vector into human or hamster cells this construct can identify mutations specifically base changes and deletions as well as recombination events e g gene conversion or homologous recombination occurring as a result of exposure to ionizing radiation Our focus has been on those events occurring in the progeny of an irradiated cell that are potentially associated with radiation induced genomic instability rather than the more conventional assays that evaluate the direct immediate effects of radiation exposure Considerable time has been spent automating analysis of surviving colonies as a function of time after irradiation in order to determine when delayed instability is induced and the consequences of this delayed instability The assay is now automated permitting the evaluation of potentially rare events associated with low dose low dose rate radiations commonly encountered in space

Linear Instability of a Uni-Directional Transversely Sheared Mean Flow

NASA Technical Reports Server (NTRS)

Wundrow, David W.

1996-01-01

The effect of spanwise-periodic mean-flow distortions (i.e. streamwise-vortex structures) on the evolution of small-amplitude, single-frequency instability waves in an otherwise two-dimensional shear flow is investigated. The streamwise-vortex structures are taken to be just weak enough so that the spatially growing instability waves behave (locally) like linear perturbations about a uni-directional transversely sheared mean flow. Numerical solutions are computed and discussed for both the mean flow and the instability waves. The influence of the streamwise-vortex wavelength on the properties of the most rapidly growing instability wave is also discussed.

Genomic instability and tumorigenic induction in immortalized human bronchial epithelial cells by heavy ions

NASA Astrophysics Data System (ADS)

Hei, T. K.; Piao, C. Q.; Wu, L. J.; Willey, J. C.; Hall, E. J.

1998-11-01

Carcinogenesis is postulated to be a progressive multistage process characterized by an increase in genomic instability and clonal selection with each mutational event endowing a selective growth advantage. Genomic instability as manifested by the amplification of specific gene fragments is common among tumor and transformed cells. In the present study, immortalized human bronchial (BEP2D) cells were irradiated with graded doses of either 1GeV/nucleon 56Fe ions or 150 keV/μm alpha particles. Transformed cells developed through a series of successive steps before becoming tumorigenic in nude mice. Tumorigenic cells showed neither ras mutations nor deletion in the p16 tumor suppressor gene. In contrast, they harbored mutations in the p53 gene and over-expressed cyclin D1. Genomic instability among transformed cells at various stage of the carcinogenic process was examined based on frequencies of PALA resistance. Incidence of genomic instability was highest among established tumor cell lines relative to transformed, non-tumorigenic and control cell lines. Treatment of BEP2D cells with a 4 mM dose of the aminothiol WR-1065 significantly reduced their neoplastic transforming response to 56Fe particles. This model provides an opportunity to study the cellular and molecular mechanisms involved in malignant transformation of human epithelial cells by heavy ions.

Radiation-induced genomic instability and its implications for radiation carcinogenesis

NASA Technical Reports Server (NTRS)

Huang, Lei; Snyder, Andrew R.; Morgan, William F.

2003-01-01

Radiation-induced genomic instability is characterized by an increased rate of genetic alterations including cytogenetic rearrangements, mutations, gene amplifications, transformation and cell death in the progeny of irradiated cells multiple generations after the initial insult. Chromosomal rearrangements are the best-characterized end point of radiation-induced genomic instability, and many of the rearrangements described are similar to those found in human cancers. Chromosome breakage syndromes are defined by chromosome instability, and individuals with these diseases are cancer prone. Consequently, chromosomal instability as a phenotype may underlie some fraction of those changes leading to cancer. Here we attempt to relate current knowledge regarding radiation-induced chromosome instability with the emerging molecular information on the chromosome breakage syndromes. The goal is to understand how genetic and epigenetic factors might influence the onset of chromosome instability and the role of chromosomal instability in carcinogenesis.

Theory for the anomalous electron transport in Hall-effect thrusters

NASA Astrophysics Data System (ADS)

Lafleur, Trevor; Baalrud, Scott; Chabert, Pascal

2016-09-01

Using insights from particle-in-cell (PIC) simulations, we develop a kinetic theory to explain the anomalous cross-field electron transport in Hall-effect thrusters (HETs). The large axial electric field in the acceleration region of HETs, together with the radially applied magnetic field, causes electrons to drift in the azimuthal direction with a very high velocity. This drives an electron cyclotron instability that produces large amplitude oscillations in the plasma density and azimuthal electric field, and which is convected downstream due to the large axial ion drift velocity. The frequency and wavelength of the instability are of the order of 5 MHz and 1 mm respectively, while the electric field amplitude can be of a similar magnitude to axial electric field itself. The instability leads to enhanced electron scattering many orders of magnitude higher than that from standard electron-neutral or electron-ion Coulomb collisions, and gives electron mobilities in good agreement with experiment. Since the instability is a strong function of almost all plasma properties, the mobility cannot in general be fitted with simple 1/B or 1/B2 scaling laws, and changes to the secondary electron emission coefficient of the HET channel walls are expected to play a role in the evolution of the instability. This work received financial support from a CNES postdoctoral research award.

Aneuploidy in immortalized human mesenchymal stem cells with non-random loss of chromosome 13 in culture.

PubMed

Takeuchi, Masao; Takeuchi, Kikuko; Ozawa, Yutaka; Kohara, Akihiro; Mizusawa, Hiroshi

2009-01-01

Aneuploidy (an abnormal number of chromosomes) is commonly observed in most human cancer cells, highlighting the need to examine chromosomal instability in tumorigenesis. Previously, the immortalized human mesenchymal stem cell line UE6E7T-3 was shown to undergo a preferential loss of one copy of chromosome 13 after prolonged culture. Here, the loss of chromosome 13 was found to be caused by chromosome missegregation during mitosis, which involved unequal segregation, exclusion of the misaligned chromosome 13 on the metaphase plate, and trapping of chromosome 13 in the midbody region, as observed by fluorescence in situ hybridization. Near-diploid aneuploidy, not tetraploidy, was the direct result. The loss of chromosome 13 was non-random, and was detected by analysis of microsatellites and single nucleotide polymorphism-based loss of heterozygosity (LOH). Of the five microsatellite loci on chromosome 13, four loci showed microsatellite instability at an early stage in culture, and LOH was apparent at a late stage in culture. These results suggest that the microsatellite mutations cause changes in centromere integrity provoking loss of this chromosome in the UE6E7T-3 cell line. Thus, these results support the use of this cell line as a useful model for understanding the mechanism of aneuploid formation in cell cultures.

Environmental stress induces trinucleotide repeat mutagenesis in human cells

PubMed Central

Chatterjee, Nimrat; Lin, Yunfu; Santillan, Beatriz A.; Yotnda, Patricia; Wilson, John H.

2015-01-01

The dynamic mutability of microsatellite repeats is implicated in the modification of gene function and disease phenotype. Studies of the enhanced instability of long trinucleotide repeats (TNRs)—the cause of multiple human diseases—have revealed a remarkable complexity of mutagenic mechanisms. Here, we show that cold, heat, hypoxic, and oxidative stresses induce mutagenesis of a long CAG repeat tract in human cells. We show that stress-response factors mediate the stress-induced mutagenesis (SIM) of CAG repeats. We show further that SIM of CAG repeats does not involve mismatch repair, nucleotide excision repair, or transcription, processes that are known to promote TNR mutagenesis in other pathways of instability. Instead, we find that these stresses stimulate DNA rereplication, increasing the proportion of cells with >4 C-value (C) DNA content. Knockdown of the replication origin-licensing factor CDT1 eliminates both stress-induced rereplication and CAG repeat mutagenesis. In addition, direct induction of rereplication in the absence of stress also increases the proportion of cells with >4C DNA content and promotes repeat mutagenesis. Thus, environmental stress triggers a unique pathway for TNR mutagenesis that likely is mediated by DNA rereplication. This pathway may impact normal cells as they encounter stresses in their environment or during development or abnormal cells as they evolve metastatic potential. PMID:25775519

Environmental stress induces trinucleotide repeat mutagenesis in human cells.

PubMed

Chatterjee, Nimrat; Lin, Yunfu; Santillan, Beatriz A; Yotnda, Patricia; Wilson, John H

2015-03-24

The dynamic mutability of microsatellite repeats is implicated in the modification of gene function and disease phenotype. Studies of the enhanced instability of long trinucleotide repeats (TNRs)-the cause of multiple human diseases-have revealed a remarkable complexity of mutagenic mechanisms. Here, we show that cold, heat, hypoxic, and oxidative stresses induce mutagenesis of a long CAG repeat tract in human cells. We show that stress-response factors mediate the stress-induced mutagenesis (SIM) of CAG repeats. We show further that SIM of CAG repeats does not involve mismatch repair, nucleotide excision repair, or transcription, processes that are known to promote TNR mutagenesis in other pathways of instability. Instead, we find that these stresses stimulate DNA rereplication, increasing the proportion of cells with >4 C-value (C) DNA content. Knockdown of the replication origin-licensing factor CDT1 eliminates both stress-induced rereplication and CAG repeat mutagenesis. In addition, direct induction of rereplication in the absence of stress also increases the proportion of cells with >4C DNA content and promotes repeat mutagenesis. Thus, environmental stress triggers a unique pathway for TNR mutagenesis that likely is mediated by DNA rereplication. This pathway may impact normal cells as they encounter stresses in their environment or during development or abnormal cells as they evolve metastatic potential.

Activation of Dun1 in response to nuclear DNA instability accounts for the increase in mitochondrial point mutations in Rad27/FEN1 deficient S. cerevisiae.

PubMed

Kaniak-Golik, Aneta; Kuberska, Renata; Dzierzbicki, Piotr; Sledziewska-Gojska, Ewa

2017-01-01

Rad27/FEN1 nuclease that plays important roles in the maintenance of DNA stability in the nucleus has recently been shown to reside in mitochondria. Accordingly, it has been established that Rad27 deficiency causes increased mutagenesis, but decreased microsatellite instability and homologous recombination in mitochondria. Our current analysis of mutations leading to erythromycin resistance indicates that only some of them arise in mitochondrial DNA and that the GC→AT transition is a hallmark of the mitochondrial mutagenesis in rad27 null background. We also show that the mitochondrial mutator phenotype resulting from Rad27 deficiency entirely depends on the DNA damage checkpoint kinase Dun1. DUN1 inactivation suppresses the mitochondrial mutator phenotype caused by Rad27 deficiency and this suppression is eliminated at least in part by subsequent deletion of SML1 encoding a repressor of ribonucleotide reductase. We conclude that Rad27 deficiency causes a mitochondrial mutator phenotype via activation of DNA damage checkpoint kinase Dun1 and that a Dun1-mediated increase of dNTP pools contributes to this phenomenon. These results point to the nuclear DNA instability as the source of mitochondrial mutagenesis. Consistently, we show that mitochondrial mutations occurring more frequently in yeast devoid of Rrm3, a DNA helicase involved in rDNA replication, are also dependent on Dun1. In addition, we have established that overproduction of Exo1, which suppresses DNA damage sensitivity and replication stress in nuclei of Rad27 deficient cells, but does not enter mitochondria, suppresses the mitochondrial mutagenesis. Exo1 overproduction restores also a great part of allelic recombination and microsatellite instability in mitochondria of Rad27 deficient cells. In contrast, the overproduction of Exo1 does not influence mitochondrial direct-repeat mediated deletions in rad27 null background, pointing to this homologous recombination pathway as the direct target of Rad27 activity in mitochondria.

Activation of Dun1 in response to nuclear DNA instability accounts for the increase in mitochondrial point mutations in Rad27/FEN1 deficient S. cerevisiae

PubMed Central

Dzierzbicki, Piotr

2017-01-01

Rad27/FEN1 nuclease that plays important roles in the maintenance of DNA stability in the nucleus has recently been shown to reside in mitochondria. Accordingly, it has been established that Rad27 deficiency causes increased mutagenesis, but decreased microsatellite instability and homologous recombination in mitochondria. Our current analysis of mutations leading to erythromycin resistance indicates that only some of them arise in mitochondrial DNA and that the GC→AT transition is a hallmark of the mitochondrial mutagenesis in rad27 null background. We also show that the mitochondrial mutator phenotype resulting from Rad27 deficiency entirely depends on the DNA damage checkpoint kinase Dun1. DUN1 inactivation suppresses the mitochondrial mutator phenotype caused by Rad27 deficiency and this suppression is eliminated at least in part by subsequent deletion of SML1 encoding a repressor of ribonucleotide reductase. We conclude that Rad27 deficiency causes a mitochondrial mutator phenotype via activation of DNA damage checkpoint kinase Dun1 and that a Dun1-mediated increase of dNTP pools contributes to this phenomenon. These results point to the nuclear DNA instability as the source of mitochondrial mutagenesis. Consistently, we show that mitochondrial mutations occurring more frequently in yeast devoid of Rrm3, a DNA helicase involved in rDNA replication, are also dependent on Dun1. In addition, we have established that overproduction of Exo1, which suppresses DNA damage sensitivity and replication stress in nuclei of Rad27 deficient cells, but does not enter mitochondria, suppresses the mitochondrial mutagenesis. Exo1 overproduction restores also a great part of allelic recombination and microsatellite instability in mitochondria of Rad27 deficient cells. In contrast, the overproduction of Exo1 does not influence mitochondrial direct-repeat mediated deletions in rad27 null background, pointing to this homologous recombination pathway as the direct target of Rad27 activity in mitochondria. PMID:28678842

[Radiation-induced genomic instability: phenomenon, molecular mechanisms, pathogenetic significance].

PubMed

Mazurik, V K; Mikhaĭlov, V F

2001-01-01

The recent data on the radiation-induced genome instability as a special state of progeny of cells irradiated in vitro as well as after a whole body exposure to ionizing radiation, that make these cells considerably different from normal, unirradiated cells, were considered. This state presents a number of cytogenetical, molecular-biological, cytological and biochemical manifestations untypical for normal cells. The state is controlled by the mechanisms of regulation of checkpoints of cell cycle, and apoptosis, that is under gene p53 control. The proof has been found that this state transfers from irradiated maternal cells to their surviving progeny by the epigenetical mechanisms and would exist until the cells restore the original state of response on the DNA damage. From the point of view of the genome instability conception, that considers the chromatine rearrangement as the adaptive-evolution mechanism of adaptation of the species to changeable environmental conditions, the radiation-induced genome instability may be considered as transition of irradiated progeny to the state of read these to adaptation changes with two alternative pathways. The first leads to adaptation to enviromental conditions and restoring of normal cell functions. The second presents the cell transition into the transformed state with remain genome instability and with increase of tumour growth probability.

Pattern Formation in Complex Fluids

NASA Astrophysics Data System (ADS)

Shelley, Michael

2000-03-01

Classical fluid instabilities -- such as the Saffman-Taylor instability in a Hele-Shaw cell -- are dramatically modified by using complex fluids. For example, polymeric liquids driven in a Hele-Shaw cell yield "dendritic" patterns with an apparent directional anisotropy. The dynamics of complex liquids can also lead to new instabilities and patterns, such as space-filling patterns formed by successive bucklings of growing "elastica" seen in the phase transition of a liquid crystalline material. Understanding such problems requires an interplay between physical modeling, mathematical analysis, and sophisticated nonlinear simulation. For the first problem, I will discuss a non-Newtonian version of Darcy's law for Hele-Shaw flow. This yields a free-boundary problem for the pattern formation, and requires the solution of a nonlinear elliptic equation in a time-dependent domain. This is pushing the development of adaptive grid methods that represent the geometry accurately and efficiently. Our simulations yield insight into how shear-thinning, as is evinced by polymeric liquids, can produce patterns reminiscent of experiment, with "dendritic fingers", side-branching, and reduced tip-splitting. In the second problem, a long filament in a smectic-A phase grows within an isotropic fluid. The splay deformation of the material gives this filament an elastic response. The macroscopic model describes the dynamics of a growing, elastic filament immersed in a Stokesian fluid. The model marries filament elasticity and tensile forces with a numerically tractable nonlocal slender-body theory. Analysis shows that growth of the filament, despite fluid drag, produces a buckling instability. When coupled to a nonlocal hydrodynamic self-interaction, our fully nonlinear simulations show that such instabilities iterate along the filament, and give "space-filling" patterns.

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

NASA Technical Reports Server (NTRS)

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

1999-01-01

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

A study of the temporal stability of multiple cell vortices

NASA Technical Reports Server (NTRS)

Khorrami, Mehdi R.

1989-01-01

The effect of initial mean velocity field on the stability characteristics of longitudinal vortices is documented in detail. The temporal stability of isolated multiple cell vortices is considered. The types of vortices studied include single cell as well as two and three cell vortices. It is shown that cell multiplicity in the vortex core has drastic effects on the stability characteristics. On the basis of numerical calculations, it is concluded that the growth rates of instabilities in multiple cell vortices are substantially larger (two to threefold increases are observed) than those of a single cell vortex. It is also determined that there is a substantial increase in the effective range of axial and azimuthal wavenumbers where instabilities are present. But most importantly, there is the appearance of a variety of viscous modes of instability. In the case of vortices, these latter instabilities which highlight the importance of viscous forces have never been reported before. These effects are discussed in detail for the case of a two cell vortex.

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.

Chromosomal instability in mouse embryonic fibroblasts null for the transcriptional co-repressor Ski

PubMed Central

Marcelain, Katherine; Armisen, Ricardo; Aguirre, Adam; Ueki, Nobuhide; Toro, Jessica; Colmenares, Clemencia; Hayman, Michael J

2011-01-01

Ski is a transcriptional regulator that has been considered an oncoprotein, given its ability to induce oncogenic transformation in avian model systems. However, studies in mouse and in some human tumor cells have also indicated a tumor suppressor activity for this protein. We found that Ski−/− mouse embryo fibroblasts exhibit high levels of genome instability, namely aneuploidy, consistent with a tumor suppressor function for Ski. Time-lapse microscopy revealed lagging chromosomes and chromatin/chromosome bridges as the major cause of micronuclei formation and the subsequent aneuploidy. Although these cells arrested in mitosis after treatment with spindle disrupting drugs and exhibited a delayed metaphase/anaphase transition, Spindle Assembly Checkpoint (SAC) was not sufficient to prevent chromosome missegregation, consistent with a weakened SAC. Our in vivo analysis also showed dynamic metaphase plate rearrangements with switches in polarity in cells arrested in metaphase. Importantly, after ectopic expression of Ski the cells that displayed this metaphase arrest died directly during metaphase or after aberrant cell division, relating SAC activation and mitotic cell death. This increased susceptibility to undergo mitosis-associated cell death reduced the number of micronuclei-containing cells. The presented data support a new role for Ski in the mitotic process and in maintenance of genetic stability, providing insights into the mechanism of tumor suppression mediated by this protein. PMID:21412778

Chromosomal instability in mouse embryonic fibroblasts null for the transcriptional co-repressor Ski.

PubMed

Marcelain, Katherine; Armisen, Ricardo; Aguirre, Adam; Ueki, Nobuhide; Toro, Jessica; Colmenares, Clemencia; Hayman, Michael J

2012-01-01

Ski is a transcriptional regulator that has been considered an oncoprotein given its ability to induce oncogenic transformation in avian model systems. However, studies in mouse and in some human tumor cells have also indicated a tumor suppressor activity for this protein. We found that Ski-/- mouse embryo fibroblasts exhibit high levels of genome instability, namely aneuploidy, consistent with a tumor suppressor function for Ski. Time-lapse microscopy revealed lagging chromosomes and chromatin/chromosome bridges as the major cause of micronuclei (MN) formation and the subsequent aneuploidy. Although these cells arrested in mitosis after treatment with spindle disrupting drugs and exhibited a delayed metaphase/anaphase transition, spindle assembly checkpoint (SAC) was not sufficient to prevent chromosome missegregation, consistent with a weakened SAC. Our in vivo analysis also showed dynamic metaphase plate rearrangements with switches in polarity in cells arrested in metaphase. Importantly, after ectopic expression of Ski the cells that displayed this metaphase arrest died directly during metaphase or after aberrant cell division, relating SAC activation and mitotic cell death. This increased susceptibility to undergo mitosis-associated cell death reduced the number of MN-containing cells. The presented data support a new role for Ski in the mitotic process and in maintenance of genetic stability, providing insights into the mechanism of tumor suppression mediated by this protein. Copyright © 2011 Wiley Periodicals, Inc.

Characteristics of chromosome instability in the human lymphoblast cell line WTK1

NASA Technical Reports Server (NTRS)

Schwartz, J. L.; Jordan, R.; Evans, H. H.

2001-01-01

The characteristics of spontaneous and radiation-induced chromosome instability were determined in each of 50 individual clones isolated from control populations of human lymphoblasts (WTK1), as well as from populations of these cells previously exposed to two different types of ionizing radiation, Fe-56 and Cs-137. The types of chromosome instability did not appear to change in clones surviving radiation exposure. Aneuploidy, polyploidy, chromosome dicentrics and translocations, and chromatid breaks and gaps were found in both control and irradiated clones. The primary effect of radiation exposure was to increase the number of cells within any one clone that had chromosome alterations. Chromosome instability was associated with telomere shortening and elevated levels of apoptosis. The results suggest that the proximal cause of chromosome instability is telomere shortening.

Buoyancy-Driven Instabilities in Single-Bubble Sonoluminescence

NASA Technical Reports Server (NTRS)

Matula, Thomas J.

2003-01-01

The principal objectives of this study are to determine how gravity affects the emission of light from single-bubble sonoluminescence (SBSL), and whether or not the bubble extinction is directly related to gravity. Our experimental task involves designing glass or quartz spherical levitation cells that generate very stable SL bubbles. The cells must have minimized vibration, and some temperature control. The experimental system will reside in a light-tight enclosure. Aside from acceleration, the frequency, pressure amplitude, and light intensity must be measured. A computer program will be constructed to perform all aspects of the experiment.

Viral Vector-Based Innovative Approaches to Directly Abolishing Tumorigenic Pluripotent Stem Cells for Safer Regenerative Medicine.

PubMed

Mitsui, Kaoru; Ide, Kanako; Takahashi, Tomoyuki; Kosai, Ken-Ichiro

2017-06-16

Human pluripotent stem cells (hPSCs) are a promising source of regenerative material for clinical applications. However, hPSC transplant therapies pose the risk of teratoma formation and malignant transformation of undifferentiated remnants. These problems underscore the importance of developing technologies that completely prevent tumorigenesis to ensure safe clinical application. Research to date has contributed to establishing safe hPSC lines, improving the efficiency of differentiation induction, and indirectly ensuring the safety of products. Despite such efforts, guaranteeing the clinical safety of regenerative medicine products remains a key challenge. Given the intrinsic genome instability of hPSCs, selective growth advantage of cancer cells, and lessons learned through failures in previous attempts at hematopoietic stem cell gene therapy, conventional strategies are unlikely to completely overcome issues related to hPSC tumorigenesis. Researchers have recently embarked on studies aimed at locating and directly treating hPSC-derived tumorigenic cells. In particular, novel approaches to directly killing tumorigenic cells by transduction of suicide genes and oncolytic viruses are expected to improve the safety of hPSC-based therapy. This article discusses the current status and future perspectives of methods aimed at directly eradicating undifferentiated tumorigenic hPSCs, with a focus on viral vector transduction.

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.

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.

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

Designing solid-liquid interphases for sodium batteries

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

Choudhury, Snehashis; Wei, Shuya; Ozhabes, Yalcin

Secondary batteries based on earth-abundant sodium metal anodes are desirable for both stationary and portable electrical energy storage. Room-temperature sodium metal batteries are impractical today because morphological instability during recharge drives rough, dendritic electrodeposition. Chemical instability of liquid electrolytes also leads to premature cell failure as a result of parasitic reactions with the anode. Here we use joint density-functional theoretical analysis to show that the surface diffusion barrier for sodium ion transport is a sensitive function of the chemistry of solid–electrolyte interphase. In particular, we find that a sodium bromide interphase presents an exceptionally low energy barrier to ion transport,more » comparable to that of metallic magnesium. We evaluate this prediction by means of electrochemical measurements and direct visualization studies. These experiments reveal an approximately three-fold reduction in activation energy for ion transport at a sodium bromide interphase. Direct visualization of sodium electrodeposition confirms large improvements in stability of sodium deposition at sodium bromide-rich interphases.« less

Cooperative motion of intrinsic and actuated semiflexible swimmers

NASA Astrophysics Data System (ADS)

Llopis, I.; Pagonabarraga, I.; Cosentino Lagomarsino, M.; Lowe, C. P.

2013-03-01

We examine the phenomenon of hydrodynamic-induced cooperativity for pairs of flagellated micro-organism swimmers, of which spermatozoa cells are an example. We consider semiflexible swimmers, where inextensible filaments are driven by an internal intrinsic force and torque-free mechanism (intrinsic swimmers). The velocity gain for swimming cooperatively, which depends on both the geometry and the driving, develops as a result of the near-field coupling of bending and hydrodynamic stresses. We identify the regimes where hydrodynamic cooperativity is advantageous and quantify the change in efficiency. When the filaments' axes are parallel, hydrodynamic interaction induces a directional instability that causes semiflexible swimmers that profit from swimming together to move apart from each other. Biologically, this implies that flagella need to select different synchronized collective states and to compensate for directional instabilities (e.g., by binding) in order to profit from swimming together. By analyzing the cooperative motion of pairs of externally actuated filaments, we assess the impact that stress distribution along the filaments has on their collective displacements.

Structural Evolution of Q-Carbon and Nanodiamonds

NASA Astrophysics Data System (ADS)

Gupta, Siddharth; Bhaumik, Anagh; Sachan, Ritesh; Narayan, Jagdish

2018-04-01

This article provides insights pertaining to the first-order phase transformation involved in the growth of densely packed Q-carbon and nanodiamonds by nanosecond laser melting and quenching of diamond-like carbon (DLC) thin films. DLC films with different sp 3 content were melted rapidly in a controlled way in super-undercooled state and quenched, leading to formation of distinct nanostructures, i.e., nanodiamonds, Q-carbon, and Q-carbon nanocomposites. This analysis provides direct evidence of the dependence of the super-undercooling on the structural evolution of Q-carbon. Finite element heat flow calculations showed that the super-undercooling varies monotonically with the sp 3 content. The phenomenon of solid-liquid interfacial instability during directional solidification from the melt state is studied in detail. The resulting lateral segregation leads to formation of cellular filamentary Q-carbon nanostructures. The dependence of the cell size and wavelength at the onset of instability on the sp 3 content of DLC thin films was modeled based on perturbation theory.

Designing solid-liquid interphases for sodium batteries

DOE PAGES

Choudhury, Snehashis; Wei, Shuya; Ozhabes, Yalcin; ...

2017-10-12

Secondary batteries based on earth-abundant sodium metal anodes are desirable for both stationary and portable electrical energy storage. Room-temperature sodium metal batteries are impractical today because morphological instability during recharge drives rough, dendritic electrodeposition. Chemical instability of liquid electrolytes also leads to premature cell failure as a result of parasitic reactions with the anode. Here we use joint density-functional theoretical analysis to show that the surface diffusion barrier for sodium ion transport is a sensitive function of the chemistry of solid–electrolyte interphase. In particular, we find that a sodium bromide interphase presents an exceptionally low energy barrier to ion transport,more » comparable to that of metallic magnesium. We evaluate this prediction by means of electrochemical measurements and direct visualization studies. These experiments reveal an approximately three-fold reduction in activation energy for ion transport at a sodium bromide interphase. Direct visualization of sodium electrodeposition confirms large improvements in stability of sodium deposition at sodium bromide-rich interphases.« less

Analysis of re-replication from deregulated origin licensing by DNA fiber spreading

PubMed Central

Dorn, Elizabeth S.; Chastain, Paul D.; Hall, Jonathan R.; Cook, Jeanette Gowen

2009-01-01

A major challenge each human cell-division cycle is to ensure that DNA replication origins do not initiate more than once, a phenomenon known as re-replication. Acute deregulation of replication control ultimately causes extensive DNA damage, cell-cycle checkpoint activation and cell death whereas moderate deregulation promotes genome instability and tumorigenesis. In the absence of detectable increases in cellular DNA content however, it has been difficult to directly demonstrate re-replication or to determine if the ability to re-replicate is restricted to a particular cell-cycle phase. Using an adaptation of DNA fiber spreading we report the direct detection of re-replication on single DNA molecules from human chromosomes. Using this method we demonstrate substantial re-replication within 1 h of S phase entry in cells overproducing the replication factor, Cdt1. Moreover, a comparison of the HeLa cancer cell line to untransformed fibroblasts suggests that HeLa cells produce replication signals consistent with low-level re-replication in otherwise unperturbed cell cycles. Re-replication after depletion of the Cdt1 inhibitor, geminin, in an untransformed fibroblast cell line is undetectable by standard assays but readily quantifiable by DNA fiber spreading analysis. Direct evaluation of re-replicated DNA molecules will promote increased understanding of events that promote or perturb genome stability. PMID:19010964

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.

Classification of instability modes in a model of aluminium reduction cells with a uniform magnetic field

NASA Astrophysics Data System (ADS)

Molokov, Sergei; El, Gennady; Lukyanov, Alexander

2011-10-01

A unified view on the interfacial instability in a model of aluminium reduction cells in the presence of a uniform, vertical, background magnetic field is presented. The classification of instability modes is based on the asymptotic theory for high values of parameter β, which characterises the ratio of the Lorentz force based on the disturbance current, and gravity. It is shown that the spectrum of the travelling waves consists of two parts independent of the horizontal cross-section of the cell: highly unstable wall modes and stable or weakly unstable centre, or Sele's modes. The wall modes with the disturbance of the interface being localised at the sidewalls of the cell dominate the dynamics of instability. Sele's modes are characterised by a distributed disturbance over the whole horizontal extent of the cell. As β increases these modes are stabilized by the field.

Mycobacterium tuberculosis promotes genomic instability in macrophages.

PubMed

Castro-Garza, Jorge; Luévano-Martínez, Miriam Lorena; Villarreal-Treviño, Licet; Gosálvez, Jaime; Fernández, José Luis; Dávila-Rodríguez, Martha Imelda; García-Vielma, Catalina; González-Hernández, Silvia; Cortés-Gutiérrez, Elva Irene

2018-03-01

Mycobacterium tuberculosis is an intracellular pathogen, which may either block cellular defensive mechanisms and survive inside the host cell or induce cell death. Several studies are still exploring the mechanisms involved in these processes. To evaluate the genomic instability of M. tuberculosis-infected macrophages and compare it with that of uninfected macrophages. We analysed the possible variations in the genomic instability of Mycobacterium-infected macrophages using the DNA breakage detection fluorescence in situ hybridisation (DBD-FISH) technique with a whole human genome DNA probe. Quantitative image analyses showed a significant increase in DNA damage in infected macrophages as compared with uninfected cells. DNA breaks were localised in nuclear membrane blebs, as confirmed with DNA fragmentation assay. Furthermore, a significant increase in micronuclei and nuclear abnormalities were observed in infected macrophages versus uninfected cells. Genomic instability occurs during mycobacterial infection and these data may be seminal for future research on host cell DNA damage in M. tuberculosis infection.

Controlling direct contact force for wet adhesion with different wedged film stabilities

NASA Astrophysics Data System (ADS)

Li, Meng; Xie, Jun; Shi, Liping; Huang, Wei; Wang, Xiaolei

2018-04-01

In solid–liquid–solid adhesive systems, wedged films often feature instability at microscopic thicknesses, which can easily disrupt the adhesive strength of their remarkable direct contact force. Here, sodium dodecyl sulfate (SDS) was employed to tune the instability of adhesion in wedged glass–water–rubber films, achieving controllable direct contact. Experimental results showed that the supplement of SDS molecules significantly weakened the direct contact force for wet adhesion and eliminated it at high concentrations. The underlying reason was suggested to be the repulsive double-layer force caused by SDS molecules, which lowers the instability of the wedged film and balances the preload, disrupting the direct contact in wet adhesion.

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

PubMed

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

2016-05-01

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

WWOX, the common fragile site FRA16D gene product, regulates ATM activation and the DNA damage response

PubMed Central

Abu-Odeh, Mohammad; Salah, Zaidoun; Herbel, Christoph; Hofmann, Thomas G.; Aqeilan, Rami I.

2014-01-01

Genomic instability is a hallmark of cancer. The WW domain-containing oxidoreductase (WWOX) is a tumor suppressor spanning the common chromosomal fragile site FRA16D. Here, we report a direct role of WWOX in DNA damage response (DDR) and DNA repair. We show that Wwox deficiency results in reduced activation of the ataxia telangiectasia-mutated (ATM) checkpoint kinase, inefficient induction and maintenance of γ-H2AX foci, and impaired DNA repair. Mechanistically, we show that, upon DNA damage, WWOX accumulates in the cell nucleus, where it interacts with ATM and enhances its activation. Nuclear accumulation of WWOX is regulated by its K63-linked ubiquitination at lysine residue 274, which is mediated by the E3 ubiquitin ligase ITCH. These findings identify a novel role for the tumor suppressor WWOX and show that loss of WWOX expression may drive genomic instability and provide an advantage for clonal expansion of neoplastic cells. PMID:25331887

How the Venus flytrap actively snaps: hydrodynamic measurements at the cellular level

NASA Astrophysics Data System (ADS)

Colombani, Mathieu; Forterre, Yoel; GEP Team

2012-11-01

Although they lack muscle, plants have evolved a remarkable range of mechanisms to create rapid motion, from the rapid folding of sensitive plants to seed dispersal. Of these spectacular examples that have long fascinated scientists, the carnivorous plant Venus flytrap, whose leaves snap together in a fraction of second to capture insects, has long been a paradigm for study. Recently, we have shown that this motion involves a snap-buckling instability due to the shell-like geometry of the leaves of the trap. However, the origin of the movement that allows the plant to cross the instability threshold and actively bend remains largely unknown. In this study, we investigate this active motion using a micro-fluidic pressure probe that gives direct hydraulic and mechanical measurements at the cellular level (osmotic pressure, cell membrane permeability, cell wall elasticity). Our results challenge the role of osmotically-driven water flows usually put forward to explain Venus flytrap's active closure.

Chromosome neighborhood composition determines translocation outcomes after exposure to high-dose radiation in primary cells.

PubMed

Brianna Caddle, Lura; Grant, Jeremy L; Szatkiewicz, Jin; van Hase, Johann; Shirley, Bobbi-Jo; Bewersdorf, Joerg; Cremer, Christoph; Arneodo, Alain; Khalil, Andre; Mills, Kevin D

2007-01-01

Radiation exposure is an occupational hazard for military personnel, some health care professionals, airport security screeners, and medical patients, with some individuals at risk for acute, high-dose exposures. Therefore, the biological effects of radiation, especially the potential for chromosome damage, are major occupational and health concerns. However, the biophysical mechanisms of chromosome instability subsequent to radiation-induced DNA damage are poorly understood. It is clear that interphase chromosomes occupy discrete structural and functional subnuclear domains, termed chromosome territories (CT), which may be organized into 'neighborhoods' comprising groups of specific CTs. We directly evaluated the relationship between chromosome positioning, neighborhood composition, and translocation partner choice in primary lymphocytes, using a cell-based system in which we could induce multiple, concentrated DNA breaks via high-dose irradiation. We critically evaluated mis-rejoining profiles and tested whether breaks occurring nearby were more likely to fuse than breaks occurring at a distance. We show that CT neighborhoods comprise heterologous chromosomes, within which inter-CT distances directly relate to translocation partner choice. These findings demonstrate that interphase chromosome arrangement is a principal factor in genomic instability outcomes in primary lymphocytes, providing a structural context for understanding the biological effects of radiation exposure, and the molecular etiology of tumor-specific translocation patterns.

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

Instability of current sheets with a localized accumulation of magnetic flux

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

Pritchett, P. L.

2015-06-15

The longstanding problem of whether a current sheet with curved magnetic field lines associated with a small “normal” B{sub z} component is stable is investigated using two-dimensional electromagnetic particle-in-cell simulations, employing closed boundary conditions analogous to those normally assumed in energy principle calculations. Energy principle arguments [Sitnov and Schindler, Geophys. Res. Lett. 37, L08102 (2010)] have suggested that an accumulation of magnetic flux at the tailward end of a thin current sheet could produce a tearing instability. Two classes of such current sheet configurations are probed: one with a monotonically increasing B{sub z} profile and the other with a localizedmore » B{sub z} “hump.” The former is found to be stable (in 2D) over any reasonable time scale, while the latter is prone to an ideal-like instability that shifts the hump peak in the direction of the curvature normal and erodes the field on the opposite side. The growth rate of this instability is smaller by an order of magnitude than previous suggestions of an instability in an open system. An example is given that suggests that such an unstable hump configuration is unlikely to be produced by external driving of a current sheet with no B{sub z} accumulation even in the presence of open boundary conditions.« less

FOXM1 upregulation is an early event in human squamous cell carcinoma and it is enhanced by nicotine during malignant transformation.

PubMed

Gemenetzidis, Emilios; Bose, Amrita; Riaz, Adeel M; Chaplin, Tracy; Young, Bryan D; Ali, Muhammad; Sugden, David; Thurlow, Johanna K; Cheong, Sok-Ching; Teo, Soo-Hwang; Wan, Hong; Waseem, Ahmad; Parkinson, Eric K; Fortune, Farida; Teh, Muy-Teck

2009-01-01

Cancer associated with smoking and drinking remains a serious health problem worldwide. The survival of patients is very poor due to the lack of effective early biomarkers. FOXM1 overexpression is linked to the majority of human cancers but its mechanism remains unclear in head and neck squamous cell carcinoma (HNSCC). FOXM1 mRNA and protein expressions were investigated in four independent cohorts (total 75 patients) consisting of normal, premalignant and HNSCC tissues and cells using quantitative PCR (qPCR), expression microarray, immunohistochemistry and immunocytochemistry. Effect of putative oral carcinogens on FOXM1 transcriptional activity was dose-dependently assayed and confirmed using a FOXM1-specific luciferase reporter system, qPCR, immunoblotting and short-hairpin RNA interference. Genome-wide single nucleotide polymorphism (SNP) array was used to 'trace' the genomic instability signature pattern in 8 clonal lines of FOXM1-induced malignant human oral keratinocytes. Furthermore, acute FOXM1 upregulation in primary oral keratinocytes directly induced genomic instability. We have shown for the first time that overexpression of FOXM1 precedes HNSCC malignancy. Screening putative carcinogens in human oral keratinocytes surprisingly showed that nicotine, which is not perceived to be a human carcinogen, directly induced FOXM1 mRNA, protein stabilisation and transcriptional activity at concentrations relevant to tobacco chewers. Importantly, nicotine also augmented FOXM1-induced transformation of human oral keratinocytes. A centrosomal protein CEP55 and a DNA helicase/putative stem cell marker HELLS, both located within a consensus loci (10q23), were found to be novel targets of FOXM1 and their expression correlated tightly with HNSCC progression. This study cautions the potential co-carcinogenic effect of nicotine in tobacco replacement therapies. We hypothesise that aberrant upregulation of FOXM1 may be inducing genomic instability through a program of malignant transformation involving the activation of CEP55 and HELLS which may facilitate aberrant mitosis and epigenetic modifications. Our finding that FOXM1 is upregulated early during oral cancer progression renders FOXM1 an attractive diagnostic biomarker for early cancer detection and its candidate mechanistic targets, CEP55 and HELLS, as indicators of malignant conversion and progression.

[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.

On the stability and control of a trailing vortex

NASA Astrophysics Data System (ADS)

Edstrand, Adam M.

Trailing vortices are both a fundamental and practical problem of fluid mechanics. Fundamentally, they provide a canonical vortex flow that is pervasive in finite aspect ratio lifting bodies, practically producing many adverse effects across aeronautical and maritime applications. These adverse effects coupled with the broad range of applicability make their active control desirable; however, they remain robust to control efforts. Experimental baseline results provided an explanation of vortex wandering, the side-to-side motion often attributed to wind-tunnel unsteadiness or a vortex instability. We extracted the wandering motion and found striking similarities with the eigenmodes, growth rates, and frequencies from a stability analysis of the Batchelor vortex. After concluding that wandering is a result of a vortex instability, we applied control to the trailing vortex flow field through blowing from a slot at the wingtip. We experimentally obtained modest reductions in the metrics, but found the parameter space for optimization unwieldy. With the ultimate goal of designing control, we performed a physics-based stability analysis in the wake of a NACA0012 wing with an aspect ratio of 1.25 positioned at a geometric angle of attack of 5 degrees. Numerically computing the base flow at a chord Reynolds number of 1000, we perform a parallel temporal and spatial stability analysis three chords downstream of the trailing edge finding seven instabilities: three temporal, four spatial. The three temporal contain a wake instability, a vortex instability, and a mixed instability, which is a higher-order wake instability. The primary instability localized to the wake results from the two-dimensional wake, while the secondary instability is the mixed instability, containing higher-order spanwise structures in the wake. These instabilities imply that although it may be intuitive to place control at the wingtip, these results show that control may be more effective at the trailing edge, which would excite these instabilities that result with the eventual break up of the vortex. Further, by performing a wave-packet analysis, we found the wave packets contained directivity, coming inward toward the vortex above and below the wing, and traveling outward in the spanwise directions. We conjecture that this directivity can be translated to receptivity, with free-stream disturbances above and below the wing being more receptive than spanwise disturbances. With this, we provide two methods for instability excitation: utilizing control devices on the wing to excite near-field instabilities directly and utilizing free-stream disturbances to such as a speaker to excite near-field instabilities through receptivity.

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.

PIC Simulations of Velocity-space Instabilities in a Decreasing Magnetic Field: Viscosity and Thermal Conduction

NASA Astrophysics Data System (ADS)

Riquelme, Mario; Quataert, Eliot; Verscharen, Daniel

2018-02-01

We use particle-in-cell (PIC) simulations of a collisionless, electron–ion plasma with a decreasing background magnetic field, {\\boldsymbol{B}}, to study the effect of velocity-space instabilities on the viscous heating and thermal conduction of the plasma. If | {\\boldsymbol{B}}| decreases, the adiabatic invariance of the magnetic moment gives rise to pressure anisotropies with {p}| | ,j> {p}\\perp ,j ({p}| | ,j and {p}\\perp ,j represent the pressure of species j (electron or ion) parallel and perpendicular to B ). Linear theory indicates that, for sufficiently large anisotropies, different velocity-space instabilities can be triggered. These instabilities in principle have the ability to pitch-angle scatter the particles, limiting the growth of the anisotropies. Our simulations focus on the nonlinear, saturated regime of the instabilities. This is done through the permanent decrease of | {\\boldsymbol{B}}| by an imposed plasma shear. We show that, in the regime 2≲ {β }j≲ 20 ({β }j\\equiv 8π {p}j/| {\\boldsymbol{B}}{| }2), the saturated ion and electron pressure anisotropies are controlled by the combined effect of the oblique ion firehose and the fast magnetosonic/whistler instabilities. These instabilities grow preferentially on the scale of the ion Larmor radius, and make {{Δ }}{p}e/{p}| | ,e≈ {{Δ }}{p}i/{p}| | ,i (where {{Δ }}{p}j={p}\\perp ,j-{p}| | ,j). We also quantify the thermal conduction of the plasma by directly calculating the mean free path of electrons, {λ }e, along the mean magnetic field, finding that {λ }e depends strongly on whether | {\\boldsymbol{B}}| decreases or increases. Our results can be applied in studies of low-collisionality plasmas such as the solar wind, the intracluster medium, and some accretion disks around black holes.

Comparative study of the loss cone-driven instabilities in the low solar corona

NASA Technical Reports Server (NTRS)

Sharma, R. R.; Vlahos, L.

1984-01-01

A comparative study of the loss cone-driven instabilities in the low solar corona is undertaken. The instabilities considered are the electron cyclotron maser, the whistler, and the electrostatic upper hybrid. It is shown that the first-harmonic extraordinary mode of the electron cyclotron maser instability is the fastest growing mode for strong magnetized plasma (the ratio of plasma frequency to cyclotron frequency being less than 0.35). For values of the ratio between 0.35 and 1.0, the first-harmonic ordinary mode of the electron cyclotron maser instability dominates the emission. For ratio values greater than 1.0, no direct electromagnetic radiation is expected since other instabilities, which do not escape directly, saturate the electron cyclotron maser (the whistler or the electrostatic upper hybrid waves). It is also shown that the second-harmonic electron cyclotron maser emission never grows to an appreciable level. Thus, it is suggested that the electron cyclotron maser instability can be the explanation for the escape of the first harmonic from a flaring loop.

Characteristics and transport effects of the electron drift instability in Hall-effect thrusters

NASA Astrophysics Data System (ADS)

Lafleur, T.; Baalrud, S. D.; Chabert, P.

2017-02-01

The large electron {E}× {B} drift (relative to the ions) in the azimuthal direction of Hall-effect thrusters is well known to excite a strong instability. In a recent paper (Lafleur et al 2016 Phys. Plasmas 23 053503) we demonstrated that this instability leads to an enhanced electron-ion friction force that increases the electron cross-field mobility to levels similar to those seen experimentally. Here we extend this work by considering in detail the onset criteria for the formation of this instability (both in xenon, and other propellants of interest), and identify a number of important characteristics that it displays within Hall-effect thrusters (HETs): including the appearance of an additional non-dimensionalized scaling parameter (the instability growth-to-convection ratio), which controls the instability evolution and amplitude. We also investigate the effect that the instability has on electron and ion heating in HETs, and show that it leads to an ion rotation in the azimuthal direction that is in agreement with that seen experimentally.

From catʼs eyes to multiple disjoint natural convection flow in tall tilted cavities: A direct primitive variables approach

NASA Astrophysics Data System (ADS)

Báez, Elsa; Nicolás, Alfredo

2013-11-01

Natural convection fluid flow in air-filled tall tilted cavities is studied numerically with a new direct projection method on the Boussinesq approximation in primitive variables. The study deals with “cat's eyes” instabilities and multiple disjoint cells as the aspect ratio A and the angle of inclination ϕ of the cavity vary. The flows are validated with those reported before using the stream function-vorticity variables. New cases, A=12 and 20 varying ϕ, lead to get more insight on the physical phenomenon.

Instability of liquid crystal elastomers

NASA Astrophysics Data System (ADS)

An, Ning; Li, Meie; Zhou, Jinxiong

2016-01-01

Nematic liquid crystal elastomers (LCEs) contract in the director direction but expand in other directions, perpendicular to the director, when heated. If the expansion of an LCE is constrained, compressive stress builds up in the LCE, and it wrinkles or buckles to release the stored elastic energy. Although the instability of soft materials is ubiquitous, the mechanism and programmable modulation of LCE instability has not yet been fully explored. We describe a finite element method (FEM) scheme to model the inhomogeneous deformation and instability of LCEs. A constrained LCE beam working as a valve for microfluidic flow, and a piece of LCE laminated with a nanoscale poly(styrene) (PS) film are analyzed in detail. The former uses the buckling of the LCE beam to occlude the microfluidic channel, while the latter utilizes wrinkling or buckling to measure the mechanical properties of hard film or to realize self-folding. Through rigorous instability analysis, we predict the critical conditions for the onset of instability, the wavelength and amplitude evolution of instability, and the instability patterns. The FEM results are found to correlate well with analytical results and reported experiments. These efforts shed light on the understanding and exploitation of the instabilities of LCEs.

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.

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

PubMed

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

2016-02-04

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

Mycobacterium tuberculosis promotes genomic instability in macrophages

PubMed Central

Castro-Garza, Jorge; Luévano-Martínez, Miriam Lorena; Villarreal-Treviño, Licet; Gosálvez, Jaime; Fernández, José Luis; Dávila-Rodríguez, Martha Imelda; García-Vielma, Catalina; González-Hernández, Silvia; Cortés-Gutiérrez, Elva Irene

2018-01-01

BACKGROUND Mycobacterium tuberculosis is an intracellular pathogen, which may either block cellular defensive mechanisms and survive inside the host cell or induce cell death. Several studies are still exploring the mechanisms involved in these processes. OBJECTIVES To evaluate the genomic instability of M. tuberculosis-infected macrophages and compare it with that of uninfected macrophages. METHODS We analysed the possible variations in the genomic instability of Mycobacterium-infected macrophages using the DNA breakage detection fluorescence in situ hybridisation (DBD-FISH) technique with a whole human genome DNA probe. FINDINGS Quantitative image analyses showed a significant increase in DNA damage in infected macrophages as compared with uninfected cells. DNA breaks were localised in nuclear membrane blebs, as confirmed with DNA fragmentation assay. Furthermore, a significant increase in micronuclei and nuclear abnormalities were observed in infected macrophages versus uninfected cells. MAIN CONCLUSIONS Genomic instability occurs during mycobacterial infection and these data may be seminal for future research on host cell DNA damage in M. tuberculosis infection. PMID:29412354

Integrative Radiation Biology

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

Barcellos-Hoff, Mary Helen

We plan to study tissue-level mechanisms important to human breast radiation carcinogenesis. We propose that the cell biology of irradiated tissues reveals a coordinated multicellular damage response program in which individual cell contributions are primarily directed towards suppression of carcinogenesis and reestablishment of homeostasis. We identified transforming growth factor β1 (TGFβ) as a pivotal signal. Notably, we have discovered that TGFβ suppresses genomic instability by controlling the intrinsic DNA damage response and centrosome integrity. However, TGFβ also mediates disruption of microenvironment interactions, which drive epithelial to mesenchymal transition in irradiated human mammary epithelial cells. This apparent paradox of positive andmore » negative controls by TGFβ is the topic of the present proposal. First, we postulate that these phenotypes manifest differentially following fractionated or chronic exposures; second, that the interactions of multiple cell types in tissues modify the responses evident in this single cell type culture models. The goals are to: 1) study the effect of low dose rate and fractionated radiation exposure in combination with TGFβ on the irradiated phenotype and genomic instability of non-malignant human epithelial cells; and 2) determine whether stromal-epithelial interactions suppress the irradiated phenotype in cell culture and the humanized mammary mouse model. These data will be used to 3) develop a systems biology model that integrates radiation effects across multiple levels of tissue organization and time. Modeling multicellular radiation responses coordinated via extracellular signaling could have a significant impact on the extrapolation of human health risks from high dose to low dose/rate radiation exposure.« less

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

Directionally asymmetric self-assembly of cadmium sulfide nanotubes using porous alumina nanoreactors: need for chemohydrodynamic instability at the nanoscale.

PubMed

Varghese, Arthur; Datta, Shouvik

2012-05-01

We explore nanoscale hydrodynamical effects on synthesis and self-assembly of cadmium sulfide nanotubes oriented along one direction. These nanotubes are synthesized by horizontal capillary flow of two different chemical reagents from opposite directions through nanochannels of porous anodic alumina which are used primarily as nanoreactors. We show that uneven flow of different chemical precursors is responsible for directionally asymmetric growth of these nanotubes. On the basis of structural observations using scanning electron microscopy, we argue that chemohydrodynamic convective interfacial instability of multicomponent liquid-liquid reactive interface is necessary for sustained nucleation of these CdS nanotubes at the edges of these porous nanochannels over several hours. However, our estimates clearly suggest that classical hydrodynamics cannot account for the occurrence of such instabilities at these small length scales. Therefore, we present a case which necessitates further investigation and understanding of chemohydrodynamic fluid flow through nanoconfined channels in order to explain the occurrence of such interfacial instabilities at nanometer length scales.

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

Controlling the numerical Cerenkov instability in PIC simulations using a customized finite difference Maxwell solver and a local FFT based current correction

DOE PAGES

Li, Fei; Yu, Peicheng; Xu, Xinlu; ...

2017-01-12

In this study we present a customized finite-difference-time-domain (FDTD) Maxwell solver for the particle-in-cell (PIC) algorithm. The solver is customized to effectively eliminate the numerical Cerenkov instability (NCI) which arises when a plasma (neutral or non-neutral) relativistically drifts on a grid when using the PIC algorithm. We control the EM dispersion curve in the direction of the plasma drift of a FDTD Maxwell solver by using a customized higher order finite difference operator for the spatial derivative along the direction of the drift (1ˆ direction). We show that this eliminates the main NCI modes with moderate |k 1|, while keepsmore » additional main NCI modes well outside the range of physical interest with higher |k 1|. These main NCI modes can be easily filtered out along with first spatial aliasing NCI modes which are also at the edge of the fundamental Brillouin zone. The customized solver has the possible advantage of improved parallel scalability because it can be easily partitioned along 1ˆ which typically has many more cells than other directions for the problems of interest. We show that FFTs can be performed locally to current on each partition to filter out the main and first spatial aliasing NCI modes, and to correct the current so that it satisfies the continuity equation for the customized spatial derivative. This ensures that Gauss’ Law is satisfied. Lastly, we present simulation examples of one relativistically drifting plasma, of two colliding relativistically drifting plasmas, and of nonlinear laser wakefield acceleration (LWFA) in a Lorentz boosted frame that show no evidence of the NCI can be observed when using this customized Maxwell solver together with its NCI elimination scheme.« less

Controlling the numerical Cerenkov instability in PIC simulations using a customized finite difference Maxwell solver and a local FFT based current correction

NASA Astrophysics Data System (ADS)

Li, Fei; Yu, Peicheng; Xu, Xinlu; Fiuza, Frederico; Decyk, Viktor K.; Dalichaouch, Thamine; Davidson, Asher; Tableman, Adam; An, Weiming; Tsung, Frank S.; Fonseca, Ricardo A.; Lu, Wei; Mori, Warren B.

2017-05-01

In this paper we present a customized finite-difference-time-domain (FDTD) Maxwell solver for the particle-in-cell (PIC) algorithm. The solver is customized to effectively eliminate the numerical Cerenkov instability (NCI) which arises when a plasma (neutral or non-neutral) relativistically drifts on a grid when using the PIC algorithm. We control the EM dispersion curve in the direction of the plasma drift of a FDTD Maxwell solver by using a customized higher order finite difference operator for the spatial derivative along the direction of the drift (1 ˆ direction). We show that this eliminates the main NCI modes with moderate |k1 | , while keeps additional main NCI modes well outside the range of physical interest with higher |k1 | . These main NCI modes can be easily filtered out along with first spatial aliasing NCI modes which are also at the edge of the fundamental Brillouin zone. The customized solver has the possible advantage of improved parallel scalability because it can be easily partitioned along 1 ˆ which typically has many more cells than other directions for the problems of interest. We show that FFTs can be performed locally to current on each partition to filter out the main and first spatial aliasing NCI modes, and to correct the current so that it satisfies the continuity equation for the customized spatial derivative. This ensures that Gauss' Law is satisfied. We present simulation examples of one relativistically drifting plasma, of two colliding relativistically drifting plasmas, and of nonlinear laser wakefield acceleration (LWFA) in a Lorentz boosted frame that show no evidence of the NCI can be observed when using this customized Maxwell solver together with its NCI elimination scheme.

Controlling the numerical Cerenkov instability in PIC simulations using a customized finite difference Maxwell solver and a local FFT based current correction

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

Li, Fei; Yu, Peicheng; Xu, Xinlu

In this study we present a customized finite-difference-time-domain (FDTD) Maxwell solver for the particle-in-cell (PIC) algorithm. The solver is customized to effectively eliminate the numerical Cerenkov instability (NCI) which arises when a plasma (neutral or non-neutral) relativistically drifts on a grid when using the PIC algorithm. We control the EM dispersion curve in the direction of the plasma drift of a FDTD Maxwell solver by using a customized higher order finite difference operator for the spatial derivative along the direction of the drift (1ˆ direction). We show that this eliminates the main NCI modes with moderate |k 1|, while keepsmore » additional main NCI modes well outside the range of physical interest with higher |k 1|. These main NCI modes can be easily filtered out along with first spatial aliasing NCI modes which are also at the edge of the fundamental Brillouin zone. The customized solver has the possible advantage of improved parallel scalability because it can be easily partitioned along 1ˆ which typically has many more cells than other directions for the problems of interest. We show that FFTs can be performed locally to current on each partition to filter out the main and first spatial aliasing NCI modes, and to correct the current so that it satisfies the continuity equation for the customized spatial derivative. This ensures that Gauss’ Law is satisfied. Lastly, we present simulation examples of one relativistically drifting plasma, of two colliding relativistically drifting plasmas, and of nonlinear laser wakefield acceleration (LWFA) in a Lorentz boosted frame that show no evidence of the NCI can be observed when using this customized Maxwell solver together with its NCI elimination scheme.« less

Jeans instability of rotating magnetized quantum plasma: Influence of radiation

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

Joshi, H., E-mail: hjoshi8525@yahoo.com; Pensia, R. K.

2015-07-31

The effect of radiative heat-loss function and rotation on the Jeans instability of quantum plasma is investigated. The basic set of equations for this problem is constructed by considering quantum magnetohydrodynamic (QMHD) model. Using normal mode analysis, the general dispersion relation is obtained. This dispersion relation is studied in both, longitudinal and transverse direction of propagations. In both case of longitudinal and transverse direction of propagation, the Jeans instability criterion is modified due to presence of radiative heat-loss function and quantum correction.

Transition to hard turbulence in thermal convection at infinite Prandtl number

NASA Technical Reports Server (NTRS)

Hansen, Ulrich; Yuen, David A.; Kroening, Sherri E.

1990-01-01

Direct numerical simulations of two-dimensional high Rayleigh (Ra) number, base-heated thermal convection in large aspect-ratio boxes are presented for infinite Prandtl number fluids, as applied to the earth's mantle. A transition is characaterized in the flow structures in the neighborhood of Ra between 10 to the 7th and 10 to the 8th. These high Ra flows consist of large-scale cells with strong intermittent, boundary-layer instabilities. For Ra exceeding 10 to the 7th it is found that the heat-transfer mechanism changes from one characterized by mushroom-like plumes to one consisting of disconnected ascending instabilities, which do not carry with them all the thermal anomaly from the bottom boundary layer. Plume-plume collisions become much more prominent in high Ra situations and have a tendency of generating a pulse-like behavior in the fixed plume. This type of instability represents a distinct mode of heat transfer in the hard turbulent regime. Predictions of this model can be used to address certain issues concerning the mode of time-dependent convection in the earth's mantle.

Multidimensional electron beam-plasma instabilities in the relativistic regime

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

Bret, A.; Gremillet, L.; Dieckmann, M. E.

2010-12-15

The interest in relativistic beam-plasma instabilities has been greatly rejuvenated over the past two decades by novel concepts in laboratory and space plasmas. Recent advances in this long-standing field are here reviewed from both theoretical and numerical points of view. The primary focus is on the two-dimensional spectrum of unstable electromagnetic waves growing within relativistic, unmagnetized, and uniform electron beam-plasma systems. Although the goal is to provide a unified picture of all instability classes at play, emphasis is put on the potentially dominant waves propagating obliquely to the beam direction, which have received little attention over the years. First, themore » basic derivation of the general dielectric function of a kinetic relativistic plasma is recalled. Next, an overview of two-dimensional unstable spectra associated with various beam-plasma distribution functions is given. Both cold-fluid and kinetic linear theory results are reported, the latter being based on waterbag and Maxwell-Juettner model distributions. The main properties of the competing modes (developing parallel, transverse, and oblique to the beam) are given, and their respective region of dominance in the system parameter space is explained. Later sections address particle-in-cell numerical simulations and the nonlinear evolution of multidimensional beam-plasma systems. The elementary structures generated by the various instability classes are first discussed in the case of reduced-geometry systems. Validation of linear theory is then illustrated in detail for large-scale systems, as is the multistaged character of the nonlinear phase. Finally, a collection of closely related beam-plasma problems involving additional physical effects is presented, and worthwhile directions of future research are outlined.« less

E × B electron drift instability in Hall thrusters: Particle-in-cell simulations vs. theory

NASA Astrophysics Data System (ADS)

Boeuf, J. P.; Garrigues, L.

2018-06-01

The E × B Electron Drift Instability (E × B EDI), also called Electron Cyclotron Drift Instability, has been observed in recent particle simulations of Hall thrusters and is a possible candidate to explain anomalous electron transport across the magnetic field in these devices. This instability is characterized by the development of an azimuthal wave with wavelength in the mm range and velocity on the order of the ion acoustic velocity, which enhances electron transport across the magnetic field. In this paper, we study the development and convection of the E × B EDI in the acceleration and near plume regions of a Hall thruster using a simplified 2D axial-azimuthal Particle-In-Cell simulation. The simulation is collisionless and the ionization profile is not-self-consistent but rather is given as an input parameter of the model. The aim is to study the development and properties of the instability for different values of the ionization rate (i.e., of the total ion production rate or current) and to compare the results with the theory. An important result is that the wavelength of the simulated azimuthal wave scales as the electron Debye length and that its frequency is on the order of the ion plasma frequency. This is consistent with the theory predicting destruction of electron cyclotron resonance of the E × B EDI in the non-linear regime resulting in the transition to an ion acoustic instability. The simulations also show that for plasma densities smaller than under nominal conditions of Hall thrusters the field fluctuations induced by the E × B EDI are no longer sufficient to significantly enhance electron transport across the magnetic field, and transit time instabilities develop in the axial direction. The conditions and results of the simulations are described in detail in this paper and they can serve as benchmarks for comparisons between different simulation codes. Such benchmarks would be very useful to study the role of numerical noise (numerical noise can also be responsible to the destruction of electron cyclotron resonance) or the influence of the period of the azimuthal domain, as well as to reach a better and consensual understanding of the physics.

Slipping and tangential discontinuity instabilities in quasi-one-dimensional planar and cylindrical flows

NASA Astrophysics Data System (ADS)

Kuzelev, M. V.

2017-09-01

An analytical linear theory of instability of an electron beam with a nonuniform directional velocity (slipping instability) against perturbations with wavelengths exceeding the transverse beam size is offered. An analogy with hydrodynamic instabilities of tangential discontinuity of an incompressible liquid flow is drawn. The instability growth rates are calculated for particular cases and in a general form in planar and cylindrical geometries. The stabilizing effect of the external magnetic field is analyzed.

GFP-based fluorescence assay for CAG repeat instability in cultured human cells.

PubMed

Santillan, Beatriz A; Moye, Christopher; Mittelman, David; Wilson, John H

2014-01-01

Trinucleotide repeats can be highly unstable, mutating far more frequently than point mutations. Repeats typically mutate by addition or loss of units of the repeat. CAG repeat expansions in humans trigger neurological diseases that include myotonic dystrophy, Huntington disease, and several spinocerebellar ataxias. In human cells, diverse mechanisms promote CAG repeat instability, and in mice, the mechanisms of instability are varied and tissue-dependent. Dissection of mechanistic complexity and discovery of potential therapeutics necessitates quantitative and scalable screens for repeat mutation. We describe a GFP-based assay for screening modifiers of CAG repeat instability in human cells. The assay exploits an engineered intronic CAG repeat tract that interferes with expression of an inducible GFP minigene. Like the phenotypes of many trinucleotide repeat disorders, we find that GFP function is impaired by repeat expansion, in a length-dependent manner. The intensity of fluorescence varies inversely with repeat length, allowing estimates of repeat tract changes in live cells. We validate the assay using transcription through the repeat and engineered CAG-specific nucleases, which have previously been reported to induce CAG repeat instability. The assay is relatively fast and should be adaptable to large-scale screens of chemical and shRNA libraries.

GFP-Based Fluorescence Assay for CAG Repeat Instability in Cultured Human Cells

PubMed Central

Santillan, Beatriz A.; Moye, Christopher; Mittelman, David; Wilson, John H.

2014-01-01

Trinucleotide repeats can be highly unstable, mutating far more frequently than point mutations. Repeats typically mutate by addition or loss of units of the repeat. CAG repeat expansions in humans trigger neurological diseases that include myotonic dystrophy, Huntington disease, and several spinocerebellar ataxias. In human cells, diverse mechanisms promote CAG repeat instability, and in mice, the mechanisms of instability are varied and tissue-dependent. Dissection of mechanistic complexity and discovery of potential therapeutics necessitates quantitative and scalable screens for repeat mutation. We describe a GFP-based assay for screening modifiers of CAG repeat instability in human cells. The assay exploits an engineered intronic CAG repeat tract that interferes with expression of an inducible GFP minigene. Like the phenotypes of many trinucleotide repeat disorders, we find that GFP function is impaired by repeat expansion, in a length-dependent manner. The intensity of fluorescence varies inversely with repeat length, allowing estimates of repeat tract changes in live cells. We validate the assay using transcription through the repeat and engineered CAG-specific nucleases, which have previously been reported to induce CAG repeat instability. The assay is relatively fast and should be adaptable to large-scale screens of chemical and shRNA libraries. PMID:25423602

Differentiation and Genomic Instability in a Human Mammary Cell Model

NASA Technical Reports Server (NTRS)

Richmond, R.; Kale, R.; Pettengill, O.; Rose, M. Franklin (Technical Monitor)

2001-01-01

Harvest of prophylactic mastectomy specimens from an obligate heterozygote for ataxia-telangiectasia provided autologous fibroblasts as well epithelial cells (HMEC). The routine availability of these autologous cells has provided an opportunity to study cell-cell interactions in coculture and monoculture, and in 3-dimensional cultures grown in the NASA rotating bioreactor. HMEC and stromal fibroblasts grown in 2-dimensional monoculture were both observed to produce extracellular matrix. Similar matrix was encountered in 3-dimensional cultures containing HMEC. Metaphases were analyzed. For stromal fibroblasts, genomic aberrations were found in 18% of metaphase spreads. For HMEC, aberrations were greater such that a majority were found to be abnormal. The level of genomic instability determined for these noncancerous cells in 2-dimensional monoculture should be useful for generating a human cell model that can correlate the effects of differentiation in 3-dimensional coculture on the level of genomic instability.

Genetic and epigenetic instability of stem cells.

PubMed

Rajamani, Karthyayani; Li, Yuan-Sheng; Hsieh, Dean-Kuo; Lin, Shinn-Zong; Harn, Horng-Jyh; Chiou, Tzyy-Wen

2014-01-01

Recently, research on stem cells has been receiving an increasing amount of attention, both for its advantages and disadvantages. Genetic and epigenetic instabilities among stem cells have been a recurring obstacle to progress in regenerative medicine using stem cells. Various reports have stated that these instabilities can transform stem cells when transferred in vivo and thus have the potential to develop tumors. Previous research has shown that various extrinsic and intrinsic factors can contribute to the stability of stem cells. The extrinsic factors include growth supplements, growth factors, oxygen tension, passage technique, and cryopreservation. Controlling these factors based on previous reports may assist researchers in developing strategies for the production and clinical application of "safe" stem cells. On the other hand, the intrinsic factors can be unpredictable and uncontrollable; therefore, to ensure the successful use of stem cells in regenerative medicine, it is imperative to develop and implement appropriate strategies and technique for culturing stem cells and to confirm the genetic and epigenetic safety of these stem cells before employing them in clinical trials.

Lateral patellar retinaculum reconstruction for medial patellar instability following lateral retinacular release: a case report.

PubMed

Udagawa, Kazuhiko; Niki, Yasuo; Matsumoto, Hiroaki; Matsumoto, Hideo; Enomoto, Hiroyuki; Toyama, Yoshiaki; Suda, Yasunori

2014-01-01

Lateral retinacular release is still being performed in patients with recurrent patellar dislocation as an additional procedure with distal realignment or medial patellofemoral ligament (MPFL) reconstruction. However, consensus remains lacking regarding suitable indications for lateral retinacular release. A 20-year-old woman presented with patellar instability in both medial and lateral directions after undergoing lateral retinacular release with MPFL reconstruction. She displayed inherent systemic joint laxity meeting all seven Carter-Wilkinson criteria. Simultaneous MPFL revision and lateral retinaculum reconstruction successfully improved patellar instability in both directions. This case provides an example of iatrogenic medial patellar instability after failed lateral retinacular release. Copyright © 2013 Elsevier B.V. All rights reserved.

Space Propulsion and Power

DTIC Science & Technology

2013-03-08

crystals with tunable band gaps possible Refractive index N is imaginary - Bulk Electromagnetic waves cannot propogate But surface plasmons...Directional wave radiation through plasmon resonances Directional wave guiding through mid-band defect wave localization Distribution A: Approved for... acoustic damping, shear- layer instability (PERTURBATION EXPANSION EXAMPLE) classical wave equation for combustion instability: model

Hexagonal pattern instabilities in rotating Rayleigh-Bénard convection of a non-Boussinesq fluid: experimental results.

PubMed

Guarino, Alessio; Vidal, Valerie

2004-06-01

Motivated by the Küppers-Lortz instability of roll patterns in the presence of rotation, we have investigated the effects of rotation on a hexagonal pattern in Rayleigh-Bénard convection. While several theoretical models have been developed, experimental data cannot be found in the literature. In order to check the validity of the predictions and to study the effects of rotation on the behavior of the system, we present experimental results for a non-Boussinesq Rayleigh-Bénard convection with rotation about the vertical axis. Rotation introduces an additional control parameter, namely the dimensionless rotation rate Omega= 2 pi f d(2)/nu, where f is the rotation rate (in Hz), d is the thickness of the cell, and nu is the kinematic viscosity. We observe that the cell rotation induces a slow rotation of the pattern in the opposite direction (approximately Omega x 10(-4) ) in the rotating frame. Moreover, it tends to destroy the convective pattern. No oscillation of the hexagonal pattern over the range of its existence (Omega< or =6) has been observed.

DNA Replication Origins and Fork Progression at Mammalian Telomeres

PubMed Central

Higa, Mitsunori; Fujita, Masatoshi; Yoshida, Kazumasa

2017-01-01

Telomeres are essential chromosomal regions that prevent critical shortening of linear chromosomes and genomic instability in eukaryotic cells. The bulk of telomeric DNA is replicated by semi-conservative DNA replication in the same way as the rest of the genome. However, recent findings revealed that replication of telomeric repeats is a potential cause of chromosomal instability, because DNA replication through telomeres is challenged by the repetitive telomeric sequences and specific structures that hamper the replication fork. In this review, we summarize current understanding of the mechanisms by which telomeres are faithfully and safely replicated in mammalian cells. Various telomere-associated proteins ensure efficient telomere replication at different steps, such as licensing of replication origins, passage of replication forks, proper fork restart after replication stress, and dissolution of post-replicative structures. In particular, shelterin proteins have central roles in the control of telomere replication. Through physical interactions, accessory proteins are recruited to maintain telomere integrity during DNA replication. Dormant replication origins and/or homology-directed repair may rescue inappropriate fork stalling or collapse that can cause defects in telomere structure and functions. PMID:28350373

A theoretical investigation on the parametric instability excited by X-mode polarized electromagnetic wave at Tromsø

NASA Astrophysics Data System (ADS)

Wang, Xiang; Cannon, Patrick; Zhou, Chen; Honary, Farideh; Ni, Binbin; Zhao, Zhengyu

2016-04-01

Recent ionospheric modification experiments performed at Tromsø, Norway, have indicated that X-mode pump wave is capable of stimulating high-frequency enhanced plasma lines, which manifests the excitation of parametric instability. This paper investigates theoretically how the observation can be explained by the excitation of parametric instability driven by X-mode pump wave. The threshold of the parametric instability has been calculated for several recent experimental observations at Tromsø, illustrating that our derived equations for the excitation of parametric instability for X-mode heating can explain the experimental observations. According to our theoretical calculation, a minimum fraction of pump wave electric field needs to be directed along the geomagnetic field direction in order for the parametric instability threshold to be met. A full-wave finite difference time domain simulation has been performed to demonstrate that a small parallel component of pump wave electric field can be achieved during X-mode heating in the presence of inhomogeneous plasma.

PRODUCTION OF HIGHLY-ALIGNED COLLAGEN LAMELLAE BY COMBINING SHEAR FORCE AND THIN-FILM CONFINEMENT

PubMed Central

Saeidi, Nima; Sander, Edward A.; Zareian, Ramin

2012-01-01

Load-bearing tissues owe their mechanical strength to their highly-anisotropic collagenous structure. To date, attempts to engineer mechanically strong connective tissue have failed mainly due to the lack of the ability to reproduce native collagen organization in constructs synthesized by cultured cells in vitro. The ability to influence the direction of the self-assembling collagen molecules and produce highly anisotropic structures has applications ranging from de novo engineering of complex tissues to the production of organized scaffolds for cell culture contact guidance. In this investigation we have used the simple technique of spin coating to produce highly-aligned arrays of collagen fibrils. By a simple modification of the method we have also successfully produced orthogonal collagen lamellae. Alternating collagen lamellae are frequently seen in load-bearing tissues such as cornea, annulus fibrosus, and cortical bone. Culturing of corneal fibroblasts onto aligned collagen shows that the cells adopt the organization of the fibrils. In this investigation, we observed the reversal of fibrillar growth direction or “hook” formation similar to those seen previously in a microfluidic shear-flow chamber. Although the results of this investigation clearly show that it is possible to produce small areas (O) 1 cm2 of collagen fibrils with enough alignment to guide fibroblasts, there is evidence that thin film instabilities are likely to be a significant barrier to producing organized collagen fibrils over larger areas. Successful application of this method to produce highly-controlled and organized collagenous structures will require the development of techniques to control thin film instability and will be the subject of the future work. PMID:21362500

Mutation of MSH3 in endometrial cancer and evidence for its functional role in heteroduplex repair.

PubMed

Risinger, J I; Umar, A; Boyd, J; Berchuck, A; Kunkel, T A; Barrett, J C

1996-09-01

Many human tumours have length alterations in repetitive sequence elements. Although this microsatellite instability has been attributed to mutations in four DNA mismatch repair genes in hereditary nonpolyposis colorectal cancer (HNPCC) kindreds, many sporadic tumours exhibit instability but no detectable mutations in these genes. It is therefore of interest to identify other genes that contribute to this instability. In yeast, mutations in several genes, including RTH and MSH3, cause microsatellite instability. Thus, we screened 16 endometrial carcinomas with microsatellite instability for alterations in FEN1 (the human homolog of RTH) and in MSH3 (refs 12-14). Although we found no FEN1 mutations, a frameshift mutation in MSH3 was observed in an endometrial carcinoma and in an endometrial carcinoma cell line. Extracts of the cell line were deficient in repair of DNA substrates containing mismatches or extra nucleotides. Introducing chromosome 5, encoding the MSH3 gene, into the mutant cell line increased the stability of some but not all microsatellites. Extracts of these cells repaired certain substrates containing extra nucleotides, but were deficient in repair of those containing mismatches or other extra nucleotides. A subsequent search revealed a second gene mutation in HHUA cells, a missense mutation in the MSH6 gene. Together the data suggest that the MSH3 gene encodes a product that functions in repair of some but not all pre-mutational intermediates, its mutation in tumours can result in genomic instability and, as in yeast, MSH3 and MSH6 are partially redundant for mismatch repair.

On the instability of wave-fields with JONSWAP spectra to inhomogeneous disturbances, and the consequent long-time evolution

NASA Astrophysics Data System (ADS)

Ribal, A.; Stiassnie, M.; Babanin, A.; Young, I.

2012-04-01

The instability of two-dimensional wave-fields and its subsequent evolution in time are studied by means of the Alber equation for narrow-banded random surface-waves in deep water subject to inhomogeneous disturbances. A linear partial differential equation (PDE) is obtained after applying an inhomogeneous disturbance to the Alber's equation and based on the solution of this PDE, the instability of the ocean wave surface is studied for a JONSWAP spectrum, which is a realistic ocean spectrum with variable directional spreading and steepness. The steepness of the JONSWAP spectrum depends on γ and α which are the peak-enhancement factor and energy scale of the spectrum respectively and it is found that instability depends on the directional spreading, α and γ. Specifically, if the instability stops due to the directional spreading, increase of the steepness by increasing α or γ can reactivate it. This result is in qualitative agreement with the recent large-scale experiment and new theoretical results. In the instability area of α-γ plane, a long-time evolution has been simulated by integrating Alber's equation numerically and recurrent evolution is obtained which is the stochastic counterpart of the Fermi-Pasta-Ulam recurrence obtained for the cubic Schrödinger equation.

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.

Anisotropic instability of a stretching film

NASA Astrophysics Data System (ADS)

Xu, Bingrui; Li, Minhao; Deng, Daosheng

2017-11-01

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

p53 Protein interacts specifically with the meiosis-specific mammalian RecA-like protein DMC1 in meiosis.

PubMed

Habu, Toshiyuki; Wakabayashi, Nobunao; Yoshida, Kayo; Yomogida, Kenntaro; Nishimune, Yoshitake; Morita, Takashi

2004-06-01

The tumor suppressor protein p53 is specifically expressed during meiosis in spermatocytes. Subsets of p53 knockout mice exhibit testicular giant cell degenerative syndrome, which suggests p53 may be associated with meiotic cell cycle and/or DNA metabolism. Here, we show that p53 binds to the mouse meiosis-specific RecA-like protein Mus musculus DMC1 (MmDMC1). The C-terminal domain (amino acid 234-340) of MmDMC1 binds to DNA-binding domain of p53 protein. p53 might be involved in homologous recombination and/or checkpoint function by directly binding to DMC1 protein to repress genomic instability in meiotic germ cells.

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.

Direct simulation Monte Carlo investigation of the Richtmyer-Meshkov instability

DOE PAGES

Gallis, Michail A.; Koehler, Timothy P.; Torczynski, John R.; ...

2015-08-14

The Rayleigh-Taylor instability (RTI) is investigated using the Direct Simulation Monte Carlo (DSMC) method of molecular gas dynamics. Here, fully resolved two-dimensional DSMC RTI simulations are performed to quantify the growth of flat and single-mode perturbed interfaces between two atmospheric-pressure monatomic gases as a function of the Atwood number and the gravitational acceleration. The DSMC simulations reproduce all qualitative features of the RTI and are in reasonable quantitative agreement with existing theoretical and empirical models in the linear, nonlinear, and self-similar regimes. At late times, the instability is seen to exhibit a self-similar behavior, in agreement with experimental observations. Formore » the conditions simulated, diffusion can influence the initial instability growth significantly.« less

Telomere attrition and genomic instability in xeroderma pigmentosum type-b deficient fibroblasts under oxidative stress

PubMed Central

Ting, Aloysius Poh Leong; Low, Grace Kah Mun; Gopalakrishnan, Kalpana; Hande, M Prakash

2010-01-01

Abstract Xeroderma pigmentosum B (XPB/ERCC3/p89) is an ATP-dependent 3′→5′ directed DNA helicase involved in basal RNA transcription and the nucleotide excision repair (NER) pathway. While the role of NER in alleviating oxidative DNA damage has been acknowledged it remains poorly understood. To study the involvement of XPB in repair of oxidative DNA damage, we utilized primary fibroblasts from a patient suffering from XP with Cockayne syndrome and hydrogen peroxide (H2O2) to induce oxidative stress. Mutant cells retained higher viability and cell cycle dysfunction after H2O2 exposure. Cytokinesis blocked micronucleus assay revealed increased genome instability induced by H2O2. Single cell gel electrophoresis (comet) assay showed that the missense mutation caused a reduced repair capacity for oxidative DNA damage. Mutant fibroblasts also displayed decreased population doubling rate, increased telomere attrition rate and early emergence of senescent characteristics under chronic low dose exposure to H2O2. Fibroblasts from a heterozygous individual displayed intermediate traits in some assays and normal traits in others, indicating possible copy number dependence. The results show that a deficiency in functional XPB paradoxically renders cells more sensitive to the genotoxic effects of oxidative stress while reducing the cytotoxic effects. These findings have implications in the mechanisms of DNA repair, mutagenesis and carcinogenesis and ageing in normal physiological systems. PMID:19840190

FOXM1 Upregulation Is an Early Event in Human Squamous Cell Carcinoma and it Is Enhanced by Nicotine during Malignant Transformation

PubMed Central

Gemenetzidis, Emilios; Bose, Amrita; Riaz, Adeel M.; Chaplin, Tracy; Young, Bryan D.; Ali, Muhammad; Sugden, David; Thurlow, Johanna K.; Cheong, Sok-Ching; Teo, Soo-Hwang; Wan, Hong; Waseem, Ahmad; Parkinson, Eric K.; Fortune, Farida; Teh, Muy-Teck

2009-01-01

Background Cancer associated with smoking and drinking remains a serious health problem worldwide. The survival of patients is very poor due to the lack of effective early biomarkers. FOXM1 overexpression is linked to the majority of human cancers but its mechanism remains unclear in head and neck squamous cell carcinoma (HNSCC). Methodology/Principal Findings FOXM1 mRNA and protein expressions were investigated in four independent cohorts (total 75 patients) consisting of normal, premalignant and HNSCC tissues and cells using quantitative PCR (qPCR), expression microarray, immunohistochemistry and immunocytochemistry. Effect of putative oral carcinogens on FOXM1 transcriptional activity was dose-dependently assayed and confirmed using a FOXM1-specific luciferase reporter system, qPCR, immunoblotting and short-hairpin RNA interference. Genome-wide single nucleotide polymorphism (SNP) array was used to ‘trace’ the genomic instability signature pattern in 8 clonal lines of FOXM1-induced malignant human oral keratinocytes. Furthermore, acute FOXM1 upregulation in primary oral keratinocytes directly induced genomic instability. We have shown for the first time that overexpression of FOXM1 precedes HNSCC malignancy. Screening putative carcinogens in human oral keratinocytes surprisingly showed that nicotine, which is not perceived to be a human carcinogen, directly induced FOXM1 mRNA, protein stabilisation and transcriptional activity at concentrations relevant to tobacco chewers. Importantly, nicotine also augmented FOXM1-induced transformation of human oral keratinocytes. A centrosomal protein CEP55 and a DNA helicase/putative stem cell marker HELLS, both located within a consensus loci (10q23), were found to be novel targets of FOXM1 and their expression correlated tightly with HNSCC progression. Conclusions/Significance This study cautions the potential co-carcinogenic effect of nicotine in tobacco replacement therapies. We hypothesise that aberrant upregulation of FOXM1 may be inducing genomic instability through a program of malignant transformation involving the activation of CEP55 and HELLS which may facilitate aberrant mitosis and epigenetic modifications. Our finding that FOXM1 is upregulated early during oral cancer progression renders FOXM1 an attractive diagnostic biomarker for early cancer detection and its candidate mechanistic targets, CEP55 and HELLS, as indicators of malignant conversion and progression. PMID:19287496

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.

The evolution of chromosomal instability in Chinese hamster cells: a changing picture?

NASA Technical Reports Server (NTRS)

Ponnaiya, B.; Limoli, C. L.; Corcoran, J.; Kaplan, M. I.; Hartmann, A.; Morgan, W. F.

1998-01-01

PURPOSE: To investigate the kinetics of chromosomal instability induced in clones of Chinese hamster cells following X-irradiation. MATERIALS AND METHODS: X-irradiated clones of GM10115, human-hamster hybrid cells containing a single human chromosome 4 (HC4), have been previously established. These clones were defined as unstable if they contained > or = three subpopulations of cells with unique rearrangements of HC4 as detected by FISH. Stable and unstable clones were analysed by FISH and Giemsa staining at various times post-irradiation. RESULTS: While most of the stable clones continued to show chromosomal stability of HC4 over time, one became marginally unstable at approximately 45 population doublings post-irradiation. Clones exhibiting chromosomal instability had one of several fates. Many of the unstable clones were showed similar levels of instability over time. However, one unstable clone became stable with time in culture, while another became even more unstable over time. Cytogenetic analyses of all clones after Giemsa staining indicated that in some clones the hamster chromosomes were rearranged independent of HC4, demonstrating increased frequencies of chromatid breaks and dicentric chromosomes. The majority of the unstable clones also had higher yields of chromatid gaps. CONCLUSIONS: These data demonstrate the dynamic nature of chromosomal instability as measured by two different cytogenetic assays.

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

PubMed

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

2015-01-01

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

Scaled laboratory experiments explain the kink behaviour of the Crab Nebula jet.

PubMed

Li, C K; Tzeferacos, P; Lamb, D; Gregori, G; Norreys, P A; Rosenberg, M J; Follett, R K; Froula, D H; Koenig, M; Seguin, F H; Frenje, J A; Rinderknecht, H G; Sio, H; Zylstra, A B; Petrasso, R D; Amendt, P A; Park, H S; Remington, B A; Ryutov, D D; Wilks, S C; Betti, R; Frank, A; Hu, S X; Sangster, T C; Hartigan, P; Drake, R P; Kuranz, C C; Lebedev, S V; Woolsey, N C

2016-10-07

The remarkable discovery by the Chandra X-ray observatory that the Crab nebula's jet periodically changes direction provides a challenge to our understanding of astrophysical jet dynamics. It has been suggested that this phenomenon may be the consequence of magnetic fields and magnetohydrodynamic instabilities, but experimental demonstration in a controlled laboratory environment has remained elusive. Here we report experiments that use high-power lasers to create a plasma jet that can be directly compared with the Crab jet through well-defined physical scaling laws. The jet generates its own embedded toroidal magnetic fields; as it moves, plasma instabilities result in multiple deflections of the propagation direction, mimicking the kink behaviour of the Crab jet. The experiment is modelled with three-dimensional numerical simulations that show exactly how the instability develops and results in changes of direction of the jet.

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.

Theory of electrohydrodynamic instabilities in electrolytic cells

NASA Technical Reports Server (NTRS)

Bruinsma, R.; Alexander, S.

1990-01-01

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

Live Imaging to Study Microtubule Dynamic Instability in Taxane-resistant Breast Cancers.

PubMed

Wang, Richard; Wang, Harris; Wang, Zhixiang

2017-02-20

Taxanes such as docetaxel belong to a group of microtubule-targeting agents (MTAs) that are commonly relied upon to treat cancer. However, taxane resistance in cancerous cells drastically reduces the effectiveness of the drugs' long-term usage. Accumulated evidence suggests that the mechanisms underlying taxane resistance include both general mechanisms, such as the development of multidrug resistance due to the overexpression of drug-efflux proteins, and taxane-specific mechanisms, such as those that involve microtubule dynamics. Because taxanes target cell microtubules, measuring microtubule dynamic instability is an important step in determining the mechanisms of taxane resistance and provides insight into how to overcome this resistance. In the experiment, an in vivo method was used to measure microtubule dynamic instability. GFP-tagged α-tubulin was expressed and incorporated into microtubules in MCF-7 cells, allowing for the recording of the microtubule dynamics by time lapse using a sensitive camera. The results showed that, as opposed to the non-resistant parental MCF-7CC cells, the microtubule dynamics of docetaxel-resistant MCF-7TXT cells are insensitive to docetaxel treatment, which causes the resistance to docetaxel-induced mitotic arrest and apoptosis. This paper will outline this in vivo method of measuring microtubule dynamic instability.

Parametric instability analysis of truncated conical shells using the Haar wavelet method

NASA Astrophysics Data System (ADS)

Dai, Qiyi; Cao, Qingjie

2018-05-01

In this paper, the Haar wavelet method is employed to analyze the parametric instability of truncated conical shells under static and time dependent periodic axial loads. The present work is based on the Love first-approximation theory for classical thin shells. The displacement field is expressed as the Haar wavelet series in the axial direction and trigonometric functions in the circumferential direction. Then the partial differential equations are reduced into a system of coupled Mathieu-type ordinary differential equations describing dynamic instability behavior of the shell. Using Bolotin's method, the first-order and second-order approximations of principal instability regions are determined. The correctness of present method is examined by comparing the results with those in the literature and very good agreement is observed. The difference between the first-order and second-order approximations of principal instability regions for tensile and compressive loads is also investigated. Finally, numerical results are presented to bring out the influences of various parameters like static load factors, boundary conditions and shell geometrical characteristics on the domains of parametric instability of conical shells.

Direct Simulation of Evolution and Control of Nonlinear Instabilities in Attachment-Line Boundary Layers

NASA Technical Reports Server (NTRS)

Joslin, Ronald D.

2004-01-01

The unsteady, incompressible Navier-Stokes equations are used for the direct numerical simulation (DNS) of spatially evolving disturbances in a three-dimensional (3-D) attachment-line boundary layer. Two-dimensional (2-D) disturbances are introduced either by forcing at the in ow or by harmonic-source generators at the wall; 3-D disturbances are introduced by harmonic-source generators at the wall. The DNS results are in good agreement with both 2-D non-parallel theory (for small-amplitude disturbances) and weakly nonlinear theory (for finite-amplitude disturbances), which validates the two theories. The 2-D DNS results indicate that nonlinear disturbance growth occurs near branch II of the neutral stability curve; however, steady suction can be used to stabilize this disturbance growth. For 3-D instabilities that are generated o the attachment line, spreading both toward and away from the attachment line causes energy transfer to the attachment-line and downstream instabilities; suction stabilizes these instabilities. Furthermore, 3-D instabilities are more stable than 2-D or quasi-2-D instabilities.

On the nonlinear stability of a high-speed, axisymmetric boundary layer

NASA Technical Reports Server (NTRS)

Pruett, C. David; Ng, Lian L.; Erlebacher, Gordon

1991-01-01

The stability of a high-speed, axisymmetric boundary layer is investigated using secondary instability theory and direct numerical simulation. Parametric studies based on the temporal secondary instability theory identify subharmonic secondary instability as a likely path to transition on a cylinder at Mach 4.5. The theoretical predictions are validated by direct numerical simulation at temporally-evolving primary and secondary disturbances in an axisymmetric boundary-layer flow. At small amplitudes of the secondary disturbance, predicted growth rates agree to several significant digits with values obtained from the spectrally-accurate solution of the compressible Navier-Stokes equations. Qualitative agreement persists to large amplitudes of the secondary disturbance. Moderate transverse curvature is shown to significantly affect the growth rate of axisymmetric second mode disturbances, the likely candidates of primary instability. The influence of curvature on secondary instability is largely indirect but most probably significant, through modulation of the primary disturbance amplitude. Subharmonic secondary instability is shown to be predominantly inviscid in nature, and to account for spikes in the Reynolds stress components at or near the critical layer.

HPV16 E6 and E7 proteins induce a chronic oxidative stress response via NOX2 that causes genomic instability and increased susceptibility to DNA damage in head and neck cancer cells

PubMed Central

Marullo, Rossella; Werner, Erica; Zhang, Hongzheng; Chen, Georgia Z.; Shin, Dong M.; Doetsch, Paul W.

2015-01-01

Human papillomavirus (HPV) is the causative agent of a subgroup of head and neck cancer characterized by an intrinsic radiosensitivity. HPV initiates cellular transformation through the activity of E6 and E7 proteins. E6 and E7 expression is necessary but not sufficient to transform the host cell, as genomic instability is required to acquire the malignant phenotype in HPV-initiated cells. This study reveals a key role played by oxidative stress in promoting genomic instability and radiosensitivity in HPV-positive head and neck cancer. By employing an isogenic human cell model, we observed that expression of E6 and E7 is sufficient to induce reactive oxygen species (ROS) generation in head and neck cancer cells. E6/E7-induced oxidative stress is mediated by nicotinamide adenine dinucleotide phosphate oxidases (NOXs) and causes DNA damage and chromosomal aberrations. This mechanism for genomic instability distinguishes HPV-positive from HPV-negative tumors, as we observed NOX-induced oxidative stress in HPV-positive but not HPV-negative head and neck cancer cells. We identified NOX2 as the source of HPV-induced oxidative stress as NOX2 silencing significantly reduced ROS generation, DNA damage and chromosomal aberrations in HPV-positive cells. Due to their state of chronic oxidative stress, HPV-positive cells are more susceptible to DNA damage induced by ROS and ionizing radiation (IR). Furthermore, exposure to IR results in the formation of complex lesions in HPV-positive cells as indicated by the higher amount of chromosomal breakage observed in this group of cells. These results reveal a novel mechanism for sustaining genomic instability in HPV-positive head and neck tumors and elucidate its contribution to their intrinsic radiosensitivity. PMID:26354779

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

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

PubMed

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

2017-11-01

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

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

Physical Model of the Dynamic Instability in an Expanding Cell Culture

PubMed Central

Mark, Shirley; Shlomovitz, Roie; Gov, Nir S.; Poujade, Mathieu; Grasland-Mongrain, Erwan; Silberzan, Pascal

2010-01-01

Abstract Collective cell migration is of great significance in many biological processes. The goal of this work is to give a physical model for the dynamics of cell migration during the wound healing response. Experiments demonstrate that an initially uniform cell-culture monolayer expands in a nonuniform manner, developing fingerlike shapes. These fingerlike shapes of the cell culture front are composed of columns of cells that move collectively. We propose a physical model to explain this phenomenon, based on the notion of dynamic instability. In this model, we treat the first layers of cells at the front of the moving cell culture as a continuous one-dimensional membrane (contour), with the usual elasticity of a membrane: curvature and surface-tension. This membrane is active, due to the forces of cellular motility of the cells, and we propose that this motility is related to the local curvature of the culture interface; larger convex curvature correlates with a stronger cellular motility force. This shape-force relation gives rise to a dynamic instability, which we then compare to the patterns observed in the wound healing experiments. PMID:20141748

Radiation-induced instability and its relation to radiation carcinogenesis

NASA Technical Reports Server (NTRS)

Ullrich, R. L.; Ponnaiya, B.

1998-01-01

PURPOSE: A model that identifies radiation-induced genetic instability as the earliest cellular event in the multi-step sequence leading to radiation-induced cancer was previously proposed. In this paper ongoing experiments are discussed which are designed to test this model and its predictions in mouse mammary epithelial cells. RESULTS: Several lines of evidence are presented that appear to support this model: first, the development of delayed mutations in p53 following irradiation in altered growth variants; secondly, the high frequencies for the induction of both instability and transformation following irradiation in mammary epithelial cells; and finally, the demonstration that susceptibility to the induction of cytogenetic instability is a heritable trait that correlates with susceptibility to transformation and radiation-induced mammary cancer. Mice resistant to transformation and mammary cancer development are also resistant to the development of instability after irradiation. In contrast, mice sensitive to transformation and cancer are also sensitive to the development of cytogenetic instability. CONCLUSIONS: Data from this laboratory and from the studies cited above suggest a specific, and perhaps unique, role for radiation-induced instability as a critical early event associated with initiation of the carcinogenic process.

The role of Myc-induced protein synthesis in cancer

PubMed Central

Ruggero, Davide

2009-01-01

Deregulation in different steps of translational control is an emerging mechanism for cancer formation. One example of an oncogene with a direct role in control of translation is the Myc transcription factor. Myc directly increases protein synthesis rates by controlling the expression of multiple components of the protein synthetic machinery, including ribosomal proteins, initiation factors of translation, Pol III and rDNA. However, the contribution of Myc-dependent increases in protein synthesis towards the multi-step process leading to cancer has remained unknown. Recent evidence strongly suggests that Myc oncogenic signaling may monopolize the translational machinery to elicit cooperative effects on cell growth, cell cycle progression, and genome instability as a mechanism for cancer initiation. Moreover, new genetic tools to restore aberrant increases in protein synthesis control are now available, which should enable the dissection of important mechanisms in cancer that rely on the translational machinery. PMID:19934336

FANCD2 limits replication stress and genome instability in cells lacking BRCA2

PubMed Central

Buffa, Francesca M.; McDermott, Ultan; Tarsounas, Madalena

2016-01-01

The tumor suppressor BRCA2 plays a key role in genome integrity by promoting replication fork stability and homologous recombination (HR) DNA repair. Here we report that human cancer cells lacking BRCA2 rely on the Fanconi anemia protein FANCD2 to limit replication fork progression and genomic instability. Our results identify a novel role for FANCD2 in limiting constitutive replication stress in BRCA2-deficient cells, which impacts on cell survival and treatment responses. PMID:27322732

Direct simulation Monte Carlo investigation of the Rayleigh-Taylor instability

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

Gallis, M. A.; Koehler, T. P.; Torczynski, J. R.

In this paper, the Rayleigh-Taylor instability (RTI) is investigated using the direct simulation Monte Carlo (DSMC) method of molecular gas dynamics. Here, fully resolved two-dimensional DSMC RTI simulations are performed to quantify the growth of flat and single-mode perturbed interfaces between two atmospheric-pressure monatomic gases as a function of the Atwood number and the gravitational acceleration. The DSMC simulations reproduce many qualitative features of the growth of the mixing layer and are in reasonable quantitative agreement with theoretical and empirical models in the linear, nonlinear, and self-similar regimes. In some of the simulations at late times, the instability enters themore » self-similar regime, in agreement with experimental observations. Finally, for the conditions simulated, diffusion can influence the initial instability growth significantly.« less

Direct simulation Monte Carlo investigation of the Rayleigh-Taylor instability

DOE PAGES

Gallis, M. A.; Koehler, T. P.; Torczynski, J. R.; ...

2016-08-31

In this paper, the Rayleigh-Taylor instability (RTI) is investigated using the direct simulation Monte Carlo (DSMC) method of molecular gas dynamics. Here, fully resolved two-dimensional DSMC RTI simulations are performed to quantify the growth of flat and single-mode perturbed interfaces between two atmospheric-pressure monatomic gases as a function of the Atwood number and the gravitational acceleration. The DSMC simulations reproduce many qualitative features of the growth of the mixing layer and are in reasonable quantitative agreement with theoretical and empirical models in the linear, nonlinear, and self-similar regimes. In some of the simulations at late times, the instability enters themore » self-similar regime, in agreement with experimental observations. Finally, for the conditions simulated, diffusion can influence the initial instability growth significantly.« less

MR arthrography in glenohumeral instability.

PubMed

Van der Woude, H J; Vanhoenacker, F M

2007-01-01

The impact of accurate imaging in the work-up of patients with glenohumeral instability is high. Results of imaging may directly influence the surgeon's strategy to perform an arthroscopic or open treatment for (recurrent) instability. Magnetic resonance (MR) imaging, and MR arthrography in particular, is the optimal technique to detect, localize and characterize injuries of the capsular-labrum complex. Besides TI-weighted sequences with fat suppression in axial, oblique sagital and coronal directions, an additional series in abduction and exoroation position is highly advocated. This ABER series optimally depicts abnormalities of the inferior capsular-labrum complex and partial undersurface tears of the spinatus tendons. Knowledge of different anatomical variants that may mimic labral tears and of variants of the classic Bankart lesion are useful in the analysis of shoulder MR arthrograms in patients with glenohumeral instability.

Mechanochemical symmetric breaking in cell motility of slime mold

NASA Astrophysics Data System (ADS)

Guy, Robert; Zhang, Shun; Del Alamo, Juan Carlos

2016-11-01

The cytoplasm of the true slime mold Physarum polycephalum exhibits regular rhythmic periodic shuttle streaming though the cell in the direction of motion. The fluid motion is driven by the periodic contraction of an actin-myosin gel that is regulated by a calcium oscillation. When the organism is small (< 100 microns) there is no shuttle streaming, but beyond this size, regular back-and-forth streaming appears and the cell begins to migrate. In this talk we analyze a mechanochemical model of the cell which includes the intracellular fluid, the active contractile cytoskeleton, the adhesion to the substrate, and the dynamics of a chemical oscillator. We use this analysis along with experimental data to identify the instability related to the onset of streaming in order to bring insight into how contraction, flow, and adhesion are coordinated during locomotion.

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

Technology Use, Preferences, and Capacity in Injured Patients at Risk for Posttraumatic Stress Disorder.

PubMed

Kelly, Cory M; Van Eaton, Erik G; Russo, Joan E; Kelly, Victoria C; Jurkovich, Gregory J; Darnell, Doyanne A; Whiteside, Lauren K; Wang, Jin; Parker, Lea E; Payne, Thomas H; Mooney, Sean D; Bush, Nigel; Zatzick, Douglas F

2017-01-01

This investigation comprehensively assessed the technology use, preferences, and capacity of diverse injured trauma survivors with posttraumatic stress disorder (PTSD) symptoms. A total of 121 patients participating in a randomized clinical trial (RCT) of stepped collaborative care targeting PTSD symptoms were administered baseline one-, three-, and six-month interviews that assessed technology use. Longitudinal data about the instability of patient cell phone ownership and phone numbers were collected from follow-up interviews. PTSD symptoms were also assessed over the course of the six months after injury. Regression analyses explored the associations between cell phone instability and PTSD symptoms. At baseline, 71.9% (n = 87) of patients reported current cell phone ownership, and over half (58.2%, n = 46) of these patients possessed basic cell phones. Only 19.0% (n = 23) of patients had no change in cell phone number or physical phone over the course of the six months postinjury. In regression models that adjusted for relevant clinical and demographic characteristics, cell phone instability was associated with higher six-month postinjury PTSD symptom levels (p < 0.001). Diverse injured patients at risk for the development of PTSD have unique technology use patterns, including high rates of cell phone instability. These observations should be strongly considered when developing technology-supported interventions for injured patients with PTSD.

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

PubMed Central

Terasawa, Masahiro; Shinohara, Akira; Shinohara, Miki

2014-01-01

Double-strand breaks (DSBs) are one of the severest types of DNA damage. Unrepaired DSBs easily induce cell death and chromosome aberrations. To maintain genomic stability, cells have checkpoint and DSB repair systems to respond to DNA damage throughout most of the cell cycle. The failure of this process often results in apoptosis or genomic instability, such as aneuploidy, deletion, or translocation. Therefore, DSB repair is essential for maintenance of genomic stability. During mitosis, however, cells seem to suppress the DNA damage response and proceed to the next G1 phase, even if there are unrepaired DSBs. The biological significance of this suppression is not known. In this review, we summarize recent studies of mitotic DSB repair and discuss the mechanisms of suppression of DSB repair during mitosis. DSB repair, which maintains genomic integrity in other phases of the cell cycle, is rather toxic to cells during mitosis, often resulting in chromosome missegregation and aberration. Cells have multiple safeguards to prevent genomic instability during mitosis: inhibition of 53BP1 or BRCA1 localization to DSB sites, which is important to promote non-homologous end joining or homologous recombination, respectively, and also modulation of the non-homologous end joining core complex to inhibit DSB repair. We discuss how DSBs during mitosis are toxic and the multiple safeguard systems that suppress genomic instability. PMID:25287622

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.

Scaled laboratory experiments explain the kink behaviour of the Crab Nebula jet

PubMed Central

Li, C. K.; Tzeferacos, P.; Lamb, D.; Gregori, G.; Norreys, P. A.; Rosenberg, M. J.; Follett, R. K.; Froula, D. H.; Koenig, M.; Seguin, F. H.; Frenje, J. A.; Rinderknecht, H. G.; Sio, H.; Zylstra, A. B.; Petrasso, R. D.; Amendt, P. A.; Park, H. S.; Remington, B. A.; Ryutov, D. D.; Wilks, S. C.; Betti, R.; Frank, A.; Hu, S. X.; Sangster, T. C.; Hartigan, P.; Drake, R. P.; Kuranz, C. C.; Lebedev, S. V.; Woolsey, N. C.

2016-01-01

The remarkable discovery by the Chandra X-ray observatory that the Crab nebula's jet periodically changes direction provides a challenge to our understanding of astrophysical jet dynamics. It has been suggested that this phenomenon may be the consequence of magnetic fields and magnetohydrodynamic instabilities, but experimental demonstration in a controlled laboratory environment has remained elusive. Here we report experiments that use high-power lasers to create a plasma jet that can be directly compared with the Crab jet through well-defined physical scaling laws. The jet generates its own embedded toroidal magnetic fields; as it moves, plasma instabilities result in multiple deflections of the propagation direction, mimicking the kink behaviour of the Crab jet. The experiment is modelled with three-dimensional numerical simulations that show exactly how the instability develops and results in changes of direction of the jet. PMID:27713403

Drive-Bys and Trade-Ups: Examining the Directionality of the Crime and Residential Instability Relationship

ERIC Educational Resources Information Center

Hipp. John R.; Tita, George E.; Greenbaum, Robert T.

2009-01-01

Most prior research testing the hypothesis of the social disorganization theory that residential instability increases crime has used cross-sectional data. Using a unique dataset linking home sales address matched to census tracts with crime data in Los Angeles, we test the direction of this relationship using a six-year panel data design. We also…

Weibel instability for a streaming electron, counterstreaming e-e, and e-p plasmas with intrinsic temperature anisotropy

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

Ghorbanalilu, M.; Physics Department, Azarbaijan Shahid Madani University, Tabriz; Sadegzadeh, S.

2014-05-15

The existence of Weibel instability for a streaming electron, counterstreaming electron-electron (e-e), and electron-positron (e-p) plasmas with intrinsic temperature anisotropy is investigated. The temperature anisotropy is included in the directions perpendicular and parallel to the streaming direction. It is shown that the beam mean speed changes the instability mode, for a streaming electron beam, from the classic Weibel to the Weibel-like mode. The analytical and numerical solutions approved that Weibel-like modes are excited for both counterstreaming e-e and e-p plasmas. The growth rates of the instabilities in e-e and e-p plasmas are compared. The growth rate is larger for e-pmore » plasmas if the thermal anisotropy is small and the opposite is true for large thermal anisotropies. The analytical and numerical solutions are in good agreement only in the small parallel temperature and wave number limits, when the instability growth rate increases linearly with normalized wave number kc∕ω{sub p}.« less

Instabilities in rapid directional solidification under weak flow

NASA Astrophysics Data System (ADS)

Kowal, Katarzyna N.; Davis, Stephen H.; Voorhees, Peter W.

2017-12-01

We examine a rapidly solidifying binary alloy under directional solidification with nonequilibrium interfacial thermodynamics viz. the segregation coefficient and the liquidus slope are speed dependent and attachment-kinetic effects are present. Both of these effects alone give rise to (steady) cellular instabilities, mode S , and a pulsatile instability, mode P . We examine how weak imposed boundary-layer flow of magnitude |V | affects these instabilities. For small |V | , mode S becomes a traveling and the flow stabilizes (destabilizes) the interface for small (large) surface energies. For small |V | , mode P has a critical wave number that shifts from zero to nonzero giving spatial structure. The flow promotes this instability and the frequencies of the complex conjugate pairs each increase (decrease) with flow for large (small) wave numbers. These results are obtained by regular perturbation theory in powers of V far from the point where the neutral curves cross, but requires a modified expansion in powers of V1 /3 near the crossing. A uniform composite expansion is then obtained valid for all small |V | .

Direct Numerical Simulation of Transition Due to Traveling Crossflow Vortices

NASA Technical Reports Server (NTRS)

Li, Fei; Choudhari, Meelan M.; Duan, Lian

2016-01-01

Previous simulations of laminar breakdown mechanisms associated with stationary crossflow instability over a realistic swept-wing configuration are extended to investigate the alternate scenario of transition due to secondary instability of traveling crossflow modes. Earlier analyses based on secondary instability theory and parabolized stability equations have shown that this alternate scenario is viable when the initial amplitude of the most amplified mode of the traveling crossflow instability is greater than approximately 0.03 times the initial amplitude of the most amplified stationary mode. The linear growth predictions based on the secondary instability theory and parabolized stability equations agree well with the direct numerical simulation. Nonlinear effects are initially stabilizing but subsequently lead to a rapid growth followed by the onset of transition when the amplitude of the secondary disturbance exceeds a threshold value. Similar to the breakdown of stationary vortices, the transition zone is rather short and the boundary layer becomes completely turbulent across a distance of less than 15 times the boundary layer thickness at the completion of transition.

Conformational antibody binding to a native, cell-free expressed GPCR in block copolymer membranes.

PubMed

de Hoog, Hans-Peter M; Lin JieRong, Esther M; Banerjee, Sourabh; Décaillot, Fabien M; Nallani, Madhavan

2014-01-01

G-protein coupled receptors (GPCRs) play a key role in physiological processes and are attractive drug targets. Their biophysical characterization is, however, highly challenging because of their innate instability outside a stabilizing membrane and the difficulty of finding a suitable expression system. We here show the cell-free expression of a GPCR, CXCR4, and its direct embedding in diblock copolymer membranes. The polymer-stabilized CXCR4 is readily immobilized onto biosensor chips for label-free binding analysis. Kinetic characterization using a conformationally sensitive antibody shows the receptor to exist in the correctly folded conformation, showing binding behaviour that is commensurate with heterologously expressed CXCR4.

Conformational Antibody Binding to a Native, Cell-Free Expressed GPCR in Block Copolymer Membranes

PubMed Central

de Hoog, Hans-Peter M.; Lin JieRong, Esther M.; Banerjee, Sourabh; Décaillot, Fabien M.; Nallani, Madhavan

2014-01-01

G-protein coupled receptors (GPCRs) play a key role in physiological processes and are attractive drug targets. Their biophysical characterization is, however, highly challenging because of their innate instability outside a stabilizing membrane and the difficulty of finding a suitable expression system. We here show the cell-free expression of a GPCR, CXCR4, and its direct embedding in diblock copolymer membranes. The polymer-stabilized CXCR4 is readily immobilized onto biosensor chips for label-free binding analysis. Kinetic characterization using a conformationally sensitive antibody shows the receptor to exist in the correctly folded conformation, showing binding behaviour that is commensurate with heterologously expressed CXCR4. PMID:25329156

A Rapid Method for Engineering Recombinant Polioviruses or Other Enteroviruses.

PubMed

Bessaud, Maël; Pelletier, Isabelle; Blondel, Bruno; Delpeyroux, Francis

2016-01-01

The cloning of large enterovirus RNA sequences is labor-intensive because of the frequent instability in bacteria of plasmidic vectors containing the corresponding cDNAs. In order to circumvent this issue we have developed a PCR-based method that allows the generation of highly modified or chimeric full-length enterovirus genomes. This method relies on fusion PCR which enables the concatenation of several overlapping cDNA amplicons produced separately. A T7 promoter sequence added upstream the fusion PCR products allows its transcription into infectious genomic RNAs directly in transfected cells constitutively expressing the phage T7 RNA polymerase. This method permits the rapid recovery of modified viruses that can be subsequently amplified on adequate cell-lines.

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

PubMed

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

2017-09-01

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

Designing solid-liquid interphases for sodium batteries.

PubMed

Choudhury, Snehashis; Wei, Shuya; Ozhabes, Yalcin; Gunceler, Deniz; Zachman, Michael J; Tu, Zhengyuan; Shin, Jung Hwan; Nath, Pooja; Agrawal, Akanksha; Kourkoutis, Lena F; Arias, Tomas A; Archer, Lynden A

2017-10-12

Secondary batteries based on earth-abundant sodium metal anodes are desirable for both stationary and portable electrical energy storage. Room-temperature sodium metal batteries are impractical today because morphological instability during recharge drives rough, dendritic electrodeposition. Chemical instability of liquid electrolytes also leads to premature cell failure as a result of parasitic reactions with the anode. Here we use joint density-functional theoretical analysis to show that the surface diffusion barrier for sodium ion transport is a sensitive function of the chemistry of solid-electrolyte interphase. In particular, we find that a sodium bromide interphase presents an exceptionally low energy barrier to ion transport, comparable to that of metallic magnesium. We evaluate this prediction by means of electrochemical measurements and direct visualization studies. These experiments reveal an approximately three-fold reduction in activation energy for ion transport at a sodium bromide interphase. Direct visualization of sodium electrodeposition confirms large improvements in stability of sodium deposition at sodium bromide-rich interphases.The chemistry at the interface between electrolyte and electrode plays a critical role in determining battery performance. Here, the authors show that a NaBr enriched solid-electrolyte interphase can lower the surface diffusion barrier for sodium ions, enabling stable electrodeposition.

Spontaneous Planar Chiral Symmetry Breaking in Cells

NASA Astrophysics Data System (ADS)

Hadidjojo, Jeremy; Lubensky, David

Recent progress in animal development has highlighted the central role played by planar cell polarity (PCP) in epithelial tissue morphogenesis. Through PCP, cells have the ability to collectively polarize in the plane of the epithelium by localizing morphogenetic proteins along a certain axis. This allows direction-dependent modulation of tissue mechanical properties that can translate into the formation of complex, non-rotationally invariant shapes. Recent experimental observations[1] show that cells, in addition to being planar-polarized, can also spontaneously develop planar chirality, perhaps in the effort of making yet more complex shapes that are reflection non-invariant. In this talk we will present our work in characterizing general mechanisms that can lead to spontaneous chiral symmetry breaking in cells. We decompose interfacial concentration of polarity proteins in a hexagonal cell packing into irreducible representations. We find that in the case of polar concentration distributions, a chiral state can only be reached from a secondary instability after the cells are polarized. However in the case of nematic distributions, we show that a finite-amplitude (subcritical, or ``first-order'') nematic transition can send the system from disorder directly to a chiral state. In addition, we find that perturbing the system by stretching the hexagonal packing enables direct (supercritical, or ``second-order'') chiral transition in the nematic case. Finally, we do a Landau expansion to study competition between stretch-induced chirality and the tendency towards a non-chiral state in packings that have retained the full 6-fold symmetry.

Scalings of Alfvén-cyclotron and ion Bernstein instabilities on temperature anisotropy of a ring-like velocity distribution in the inner magnetosphere

DOE PAGES

Min, Kyungguk; Liu, Kaijun; Gary, S. Peter

2016-03-18

Here, a ring-like proton velocity distribution with ∂f p(v ⊥)/∂v ⊥>0 and which is sufficiently anisotropic can excite two distinct types of growing modes in the inner magnetosphere: ion Bernstein instabilities with multiple ion cyclotron harmonics and quasi-perpendicular propagation and an Alfvén-cyclotron instability at frequencies below the proton cyclotron frequency and quasi-parallel propagation. Recent particle-in-cell simulations have demonstrated that even if the maximum linear growth rate of the latter instability is smaller than the corresponding growth of the former instability, the saturation levels of the fluctuating magnetic fields can be greater for the Alfvén-cyclotron instability than for the ion Bernsteinmore » instabilities. In this study, linear dispersion theory and two-dimensional particle-in-cell simulations are used to examine scalings of the linear growth rate and saturation level of the two types of growing modes as functions of the temperature anisotropy T ⊥/T || for a general ring-like proton distribution with a fixed ring speed of 2v A, where v A is the Alfvén speed. For the proton distribution parameters chosen, the maximum linear theory growth rate of the Alfvén-cyclotron waves is smaller than that of the fastest-growing Bernstein mode for the wide range of anisotropies (1≤T ⊥/T ||≤7) considered here. Yet the corresponding particle-in-cell simulations yield a higher saturation level of the fluctuating magnetic fields for the Alfvén-cyclotron instability than for the Bernstein modes as long as inline image. Since fast magnetosonic waves with ion Bernstein instability properties observed in the magnetosphere are often not accompanied by electromagnetic ion cyclotron waves, the results of the present study indicate that the ring-like proton distributions responsible for the excitation of these fast magnetosonic waves should not be very anisotropic.« less

Effect of rotation on gravitational instability of optically thick magnetized quantum plasma in the presence of radiation

NASA Astrophysics Data System (ADS)

Kumar, A.; Pensia, R. K.

2018-05-01

This paper deals with the effect of rotation on the gravitational instability of optically thick magnetized quantum plasma in the presence of radiation. By using linearized perturbation equations of the problem, general dispersion relation is obtained which is reduced for longitudinal and transverse modes of propagation. For each mode, the problem is analyzed for two cases, when the direction of axis of rotation is parallel or perpendicular to the direction of magnetic field. Rotation parameter is found to modify the Jeans criterion of instability and expression for Jeans wavelength for transverse mode, when the axis of rotation is along the direction of magnetic field and it has stabilizing effect on the system. Magnetic field, radiation pressure and quantum correction also found to have stabilizing effect.

Lens epithelial cells derived from alphaB-crystallin knockout mice demonstrate hyperproliferation and genomic instability.

PubMed

Andley, U P; Song, Z; Wawrousek, E F; Brady, J P; Bassnett, S; Fleming, T P

2001-01-01

alphaB-crystallin is a member of the small heat shock protein family and can act as a molecular chaperone preventing the in vitro aggregation of other proteins denatured by heat or other stress conditions. Expression of alphaB-crystallin increases in cells exposed to stress and enhanced in tumors of neuroectodermal origin and in many neurodegenerative diseases. In the present study, we examined the properties of lens epithelial cells derived from mice in which the alphaB-crystallin gene had been knocked out. Primary rodent cells immortalize spontaneously in tissue culture with a frequency of 10(-5) to 10(-6). Primary lens epithelial cells derived from alphaB-crystallin-/- mice produced hyperproliferative clones at a frequency of 7.6 x 10(-2), four orders of magnitude greater than predicted by spontaneous immortalization (1). Hyperproliferative alphaB-crystallin-/- cells were shown to be truly immortal since they have been passaged for more than 100 population doublings without any diminution in growth potential. In striking contrast to the wild-type cells, which were diploid, the alphaB-crystallin-/- cultures had a high proportion of tetraploid and higher ploidy cells, indicating that the loss of alphaB-crystallin is associated with an increase in genomic instability. Further evidence of genomic instability of alphaB-crystallin-/- cells was observed when primary cultures were infected with Ad12-SV40 hybrid virus. In striking contrast to wild-type cells, alphaB-crystallin-/- cells expressing SV40 T antigen exhibited a widespread cytocidal response 2 to 3 days after attaining confluence, indicating that SV40 T antigen enhanced the intrinsic genomic instability of alphaB-crystallin-/- lens epithelial cells. These observations suggest that the widely distributed molecular chaperone alphaB-crystallin may play an important nuclear role in maintaining genomic integrity.

Ion dynamics during the parametric instabilities of a left-hand polarized Alfvén wave in a proton-electron-alpha plasma

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

Gao, Xinliang; Lu, Quanming; Hao, Yufei

2014-01-01

The parametric instabilities of an Alfvén wave in a proton-electron plasma system are found to have great influence on proton dynamics, where part of the protons can be accelerated through the Landau resonance with the excited ion acoustic waves, and a beam component along the background magnetic field is formed. In this paper, with a one-dimensional hybrid simulation model, we investigate the evolution of the parametric instabilities of a monochromatic left-hand polarized Alfvén wave in a proton-electron-alpha plasma with a low beta. When the drift velocity between the protons and alpha particles is sufficiently large, the wave numbers of themore » backward daughter Alfvén waves can be cascaded toward higher values due to the modulational instability during the nonlinear evolution of the parametric instabilities, and the alpha particles are resonantly heated in both the parallel and perpendicular direction by the backward waves. On the other hand, when the drift velocity of alpha particles is small, the alpha particles are heated in the linear growth stage of the parametric instabilities due to the Landau resonance with the excited ion acoustic waves. Therefore, the heating occurs only in the parallel direction, and there is no obvious heating in the perpendicular direction. The relevance of our results to the preferential heating of heavy ions observed in the solar wind within 0.3 AU is also discussed in this paper.« less

HTLV-1 Infection and Adult T-Cell Leukemia/Lymphoma-A Tale of Two Proteins: Tax and HBZ.

PubMed

Giam, Chou-Zen; Semmes, Oliver John

2016-06-16

HTLV-1 (Human T-cell lymphotropic virus type 1) is a complex human delta retrovirus that currently infects 10-20 million people worldwide. While HTLV-1 infection is generally asymptomatic, 3%-5% of infected individuals develop a highly malignant and intractable T-cell neoplasm known as adult T-cell leukemia/lymphoma (ATL) decades after infection. How HTLV-1 infection progresses to ATL is not well understood. Two viral regulatory proteins, Tax and HTLV-1 basic zipper protein (HBZ), encoded by the sense and antisense viral transcripts, respectively, are thought to play indispensable roles in the oncogenic process of ATL. This review focuses on the roles of Tax and HBZ in viral replication, persistence, and oncogenesis. Special emphasis is directed towards recent literature on the mechanisms of action of these two proteins and the roles of Tax and HBZ in influencing the outcomes of HTLV-1 infection including senescence induction, viral latency and persistence, genome instability, cell proliferation, and ATL development. Attempts are made to integrate results from cell-based studies of HTLV-1 infection and studies of HTLV-1 proviral integration site preference, clonality, and clonal expansion based on high throughput DNA sequencing. Recent data showing that Tax hijacks key mediators of DNA double-strand break repair signaling-the ubiquitin E3 ligase, ring finger protein 8 (RNF8) and the ubiquitin E2 conjugating enzyme (UBC13)-to activate the canonical nuclear factor kappa-light-chain-enhancer of activated B-cells (NF-κB) and other signaling pathways will be discussed. A perspective on how the Tax-RNF8 signaling axis might impact genomic instability and how Tax may collaborate with HBZ to drive oncogenesis is provided.

HTLV-1 Infection and Adult T-Cell Leukemia/Lymphoma—A Tale of Two Proteins: Tax and HBZ

PubMed Central

Giam, Chou-Zen; Semmes, Oliver John

2016-01-01

HTLV-1 (Human T-cell lymphotropic virus type 1) is a complex human delta retrovirus that currently infects 10–20 million people worldwide. While HTLV-1 infection is generally asymptomatic, 3%–5% of infected individuals develop a highly malignant and intractable T-cell neoplasm known as adult T-cell leukemia/lymphoma (ATL) decades after infection. How HTLV-1 infection progresses to ATL is not well understood. Two viral regulatory proteins, Tax and HTLV-1 basic zipper protein (HBZ), encoded by the sense and antisense viral transcripts, respectively, are thought to play indispensable roles in the oncogenic process of ATL. This review focuses on the roles of Tax and HBZ in viral replication, persistence, and oncogenesis. Special emphasis is directed towards recent literature on the mechanisms of action of these two proteins and the roles of Tax and HBZ in influencing the outcomes of HTLV-1 infection including senescence induction, viral latency and persistence, genome instability, cell proliferation, and ATL development. Attempts are made to integrate results from cell-based studies of HTLV-1 infection and studies of HTLV-1 proviral integration site preference, clonality, and clonal expansion based on high throughput DNA sequencing. Recent data showing that Tax hijacks key mediators of DNA double-strand break repair signaling—the ubiquitin E3 ligase, ring finger protein 8 (RNF8) and the ubiquitin E2 conjugating enzyme (UBC13)—to activate the canonical nuclear factor kappa-light-chain-enhancer of activated B-cells (NF-κB) and other signaling pathways will be discussed. A perspective on how the Tax-RNF8 signaling axis might impact genomic instability and how Tax may collaborate with HBZ to drive oncogenesis is provided. PMID:27322308

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.

The NEIL1 G83D germline DNA glycosylase variant induces genomic instability and cellular transformation

PubMed Central

Galick, Heather A.; Marsden, Carolyn G.; Kathe, Scott; Dragon, Julie A.; Volk, Lindsay; Nemec, Antonia A.; Wallace, Susan S.; Prakash, Aishwarya; Doublié, Sylvie; Sweasy, Joann B.

2017-01-01

Base excision repair (BER) is a key genome maintenance pathway. The NEIL1 DNA glycosylase recognizes oxidized bases, and likely removes damage in advance of the replication fork. The rs5745906 SNP of the NEIL1 gene is a rare human germline variant that encodes the NEIL1 G83D protein, which is devoid of DNA glycosylase activity. Here we show that expression of G83D NEIL1 in MCF10A immortalized but non-transformed mammary epithelial cells leads to replication fork stress. Upon treatment with hydrogen peroxide, we observe increased levels of stalled replication forks in cells expressing G83D NEIL1 versus cells expressing the wild-type (WT) protein. Double-strand breaks (DSBs) arise in G83D-expressing cells during the S and G2/M phases of the cell cycle. Interestingly, these breaks result in genomic instability in the form of high levels of chromosomal aberrations and micronuclei. Cells expressing G83D also grow in an anchorage independent manner, suggesting that the genomic instability results in a carcinogenic phenotype. Our results are consistent with the idea that an inability to remove oxidative damage in an efficient manner at the replication fork leads to genomic instability and mutagenesis. We suggest that individuals who harbor the G83D NEIL1 variant face an increased risk for human cancer. PMID:29156764

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.

Genomic instability in human lymphoid cells exposed to 1 GeV/amu Fe ions

NASA Technical Reports Server (NTRS)

Grosovsky, A.; Bethel, H.; Parks, K.; Ritter, L.; Giver, C.; Gauny, S.; Wiese, C.; Kronenberg, A.

2001-01-01

The goal of this study was to assess whether charged particle radiations of importance to spaceflight elicit genomic instability in human TK6 lymphoblasts. The incidence of genomic instability in TK6 cells was assessed 21 days after exposure to 2, 4, or 6 Fe ions (1 GeV/amu, LET= 146 keV/micrometers). Three indices of instability were used: intraclonal karyotypic heterogeneity, mutation rate analysis at the thymidine kinase (TK1) locus, and re-cloning efficiency. Fifteen of sixty clones demonstrated karyotypic heterogeneity. Five clones had multiple indicators of karyotypic change. One clone was markedly hypomutable and polyploid. Six clones were hypomutable, while 21 clones were mutators. Of these, seven were karyotypically unstable. Six clones had low re-cloning efficiencies, one of which was a mutator. All had normal karyotypes. In summary, many clones that survived exposure to a low fluence of Fe ions manifested one or more forms of genomic instability that may hasten the development of neoplasia through deletion or by recombination.

Genomic instability in human lymphoid cells exposed to 1 GeV/amu Fe ions.

PubMed

Grosovsky, A; Bethel, H; Parks, K; Ritter, L; Giver, C; Gauny, S; Wiese, C; Kronenberg, A

2001-01-01

The goal of this study was to assess whether charged particle radiations of importance to spaceflight elicit genomic instability in human TK6 lymphoblasts. The incidence of genomic instability in TK6 cells was assessed ~21 days after exposure to 2, 4, or 6 Fe ions (1 GeV/amu, LET= 146 keV/micrometers). Three indices of instability were used: intraclonal karyotypic heterogeneity, mutation rate analysis at the thymidine kinase (TK1) locus, and re-cloning efficiency. Fifteen of sixty clones demonstrated karyotypic heterogeneity. Five clones had multiple indicators of karyotypic change. One clone was markedly hypomutable and polyploid. Six clones were hypomutable, while 21 clones were mutators. Of these, seven were karyotypically unstable. Six clones had low re-cloning efficiencies, one of which was a mutator. All had normal karyotypes. In summary, many clones that survived exposure to a low fluence of Fe ions manifested one or more forms of genomic instability that may hasten the development of neoplasia through deletion or by recombination.

Role of genetic background in induced instability

NASA Technical Reports Server (NTRS)

Kadhim, Munira A.; Nelson, G. A. (Principal Investigator)

2003-01-01

Genomic instability is effectively induced by ionizing radiation. Recently, evidence has accumulated supporting a relationship between genetic background and the radiation-induced genomic instability phenotype. This is possibly due to alterations in proteins responsible for maintenance of genomic integrity or altered oxidative metabolism. Studies in human cell lines, human primary cells, and mouse models have been performed predominantly using high linear energy transfer (LET) radiation, or high doses of low LET radiation. The interplay between genetics, radiation response, and genomic instability has not been fully determined at low doses of low LET radiation. However, recent studies using low doses of low LET radiation suggest that the relationship between genetic background and radiation-induced genomic instability may be more complicated than these same relationships at high LET or high doses of low LET radiation. The complexity of this relationship at low doses of low LET radiation suggests that more of the population may be at risk than previously recognized and may have implications for radiation risk assessment.

Predictors of chronic ankle instability: Analysis of peroneal reaction time, dynamic balance and isokinetic strength.

PubMed

Sierra-Guzmán, Rafael; Jiménez, Fernando; Abián-Vicén, Javier

2018-05-01

Previous studies have reported the factors contributing to chronic ankle instability, which could lead to more effective treatments. However, factors such as the reflex response and ankle muscle strength have not been taken into account in previous investigations. Fifty recreational athletes with chronic ankle instability and 55 healthy controls were recruited. Peroneal reaction time in response to sudden inversion, isokinetic evertor muscle strength and dynamic balance with the Star Excursion Balance Test and the Biodex Stability System were measured. The relationship between the Cumberland Ankle Instability Tool score and performance on each test was assessed and a backward multiple linear regression analysis was conducted. Participants with chronic ankle instability showed prolonged peroneal reaction time, poor performance in the Biodex Stability System and decreased reach distance in the Star Excursion Balance Test. No significant differences were found in eversion and inversion peak torque. Moderate correlations were found between the Cumberland Ankle Instability Tool score and the peroneal reaction time and performance on the Star Excursion Balance Test. Peroneus brevis reaction time and the posteromedial and lateral directions of the Star Excursion Balance Test accounted for 36% of the variance in the Cumberland Ankle Instability Tool. Dynamic balance deficits and delayed peroneal reaction time are present in participants with chronic ankle instability. Peroneus brevis reaction time and the posteromedial and lateral directions of the Star Excursion Balance Test were the main contributing factors to the Cumberland Ankle Instability Tool score. No clear strength impairments were reported in unstable ankles. Copyright © 2018 Elsevier Ltd. All rights reserved.

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.

Stripes instability of an oscillating non-Brownian iso-dense suspension of spheres

NASA Astrophysics Data System (ADS)

Roht, Y. L.; Ippolito, I.; Hulin, J. P.; Salin, D.; Gauthier, G.

2018-03-01

We analyze experimentally the behavior of a non-Brownian, iso-dense suspension of spheres submitted to periodic square wave oscillations of the flow in a Hele-Shaw cell of gap H. We do observe an instability of the initially homogeneous concentration in the form of concentration variation stripes transverse to the flow. The wavelength of these regular spatial structures scales roughly as the gap of the cell and is independent of the particle concentration and of the period of oscillation. This instability requires large enough particle volume fractions φ≥ 0.25 and a gap large enough compared to the sphere diameter (H/d ≥ 8) . Mapping the domain of the existence of this instability in the space of the control parameters shows that it occurs only in a limited range of amplitudes of the fluid displacement. The analysis of the concentration distribution across the gap supports a scenario of particle migration towards the wall followed by an instability due to a particle concentration gradient with a larger concentration at the walls. In order to account for the main features of this stripes instability, we use the theory of longitudinal instability due to normal stresses difference and recent observations of a dependence of the first normal stresses difference on the particle concentration.

Subcritical Kelvin-Helmholtz instability in a Hele-Shaw cell.

PubMed

Meignin, L; Gondret, P; Ruyer-Quil, C; Rabaud, M

2003-06-13

We investigate experimentally the subcritical behavior of the Kelvin-Helmholtz instability for a gas-liquid shearing flow in a Hele-Shaw cell. The subcritical curve separating the solutions of a stable plane interface and a fully saturated nonlinear wave train is determined. Experimental results are fitted by a fifth order complex Ginzburg-Landau equation whose linear coefficients are compared to theoretical ones.

Linear stability of an active fluid interface

NASA Astrophysics Data System (ADS)

Nagilla, Amarender; Prabhakar, Ranganathan; Jadhav, Sameer

2018-02-01

Motivated by studies suggesting that the patterns exhibited by the collectively expanding fronts of thin cells during the closing of a wound [S. Mark et al., "Physical model of the dynamic instability in an expanding cell culture," Biophys. J. 98(3), 361-370 (2010)] and the shapes of single cells crawling on surfaces [A. C. Callan-Jones et al., "Viscous-fingering-like instability of cell fragments," Phys. Rev. Lett. 100(25), 258106 (2008)] are due to fingering instabilities, we investigate the stability of actively driven interfaces under the Hele-Shaw confinement. An initially radial interface between a pair of viscous fluids is driven by active agents. Surface tension and bending rigidity resist the deformation of the interface. A point source at the origin and a distributed source are also included to model the effects of injection or suction and growth or depletion, respectively. Linear stability analysis reveals that for any given initial radius of the interface, there are two key dimensionless driving rates that determine interfacial stability. We discuss stability regimes in a state space of these parameters and their implications for biological systems. An interesting finding is that an actively mobile interface is susceptible to the fingering instability irrespective of viscosity contrast.

The Pattern of Visual Fixation Eccentricity and Instability in Optic Neuropathy and Its Spatial Relationship to Retinal Ganglion Cell Layer Thickness.

PubMed

Mallery, Robert M; Poolman, Pieter; Thurtell, Matthew J; Wang, Jui-Kai; Garvin, Mona K; Ledolter, Johannes; Kardon, Randy H

2016-07-01

The purpose of this study was to assess whether clinically useful measures of fixation instability and eccentricity can be derived from retinal tracking data obtained during optical coherence tomography (OCT) in patients with optic neuropathy (ON) and to develop a method for relating fixation to the retinal ganglion cell complex (GCC) thickness. Twenty-nine patients with ON underwent macular volume OCT with 30 seconds of confocal scanning laser ophthalmoscope (cSLO)-based eye tracking during fixation. Kernel density estimation quantified fixation instability and fixation eccentricity from the distribution of fixation points on the retina. Preferred ganglion cell layer loci (PGCL) and their relationship to the GCC thickness map were derived, accounting for radial displacement of retinal ganglion cell soma from their corresponding cones. Fixation instability was increased in ON eyes (0.21 deg2) compared with normal eyes (0.06982 deg2; P < 0.001), and fixation eccentricity was increased in ON eyes (0.48°) compared with normal eyes (0.24°; P = 0.03). Fixation instability and eccentricity each correlated moderately with logMAR acuity and were highly predictive of central visual field loss. Twenty-six of 35 ON eyes had PGCL skewed toward local maxima of the GCC thickness map. Patients with bilateral dense central scotomas had PGCL in homonymous retinal locations with respect to the fovea. Fixation instability and eccentricity measures obtained during cSLO-OCT assess the function of perifoveal retinal elements and predict central visual field loss in patients with ON. A model relating fixation to the GCC thickness map offers a method to assess the structure-function relationship between fixation and areas of preserved GCC in patients with ON.

The Pattern of Visual Fixation Eccentricity and Instability in Optic Neuropathy and Its Spatial Relationship to Retinal Ganglion Cell Layer Thickness

PubMed Central

M. Mallery, Robert; Poolman, Pieter; J. Thurtell, Matthew; Wang, Jui-Kai; K. Garvin, Mona; Ledolter, Johannes; Kardon, Randy H.

2016-01-01

Purpose The purpose of this study was to assess whether clinically useful measures of fixation instability and eccentricity can be derived from retinal tracking data obtained during optical coherence tomography (OCT) in patients with optic neuropathy (ON) and to develop a method for relating fixation to the retinal ganglion cell complex (GCC) thickness. Methods Twenty-nine patients with ON underwent macular volume OCT with 30 seconds of confocal scanning laser ophthalmoscope (cSLO)-based eye tracking during fixation. Kernel density estimation quantified fixation instability and fixation eccentricity from the distribution of fixation points on the retina. Preferred ganglion cell layer loci (PGCL) and their relationship to the GCC thickness map were derived, accounting for radial displacement of retinal ganglion cell soma from their corresponding cones. Results Fixation instability was increased in ON eyes (0.21 deg2) compared with normal eyes (0.06982 deg2; P < 0.001), and fixation eccentricity was increased in ON eyes (0.48°) compared with normal eyes (0.24°; P = 0.03). Fixation instability and eccentricity each correlated moderately with logMAR acuity and were highly predictive of central visual field loss. Twenty-six of 35 ON eyes had PGCL skewed toward local maxima of the GCC thickness map. Patients with bilateral dense central scotomas had PGCL in homonymous retinal locations with respect to the fovea. Conclusions Fixation instability and eccentricity measures obtained during cSLO-OCT assess the function of perifoveal retinal elements and predict central visual field loss in patients with ON. A model relating fixation to the GCC thickness map offers a method to assess the structure–function relationship between fixation and areas of preserved GCC in patients with ON. PMID:27409502

Concentrating small particles in protoplanetary disks through the streaming instability

NASA Astrophysics Data System (ADS)

Yang, C.-C.; Johansen, A.; Carrera, D.

2017-10-01

Laboratory experiments indicate that direct growth of silicate grains via mutual collisions can only produce particles up to roughly millimeters in size. On the other hand, recent simulations of the streaming instability have shown that mm/cm-sized particles require an excessively high metallicity for dense filaments to emerge. Using a numerical algorithm for stiff mutual drag force, we perform simulations of small particles with significantly higher resolutions and longer simulation times than in previous investigations. We find that particles of dimensionless stopping time τs = 10-2 and 10-3 - representing cm- and mm-sized particles interior of the water ice line - concentrate themselves via the streaming instability at a solid abundance of a few percent. We thus revise a previously published critical solid abundance curve for the regime of τs ≪ 1. The solid density in the concentrated regions reaches values higher than the Roche density, indicating that direct collapse of particles down to mm sizes into planetesimals is possible. Our results hence bridge the gap in particle size between direct dust growth limited by bouncing and the streaming instability.

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

PubMed

Terasawa, Masahiro; Shinohara, Akira; Shinohara, Miki

2014-12-01

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

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

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

Sharma, Prerana, E-mail: preranaiitd@rediffmail.com; Chhajlani, R. K.

2014-03-15

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

Nonlinear wave particle interaction in the Earth's foreshock

NASA Technical Reports Server (NTRS)

Mazelle, C.; LeQueau, D.; Meziane, K.; Lin, R. P.; Parks, G.; Reme, H.; Sanderson, T.; Lepping, R. P.

1997-01-01

The possibility that ion beams could provide a free energy source for driving an ion/ion instability responsible for the ULF wave occurrence is investigated. For this, the wave dispersion relation with the observed parameters is solved. Secondly, it is shown that the ring-like distributions could then be produced by a coherent nonlinear wave-particle interaction. It tends to trap the ions into narrow cells in velocity space centered around a well-defined pitch-angle, directly related to the saturation wave amplitude in the analytical theory. The theoretical predictions with the observations are compared.

Scaling of induction-cell transverse impedance: effect on accelerator design

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

Ekdahl, Carl August

2016-08-09

The strength of the dangerous beam breakup (BBU) instability in linear induction accelerators (LIAs) is characterized by the transverse coupling impedance Z ⊥. This note addresses the dimensional scaling of Z ⊥, which is important when comparing new LIA designs to existing accelerators with known i BBU growth. Moreover, it is shown that the scaling of Z ⊥ with the accelerating gap size relates BBU growth directly to high-voltage engineering considerations. It is proposed to firmly establish this scaling though a series of AMOS calculations.

Balance between senescence and apoptosis is regulated by telomere damage-induced association between p16 and caspase-3.

PubMed

Panneer Selvam, Shanmugam; Roth, Braden M; Nganga, Rose; Kim, Jisun; Cooley, Marion A; Helke, Kristi L; Smith, Charles D; Ogretmen, Besim

2018-05-10

Telomerase activation protects cells from telomere damage by delaying senescence and inducing cell immortalization, whereas telomerase inhibition mediates rapid senescence or apoptosis. However, the cellular mechanisms that determine telomere damage-dependent senescence versus apoptosis induction are largely unknown. Here, we demonstrate that telomerase instability mediated by silencing of sphingosine kinase 2 (SPHK2) and sphingosine 1-phosphate (S1P), which binds and stabilizes telomerase, induces telomere damage-dependent caspase-3 activation and apoptosis, but not senescence, in p16-deficient lung cancer cells or tumors. These outcomes were prevented by knockdown of a tumor-suppressor protein, transcription factor 21 (TCF21), or by ectopic expression of WT human telomerase reverse transcriptase (hTERT), but not mutant hTERT with altered S1P binding. Interestingly, SphK2-deficient mice exhibited accelerated aging and telomerase instability that increased telomere damage and senescence via p16 activation especially in testes tissues, but not in apoptosis. Moreover, p16 silencing in SphK2-/- mouse embryonic fibroblasts activated caspase-3 and apoptosis without inducing senescence. Further, ectopic WT p16 expression in p16-deficient A549 lung cancer cells prevented TCF21 and caspase-3 activation, and resulted in senescence in response to SphK2/S1P inhibition and telomere damage. Mechanistically, a p16 mutant with impaired [MS2] caspase-3 association did not prevent telomere damage-induced apoptosis, indicating that an association between p16 and caspase-3 proteins forces senescence induction by inhibiting caspase-3 activation and apoptosis.[MS3]  These results suggest that p16 plays a direct role in telomere damage-dependent senescence by limiting apoptosis via binding to caspase-3, revealing a direct link between telomere damage-dependent senescence and apoptosis with regards to aging and cancer. Published under license by The American Society for Biochemistry and Molecular Biology, Inc.

Clonal evolution and progression of 20-methylcholanthrene-induced squamous cell carcinoma of mouse epidermis as revealed by DNA instability and other malignancy markers.

PubMed

Hirai, K; Kumakiri, M; Ueda, K; Imamura, Y; Noriki, S; Nishi, Y; Kato, H; Fukuda, M

2001-01-01

We examined the clonal evolution of skin malignant lesions by repeated topical applications of 20-methylcholanthrene (20-MC) to the skin, which induces hyperplastic epidermis, papillomatous lesion and invasive carcinoma in mice. The lesions were examined histologically and immunohistochemically with anti-single-stranded DNA after acid hydrolysis (DNA-instability test), p53, VEGF, DFF45, PCNA and AgNORs parameters analyses. Multiple clones with increased DNA instability comparable to that of invasive carcinoma were noted in early-stage (2-6 weeks) hyperplastic epidermis, and their number increased in middle (7-11 weeks), and late-stages (12-25 weeks) of hyperplastic epidermis, indicating that they belong to the malignancy category. All papillomatous lesions and invasive carcinomas showed a positive DNA-instability test. Positive immunostaining for various biomarkers and AgNORs parameters appeared in clones with a positive DNA-instability test in early-or middle-stage hyperplastic epidermis, and markedly increased in late-stage hyperplastic epidermis, papillomatous lesions and invasive carcinomas. The percentage of PCNA-positive vascular endothelial cells was significantly higher in VEGF-positive lesions with a positive DNA-instability test and became higher toward the late-stage of progression. Cut-woundings were made to papillomatous and invasive carcinoma lesions, and the regeneration activity of vascular endothelial cells was determined by using flash labeling with tritiated thymidine (3H-TdR). In small papillomatous lesions, vascular endothelial cells showed regenerative response, but the response was weak in large lesions. No such response was noted in invasive carcinomas; rather, cut-wounding induced collapse of blood vessels, which in turn induced massive coagulative necrosis of cancer cells. These responses can be interpreted to reflect exhausted vascular growth activity due to excessive stimulation by VEGF-overexpression, which was persistently seen from hyperplastic epidermis to invasive carcinoma.

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

Analysis of coupled-bunch instabilities for the NSLS-II storage ring with a 500MHz 7-cell PETRA-III cavity

DOE PAGES

Bassi, G.; Blednykh, A.; Cheng, W.; ...

2015-12-11

We present the NSLS-II storage ring that is designed to operate with superconducting RF-cavities with the aim to store an average current of 500 mA distributed in 1080 bunches, with a gap in the uniform filling for ion clearing. At the early stage of the commissioning (phase 1), characterized by a bare lattice without damping wigglers and without Landau cavities, a normal conducting 7-cell PETRA-III RF-cavity structure has been installed with the goal to store an average current of 25 mA. In this paper we discuss our analysis of coupled-bunch instabilities driven by the Higher Order Modes (HOMs) of themore » 7-cell PETRA-III RF-cavity. As a cure of the instabilities, we apply a well-known scheme based on a proper detuning of the HOMs frequencies based upon cavity temperature change, and the use of the beneficial effect of the slow head–tail damping at positive chromaticity to increase the transverse coupled-bunch instability thresholds. In addition, we discuss measurements of coupled-bunch instabilities observed during the phase 1 commissioning of the NSLS-II storage ring. In our analysis we rely, in the longitudinal case, on the theory of coupled-bunch instability for uniform fillings, while in the transverse case we complement our studies with numerical simulations with OASIS, a novel parallel particle tracking code for self-consistent simulations of collective effects driven by short and long-range wakefields.« less

Elastocapillary Instability in Mitochondrial Fission

NASA Astrophysics Data System (ADS)

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

2015-08-01

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

Field experiences with rub induced instabilities in turbomachinery

NASA Technical Reports Server (NTRS)

Goggin, D. G.

1982-01-01

Rotordynamic instability problems are not uncommon in high speed industrial turbomachinery. One type of the many destabilizing forces that can occur is caused by a rub between the stationary and rotating parts. Descriptions are given of several cases of rub induced instabilities. Included in the descriptions are the conditions at onset, the whirl frequency and direction, and the steps taken to eliminate the problem.

Bystander effects in radiation-induced genomic instability

NASA Technical Reports Server (NTRS)

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

2002-01-01

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

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.

Lattice Boltzmann methods for global linear instability analysis

NASA Astrophysics Data System (ADS)

Pérez, José Miguel; Aguilar, Alfonso; Theofilis, Vassilis

2017-12-01

Modal global linear instability analysis is performed using, for the first time ever, the lattice Boltzmann method (LBM) to analyze incompressible flows with two and three inhomogeneous spatial directions. Four linearization models have been implemented in order to recover the linearized Navier-Stokes equations in the incompressible limit. Two of those models employ the single relaxation time and have been proposed previously in the literature as linearization of the collision operator of the lattice Boltzmann equation. Two additional models are derived herein for the first time by linearizing the local equilibrium probability distribution function. Instability analysis results are obtained in three benchmark problems, two in closed geometries and one in open flow, namely the square and cubic lid-driven cavity flow and flow in the wake of the circular cylinder. Comparisons with results delivered by classic spectral element methods verify the accuracy of the proposed new methodologies and point potential limitations particular to the LBM approach. The known issue of appearance of numerical instabilities when the SRT model is used in direct numerical simulations employing the LBM is shown to be reflected in a spurious global eigenmode when the SRT model is used in the instability analysis. Although this mode is absent in the multiple relaxation times model, other spurious instabilities can also arise and are documented herein. Areas of potential improvements in order to make the proposed methodology competitive with established approaches for global instability analysis are discussed.

Experimental Studies of the Interaction Between a Parallel Shear Flow and a Directionally-Solidifying Front

NASA Technical Reports Server (NTRS)

Zhang, Meng; Maxworthy, Tony

1999-01-01

It has long been recognized that flow in the melt can have a profound influence on the dynamics of a solidifying interface and hence the quality of the solid material. In particular, flow affects the heat and mass transfer, and causes spatial and temporal variations in the flow and melt composition. This results in a crystal with nonuniform physical properties. Flow can be generated by buoyancy, expansion or contraction upon phase change, and thermo-soluto capillary effects. In general, these flows can not be avoided and can have an adverse effect on the stability of the crystal structures. This motivates crystal growth experiments in a microgravity environment, where buoyancy-driven convection is significantly suppressed. However, transient accelerations (g-jitter) caused by the acceleration of the spacecraft can affect the melt, while convection generated from the effects other than buoyancy remain important. Rather than bemoan the presence of convection as a source of interfacial instability, Hurle in the 1960s suggested that flow in the melt, either forced or natural convection, might be used to stabilize the interface. Delves considered the imposition of both a parabolic velocity profile and a Blasius boundary layer flow over the interface. He concluded that fast stirring could stabilize the interface to perturbations whose wave vector is in the direction of the fluid velocity. Forth and Wheeler considered the effect of the asymptotic suction boundary layer profile. They showed that the effect of the shear flow was to generate travelling waves parallel to the flow with a speed proportional to the Reynolds number. There have been few quantitative, experimental works reporting on the coupling effect of fluid flow and morphological instabilities. Huang studied plane Couette flow over cells and dendrites. It was found that this flow could greatly enhance the planar stability and even induce the cell-planar transition. A rotating impeller was buried inside the sample cell, driven by an outside rotating magnet, in order to generate the flow. However, it appears that this was not a well-controlled flow and may also have been unsteady. In the present experimental study, we want to study how a forced parallel shear flow in a Hele-Shaw cell interacts with the directionally solidifying crystal interface. The comparison of experimental data show that the parallel shear flow in a Hele-Shaw cell has a strong stabilizing effect on the planar interface by damping the existing initial perturbations. The flow also shows a stabilizing effect on the cellular interface by slightly reducing the exponential growth rate of cells. The left-right symmetry of cells is broken by the flow with cells tilting toward the incoming flow direction. The tilting angle increases with the velocity ratio. The experimental results are explained through the parallel flow effect on lateral solute transport. The phenomenon of cells tilting against the flow is consistent with the numerical result of Dantzig and Chao.

Human T-cell leukemia virus-I tax oncoprotein functionally targets a subnuclear complex involved in cellular DNA damage-response.

PubMed

Haoudi, Abdelali; Daniels, Rodney C; Wong, Eric; Kupfer, Gary; Semmes, O John

2003-09-26

The virally encoded oncoprotein Tax has been implicated in HTLV-1-mediated cellular transformation. The exact mechanism by which this protein contributes to the oncogenic process is not known. However, it has been hypothesized that Tax induces genomic instability via repression of cellular DNA repair. We examined the effect of de novo Tax expression upon the cell cycle, because appropriate activation of cell cycle checkpoints is essential to a robust damage-repair response. Upon induction of tax expression, Jurkat T-cells displayed a pronounced accumulation in G2/M that was reversible by caffeine. We examined the G2-specific checkpoint signaling response in these cells and found activation of the ATM/chk2-mediated pathway, whereas the ATR/chk1-mediated response was unaffected. Immunoprecipitation with anti-chk2 antibody results in co-precipitation of Tax demonstrating a direct interaction of Tax with a chk2-containing complex. We also show that Tax targets a discrete nuclear site and co-localizes with chk2 and not chk1. This nuclear site, previously identified as Tax Speckled Structures (TSS), also contains the early damage response factor 53BP1. The recruitment of 53BP1 to TSS is dependent upon ATM signaling and requires expression of Tax. Specifically, Tax expression induces redistribution of diffuse nuclear 53BP1 to the TSS foci. Taken together these data suggest that the TSS describe a unique nuclear site involved in DNA damage recognition, repair response, and cell cycle checkpoint activation. We suggest that association of Tax with this multifunctional subnuclear site results in disruption of a subset of the site-specific activities and contributes to cellular genomic instability.

Particle Acceleration, Magnetic Field Generation in Relativistic Shocks

NASA Technical Reports Server (NTRS)

Nishikawa, Ken-Ichi; Hardee, P.; Hededal, C. B.; Richardson, G.; Sol, H.; Preece, R.; Fishman, G. J.

2005-01-01

Shock acceleration is an ubiquitous phenomenon in astrophysical plasmas. Plasma waves and their associated instabilities (e.g., the Buneman instability, two-streaming instability, and the Weibel instability) created in the shocks are responsible for particle (electron, positron, and ion) acceleration. Using a 3-D relativistic electromagnetic particle (REMP) code, we have investigated particle acceleration associated with a relativistic jet front propagating through an ambient plasma with and without initial magnetic fields. We find only small differences in the results between no ambient and weak ambient parallel magnetic fields. Simulations show that the Weibel instability created in the collisionless shock front accelerates particles perpendicular and parallel to the jet propagation direction. New simulations with an ambient perpendicular magnetic field show the strong interaction between the relativistic jet and the magnetic fields. The magnetic fields are piled up by the jet and the jet electrons are bent, which creates currents and displacement currents. At the nonlinear stage, the magnetic fields are reversed by the current and the reconnection may take place. Due to these dynamics the jet and ambient electron are strongly accelerated in both parallel and perpendicular directions.

Particle Acceleration, Magnetic Field Generation, and Emission in Relativistic Shocks

NASA Technical Reports Server (NTRS)

Nishikawa, Ken-IchiI.; Hededal, C.; Hardee, P.; Richardson, G.; Preece, R.; Sol, H.; Fishman, G.

2004-01-01

Shock acceleration is an ubiquitous phenomenon in astrophysical plasmas. Plasma waves and their associated instabilities (e.g., the Buneman instability, two-streaming instability, and the Weibel instability) created in the shocks are responsible for particle (electron, positron, and ion) acceleration. Using a 3-D relativistic electromagnetic particle (m) code, we have investigated particle acceleration associated with a relativistic jet front propagating through an ambient plasma with and without initial magnetic fields. We find only small differences in the results between no ambient and weak ambient parallel magnetic fields. Simulations show that the Weibel instability created in the collisionless shock front accelerates particles perpendicular and parallel to the jet propagation direction. New simulations with an ambient perpendicular magnetic field show the strong interaction between the relativistic jet and the magnetic fields. The magnetic fields are piled up by the jet and the jet electrons are bent, which creates currents and displacement currents. At the nonlinear stage, the magnetic fields are reversed by the current and the reconnection may take place. Due to these dynamics the jet and ambient electron are strongly accelerated in both parallel and perpendicular directions.

Microsegregation during directional solidification

NASA Technical Reports Server (NTRS)

Coriell, S. R.; Mcfadden, G. B.

1984-01-01

During the directional solidification of alloys, solute inhomogeneities transverse to the growth direction arise due to morphological instabilities (leading to cellular or dendritic growth) and/or due to convection in the melt. In the absence of convection, the conditions for the onset of morphological instability are given by the linear stability analysis of Mullins and Sekerka. For ordinary solidification rates, the predictions of linear stability analysis are similar to the constitutional supercooling criterion. However, at very rapid solidification rates, linear stability analysis predicts a vast increase in stabilization in comparison to constitutional supercooling.

Progress in indirect and direct-drive planar experiments on hydrodynamic instabilities at the ablation front

DOE PAGES

Casner, A.; Masse, L.; Delorme, B.; ...

2014-12-01

Understanding and mitigating hydrodynamic instabilities and the fuel mix are the key elements for achieving ignition in Inertial Confinement Fusion. Cryogenic indirect-drive implosions on the National Ignition Facility have evidenced that the ablative Rayleigh-Taylor Instability (RTI) is a driver of the hot spot mix. This motivates the switch to a more flexible higher adiabat implosion design [O. A. Hurricane et al., Phys. Plasmas 21, 056313 (2014)]. The shell instability is also the main candidate for performance degradation in low-adiabat direct drive cryogenic implosions [Goncharov et al., Phys. Plasmas 21, 056315 (2014)]. This paper reviews recent results acquired in planar experimentsmore » performed on the OMEGA laser facility and devoted to the modeling and mitigation of hydrodynamic instabilities at the ablation front. In application to the indirect-drive scheme, we describe results obtained with a specific ablator composition such as the laminated ablator or a graded-dopant emulator. In application to the direct drive scheme, we discuss experiments devoted to the study of laser imprinted perturbations with special phase plates. The simulations of the Richtmyer-Meshkov phase reversal during the shock transit phase are challenging, and of crucial interest because this phase sets the seed of the RTI growth. Recent works were dedicated to increasing the accuracy of measurements of the phase inversion. We conclude by presenting a novel imprint mitigation mechanism based on the use of underdense foams. Lastly, the foams induce laser smoothing by parametric instabilities thus reducing the laser imprint on the CH foil.« less

Repair of osteochondral defects with in vitro engineered cartilage based on autologous bone marrow stromal cells in a swine model.

PubMed

He, Aijuan; Liu, Lina; Luo, Xusong; Liu, Yu; Liu, Yi; Liu, Fangjun; Wang, Xiaoyun; Zhang, Zhiyong; Zhang, Wenjie; Liu, Wei; Cao, Yilin; Zhou, Guangdong

2017-01-13

Functional reconstruction of large osteochondral defects is always a major challenge in articular surgery. Some studies have reported the feasibility of repairing articular osteochondral defects using bone marrow stromal cells (BMSCs) and biodegradable scaffolds. However, no significant breakthroughs have been achieved in clinical translation due to the instability of in vivo cartilage regeneration based on direct cell-scaffold construct implantation. To overcome the disadvantages of direct cell-scaffold construct implantation, the current study proposed an in vitro cartilage regeneration strategy, providing relatively mature cartilage-like tissue with superior mechanical properties. Our strategy involved in vitro cartilage engineering, repair of osteochondral defects, and evaluation of in vivo repair efficacy. The results demonstrated that BMSC engineered cartilage in vitro (BEC-vitro) presented a time-depended maturation process. The implantation of BEC-vitro alone could successfully realize tissue-specific repair of osteochondral defects with both cartilage and subchondral bone. Furthermore, the maturity level of BEC-vitro had significant influence on the repaired results. These results indicated that in vitro cartilage regeneration using BMSCs is a promising strategy for functional reconstruction of osteochondral defect, thus promoting the clinical translation of cartilage regeneration techniques incorporating BMSCs.

ZSCAN10 expression corrects the genomic instability of iPSCs from aged donors

PubMed Central

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

2018-01-01

Induced pluripotent stem cells (iPSCs), which are used to produce transplantable tissues, may particularly benefit older patients, who are more likely to suffer from degenerative diseases. However, iPSCs generated from aged donors (A-iPSCs) exhibit higher genomic instability, defects in apoptosis and a blunted DNA damage response compared with iPSCs generated from younger donors. We demonstrated that A-iPSCs exhibit excessive glutathione-mediated reactive oxygen species (ROS) scavenging activity, which blocks the DNA damage response and apoptosis and permits survival of cells with genomic instability. We found that the pluripotency factor ZSCAN10 is poorly expressed in A-iPSCs and addition of ZSCAN10 to the four Yamanaka factors (OCT4, SOX2, KLF4 and c-MYC) during A-iPSC reprogramming normalizes ROS–glutathione homeostasis and the DNA damage response, and recovers genomic stability. Correcting the genomic instability of A-iPSCs will ultimately enhance our ability to produce histocompatible functional tissues from older patients’ own cells that are safe for transplantation. PMID:28846095

Evaluation of Chromosomal Instability in Diabetic Rats Treated with Naringin

PubMed Central

A. Bakheet, Saleh; M. Attia, Sabry

2011-01-01

We used the bone marrow DNA strand breaks, micronucleus formations, spermatocyte chromosomal aberrations, and sperm characteristic assays to investigate the chromosomal instability in somatic and germinal cells of diabetic rats treated with multiple doses of naringin. The obtained results revealed that naringin was neither cytotoxic nor genotoxic for the rats at all tested doses. Moreover, naringin significantly reduced the diabetes-induced chromosomal instability in somatic and germinal cells in a dose-dependent manner. In addition, diabetes induced marked biochemical alterations characteristic of oxidative stress including enhanced lipid peroxidation, accumulation of oxidized glutathione, reduction in reduced glutathione, and accumulation of intracellular reactive oxygen species. Treatment with naringin ameliorated these biochemical markers dose-dependently. In conclusion, naringin confers an appealing protective effect against diabetes-induced chromosomal instability towards rat somatic and germinal cells which might be explained partially via diminishing the de novo free radical generation induced by hyperglycemia. Thus, naringin might be a good candidate to reduce genotoxic risk associated with hyperglycemia and may provide decreases in the development of secondary malignancy and abnormal reproductive outcomes risks, which seems especially important for diabetic patients. PMID:21941606

Carbon nanotube-mediated siRNA delivery for gene silencing in cancer cells

NASA Astrophysics Data System (ADS)

Hong, Tu; Guo, Honglian; Xu, Yaqiong

2011-10-01

Small interfering RNA (siRNA) is potentially a promising tool in influencing gene expression with a high degree of target specificity. However, its poor intracellular uptake, instability in vivo, and non-specific immune stimulations impeded its effect in clinical applications. In this study, carbon nanotubes (CNTs) functionalized with two types of phospholipid-polyethylene glycol (PEG) have shown capabilities to stabilize siRNA in cell culture medium during the transfection and efficiently deliver siRNA into neuroblastoma and breast cancer cells. Moreover, the intrinsic optical properties of CNTs have been investigated through absorption and fluorescence measurements. We have found that the directly-functionalized groups play an important role on the fluorescence imaging of functionalized CNTs. The unique fluorescence imaging and high delivery efficiency make CNTs a promising material to deliver drugs and evaluate the treatment effect simultaneously.

The Electric Honeycomb; an investigation of the Rose window instability

NASA Astrophysics Data System (ADS)

Niazi, Muhammad Shaheer

2017-10-01

The Rose window instability is a little-explored electrohydrodynamic instability that manifests when a layer of low-conducting oil is placed in an electric field generated by corona discharge in a point-to-plane configuration. Above a critical voltage, the instability starts as a single dimple in the oil layer right below the point electrode and subsequently evolves into a characteristic pattern of polygonal cells. In this study, we experimentally explore governing parameters that guide the instability and document geometric attributes of the characteristic cellular pattern. The driving force for the instability has been attributed to the buildup of charged ions which in turn apply an electric pressure on the oil surface. We confirm the charged surface distribution using thermal imaging and demonstrate that the instability can be locally inhibited by preventing charge buildup under an ion shadow.

The Electric Honeycomb; an investigation of the Rose window instability

PubMed Central

2017-01-01

The Rose window instability is a little-explored electrohydrodynamic instability that manifests when a layer of low-conducting oil is placed in an electric field generated by corona discharge in a point-to-plane configuration. Above a critical voltage, the instability starts as a single dimple in the oil layer right below the point electrode and subsequently evolves into a characteristic pattern of polygonal cells. In this study, we experimentally explore governing parameters that guide the instability and document geometric attributes of the characteristic cellular pattern. The driving force for the instability has been attributed to the buildup of charged ions which in turn apply an electric pressure on the oil surface. We confirm the charged surface distribution using thermal imaging and demonstrate that the instability can be locally inhibited by preventing charge buildup under an ion shadow. PMID:29134066

'Dancing eyes, dancing feet syndrome' in small cell lung carcinoma.

PubMed

Sharma, Chandramohan; Acharya, Mihir; Kumawat, Bansi Lal; Kochar, Abhishek

2014-04-23

A 60-year-old man presented with a 25-day history of acute onset instability of gait, tremulousness of limbs and involuntary eye movements. Examination revealed presence of opsoclonus, myoclonus and ataxia, without any loss of motor power in the limbs. Prompt investigations were directed towards identifying an underlying malignancy which is often associated with this type of clinical scenario. CT of the brain was normal and cerebrospinal fluid examination showed lymphocytic pleocytosis. A cavitatory lesion was found in the right lung base on the high-resolution CT of the chest and histopathological examination of this lung mass showed small cell lung carcinoma. The patient was managed symptomatically with levetiracetam and baclofen and referred to oncology department for resection of the lung mass.

Joint Instability and Osteoarthritis

PubMed Central

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

2015-01-01

Joint instability creates a clinical and economic burden in the health care system. Injuries and disorders that directly damage the joint structure or lead to joint instability are highly associated with osteoarthritis (OA). Thus, understanding the physiology of joint stability and the mechanisms of joint instability-induced OA is of clinical significance. The first section of this review discusses the structure and function of major joint tissues, including periarticular muscles, which play a significant role in joint stability. Because the knee, ankle, and shoulder joints demonstrate a high incidence of ligament injury and joint instability, the second section summarizes the mechanisms of ligament injury-associated joint instability of these joints. The final section highlights the recent advances in the understanding of the mechanical and biological mechanisms of joint instability-induced OA. These advances may lead to new opportunities for clinical intervention in the prevention and early treatment of OA. PMID:25741184

Joint instability and osteoarthritis.

PubMed

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

2015-01-01

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

Mechanical instability and percolation of deformable particles through porous networks

NASA Astrophysics Data System (ADS)

Benet, Eduard; Lostec, Guillaume; Pellegrino, John; Vernerey, Franck

2018-04-01

The transport of micron-sized particles such as bacteria, cells, or synthetic lipid vesicles through porous spaces is a process relevant to drug delivery, separation systems, or sensors, to cite a few examples. Often, the motion of these particles depends on their ability to squeeze through small constrictions, making their capacity to deform an important factor for their permeation. However, it is still unclear how the mechanical behavior of these particles affects collective transport through porous networks. To address this issue, we present a method to reconcile the pore-scale mechanics of the particles with the Darcy scale to understand the motion of a deformable particle through a porous network. We first show that particle transport is governed by a mechanical instability occurring at the pore scale, which leads to a binary permeation response on each pore. Then, using the principles of directed bond percolation, we are able to link this microscopic behavior to the probability of permeating through a random porous network. We show that this instability, together with network uniformity, are key to understanding the nonlinear permeation of particles at a given pressure gradient. The results are then summarized by a phase diagram that predicts three distinct permeation regimes based on particle properties and the randomness of the pore network.

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

TGFβ signaling supports survival and metastasis of endometrial cancer cells

PubMed Central

Lei, XiuFen; Wang, Long; Yang, Junhua; Sun, Lu-Zhe

2009-01-01

The association of mutation of the transforming growth factor beta (TGFβ) type II receptor (RII) with microsatellite instability revealed a significant molecular mechanism of tumorigenesis and tumor progression in gastrointestinal carcinomas with DNA replication error. However, mutation of RII is rare in other types of carcinomas with microsatellite instability including endometrial adenocarcinoma suggesting that TGFβ receptor signaling may be necessary for tumor progression. To test this hypothesis, we abrogated TGFβ signaling with ectopic expression of a dominant-negative RII (DNRII) in human endometrial carcinoma HEC-1-A cells with microsatellite instability. Our study showed that over-expression of DNRII blocked the TGFβ signaling, inhibited anchorage-dependent and -independent growth, and stimulated apoptosis in vitro. Interestingly, the expression of DNRII expression showed little effect on tumor growth of subcutaneously inoculated cells in vivo. On the other hand, the DNRII cells showed more epithelial features whereas the control cells showed more mesenchymal features suggesting a reversal of autocrine TGFβ-induced epithelial–mesenchymal transition (EMT). Consistent with these findings, DNRII cells were much less migratory and invasive in vitro and metastatic in vivo than the control cells. Therefore, an intact TGFβ signaling pathway appears necessary for the metastatic phenotypes of this carcinoma model. PMID:20622970

Filtering of non-linear instabilities. [from finite difference solution of fluid dynamics equations

NASA Technical Reports Server (NTRS)

Khosla, P. K.; Rubin, S. G.

1979-01-01

For Courant numbers larger than one and cell Reynolds numbers larger than two, oscillations and in some cases instabilities are typically found with implicit numerical solutions of the fluid dynamics equations. This behavior has sometimes been associated with the loss of diagonal dominance of the coefficient matrix. It is shown here that these problems can in fact be related to the choice of the spatial differences, with the resulting instability related to aliasing or nonlinear interaction. Appropriate 'filtering' can reduce the intensity of these oscillations and in some cases possibly eliminate the instability. These filtering procedures are equivalent to a weighted average of conservation and non-conservation differencing. The entire spectrum of filtered equations retains a three-point character as well as second-order spatial accuracy. Burgers equation has been considered as a model. Several filters are examined in detail, and smooth solutions have been obtained for extremely large cell Reynolds numbers.

Tumor-Specific Chromosome Mis-Segregation Controls Cancer Plasticity by Maintaining Tumor Heterogeneity

PubMed Central

Hu, Yuanjie; Ru, Ning; Xiao, Huasheng; Chaturbedi, Abhishek; Hoa, Neil T.; Tian, Xiao-Jun; Zhang, Hang; Ke, Chao; Yan, Fengrong; Nelson, Jodi; Li, Zhenzhi; Gramer, Robert; Yu, Liping; Siegel, Eric; Zhang, Xiaona; Jia, Zhenyu; Jadus, Martin R.; Limoli, Charles L.; Linskey, Mark E.; Xing, Jianhua; Zhou, Yi-Hong

2013-01-01

Aneuploidy with chromosome instability is a cancer hallmark. We studied chromosome 7 (Chr7) copy number variation (CNV) in gliomas and in primary cultures derived from them. We found tumor heterogeneity with cells having Chr7-CNV commonly occurs in gliomas, with a higher percentage of cells in high-grade gliomas carrying more than 2 copies of Chr7, as compared to low-grade gliomas. Interestingly, all Chr7-aneuploid cell types in the parental culture of established glioma cell lines reappeared in single-cell-derived subcultures. We then characterized the biology of three syngeneic glioma cultures dominated by different Chr7-aneuploid cell types. We found phenotypic divergence for cells following Chr7 mis-segregation, which benefited overall tumor growth in vitro and in vivo. Mathematical modeling suggested the involvement of chromosome instability and interactions among cell subpopulations in restoring the optimal equilibrium of tumor cell types. Both our experimental data and mathematical modeling demonstrated that the complexity of tumor heterogeneity could be enhanced by the existence of chromosomes with structural abnormality, in addition to their mis-segregations. Overall, our findings show, for the first time, the involvement of chromosome instability in maintaining tumor heterogeneity, which underlies the enhanced growth, persistence and treatment resistance of cancers. PMID:24282558

Mechanisms of kinetic stabilization by the drugs paclitaxel and vinblastine

PubMed Central

Castle, Brian T.; McCubbin, Seth; Prahl, Louis S.; Bernens, Jordan N.; Sept, David; Odde, David J.

2017-01-01

Microtubule-targeting agents (MTAs), widely used as biological probes and chemotherapeutic drugs, bind directly to tubulin subunits and “kinetically stabilize” microtubules, suppressing the characteristic self-assembly process of dynamic instability. However, the molecular-level mechanisms of kinetic stabilization are unclear, and the fundamental thermodynamic and kinetic requirements for dynamic instability and its elimination by MTAs have yet to be defined. Here we integrate a computational model for microtubule assembly with nanometer-scale fluorescence microscopy measurements to identify the kinetic and thermodynamic basis of kinetic stabilization by the MTAs paclitaxel, an assembly promoter, and vinblastine, a disassembly promoter. We identify two distinct modes of kinetic stabilization in live cells, one that truly suppresses on-off kinetics, characteristic of vinblastine, and the other a “pseudo” kinetic stabilization, characteristic of paclitaxel, that nearly eliminates the energy difference between the GTP- and GDP-tubulin thermodynamic states. By either mechanism, the main effect of both MTAs is to effectively stabilize the microtubule against disassembly in the absence of a robust GTP cap. PMID:28298489

Mitotic spindle defects and chromosome mis-segregation induced by LDL/cholesterol-implications for Niemann-Pick C1, Alzheimer's disease, and atherosclerosis.

PubMed

Granic, Antoneta; Potter, Huntington

2013-01-01

Elevated low-density lipoprotein (LDL)-cholesterol is a risk factor for both Alzheimer's disease (AD) and Atherosclerosis (CVD), suggesting a common lipid-sensitive step in their pathogenesis. Previous results show that AD and CVD also share a cell cycle defect: chromosome instability and up to 30% aneuploidy-in neurons and other cells in AD and in smooth muscle cells in atherosclerotic plaques in CVD. Indeed, specific degeneration of aneuploid neurons accounts for 90% of neuronal loss in AD brain, indicating that aneuploidy underlies AD neurodegeneration. Cell/mouse models of AD develop similar aneuploidy through amyloid-beta (Aß) inhibition of specific microtubule motors and consequent disruption of mitotic spindles. Here we tested the hypothesis that, like upregulated Aß, elevated LDL/cholesterol and altered intracellular cholesterol homeostasis also causes chromosomal instability. Specifically we found that: 1) high dietary cholesterol induces aneuploidy in mice, satisfying the hypothesis' first prediction, 2) Niemann-Pick C1 patients accumulate aneuploid fibroblasts, neurons, and glia, demonstrating a similar aneugenic effect of intracellular cholesterol accumulation in humans 3) oxidized LDL, LDL, and cholesterol, but not high-density lipoprotein (HDL), induce chromosome mis-segregation and aneuploidy in cultured cells, including neuronal precursors, indicating that LDL/cholesterol directly affects the cell cycle, 4) LDL-induced aneuploidy requires the LDL receptor, but not Aß, showing that LDL works differently than Aß, with the same end result, 5) cholesterol treatment disrupts the structure of the mitotic spindle, providing a cell biological mechanism for its aneugenic activity, and 6) ethanol or calcium chelation attenuates lipoprotein-induced chromosome mis-segregation, providing molecular insights into cholesterol's aneugenic mechanism, specifically through its rigidifying effect on the cell membrane, and potentially explaining why ethanol consumption reduces the risk of developing atherosclerosis or AD. These results suggest a novel, cell cycle mechanism by which aberrant cholesterol homeostasis promotes neurodegeneration and atherosclerosis by disrupting chromosome segregation and potentially other aspects of microtubule physiology.

Mitotic Spindle Defects and Chromosome Mis-Segregation Induced by LDL/Cholesterol—Implications for Niemann-Pick C1, Alzheimer’s Disease, and Atherosclerosis

PubMed Central

Granic, Antoneta; Potter, Huntington

2013-01-01

Elevated low-density lipoprotein (LDL)-cholesterol is a risk factor for both Alzheimer’s disease (AD) and Atherosclerosis (CVD), suggesting a common lipid-sensitive step in their pathogenesis. Previous results show that AD and CVD also share a cell cycle defect: chromosome instability and up to 30% aneuploidy–in neurons and other cells in AD and in smooth muscle cells in atherosclerotic plaques in CVD. Indeed, specific degeneration of aneuploid neurons accounts for 90% of neuronal loss in AD brain, indicating that aneuploidy underlies AD neurodegeneration. Cell/mouse models of AD develop similar aneuploidy through amyloid-beta (Aß) inhibition of specific microtubule motors and consequent disruption of mitotic spindles. Here we tested the hypothesis that, like upregulated Aß, elevated LDL/cholesterol and altered intracellular cholesterol homeostasis also causes chromosomal instability. Specifically we found that: 1) high dietary cholesterol induces aneuploidy in mice, satisfying the hypothesis’ first prediction, 2) Niemann-Pick C1 patients accumulate aneuploid fibroblasts, neurons, and glia, demonstrating a similar aneugenic effect of intracellular cholesterol accumulation in humans 3) oxidized LDL, LDL, and cholesterol, but not high-density lipoprotein (HDL), induce chromosome mis-segregation and aneuploidy in cultured cells, including neuronal precursors, indicating that LDL/cholesterol directly affects the cell cycle, 4) LDL-induced aneuploidy requires the LDL receptor, but not Aß, showing that LDL works differently than Aß, with the same end result, 5) cholesterol treatment disrupts the structure of the mitotic spindle, providing a cell biological mechanism for its aneugenic activity, and 6) ethanol or calcium chelation attenuates lipoprotein-induced chromosome mis-segregation, providing molecular insights into cholesterol’s aneugenic mechanism, specifically through its rigidifying effect on the cell membrane, and potentially explaining why ethanol consumption reduces the risk of developing atherosclerosis or AD. These results suggest a novel, cell cycle mechanism by which aberrant cholesterol homeostasis promotes neurodegeneration and atherosclerosis by disrupting chromosome segregation and potentially other aspects of microtubule physiology. PMID:23593294

A discrete cell model with adaptive signalling for aggregation of Dictyostelium discoideum.

PubMed Central

Dallon, J C; Othmer, H G

1997-01-01

Dictyostelium discoideum (Dd) is a widely studied model system from which fundamental insights into cell movement, chemotaxis, aggregation and pattern formation can be gained. In this system aggregation results from the chemotactic response by dispersed amoebae to a travelling wave of the chemoattractant cAMP. We have developed a model in which the cells are treated as discrete points in a continuum field of the chemoattractant, and transduction of the extracellular cAMP signal into the intracellular signal is based on the G protein model developed by Tang & Othmer. The model reproduces a number of experimental observations and gives further insight into the aggregation process. We investigate different rules for cell movement the factors that influence stream formation the effect on aggregation of noise in the choice of the direction of movement and when spiral waves of chemoattractant and cell density are likely to occur. Our results give new insight into the origin of spiral waves and suggest that streaming is due to a finite amplitude instability. PMID:9134569

Growth rates of the buoyancy-driven instability of an autocatalytic reaction front in a narrow cell

PubMed

Bockmann; Muller

2000-09-18

Experimental studies were performed on the buoyancy-driven instability of an autocatalytic reaction front in a quasi-2D cell. The unstable density stratification at an ascending front leads to convection that results in a fingerlike front deformation. The growth rates of the spatial modes of the instability are determined at the initial stage. A stabilization is found at higher wave numbers, while the system is unstable against low wave number perturbations. Whereas comparison with a reported model governed by Hele-Shaw flow fails, a two-dimensional Navier-Stokes model yields more satisfactory results. Still, present deviations suggest the presence of an additional mechanism that suppresses the growth.

Methods and compositions for protection of cells and tissues from computed tomography radiation

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

Grdina, David J.

Described are methods for preventing or inhibiting genomic instability and in cells affected by diagnostic radiology procedures employing ionizing radiation. Embodiments include methods of preventing or inhibiting genomic instability and in cells affected by computed tomography (CT) radiation. Subjects receiving ionizing radiation may be those persons suspected of having cancer, or cancer patients having received or currently receiving cancer therapy, and or those patients having received previous ionizing radiation, including those who are approaching or have exceeded the recommended total radiation dose for a person.

Mustard Gas Surrogate, 2-Chloroethyl Ethylsulfide (2-CEES), Induces Centrosome Amplification and Aneuploidy in Human and Mouse Cells

DTIC Science & Technology

2014-03-01

studies , we show that subtoxic levels of 2-chloroethyl ethylsulfide (2-CEES), a mustard gas analog, also induce centrosome amplification and chromosome...instability in cells, which may hasten the mutation rate necessary for tumorigenesis. These studies offer an explanation why those exposed to mustard...unequally, resulting in chromosome  instability,  a common  phenotype of cancer cells.  In our  studies , we show that subtoxic levels of 2

Overexpressed thioredoxin compensates Fanconi anemia related chromosomal instability.

PubMed

Kontou, Maria; Adelfalk, Caroline; Ramirez, Maria Helena; Ruppitsch, Werner; Hirsch-Kauffmann, Monica; Schweiger, Manfred

2002-04-04

The cause of the molecular defect of Fanconi anemia (FA) remains unknown. Cells from patients with FA exert an elevated spontaneous chromosomal instability which is further triggered by mitomycin C. The induced lability is reduced by overexpression of thioredoxin which is not the case for spontaneous instability. However, both are eliminated by overexpression of thioredoxin cDNA with an added nuclear localization signal. This implies that thioredoxin is lacking in the nuclei of FA cells. The total thioredoxin content in all FA cells tested is reduced. The resultant lack of nuclear thioredoxin can be the explanation for the major symptomatology in FA. Since thioredoxin is known to be the reactive cofactor of ribonucleotid reductase its shortcoming reduces the supply of deoxyribonucleotides thus hindering the DNA and replication repair with resultant chromosomal breaks. Furthermore, depression of tyrosine hydroxylase, the key enzyme of melanine synthesis, could be the basis for the pathognomotic 'café au lait' spots of FA. The observation of thioredoxin reduction in FA cells permits insight into the molecular phathophysiology of FA.

Surface instabilities in shock loaded granular media

NASA Astrophysics Data System (ADS)

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

2017-12-01

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

Importance of Resolving the Spectral Support of Beam-plasma Instabilities in Simulations

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

Shalaby, Mohamad; Broderick, Avery E.; Chang, Philip

2017-10-20

Many astrophysical plasmas are prone to beam-plasma instabilities. For relativistic and dilute beams, the spectral support of the beam-plasma instabilities is narrow, i.e., the linearly unstable modes that grow with rates comparable to the maximum growth rate occupy a narrow range of wavenumbers. This places stringent requirements on the box-sizes when simulating the evolution of the instabilities. We identify the implied lower limits on the box size imposed by the longitudinal beam plasma instability, i.e., typically the most stringent condition required to correctly capture the linear evolution of the instabilities in multidimensional simulations. We find that sizes many orders ofmore » magnitude larger than the resonant wavelength are typically required. Using one-dimensional particle-in-cell simulations, we show that the failure to sufficiently resolve the spectral support of the longitudinal instability yields slower growth and lower levels of saturation, potentially leading to erroneous physical conclusion.« less

Direct Numerical Simulation of Transition in a Swept-Wing Boundary Layer

NASA Technical Reports Server (NTRS)

Duan, Lian; Choudhari, Meelan M.; Li, Fei

2013-01-01

Direct numerical simulation (DNS) is performed to examine laminar to turbulent transition due to high-frequency secondary instability of stationary crossflow vortices in a subsonic swept-wing boundary layer for a realistic natural-laminar-flow airfoil configuration. The secondary instability is introduced via inflow forcing derived from a two-dimensional, partial-differential-equation based eigenvalue computation; and the mode selected for forcing corresponds to the most amplified secondary instability mode which, in this case, derives a majority of its growth from energy production mechanisms associated with the wall-normal shear of the stationary basic state. Both the growth of the secondary instability wave and the resulting onset of laminar-turbulent transition are captured within the DNS computations. The growth of the secondary instability wave in the DNS solution compares well with linear secondary instability theory when the amplitude is small; the linear growth is followed by a region of reduced growth resulting from nonlinear effects before an explosive onset of laminar breakdown to turbulence. The peak fluctuations are concentrated near the boundary layer edge during the initial stage of transition, but rapidly propagates towards the surface during the process of laminar breakdown. Both time-averaged statistics and flow visualization based on the DNS reveal a sawtooth transition pattern that is analogous to previously documented surface flow visualizations of transition due to stationary crossflow instability. The memory of the stationary crossflow vortex is found to persist through the transition zone and well beyond the location of the maximum skin friction.

Radiation-induced chromosomal instability in BALB/c and C57BL/6 mice: the difference is as clear as black and white

NASA Technical Reports Server (NTRS)

Ponnaiya, B.; Cornforth, M. N.; Ullrich, R. L.

1997-01-01

Genomic instability has been proposed to be the earliest step in radiation-induced tumorigenesis. It follows from this hypothesis that individuals highly susceptible to induction of tumors by radiation should exhibit enhanced radiation-induced instability. BALB/c white mice are considerably more sensitive to radiation-induced mammary cancer than C57BL/6 black mice. In this study, primary mammary epithelial cell cultures from these two strains were examined for the "delayed" appearance of chromosomal aberrations after exposure to 137Cs gamma radiation, as a measure of radiation-induced genomic instability. As expected, actively dividing cultures from both strains showed a rapid decline of initial asymmetrical aberrations with time postirradiation. However, after 16 population doublings, cells from BALB/c mice exhibited a marked increase in the frequency of chromatid-type breaks and gaps which remained elevated throughout the time course of the experiment (28 doublings). No such effect was observed for the cells of C57BL/6 mice; after the rapid clearance of initial aberrations, the frequency of chromatid-type aberrations in the irradiated population remained at or near those of nonirradiated controls. These results demonstrate a correlation between the latent expression of chromosomal damage in vitro and susceptibility for mammary tumors, and provide further support for the central role of radiation-induced instability in the process of tumorigenesis.

Posterior shoulder instability in the athletic population: Variations in assessment, clinical outcomes, and return to sport.

PubMed

DeLong, Jeffrey M; Bradley, James P

2015-12-18

Posterior instability of the shoulder is becoming an increasingly recognized shoulder injury in the athletic population. Diagnostic elements, such as etiology, directionality, and degree of instability are essential factors to assess in the unstable athletic shoulder. Concomitant injuries and associated pathologic lesions continue to be a significant challenge in the surgical management of posterior shoulder instability. Return to sport and previous level of play is ultimately the goal for every committed athlete and surgeon, thus subpopulations of athletes should be recognized as distinct entities requiring unique diagnostic, functional outcome measures, and surgical approaches.

Role of Replication and CpG Methylation in Fragile X Syndrome CGG Deletions in Primate Cells

PubMed Central

Nichol Edamura, Kerrie; Leonard, Michelle R.; Pearson, Christopher E.

2005-01-01

Instability of the fragile X CGG repeat involves both maternally derived expansions and deletions in the gametes of full-mutation males. It has also been suggested that the absence of aberrant CpG methylation may enhance repeat deletions through an unknown process. The effect of CGG tract length, DNA replication direction, location of replication initiation, and CpG methylation upon CGG stability were investigated using an SV40 primate replication system. Replication-dependant deletions with 53 CGG repeats were observed when replication was initiated proximal to the repeat, with CGG as the lagging-strand template. When we initiated replication further from the repeat, while maintaining CGG as the lagging-strand template or using CCG as the lagging-strand template, significant instability was not observed. CpG methylation of the unstable template stabilized the repeat, decreasing both the frequency and the magnitude of deletion events. Furthermore, CpG methylation slowed the efficiency of replication for all templates. Interestingly, replication forks displayed no evidence of a block at the CGG repeat tract, regardless of replication direction or CpG methylation status. Templates with 20 CGG repeats were stable under all circumstances. These results reveal that CGG deletions occur during replication and are sensitive to replication-fork dynamics, tract length, and CpG methylation. PMID:15625623

Monoenergetic ion acceleration and Rayleigh-Taylor instability of the composite target irradiated by the laser pulse

NASA Astrophysics Data System (ADS)

Khudik, Vladimir; Yi, S. Austin; Shvets, Gennady

2012-10-01

Acceleration of ions in the two-specie composite target irradiated by a circularly polarized laser pulse is studied analytically and via particle-in-cell (PIC) simulations. A self-consistent analytical model of the composite target is developed. In this model, target parameters are stationary in the center of mass of the system: heavy and light ions are completely separated from each other and form two layers, while electrons are bouncing in the potential well formed by the laser ponderomotive and electrostatic potentials. They are distributed in the direction of acceleration by the Boltzmann law and over velocities by the Maxwell-Juttner law. The laser pulse interacts directly only with electrons in a thin sheath layer, and these electrons transfer the laser pressure to the target ions. In the fluid approximation it is shown, the composite target is still susceptible to the Rayleigh-Taylor instability [1]. Using PIC simulations we found the growth rate of initially seeded perturbations as a function of their wavenumber for different composite target parameters and compare it with analytical results. Useful scaling laws between this rate and laser pulse pressure and target parameters are discussed.[4pt] [1] T.P. Yu, A. Pukhov, G. Shvets, M. Chen, T. H. Ratliff, S. A. Yi, and V. Khudik, Phys. Plasmas, 18, 043110 (2011).

Quantum theory of shuttling instability in a movable quantum dot array

NASA Astrophysics Data System (ADS)

Donarini, Andrea; Novotný, Tomás; Jauho, Antti-Pekka

2004-04-01

We study the shuttling instability in an array of three quantum dots the central one of which is movable. We extend the results by Armour and MacKinnon on this problem to a broader parameter regime. The results obtained by an efficient numerical method are interpreted directly using the Wigner distributions. We emphasize that the instability should be viewed as a crossover phenomenon rather than a clear-cut transition.

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.

Anomalous electron transport in Hall-effect thrusters: Comparison between quasi-linear kinetic theory and particle-in-cell simulations

NASA Astrophysics Data System (ADS)

Lafleur, T.; Martorelli, R.; Chabert, P.; Bourdon, A.

2018-06-01

Kinetic drift instabilities have been implicated as a possible mechanism leading to anomalous electron cross-field transport in E × B discharges, such as Hall-effect thrusters. Such instabilities, which are driven by the large disparity in electron and ion drift velocities, present a significant challenge to modelling efforts without resorting to time-consuming particle-in-cell (PIC) simulations. Here, we test aspects of quasi-linear kinetic theory with 2D PIC simulations with the aim of developing a self-consistent treatment of these instabilities. The specific quantities of interest are the instability growth rate (which determines the spatial and temporal evolution of the instability amplitude), and the instability-enhanced electron-ion friction force (which leads to "anomalous" electron transport). By using the self-consistently obtained electron distribution functions from the PIC simulations (which are in general non-Maxwellian), we find that the predictions of the quasi-linear kinetic theory are in good agreement with the simulation results. By contrast, the use of Maxwellian distributions leads to a growth rate and electron-ion friction force that is around 2-4 times higher, and consequently significantly overestimates the electron transport. A possible method for self-consistently modelling the distribution functions without requiring PIC simulations is discussed.

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

Comparative biology approaches for charged particle exposures and cancer development processes

NASA Astrophysics Data System (ADS)

Kronenberg, Amy; Gauny, Stacey; Kwoh, Ely; Sudo, Hiroko; Wiese, Claudia; Dan, Cristian; Turker, Mitchell

Comparative biology studies can provide useful information for the extrapolation of results be-tween cells in culture and the more complex environment of the tissue. In other circumstances, they provide a method to guide the interpretation of results obtained for cells from differ-ent species. We have considered several key cancer development processes following charged particle exposures using comparative biology approaches. Our particular emphases have been mutagenesis and genomic instability. Carcinogenesis requires the accumulation of mutations and most of htese mutations occur on autosomes. Two loci provide the greatest avenue for the consideration of charged particle-induced mutation involving autosomes: the TK1 locus in human cells and the APRT locus in mouse cells. Each locus can provide information on a wide variety of mutational changes, from small intragenic mutations through multilocus dele-tions and extensive tracts of mitotic recombination. In addition, the mouse model can provide a direct measurement of chromosome loss which cannot be accomplished in the human cell system. Another feature of the mouse APRT model is the ability to examine effects for cells exposed in vitro with those obtained for cells exposed in situ. We will provide a comparison of the results obtained for the TK1 locus following 1 GeV/amu Fe ion exposures to the human lymphoid cells with those obtained for the APRT locus for mouse kidney epithelial cells (in vitro or in situ). Substantial conservation of mechanisms is found amongst these three exposure scenarios, with some differences attributable to the specific conditions of exposure. A similar approach will be applied to the consideraiton of proton-induced autosomal mutations in the three model systems. A comparison of the results obtained for Fe ions vs. protons in each case will highlight LET-specificc differences in response. Another cancer development process that is receiving considerable interest is genomic instability. We have examined this process following exposure to sparsely and densely ionizing charged particles in human lymphoid cells and in human epithelial cells. A comparison of the results in these systems can reveal similari-ties and differences as a function of cell type and LET. Last, we will approach the question of the relevance of genomic instability in the context of charged particle mutagenesis. In many models, it has been difficult to link these two processes. We will present data regarding the mechanistic associations between these processes. Taken together, these studies will allow the definition of conserved pathways that are likely to contribute strongly to the cancer risks for astronauts exposed to charged particle radiations. Supported by NASA grant NNJ07HC721 to A. Kronenberg and NASA grant NNX10AC12G to M. Turker.

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.

Transient and diffusion analysis of HgCdTe

NASA Technical Reports Server (NTRS)

Clayton, J. C.

1982-01-01

Solute redistribution during directional solidification of HgCdTe is addressed. Both one-dimensional and two-dimensional models for solute redistribution are treated and model results compared to experiment. The central problem studied is the cause of radial inhomogeneities found in directionally solidified HgCdTe. A large scale gravity-driven interface instability, termed shape instability, is postulated to be the cause of radial inhomogeneities. Recommendations for future work, along with appropriate computer programs, are included.

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

NASA Astrophysics Data System (ADS)

Squire, Jonathan; Hopkins, Philip F.

2018-04-01

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

Formation and evolution of quasi-interchange convection cell on the HL-2A tokamak

NASA Astrophysics Data System (ADS)

Shi, P. W.; Chen, W.; Shi, Z. B.; Duan, X. R.; Zhong, W. L.; Jiang, M.; Yang, Z. C.; Yu, L. M.; Wen, J.; Liang, A. S.; Yu, D. L.; Liu, Y.; Yang, Q. W.

2018-06-01

Formation and evolution of quasi-interchange convection cell have been observed for the first time by an electron cyclotron emission imaging (ECEI) system on the HL-2A tokamak. The instability with mode numbers of m/n = -1/-1 and a frequency of 2-4 kHz propagates in the electron diamagnetic drift direction. The mode downgrades the inner stored energy WE and enhances the divertor Hα signal, which indicates a degradation of plasma confinement. The ECEI reveals that the colder core temperature fluctuation distorts to a crescent shape, while a bubble originates from hot fluctuation gradually and draws into the concave side of the crescent. A finger-like structure can be observed during the convection process, and it presents a typical feature of the quasi-interchange model. The radial structure of the interchange mode obtained from electron cyclotron emission is quite narrow at the high field side but relatively wider at the low field side. Further analysis suggests that the discharge parameters are favorable for the excitation of interchange mode, and the stability criterion is violated in the core region. Moreover, the experimental frequency agrees with that given by the linear dispersion relation of interchange instability. The large grow rate suggests that the mode grows on a very short time scale.

Protease-Activated Receptor-2 Deficiency Attenuates Atherosclerotic Lesion Progression and Instability in Apolipoprotein E-Deficient Mice

PubMed Central

Zuo, Pengfei; Zuo, Zhi; Zheng, Yueyue; Wang, Xin; Zhou, Qianxing; Chen, Long; Ma, Genshan

2017-01-01

Inflammatory mechanisms are involved in the process of atherosclerotic plaque formation and rupture. Accumulating evidence suggests that protease-activated receptor (PAR)-2 contributes to the pathophysiology of chronic inflammation on the vasculature. To directly examine the role of PAR-2 in atherosclerosis, we generated apolipoprotein E/PAR-2 double-deficient mice. Mice were fed with high-fat diet for 12 weeks starting at ages of 6 weeks. PAR-2 deficiency attenuated atherosclerotic lesion progression with reduced total lesion area, reduced percentage of stenosis and reduced total necrotic core area. PAR-2 deficiency increased fibrous cap thickness and collagen content of plaque. Moreover, PAR-2 deficiency decreased smooth muscle cell content, macrophage accumulation, matrix metallopeptidase-9 expression and neovascularization in plaque. Relative quantitative PCR assay using thoracic aorta revealed that PAR-2 deficiency reduced mRNA expression of inflammatory molecules, such as vascular cell adhesion molecule-1, intercellular adhesion molecule-1, tumor necrosis factor (TNF)-α and monocyte chemoattractant protein (MCP)-1. In vitro experiment, we found that PAR-2 deficiency reduced mRNA expression of interferon-γ, interleukin-6, TNF-α and MCP-1 in macrophage under unstimulated and lipopolysaccharide-stimulated conditions. These results suggest that PAR-2 deficiency attenuates the progression and instability of atherosclerotic plaque. PMID:28959204

Mechanisms of kinetic stabilization by the drugs paclitaxel and vinblastine.

PubMed

Castle, Brian T; McCubbin, Seth; Prahl, Louis S; Bernens, Jordan N; Sept, David; Odde, David J

2017-05-01

Microtubule-targeting agents (MTAs), widely used as biological probes and chemotherapeutic drugs, bind directly to tubulin subunits and "kinetically stabilize" microtubules, suppressing the characteristic self-assembly process of dynamic instability. However, the molecular-level mechanisms of kinetic stabilization are unclear, and the fundamental thermodynamic and kinetic requirements for dynamic instability and its elimination by MTAs have yet to be defined. Here we integrate a computational model for microtubule assembly with nanometer-scale fluorescence microscopy measurements to identify the kinetic and thermodynamic basis of kinetic stabilization by the MTAs paclitaxel, an assembly promoter, and vinblastine, a disassembly promoter. We identify two distinct modes of kinetic stabilization in live cells, one that truly suppresses on-off kinetics, characteristic of vinblastine, and the other a "pseudo" kinetic stabilization, characteristic of paclitaxel, that nearly eliminates the energy difference between the GTP- and GDP-tubulin thermodynamic states. By either mechanism, the main effect of both MTAs is to effectively stabilize the microtubule against disassembly in the absence of a robust GTP cap. © 2017 Castle et al. This article is distributed by The American Society for Cell Biology under license from the author(s). Two months after publication it is available to the public under an Attribution–Noncommercial–Share Alike 3.0 Unported Creative Commons License (http://creativecommons.org/licenses/by-nc-sa/3.0).

Dynamic balance deficits in individuals with chronic ankle instability compared to ankle sprain copers 1 year after a first-time lateral ankle sprain injury.

PubMed

Doherty, Cailbhe; Bleakley, Chris; Hertel, Jay; Caulfield, Brian; Ryan, John; Delahunt, Eamonn

2016-04-01

To quantify the dynamic balance deficits that characterise a group with chronic ankle instability compared to lateral ankle sprain copers and non-injured controls using kinematic and kinetic outcomes. Forty-two participants with chronic ankle instability and twenty-eight lateral ankle sprain copers were initially recruited within 2 weeks of sustaining a first-time, acute lateral ankle sprain and required to attend our laboratory 1 year later to complete the current study protocol. An additional group of non-injured individuals were also recruited to act as a control group. All participants completed the anterior, posterior-lateral and posterior-medial reach directions of the star excursion balance test. Sagittal plane kinematics of the lower extremity and associated fractal dimension of the centre of pressure path were also acquired. Participants with chronic ankle instability displayed poorer performance in the anterior, posterior-medial and posterior-lateral reach directions compared with controls bilaterally, and in the posterior-lateral direction compared with lateral ankle sprain copers on their 'involved' limb only. These performance deficits in the posterior-lateral and posterior-medial directions were associated with reduced flexion and dorsiflexion displacements at the hip, knee and ankle at the point of maximum reach, and coincided with reduced complexity of the centre of pressure path. In comparison with lateral ankle sprain copers and controls, participants with chronic ankle instability were characterised by dynamic balance deficits as measured using the SEBT. This was attested to reduced sagittal plane motions at the hip, knee and ankle joints, and reduced capacity of the stance limb to avail of its supporting base. III.

Melanoma cells present high levels of HLA-A2-tyrosinase in association with instability and aberrant intracellular processing of tyrosinase.

PubMed

Michaeli, Yael; Sinik, Keren; Haus-Cohen, Maya; Reiter, Yoram

2012-04-01

Short-lived protein translation products are proposed to be a major source of substrates for major histocompatibility complex (MHC) class I antigen processing and presentation; however, a direct link between protein stability and the presentation level of MHC class I-peptide complexes has not been made. We have recently discovered that the peptide Tyr((369-377)) , derived from the tyrosinase protein is highly presented by HLA-A2 on the surface of melanoma cells. To examine the molecular mechanisms responsible for this presentation, we compared characteristics of tyrosinase in melanoma cells lines that present high or low levels of HLA-A2-Tyr((369-377)) complexes. We found no correlation between mRNA levels and the levels of HLA-A2-Tyr((369-377)) presentation. Co-localization experiments revealed that, in cell lines presenting low levels of HLA-A2-Tyr((369-377)) complexes, tyrosinase co-localizes with LAMP-1, a melanosome marker, whereas in cell lines presenting high HLA-A2-Tyr((369-377)) levels, tyrosinase localizes to the endoplasmic reticulum. We also observed differences in tyrosinase molecular weight and glycosylation composition as well as major differences in protein stability (t(1/2) ). By stabilizing the tyrosinase protein, we observed a dramatic decrease in HLA-A2-tyrosinase presentation. Our findings suggest that aberrant processing and instability of tyrosinase are responsible for the high presentation of HLA-A2-Tyr((369-377)) complexes and thus shed new light on the relationship between intracellular processing, stability of proteins, and MHC-restricted peptide presentation. © 2012 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

Mislocalization of centromeric histone H3 variant CENP-A contributes to chromosomal instability (CIN) in human cells

PubMed Central

Shrestha, Roshan L.; Ahn, Grace S.; Staples, Mae I.; Sathyan, Kizhakke M.; Karpova, Tatiana S.; Foltz, Daniel R.; Basrai, Munira A.

2017-01-01

Chromosomal instability (CIN) is a hallmark of many cancers and a major contributor to tumorigenesis. Centromere and kinetochore associated proteins such as the evolutionarily conserved centromeric histone H3 variant CENP-A, associate with centromeric DNA for centromere function and chromosomal stability. Stringent regulation of cellular CENP-A levels prevents its mislocalization in yeast and flies to maintain genome stability. CENP-A overexpression and mislocalization are observed in several cancers and reported to be associated with increased invasiveness and poor prognosis. We examined whether there is a direct relationship between mislocalization of overexpressed CENP-A and CIN using HeLa and chromosomally stable diploid RPE1 cell lines as model systems. Our results show that mislocalization of overexpressed CENP-A to chromosome arms leads to chromosome congression defects, lagging chromosomes, micronuclei formation and a delay in mitotic exit. CENP-A overexpressing cells showed altered localization of centromere and kinetochore associated proteins such as CENP-C, CENP-T and Nuf2 leading to weakened native kinetochores as shown by reduced interkinetochore distance and CIN. Importantly, our results show that mislocalization of CENP-A to chromosome arms is one of the major contributors for CIN as depletion of histone chaperone DAXX prevents CENP-A mislocalization and rescues the reduced interkinetochore distance and CIN phenotype in CENP-A overexpressing cells. In summary, our results establish that CENP-A overexpression and mislocalization result in a CIN phenotype in human cells. This study provides insights into how overexpression of CENP-A may contribute to CIN in cancers and underscore the importance of understanding the pathways that prevent CENP-A mislocalization for genome stability. PMID:28596481

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

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

PubMed Central

Hamperl, Stephan; Cimprich, Karlene A.

2014-01-01

Accurate DNA replication and DNA repair are crucial for the maintenance of genome stability, and it is generally accepted that failure of these processes is a major source of DNA damage in cells. Intriguingly, recent evidence suggests that DNA damage is more likely to occur at genomic loci with high transcriptional activity. Furthermore, loss of certain RNA processing factors in eukaryotic cells is associated with increased formation of co-transcriptional RNA:DNA hybrid structures known as R-loops, resulting in double-strand breaks (DSBs) and DNA damage. However, the molecular mechanisms by which R-loop structures ultimately lead to DNA breaks and genome instability is not well understood. In this review, we summarize the current knowledge about the formation, recognition and processing of RNA:DNA hybrids, and discuss possible mechanisms by which these structures contribute to DNA damage and genome instability in the cell. PMID:24746923

Kinase-dead ATM protein causes genomic instability and early embryonic lethality in mice.

PubMed

Yamamoto, Kenta; Wang, Yunyue; Jiang, Wenxia; Liu, Xiangyu; Dubois, Richard L; Lin, Chyuan-Sheng; Ludwig, Thomas; Bakkenist, Christopher J; Zha, Shan

2012-08-06

Ataxia telangiectasia (A-T) mutated (ATM) kinase orchestrates deoxyribonucleic acid (DNA) damage responses by phosphorylating numerous substrates implicated in DNA repair and cell cycle checkpoint activation. A-T patients and mouse models that express no ATM protein undergo normal embryonic development but exhibit pleiotropic DNA repair defects. In this paper, we report that mice carrying homozygous kinase-dead mutations in Atm (Atm(KD/KD)) died during early embryonic development. Atm(KD/-) cells exhibited proliferation defects and genomic instability, especially chromatid breaks, at levels higher than Atm(-/-) cells. Despite this increased genomic instability, Atm(KD/-) lymphocytes progressed through variable, diversity, and joining recombination and immunoglobulin class switch recombination, two events requiring nonhomologous end joining, at levels comparable to Atm(-/-) lymphocytes. Together, these results reveal an essential function of ATM during embryogenesis and an important function of catalytically inactive ATM protein in DNA repair.

Oxidative stress in cancer associated fibroblasts drives tumor-stroma co-evolution: A new paradigm for understanding tumor metabolism, the field effect and genomic instability in cancer cells.

PubMed

Martinez-Outschoorn, Ubaldo E; Balliet, Renee M; Rivadeneira, Dayana B; Chiavarina, Barbara; Pavlides, Stephanos; Wang, Chenguang; Whitaker-Menezes, Diana; Daumer, Kristin M; Lin, Zhao; Witkiewicz, Agnieszka K; Flomenberg, Neal; Howell, Anthony; Pestell, Richard G; Knudsen, Erik S; Sotgia, Federica; Lisanti, Michael P

2010-08-15

Loss of stromal fibroblast caveolin-1 (Cav-1) is a powerful single independent predictor of poor prognosis in human breast cancer patients, and is associated with early tumor recurrence, lymph node metastasis and tamoxifen-resistance. We developed a novel co-culture system to understand the mechanism(s) by which a loss of stromal fibroblast Cav-1 induces a "lethal tumor micro-environment." Here, we propose a new paradigm to explain the powerful prognostic value of stromal Cav-1. In this model, cancer cells induce oxidative stress in cancer-associated fibroblasts, which then acts as a "metabolic" and "mutagenic" motor to drive tumor-stroma co-evolution, DNA damage and aneuploidy in cancer cells. More specifically, we show that an acute loss of Cav-1 expression leads to mitochondrial dysfunction, oxidative stress and aerobic glycolysis in cancer associated fibroblasts. Also, we propose that defective mitochondria are removed from cancer-associated fibroblasts by autophagy/mitophagy that is induced by oxidative stress. As a consequence, cancer associated fibroblasts provide nutrients (such as lactate) to stimulate mitochondrial biogenesis and oxidative metabolism in adjacent cancer cells (the "Reverse Warburg Effect"). We provide evidence that oxidative stress in cancer-associated fibroblasts is sufficient to induce genomic instability in adjacent cancer cells, via a bystander effect, potentially increasing their aggressive behavior. Finally, we directly demonstrate that nitric oxide (NO) over-production, secondary to Cav-1 loss, is the root cause for mitochondrial dysfunction in cancer associated fibroblasts. In support of this notion, treatment with anti-oxidants (such as N-acetyl-cysteine, metformin and quercetin) or NO inhibitors (L-NAME) was sufficient to reverse many of the cancer-associated fibroblast phenotypes that we describe. Thus, cancer cells use "oxidative stress" in adjacent fibroblasts (i) as an "engine" to fuel their own survival via the stromal production of nutrients and (ii) to drive their own mutagenic evolution towards a more aggressive phenotype, by promoting genomic instability. We also present evidence that the "field effect" in cancer biology could also be related to the stromal production of ROS and NO species. eNOS-expressing fibroblasts have the ability to downregulate Cav-1 and induce mitochondrial dysfunction in adjacent fibroblasts that do not express eNOS. As such, the effects of stromal oxidative stress can be laterally propagated, amplified and are effectively "contagious"--spread from cell-to-cell like a virus--creating an "oncogenic/mutagenic" field promoting widespread DNA damage.

Inefficient differentiation response to cell cycle stress leads to genomic instability and malignant progression of squamous carcinoma cells

PubMed Central

Alonso-Lecue, Pilar; de Pedro, Isabel; Coulon, Vincent; Molinuevo, Rut; Lorz, Corina; Segrelles, Carmen; Ceballos, Laura; López-Aventín, Daniel; García-Valtuille, Ana; Bernal, José M; Mazorra, Francisco; Pujol, Ramón M; Paramio, Jesús; Ramón Sanz, J; Freije, Ana; Toll, Agustí; Gandarillas, Alberto

2017-01-01

Squamous cell carcinoma (SCC) or epidermoid cancer is a frequent and aggressive malignancy. However in apparent paradox it retains the squamous differentiation phenotype except for very dysplastic lesions. We have shown that cell cycle stress in normal epidermal keratinocytes triggers a squamous differentiation response involving irreversible mitosis block and polyploidisation. Here we show that cutaneous SCC cells conserve a partial squamous DNA damage-induced differentiation response that allows them to overcome the cell division block. The capacity to divide in spite of drug-induced mitotic stress and DNA damage made well-differentiated SCC cells more genomically instable and more malignant in vivo. Consistently, in a series of human biopsies, non-metastatic SCCs displayed a higher degree of chromosomal alterations and higher expression of the S phase regulator Cyclin E and the DNA damage signal γH2AX than the less aggressive, non-squamous, basal cell carcinomas. However, metastatic SCCs lost the γH2AX signal and Cyclin E, or accumulated cytoplasmic Cyclin E. Conversely, inhibition of endogenous Cyclin E in well-differentiated SCC cells interfered with the squamous phenotype. The results suggest a dual role of cell cycle stress-induced differentiation in squamous cancer: the resulting mitotic blocks would impose, when irreversible, a proliferative barrier, when reversible, a source of genomic instability, thus contributing to malignancy. PMID:28661481

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.

Dynamical instabilities in axisymmetric stellar systems. I - Oblate E6 models

NASA Technical Reports Server (NTRS)

Levison, Harold F.; Duncan, Martin J.; Smith, Bruce F.

1990-01-01

The stability of a set of models based on isothermal oblate E6 elliptical galaxies is studied using N-body techniques. The only stable models are those that are near the isotropic model and have nearly equal number of stars in retrograde and prograde orbits. Fast rotators are unstable to modes that appear to be analogous to the classical streaming instability seen in many disk systems. Systems with a large velocity dispersion in the direction of the cylindrical radius are unstable to modes that appear to be similar to the radial orbit instability observed in some spherical systems. However, evidence is presented that these two instabilities may be related, and an instability criterion that applies to both is constructed.

Frozen-wave instability in near-critical hydrogen subjected to horizontal vibration under various gravity fields.

PubMed

Gandikota, G; Chatain, D; Amiroudine, S; Lyubimova, T; Beysens, D

2014-01-01

The frozen-wave instability which appears at a liquid-vapor interface when a harmonic vibration is applied in a direction tangential to it has been less studied until now. The present paper reports experiments on hydrogen (H2) in order to study this instability when the temperature is varied near its critical point for various gravity levels. Close to the critical point, a liquid-vapor density difference and surface tension can be continuously varied with temperature in a scaled, universal way. The effect of gravity on the height of the frozen waves at the interface is studied by performing the experiments in a magnetic facility where effective gravity that results from the coupling of the Earth's gravity and magnetic forces can be varied. The stability diagram of the instability is obtained. The experiments show a good agreement with an inviscid model [Fluid Dyn. 21 849 (1987)], irrespective of the gravity level. It is observed in the experiments that the height of the frozen waves varies weakly with temperature and increases with a decrease in the gravity level, according to a power law with an exponent of 0.7. It is concluded that the wave height becomes of the order of the cell size as the gravity level is asymptotically decreased to zero. The interface pattern thus appears as a bandlike pattern of alternate liquid and vapor phases, a puzzling phenomenon that was observed with CO2 and H2 near their critical point in weightlessness [Acta Astron. 61 1002 (2007); Europhys. Lett. 86 16003 (2009)].

Identification of defective illegitimate recombinational repair of oxidatively-induced DNA double-strand breaks in ataxia-telangiectasia cells

NASA Technical Reports Server (NTRS)

Dar, M. E.; Winters, T. A.; Jorgensen, T. J.

1997-01-01

Ataxia-telangiectasia (A-T) is an autosomal-recessive lethal human disease. Homozygotes suffer from a number of neurological disorders, as well as very high cancer incidence. Heterozygotes may also have a higher than normal risk of cancer, particularly for the breast. The gene responsible for the disease (ATM) has been cloned, but its role in mechanisms of the disease remain unknown. Cellular A-T phenotypes, such as radiosensitivity and genomic instability, suggest that a deficiency in the repair of DNA double-strand breaks (DSBs) may be the primary defect; however, overall levels of DSB rejoining appear normal. We used the shuttle vector, pZ189, containing an oxidatively-induced DSB, to compare the integrity of DSB rejoining in one normal and two A-T fibroblast cells lines. Mutation frequencies were two-fold higher in A-T cells, and the mutational spectrum was different. The majority of the mutations found in all three cell lines were deletions (44-63%). The DNA sequence analysis indicated that 17 of the 17 plasmids with deletion mutations in normal cells occurred between short direct-repeat sequences (removing one of the repeats plus the intervening sequences), implicating illegitimate recombination in DSB rejoining. The combined data from both A-T cell lines showed that 21 of 24 deletions did not involve direct-repeats sequences, implicating a defect in the illegitimate recombination pathway. These findings suggest that the A-T gene product may either directly participate in illegitimate recombination or modulate the pathway. Regardless, this defect is likely to be important to a mechanistic understanding of this lethal disease.

Comparison of dynamic postural stability scores between athletes with and without chronic ankle instability during lateral jump landing.

PubMed

Shiravi, Zeinab; Shadmehr, Azadeh; Moghadam, Saeed Talebian; Moghadam, Behrouz Attarbashi

2017-01-01

Many ankle injuries occur while participating in sports that require jumping and landing such as basketball, volleyball and soccer. Most recent studies have investigated dynamic postural stability of patients with chronic ankle instability after landing from a forward jump. The present study aimed to investigate the dynamic postural stability of the athletes who suffer from chronic ankle sprain while landing from a lateral jump. Twelve athletes with self-reported unilateral chronic ankle instability (4 females and 8 males) and 12 matched controls (3 females and 9 males) voluntarily participated in the study. Dynamic postural stability index and its directional indices were measured while performing lateral jump landing test. No differences were found between athletes with and without chronic ankle instability during our landing protocol by means of the dynamic postural stability index and its directional indices. Findings showed that in each group, medial/lateral stability index is significantly higher than anterior/posterior and vertical stability indexes. Findings showed that dynamic postural stability was not significantly different between the two groups. Future studies should examine chronic ankle instability patients with more severe disabilities and expose them to more challenging dynamic balance conditions to further explore postural stability. IIIa.

Experiments on the Richtmyer-Meshkov Instability of Incompressible Fluids

NASA Technical Reports Server (NTRS)

Jacobs, J.; Niederhaus, C.

2000-01-01

Richtmyer-Meshkov (R-M) 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 possibly become turbulent given the proper initial conditions. R-M instability is similar to the Rayleigh-Taylor (R-T) instability, which is generated when the two fluids undergo a constant acceleration. R-M instability is a fundamental fluid instability that is important to fields ranging from astrophysics to high-speed combustion. For example, R-M instability is currently the limiting factor in achieving a net positive yield with inertial confinement fusion. The experiments described here utilize a novel technique that circumvents many of the experimental difficulties previously limiting the study of the R-M instability. A Plexiglas tank contains two unequal density liquids and is gently oscillated horizontally to produce a controlled initial fluid interface shape. The tank is mounted to a sled on a high speed, low friction linear rail system, constraining the main motion to the vertical direction. The sled is released from an initial height and falls vertically until it bounces off of a movable spring, imparting an impulsive acceleration in the upward direction. As the sled travels up and down the rails, the spring retracts out of the way, allowing the instability to evolve in free-fall until impacting a shock absorber at the end of the rails. The impulsive acceleration provided to the system is measured by a piezoelectric accelerometer mounted on the tank, and a capacitive accelerometer measures the low-level drag of the bearings. Planar Laser-Induced Fluorescence is used for flow visualization, which uses an Argon ion laser to illuminate the flow and a CCD camera, mounted to the sled, to capture images of the interface. This experimental study investigates the instability of an interface between incompressible, miscible liquids with an initial sinusoidal perturbation. The amplitude of the disturbance during the experiment is measured and compared to theory. The results show good agreement (within 10%) with linear stability theory up to nondimensional amplitude ka = 0.7 (wavenumber x amplitude). These results hold true for an initial ka (before acceleration) of -0.7 less than ka less than -0.06, while the linear theory was developed for absolute value of ka much less than 1. In addition, a third order weakly nonlinear perturbation theory is shown to be accurate for amplitudes as large as ka = 1.3, even though the interface becomes double-valued at ka = 1.1. As time progresses, the vorticity on the interface concentrates, and the interface spirals around the alternating sign vortex centers to form a mushroom pattern. At higher Reynolds Number (based on circulation), an instability of the vortex cores has been observed. While time limitations of the apparatus prevent determination of a critical Reynolds Number, the lowest Reynolds Number this vortex instability has been observed at is 5000.

Corrugation Instability of a Coronal Arcade

NASA Astrophysics Data System (ADS)

Klimushkin, D. Y.; Nakariakov, V. M.; Mager, P. N.; Cheremnykh, O. K.

2017-12-01

We analyse the behaviour of linear magnetohydrodynamic perturbations of a coronal arcade modelled by a half-cylinder with an azimuthal magnetic field and non-uniform radial profiles of the plasma pressure, temperature, and the field. Attention is paid to the perturbations with short longitudinal (in the direction along the arcade) wavelengths. The radial structure of the perturbations, either oscillatory or evanescent, is prescribed by the radial profiles of the equilibrium quantities. Conditions for the corrugation instability of the arcade are determined. It is established that the instability growth rate increases with decreases in the longitudinal wavelength and the radial wave number. In the unstable mode, the radial perturbations of the magnetic field are stronger than the longitudinal perturbations, creating an almost circularly corrugated rippling of the arcade in the longitudinal direction. For coronal conditions, the growth time of the instability is shorter than one minute, decreasing with an increase in the temperature. Implications of the developed theory for the dynamics of coronal active regions are discussed.

Flux tube gyrokinetic simulations of the edge pedestal

NASA Astrophysics Data System (ADS)

Parker, Scott; Wan, Weigang; Chen, Yang

2011-10-01

The linear instabilities of DIII-D H-mode pedestal are studied with gyrokinetic micro-turbulence simulations. The simulation code GEM is an electromagnetic δf code with global tokamak geometry in the form of Miller equilibrium. Local flux tube simulations are carried out for multiple positions of two DIII-D profiles: shot #98889 and shot #131997. Near the top of the pedestal, the instability is clearly ITG. The dominant instability of the pedestal appears at the steep gradient region, and it is identified as a low frequency mode mostly driven by electron temperature gradient. The mode propagates along the electron diamagnetic direction for low n and may propagate along the ion direction for high n. At some positions near the steep gradient region, an ion instability is found which shows some characteristics of kinetic ballooning mode (KBM). These results will be compared to the results of E. Wang et al. and D. Fulton et al. in the same session. We thank R. Groebner and P. Snyder for providing experimental profiles and helpful discussions.

Current flow instability and nonlinear structures in dissipative two-fluid plasmas

NASA Astrophysics Data System (ADS)

Koshkarov, O.; Smolyakov, A. I.; Romadanov, I. V.; Chapurin, O.; Umansky, M. V.; Raitses, Y.; Kaganovich, I. D.

2018-01-01

The current flow in two-fluid plasma is inherently unstable if plasma components (e.g., electrons and ions) are in different collisionality regimes. A typical example is a partially magnetized E ×B plasma discharge supported by the energy released from the dissipation of the current in the direction of the applied electric field (perpendicular to the magnetic field). Ions are not magnetized so they respond to the fluctuations of the electric field ballistically on the inertial time scale. In contrast, the electron current in the direction of the applied electric field is dissipatively supported either by classical collisions or anomalous processes. The instability occurs due to a positive feedback between the electron and ion current coupled by the quasi-neutrality condition. The theory of this instability is further developed taking into account the electron inertia, finite Larmor radius and nonlinear effects. It is shown that this instability results in highly nonlinear quasi-coherent structures resembling breathing mode oscillations in Hall thrusters.

An Inducible, Isogenic Cancer Cell Line System for Targeting the State of Mismatch Repair Deficiency

PubMed Central

Bailis, Julie M.; Gordon, Marcia L.; Gurgel, Jesse L.; Komor, Alexis C.; Barton, Jacqueline K.; Kirsch, Ilan R.

2013-01-01

The DNA mismatch repair system (MMR) maintains genome stability through recognition and repair of single-base mismatches and small insertion-deletion loops. Inactivation of the MMR pathway causes microsatellite instability and the accumulation of genomic mutations that can cause or contribute to cancer. In fact, 10-20% of certain solid and hematologic cancers are MMR-deficient. MMR-deficient cancers do not respond to some standard of care chemotherapeutics because of presumed increased tolerance of DNA damage, highlighting the need for novel therapeutic drugs. Toward this goal, we generated isogenic cancer cell lines for direct comparison of MMR-proficient and MMR-deficient cells. We engineered NCI-H23 lung adenocarcinoma cells to contain a doxycycline-inducible shRNA designed to suppress the expression of the mismatch repair gene MLH1, and compared single cell subclones that were uninduced (MLH1-proficient) versus induced for the MLH1 shRNA (MLH1-deficient). Here we present the characterization of these MMR-inducible cell lines and validate a novel class of rhodium metalloinsertor compounds that differentially inhibit the proliferation of MMR-deficient cancer cells. PMID:24205301

Particle in cell simulation of instabilities in space and astrophysical plasmas

NASA Astrophysics Data System (ADS)

Tonge, John William

Several plasma instabilities relevant to space physics are investigated using the parallel PIC plasma simulation code P3arsec. This thesis addresses electrostatic micro-instabilities relevant to ion ring distributions, proceeds to electromagnetic micro-instabilities pertinent to streaming plasmas, and then to the stability of a plasma held in the field of a current rod. The physical relevance of each of these instabilities is discussed, a phenomenological description is given, and analytic and simulation results are presented and compared. Instability of a magnetized plasma with a portion of the ions in a velocity ring distribution around the magnetic field is investigated using simulation and analytic theory. The physics of this distribution is relevant to solar flares, x-ray emission by comets, and pulsars. Physical parameters, including the mass ratio, are near those of a solar flare in the simulation. The simulation and analytic results show agreement in the linear regime. In the nonlinear stage the simulation shows highly accelerated electrons in agreement with the observed spectrum of x-rays emitted by solar flares. A mildly relativistic streaming electron positron plasma with no ambient magnetic field is known to be unstable to electrostatic (two-stream/beam instability) and purely electromagnetic (Weibel) modes. This instability is relevant to highly energetic interstellar phenomena, including pulsars, supernova remnants, and the early universe. It is also important for experiments in which relativistic beams penetrate a background plasma, as in fast ignitor scenarios. Cold analytic theory is presented and compared to simulations. There is good agreement in the regime where cold theory applies. The simulation and theory shows that to properly characterize the instability, directions parallel and perpendicular to propagation of the beams must be considered. A residual magnetic field is observed which may be of astro-physical significance. The stability of a plasma in the magnetic field of a current rod is investigated for various temperature and density profiles. Such a plasma obeys similar physics to a plasma in a dipole magnetic field, while the current rod is much easier to analyze theoretically and realize in simulations. The stability properties of a plasma confined in a dipole field are important for understanding a variety of space phenomena and the Levitated Dipole eXperiment (LDX). Simple energy principle calculations and simulations with a variety of temperature and density profiles show that the plasma is stable to interchange for pressure profiles ∝ r-10/3. The simulations also show that the density profile will be stationary as long as density ∝ r -2 even though the temperature profile may not be stable.

DNA Repair in Human Pluripotent Stem Cells Is Distinct from That in Non-Pluripotent Human Cells

PubMed Central

Luo, Li Z.; Park, Sang-Won; Bates, Steven E.; Zeng, Xianmin; Iverson, Linda E.; O'Connor, Timothy R.

2012-01-01

The potential for human disease treatment using human pluripotent stem cells, including embryonic stem cells and induced pluripotent stem cells (iPSCs), also carries the risk of added genomic instability. Genomic instability is most often linked to DNA repair deficiencies, which indicates that screening/characterization of possible repair deficiencies in pluripotent human stem cells should be a necessary step prior to their clinical and research use. In this study, a comparison of DNA repair pathways in pluripotent cells, as compared to those in non-pluripotent cells, demonstrated that DNA repair capacities of pluripotent cell lines were more heterogeneous than those of differentiated lines examined and were generally greater. Although pluripotent cells had high DNA repair capacities for nucleotide excision repair, we show that ultraviolet radiation at low fluxes induced an apoptotic response in these cells, while differentiated cells lacked response to this stimulus, and note that pluripotent cells had a similar apoptotic response to alkylating agent damage. This sensitivity of pluripotent cells to damage is notable since viable pluripotent cells exhibit less ultraviolet light-induced DNA damage than do differentiated cells that receive the same flux. In addition, the importance of screening pluripotent cells for DNA repair defects was highlighted by an iPSC line that demonstrated a normal spectral karyotype, but showed both microsatellite instability and reduced DNA repair capacities in three out of four DNA repair pathways examined. Together, these results demonstrate a need to evaluate DNA repair capacities in pluripotent cell lines, in order to characterize their genomic stability, prior to their pre-clinical and clinical use. PMID:22412831

Particle-in-cell Simulations of Continuously Driven Mirror and Ion Cyclotron Instabilities in High Beta Astrophysical and Heliospheric Plasmas

NASA Astrophysics Data System (ADS)

Riquelme, Mario A.; Quataert, Eliot; Verscharen, Daniel

2015-02-01

We use particle-in-cell simulations to study the nonlinear evolution of ion velocity space instabilities in an idealized problem in which a background velocity shear continuously amplifies the magnetic field. We simulate the astrophysically relevant regime where the shear timescale is long compared to the ion cyclotron period, and the plasma beta is β ~ 1-100. The background field amplification in our calculation is meant to mimic processes such as turbulent fluctuations or MHD-scale instabilities. The field amplification continuously drives a pressure anisotropy with p > p ∥ and the plasma becomes unstable to the mirror and ion cyclotron instabilities. In all cases, the nonlinear state is dominated by the mirror instability, not the ion cyclotron instability, and the plasma pressure anisotropy saturates near the threshold for the linear mirror instability. The magnetic field fluctuations initially undergo exponential growth but saturate in a secular phase in which the fluctuations grow on the same timescale as the background magnetic field (with δB ~ 0.3 langBrang in the secular phase). At early times, the ion magnetic moment is well-conserved but once the fluctuation amplitudes exceed δB ~ 0.1 langBrang, the magnetic moment is no longer conserved but instead changes on a timescale comparable to that of the mean magnetic field. We discuss the implications of our results for low-collisionality astrophysical plasmas, including the near-Earth solar wind and low-luminosity accretion disks around black holes.

Genomic Instability Associated with p53 Knockdown in the Generation of Huntington’s Disease Human Induced Pluripotent Stem Cells

PubMed Central

Tidball, Andrew M.; Neely, M. Diana; Chamberlin, Reed; Aboud, Asad A.; Kumar, Kevin K.; Han, Bingying; Bryan, Miles R.; Aschner, Michael; Ess, Kevin C.; Bowman, Aaron B.

2016-01-01

Alterations in DNA damage response and repair have been observed in Huntington’s disease (HD). We generated induced pluripotent stem cells (iPSC) from primary dermal fibroblasts of 5 patients with HD and 5 control subjects. A significant fraction of the HD iPSC lines had genomic abnormalities as assessed by karyotype analysis, while none of our control lines had detectable genomic abnormalities. We demonstrate a statistically significant increase in genomic instability in HD cells during reprogramming. We also report a significant association with repeat length and severity of this instability. Our karyotypically normal HD iPSCs also have elevated ATM-p53 signaling as shown by elevated levels of phosphorylated p53 and H2AX, indicating either elevated DNA damage or hypersensitive DNA damage signaling in HD iPSCs. Thus, increased DNA damage responses in the HD genotype is coincidental with the observed chromosomal aberrations. We conclude that the disease causing mutation in HD increases the propensity of chromosomal instability relative to control fibroblasts specifically during reprogramming to a pluripotent state by a commonly used episomal-based method that includes p53 knockdown. PMID:26982737

[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.

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.

Resolving the evolutionary paradox of genetic instability: a cost-benefit analysis of DNA repair in changing environments.

PubMed

Breivik, Jarle; Gaudernack, Gustav

2004-04-09

Loss of genetic stability is a critical phenomenon in cancer and antibiotic resistance, and the prevailing dogma is that unstable cells survive because instability provides adaptive mutations. Challenging this view, we have argued that genetic instability arises because DNA repair may be a counterproductive strategy in mutagenic environments. This paradoxical relationship has also been confirmed by explicit experiments, but the underlying evolutionary principles remain controversial. This paper aims to clarify the issue, and presents a model that explains genetic instability from the basic perspective of molecular evolution and information processing.

Telomere dysfunction and chromosome structure modulate the contribution of individual chromosomes in abnormal nuclear morphologies.

PubMed

Pampalona, J; Soler, D; Genescà, A; Tusell, L

2010-01-05

The cytokinesis-block micronucleus assay has emerged as a biomarker of chromosome damage relevant to cancer. Although it was initially developed to measure micronuclei, it is also useful for measuring nucleoplasmic bridges and nuclear buds. Abnormal nuclear morphologies are frequently observed in malignant tissues and short-term tumour cell cultures. Changes in chromosome structure and number resulting from chromosome instability are important factors in oncogenesis. Telomeres have become key players in the initiation of chromosome instability related to carcinogenesis by means of breakage-fusion-bridge cycles. To better understand the connection between telomere dysfunction and the appearance of abnormal nuclear morphologies, we have characterised the presence of micronuclei, nucleoplasmic bridges and nuclear buds in human mammary primary epithelial cells. These cells can proliferate beyond the Hayflick limit by spontaneously losing expression of the p16(INK4a) protein. Progressive telomere shortening leads to the loss of the capping function, and the appearance of end-to-end chromosome fusions that can enter into breakage-fusion-bridge cycles generating massive chromosomal instability. In human mammary epithelial cells, different types of abnormal nuclear morphologies were observed, however only nucleoplasmatic bridges and buds increased significantly with population doublings. Fluorescent in situ hybridisation using centromeric and painting specific probes for chromosomes with eroded telomeres has revealed that these chromosomes are preferentially included in the different types of abnormal nuclear morphologies observed, thus reflecting their common origin. Accordingly, real-time imaging of cell divisions enabled us to determine that anaphase bridge resolution was mainly through chromatin breakage and the formation of symmetric buds in daughter nuclei. Few micronuclei emerged in this cell system thus validating the scoring of nucleoplasmic bridges and nuclear buds for measuring chromosome instability in telomere-dysfunction cell environments.

Direct conversion of human amniotic cells into endothelial cells without transitioning through a pluripotent state

PubMed Central

Ginsberg, Michael; Schachterle, William; Shido, Koji; Rafii, Shahin

2016-01-01

Endothelial cells (ECs) have essential roles in organ development and regeneration, and therefore they could be used for regenerative therapies. However, generation of abundant functional endothelium from pluripotent stem cells has been difficult because ECs generated by many existing strategies have limited proliferative potential and display vascular instability. The latter difficulty is of particular importance because cells that lose their identity over time could be unsuitable for therapeutic use. Here, we describe a 3-week platform for directly converting human mid-gestation lineage-committed amniotic fluid–derived cells (ACs) into a stable and expandable population of vascular ECs (rAC-VECs) without using pluripotency factors. By transient expression of the ETS transcription factor ETV2 for 2 weeks and constitutive expression the ETS transcription factors FLI1 and ERG1, concomitant with TGF-β inhibition for 3 weeks, epithelial and mesenchymal ACs are converted, with high efficiency, into functional rAC-VECs. These rAC-VECs maintain their vascular repertoire and morphology over numerous passages in vitro, and they form functional vessels when implanted in vivo. rAC-VECs can be detected in recipient mice months after implantation. Thus, rAC-VECs can be used to establish a cellular platform to uncover the molecular determinants of vascular development and heterogeneity and potentially represent ideal ECs for the treatment of regenerative disorders. PMID:26540589

Impact of porosity on Jeans instability in viscous quantum magnetoplasma

NASA Astrophysics Data System (ADS)

Prajapat, V.; Sutar, D. L.; Pensia, R. K.

2018-05-01

This paper treats the Jeans instability improved at the theoretical investigation of the presence of viscosity and resistivity in the porous medium. Following the normal mode analysis using the QMHD model, the dispersion relation is discussed for wave propagation in longitudinal and transverse direction. The Jeans criteria of instability are affected by the presence of porosity. The graphical presentation shows that porosity has a stabilizing effect while resistivity has destabilizing effect in the system.

Jeans Instability of the Self-Gravitating Viscoelastic Ferromagnetic Cylinder with Axial Nonuniform Rotation and Magnetic Field

NASA Astrophysics Data System (ADS)

Dhiman, Joginder Singh; Sharma, Rajni

2017-12-01

The effects of nonuniform rotation and magnetic field on the instability of a self gravitating infinitely extending axisymmetric cylinder of viscoelastic ferromagnetic medium have been studied using the Generalised Hydrodynamic (GH) model. The non-uniform magnetic field and rotation are acting along the axial direction of the cylinder and the propagation of the wave is considered along the radial direction, while the ferrofluid magnetization is taken collinear with the magnetic field. A general dispersion relation representing magnetization, magnetic permeability and viscoelastic relaxation time parameters is obtained using the normal mode analysis method in the linearized perturbation equation system. Jeans criteria which represent the onset of instability of self gravitating medium are obtained under the limits; when the medium behaves like a viscous liquid (strongly coupled limit) and a Newtonian liquid (weakly coupled limit). The effects of various parameters on the Jeans instability criteria and on the growth rate of self gravitating viscoelastic ferromagnetic medium have been discussed. It is found that the magnetic polarizability due to ferromagnetization of medium marginalizes the effect of non-uniform magnetic field on the Jeans instability, whereas the viscoelasticity of the medium has the usual stabilizing effect on the instability of the system. Further, it is found that the cylindrical geometry is more stable than the Cartesian one. The variation of growth rate against the wave number and radial distance has been depicted graphically.

Direct Measurements of the Baroclinic Instability in the Ocean

NASA Astrophysics Data System (ADS)

Sadek, Mahmoud; Aluie, Hussein; Hecht, Matthew; Vallis, Geoffrey

2016-11-01

The ocean is mechanically driven by wind and buoyancy at the surface which produce sloping isopycnals with a reservoir of available potential energy (APE). Large scale APE can be converted to kinetic energy via the baroclinic instability, which produces mesoscale eddies. Mesoscale eddies are ubiquitous in mid- and high-latitudes, and play a primary role in determining the strength and trajectories of currents and in generating intrinsic climate variability. The widespread belief that mesoscale eddies are generated through baroclinic instability is based on general accord between observations and linear stability analysis and the predicted behavior of nonlinear models. However, these models are unable to give us quantitative evidence of the extent to which the instability is responsible for eddy generation at various locations in the ocean. To this end, we implement a new coarse-graining framework, recently developed to study flow on a sphere, to directly analyze the baroclinic instability as a function of scale and geographic location, and implement it using strongly eddying high-resolution simulations in the North Atlantic and in the Southern Ocean. The results give us new information about location and intensity of the instability in both physical and spectral space. Partial support was provided by National Science Foundation (NSF) Grant OCE-1259794, US Department of Energy (US DOE) Grant DE-SC0014318, and the LANL LDRD program through Project Number 20150568ER.

Interplay of migratory and division forces as a generic mechanism for stem cell patterns

NASA Astrophysics Data System (ADS)

Hannezo, Edouard; Coucke, Alice; Joanny, Jean-François

2016-02-01

In many adult tissues, stem cells and differentiated cells are not homogeneously distributed: stem cells are arranged in periodic "niches," and differentiated cells are constantly produced and migrate out of these niches. In this article, we provide a general theoretical framework to study mixtures of dividing and actively migrating particles, which we apply to biological tissues. We show in particular that the interplay between the stresses arising from active cell migration and stem cell division give rise to robust stem cell patterns. The instability of the tissue leads to spatial patterns which are either steady or oscillating in time. The wavelength of the instability has an order of magnitude consistent with the biological observations. We also discuss the implications of these results for future in vitro and in vivo experiments.

No significant level of inheritable interchromosomal aberrations in the progeny of bystander primary human fibroblasts after alpha particle irradiation

NASA Astrophysics Data System (ADS)

Hu, Burong; Zhu, Jiayun; Zhou, Hongning; Hei, Tom K.

2013-02-01

A major concern for bystander effects is the probability that normal healthy cells adjacent to the irradiated cells become genomically unstable and undergo further carcinogenesis after therapeutic irradiation or space mission where astronauts are exposed to low dose of heavy ions. Genomic instability is a hallmark of cancer cells. In the present study, two irradiation protocols were performed in order to ensure pure populations of bystander cells and the genomic instability in their progeny were investigated. After irradiation, chromosomal aberrations of cells were analyzed at designated time points using G2 phase premature chromosome condensation (G2-PCC) coupled with Giemsa staining and with multiplex fluorescent in situ hybridization (mFISH). Our Giemsa staining assay demonstrated that elevated yields of chromatid breaks were induced in the progeny of pure bystander primary fibroblasts up to 20 days after irradiation. mFISH assay showed no significant level of inheritable interchromosomal aberrations were induced in the progeny of the bystander cell groups, while the fractions of gross aberrations (chromatid breaks or chromosomal breaks) significantly increased in some bystander cell groups. These results suggest that genomic instability occurred in the progeny of the irradiation associated bystander normal fibroblasts exclude the inheritable interchromosomal aberration.

Magnetorotational Dynamo Action in the Shearing Box

NASA Astrophysics Data System (ADS)

Walker, Justin; Boldyrev, Stanislav

2017-10-01

Magnetic dynamo action caused by the magnetorotational instability is studied in the shearing-box approximation with no imposed net magnetic flux. Consistent with recent studies, the dynamo action is found to be sensitive to the aspect ratio of the box: it is much easier to obtain in tall boxes (stretched in the direction normal to the disk plane) than in long boxes (stretched in the radial direction). Our direct numerical simulations indicate that the dynamo is possible in both cases, given a large enough magnetic Reynolds number. To explain the relatively larger effort required to obtain the dynamo action in a long box, we propose that the turbulent eddies caused by the instability most efficiently fold and mix the magnetic field lines in the radial direction. As a result, in the long box the scale of the generated strong azimuthal (stream-wise directed) magnetic field is always comparable to the scale of the turbulent eddies. In contrast, in the tall box the azimuthal magnetic flux spreads in the vertical direction over a distance exceeding the scale of the turbulent eddies. As a result, different vertical sections of the tall box are permeated by large-scale nonzero azimuthal magnetic fluxes, facilitating the instability. NSF AGS-1261659, Vilas Associates Award, NSF-Teragrid Project TG-PHY110016.

No significant level of inheritable interchromosomal aberrations in the progeny of bystander primary human fibroblast after alpha particle irradiation.

PubMed

Hu, Burong; Zhu, Jiayun; Zhou, Hongning; Hei, Tom K

2013-02-01

A major concern for bystander effects is the probability that normal healthy cells adjacent to the irradiated cells become genomically unstable and undergo further carcinogenesis after therapeutic irradiation or space mission where astronauts are exposed to low dose of heavy ions. Genomic instability is a hallmark of cancer cells. In the present study, two irradiation protocols were performed in order to ensure pure populations of bystander cells and the genomic instability in their progeny were investigated. After irradiation, chromosomal aberrations of cells were analyzed at designated time points using G 2 phase premature chromosome condensation (G 2 -PCC) coupled with Giemsa staining and with multiplex fluorescent in situ hybridization (mFISH). Our Giemsa staining assay demonstrated that elevated yields of chromatid breaks were induced in the progeny of pure bystander primary fibroblasts up to 20 days after irradiation. MFISH assay showed no significant level of inheritable interchromosomal aberrations were induced in the progeny of the bystander cell groups, while the fractions of gross aberrations (chromatid breaks or chromosomal breaks) significantly increased in some bystander cell groups. These results suggest that genomic instability occurred in the progeny of the irradiation associated bystander normal fibroblasts exclude the inheritable interchromosomal aberration.

Cytokinesis Failure Leading to Chromosome Instability in v-Src-Induced Oncogenesis.

PubMed

Nakayama, Yuji; Soeda, Shuhei; Ikeuchi, Masayoshi; Kakae, Keiko; Yamaguchi, Naoto

2017-04-12

v-Src, an oncogene found in Rous sarcoma virus, is a constitutively active variant of c-Src. Activation of Src is observed frequently in colorectal and breast cancers, and is critical in tumor progression through multiple processes. However, in some experimental conditions, v-Src causes growth suppression and apoptosis. In this review, we highlight recent progress in our understanding of cytokinesis failure and the attenuation of the tetraploidy checkpoint in v-Src-expressing cells. v-Src induces cell cycle changes-such as the accumulation of the 4N cell population-and increases the number of binucleated cells, which is accompanied by an excess number of centrosomes. Time-lapse analysis of v-Src-expressing cells showed that cytokinesis failure is caused by cleavage furrow regression. Microscopic analysis revealed that v-Src induces delocalization of cytokinesis regulators including Aurora B and Mklp1. Tetraploid cell formation is one of the causes of chromosome instability; however, tetraploid cells can be eliminated at the tetraploidy checkpoint. Interestingly, v-Src weakens the tetraploidy checkpoint by inhibiting the nuclear exclusion of the transcription coactivator YAP, which is downstream of the Hippo pathway and its nuclear exclusion is critical in the tetraploidy checkpoint. We also discuss the relationship between v-Src-induced chromosome instability and growth suppression in v-Src-induced oncogenesis.

Abnormal RNA splicing and genomic instability after induction of DNMT3A mutations by CRISPR/Cas9 gene editing.

PubMed

Banaszak, Lauren G; Giudice, Valentina; Zhao, Xin; Wu, Zhijie; Gao, Shouguo; Hosokawa, Kohei; Keyvanfar, Keyvan; Townsley, Danielle M; Gutierrez-Rodrigues, Fernanda; Fernandez Ibanez, Maria Del Pilar; Kajigaya, Sachiko; Young, Neal S

2018-03-01

DNA methyltransferase 3A (DNMT3A) mediates de novo DNA methylation. Mutations in DNMT3A are associated with hematological malignancies, most frequently acute myeloid leukemia. DNMT3A mutations are hypothesized to establish a pre-leukemic state, rendering cells vulnerable to secondary oncogenic mutations and malignant transformation. However, the mechanisms by which DNMT3A mutations contribute to leukemogenesis are not well-defined. Here, we successfully created four DNMT3A-mutated K562 cell lines with frameshift mutations resulting in truncated DNMT3A proteins. DNMT3A-mutated cell lines exhibited significantly impaired growth and increased apoptotic activity compared to wild-type (WT) cells. Consistent with previous studies, DNMT3A-mutated cells displayed impaired differentiation capacity. RNA-seq was used to compare transcriptomes of DNMT3A-mutated and WT cells; DNMT3A ablation resulted in downregulation of genes involved in spliceosome function, causing dysfunction of RNA splicing. Unexpectedly, we observed DNMT3A-mutated cells to exhibit marked genomic instability and an impaired DNA damage response compared to WT. CRISPR/Cas9-mediated DNMT3A-mutated K562 cells may be used to model effects of DNMT3A mutations in human cells. Our findings implicate aberrant splicing and induction of genomic instability as potential mechanisms by which DNMT3A mutations might predispose to malignancy. Published by Elsevier Inc.

Paternal Multiple Partner Fertility and Environmental Chaos Among Unmarried Nonresident Fathers

PubMed Central

Petren, Raymond E.

2017-01-01

This study examined the association between paternal multiple partner fertility (MPF; having children with two or more partners) and indicators of environmental chaos (partnership instability, residential instability, work stability, material hardship, and perceived social support) among unmarried, non-resident fathers. Survey data from the Fragile Families and Child Wellbeing Study (N = 873) were used to compare unmarried non-resident fathers who experienced MPF to those who had children with one partner. Results show that paternal MPF is associated with most indicators of environmental chaos (greater partnership instability, residential instability, work instability, material hardship), but not social support. Results suggest that fathers who experience MPF face challenges beyond those of other non-resident fathers. Policies and interventions should address aspects of instability and hardship that are unique to paternal MPF in order to encourage fathers’ positive contributions to children and families. Directions for future research are discussed. PMID:29755155

Onset of dissolution-driven instabilities in fluids with nonmonotonic density profile

NASA Astrophysics Data System (ADS)

Jafari Raad, Seyed Mostafa; Hassanzadeh, Hassan

2015-11-01

Analog systems have recently been used in several experiments in the context of convective mixing of C O2 . We generalize the nonmonotonic density dependence of the growth of instabilities and provide a scaling relation for the onset of instability. The results of linear stability analysis and direct numerical simulations show that these fluids do not resemble the dynamics of C O2 -water convective instabilities. A typical analog system, such as water-propylene glycol, is found to be less unstable than C O2 -water. These results provide a basis for further research and proper selection of analog systems and are essential to the interpretation of experiments.

Instability timescale for the inclination instability in the solar system

NASA Astrophysics Data System (ADS)

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

2018-04-01

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

Influence of temperature on linear stability in buoyancy-driven fingering of reaction-diffusion fronts.

PubMed

Levitán, D; D'Onofrio, A

2012-09-01

A vertical Hele-Shaw cell was used to study the influence of temperature on Rayleigh-Taylor instabilities on reaction-diffusion fronts. The propagation of the chemical front can thus be observed, and experimental results can be obtained via image treatment. A chemical front produced by the coupling between molecular diffusion and the auto-catalysis of the chlorite-tetrathionate reaction, descends through the cell, consuming the reactants below while the product is formed above. Buoyancy-driven instabilities are formed due to the density difference between reactants and products, and the front takes a fingering pattern, whose growth rate has temperature dependence. In this study, the effect of temperature on the linear regime of the instability (that is, when the effects of such instability start to appear) was analyzed. To measure the instability, Fourier transform analysis is performed, in order to obtain the different wave numbers and their power as a function of time. Thus, the growth rate for each wave number and the most unstable wave number is obtained for each of the temperatures under study. Based on repeated experiments, a decrease in the growth rate for the most unstable wave number can be observed with the increase of temperature.

Metastable and unstable cellular solidification of colloidal suspensions

NASA Astrophysics Data System (ADS)

Deville, Sylvain; Maire, Eric; Bernard-Granger, Guillaume; Lasalle, Audrey; Bogner, Agnès; Gauthier, Catherine; Leloup, Jérôme; Guizard, Christian

2009-12-01

Colloidal particles are often seen as big atoms that can be directly observed in real space. They are therefore becoming increasingly important as model systems to study processes of interest in condensed-matter physics such as melting, freezing and glass transitions. The solidification of colloidal suspensions has long been a puzzling phenomenon with many unexplained features. Here, we demonstrate and rationalize the existence of instability and metastability domains in cellular solidification of colloidal suspensions, by direct in situ high-resolution X-ray radiography and tomography observations. We explain such interface instabilities by a partial Brownian diffusion of the particles leading to constitutional supercooling situations. Processing under unstable conditions leads to localized and global kinetic instabilities of the solid/liquid interface, affecting the crystal morphology and particle redistribution behaviour.

Evolution of the magnetic field generated by the Kelvin-Helmholtz instability

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

Modestov, M.; Bychkov, V.; Brodin, G.

2014-07-15

The Kelvin-Helmholtz instability in an ionized plasma is studied with a focus on the magnetic field generation via the Biermann battery (baroclinic) mechanism. The problem is solved by using direct numerical simulations of two counter-directed flows in 2D geometry. The simulations demonstrate the formation of eddies and their further interaction and merging resulting in a large single vortex. In contrast to general belief, it is found that the instability generated magnetic field may exhibit significantly different structures from the vorticity field, despite the mathematically identical equations controlling the magnetic field and vorticity evolution. At later stages of the nonlinear instabilitymore » development, the magnetic field may keep growing even after the hydrodynamic vortex strength has reached its maximum and started decaying due to dissipation.« less

Drying paint: from micro-scale dynamics to mechanical instabilities

NASA Astrophysics Data System (ADS)

Goehring, Lucas; Li, Joaquim; Kiatkirakajorn, Pree-Cha

2017-04-01

Charged colloidal dispersions make up the basis of a broad range of industrial and commercial products, from paints to coatings and additives in cosmetics. During drying, an initially liquid dispersion of such particles is slowly concentrated into a solid, displaying a range of mechanical instabilities in response to highly variable internal pressures. Here we summarize the current appreciation of this process by pairing an advection-diffusion model of particle motion with a Poisson-Boltzmann cell model of inter-particle interactions, to predict the concentration gradients in a drying colloidal film. We then test these predictions with osmotic compression experiments on colloidal silica, and small-angle X-ray scattering experiments on silica dispersions drying in Hele-Shaw cells. Finally, we use the details of the microscopic physics at play in these dispersions to explore how two macroscopic mechanical instabilities-shear-banding and fracture-can be controlled. This article is part of the themed issue 'Patterning through instabilities in complex media: theory and applications.'

The NF-κB pathway: regulation of the instability of atherosclerotic plaques activated by Fg, Fb, and FDPs.

PubMed

Cao, Yongjun; Zhou, Xiaomei; Liu, Huihui; Zhang, Yanlin; Yu, Xiaoyan; Liu, Chunfeng

2013-11-01

Recently, the molecular mechanism responsible for the instability of atherosclerotic plaques has gradually become a hot topic among researchers and clinicians. Matrix metalloproteinases (MMPs) and vascular endothelial growth factor (VEGF) play an important role in the processes of formation and development of atherosclerosis. In this study, we established and employed the transwell co-culture system of rabbit aortic endothelial cells and smooth muscle cells to explore the relationship between fibrin (Fb), fibrinogen (Fg), and/or their degradation products (FDPs) in relation to the instability of atherosclerotic plaques; meanwhile, we observed the effects of Fg, Fb, and FDPs on the mRNA levels of MMPs and VEGF as well as on the activation of nuclear factor-kappa B (NF-κB). We concluded that Fb, Fg, and FDPs are involved in the progression of the instability of atherosclerotic plaques via increasing the expression of MMPs and VEGF. This effect might be mediated by the NF-кB pathway.

Hydrodynamic fingering instability induced by a precipitation reaction

NASA Astrophysics Data System (ADS)

De Wit, Anne; Nagatsu, Yuichiro

2014-05-01

We experimentally demonstrate that a precipitation reaction at the miscible interface between two reactive solutions can trigger a hydrodynamic instability due to the build-up of a locally adverse mobility gradient related to a decrease in permeability. The precipitate results from an A+B → C type of reaction when a solution containing one of the reactant is injected into a solution of the other reactant in a porous medium or a Hele-Shaw cell. Finger-like precipitation patterns are observed upon displacement, the properties of which depend on whether A displaces B or vice-versa. A mathematical modeling of the underlying mobility profile in the cell reconstructed on the basis of one-dimensional reaction-diffusion concentration profiles confirms that the instability originates from a local decrease in mobility driven by the precipitation. Nonlinear simulations of the related reaction-diffusion-convection model reproduce the properties of the instability observed experimentally. In particular, the simulations suggest that differences in diffusivity between A and B may contribute to the asymmetric characteristics of the fingering precipitation patterns.

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.

High Mitochondrial DNA Stability in B-Cell Chronic Lymphocytic Leukemia

PubMed Central

Cerezo, María; Bandelt, Hans-Jürgen; Martín-Guerrero, Idoia; Ardanaz, Maite; Vega, Ana; Carracedo, Ángel; García-Orad, África; Salas, Antonio

2009-01-01

Background Chronic Lymphocytic Leukemia (CLL) leads to progressive accumulation of lymphocytes in the blood, bone marrow, and lymphatic tissues. Previous findings have suggested that the mtDNA could play an important role in CLL. Methodology/Principal Findings The mitochondrial DNA (mtDNA) control-region was analyzed in lymphocyte cell DNA extracts and compared with their granulocyte counterpart extract of 146 patients suffering from B-Cell CLL; B-CLL (all recruited from the Basque country). Major efforts were undertaken to rule out methodological artefacts that would render a high false positive rate for mtDNA instabilities and thus lead to erroneous interpretation of sequence instabilities. Only twenty instabilities were finally confirmed, most of them affecting the homopolymeric stretch located in the second hypervariable segment (HVS-II) around position 310, which is well known to constitute an extreme mutational hotspot of length polymorphism, as these mutations are frequently observed in the general human population. A critical revision of the findings in previous studies indicates a lack of proper methodological standards, which eventually led to an overinterpretation of the role of the mtDNA in CLL tumorigenesis. Conclusions/Significance Our results suggest that mtDNA instability is not the primary causal factor in B-CLL. A secondary role of mtDNA mutations cannot be fully ruled out under the hypothesis that the progressive accumulation of mtDNA instabilities could finally contribute to the tumoral process. Recommendations are given that would help to minimize erroneous interpretation of sequencing results in mtDNA studies in tumorigenesis. PMID:19924307

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

Spatiotemporal character of the Bobylev-Pikin flexoelectric instability in a twisted nematic bent-core liquid crystal exposed to very low frequency fields.

PubMed

Krishnamurthy, K S

2014-05-01

The Bobylev-Pikin striped-pattern state induced by a homogeneous electric field is a volume flexoelectric instability, originating in the midregion of a planarly aligned nematic liquid crystal layer. We find that the instability acquires a spatiotemporal character upon excitation by a low frequency (0.5 Hz) square wave field. This is demonstrated using a bent-core liquid crystal, initially in the 90°-twisted planar configuration. The flexoelectric modulation appears close to the cathode at each polarity reversal and, at low voltage amplitudes, decays completely as the field becomes steady. Correspondingly, at successive polarity changes, the stripe direction switches between the alignment directions at the two substrates. For large voltages, the stripes formed nearly along the alignment direction at the cathode gradually reorient toward the midplane director. These observations are generally attributed to inhomogeneous and time-dependent field conditions that come to exist after each polarity reversal. Polarity dependence of the instability is attributed to the formation of intrinsic double layers that bring about an asymmetry in surface fields. Momentary field elevation near the cathode following a voltage sign reversal and concomitant gradient flexoelectric polarization are considered the key factors in accounting for the surfacelike modulation observed at low voltages.

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.

A Comparison between Growth Morphology of "Eutectic" Cells/Dendrites and Single-Phase Cells/Dendrites

NASA Technical Reports Server (NTRS)

Tewari, S. N.; Raj, S. V.; Locci, I. E.

2003-01-01

Directionally solidified (DS) intermetallic and ceramic-based eutectic alloys with an in-situ composite microstructure containing finely distributed, long aspect ratio, fiber, or plate reinforcements are being seriously examined for several advanced aero-propulsion applications. In designing these alloys, additional solutes need to be added to the base eutectic composition in order to improve heir high-temperature strength, and provide for adequate toughness and resistance to environmental degradation. Solute addition, however, promotes instability at the planar liquid-solid interface resulting in the formation of two-phase eutectic "colonies." Because morphology of eutectic colonies is very similar to the single-phase cells and dendrites, the stability analysis of Mullins and Sekerka has been extended to describe their formation. Onset of their formation shows a good agreement with this approach; however, unlike the single-phase cells and dendrites, there is limited examination of their growth speed dependence of spacing, morphology, and spatial distribution. The purpose of this study is to compare the growth speed dependence of the morphology, spacing, and spatial distribution of eutectic cells and dendrites with that for the single-phase cells and dendrites.

Long waves in parallel flow in Hele-Shaw cells

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

Zeybek, M.; Yortsos, Y.C.

During the past several years the flow of immiscible flow in Hele-Shaw cells and porous media has been investigated extensively. Of particular interest to most studies has been frontal displacement, specifically viscous fingering instabilities and finger growth. The practical ramifications regarding oil recovery, as well as many other industrial processes in porous media, have served as the primary driving force for most of these investigations. By contrast, little attention has been paid to the motion of lateral fluid interface, which are parallel to the main flow direction. Parallel flow is an often encountered, although much overlooked regime. The evolution ofmore » fluid interfaces in parallel flow in Hele-Shaw cells is studied both theoretically and experimentally in the large capillary number limit. It is shown that such interfaces support wave motion, the amplitude of which for long waves is governed by the KdV equation. Experiments are conducted in a long Hele-Shaw cell that validate the theory in the symmetric case. 35 refs., 16 figs.« less

Rayleigh-Benard Convection in a Fluid with Prandtl Number Near One

NASA Astrophysics Data System (ADS)

Hu, Yuchou

1995-01-01

Studies of Rayleigh-Benard convection rotated about a vertical axis in cylindrical geometries with the shadowgraph imaging method are reported. The convection cells had radius-to-height ratios Gamma of between 23 and 52. The working fluid was CO _2 at 16 to 32 bar with Prandtl numbers ranging from 0.85 to 0.98. The results at zero rotation are presented first. For one of the cells (Gamma = 43), axisymmetric convection rolls were stable above onset up to epsilonequivDelta T/Delta T_{c}-1=0.19, where Delta T_{c} is the critical temperature difference. The amplitude of the center of the concentric patterns, the umbilicus, much larger near onset than that of the outlying region, grew as epsilon^{beta_ 1}, with beta_1=0.27 +/-0.04. Outside the umbilicus, the amplitude grew as epsilon^{beta_2 }, with beta_2 = 0.48 +/- 0.04. Pattern dynamics, wavenumbers, spatially-averaged roll-curvature, and sidewall roll-orientation as a function of epsilon are presented for a Gamma = 40 cell. As epsilon was increased, the skewed-varicose instability was first observed at epsilon~ 0.09, and roll -nucleating sidewall-foci were seen for epsilon _sp{~}{>} 0.15. The average roll curvature remained relatively constant for 0.2 _sp{~} {<} epsilon _sp{ ~}{<} 0.5, contrary to general expectation of increasing curvature with epsilon . Spiral-defect chaos appeared at epsilon ~ 0.55. Coincident with the increase in spiral-defect activity was a decrease in the average wavenumber and a marked increase in the sidewall-foci roll -nucleation frequency and average roll curvature. The thresholds of the onset of spiral-defect chaos for Gamma = 28, 40, and 52 were all at epsilon ~ 0.55. For rotating convection, pattern evolution at Gamma = 40 are described for dimensionless rotation rate Omega up to 20 and compared with observations at zero rotation. The Kuppers -Lortz instability was observed at the onset of convection at Omega~9 and co-existed with the skewed-varicose instability. For Omega _sp{~}{<} 11, the Kuppers-Lortz instability occurred via propagation of fronts initiated near the sidewall whereas at higher Omega fronts appearing spontaneously away from the sidewall became dominant. For Omega _sp{~}{>} 13, the Kuppers-Lortz angle was 60^{ circ}+/-1^{circ} , and the time scaling of the pattern dynamics showed a power-law dependence on epsilon with an exponent of 0.6 +/- 0.1. The threshold for spiral-defect chaos was depressed by rotation with spirals appearing at epsilon~0.40 at Omega = 8.8. The preferential inward-winding direction of the spirals was the same as the direction of the system rotation. The average wavenumber at onset of convection agreed with theoretical calculations and decreased with increasing epsilon. Quantitative measurements of the sidewall obliqueness show a general trend of rolls ending less perpendicular to the sidewall with increasing Omega for Omega<=q 9.

JAK2 and genomic instability in the myeloproliferative neoplasms: a case of the chicken or the egg?

PubMed Central

Scott, Linda M.; Rebel, Vivienne I.

2012-01-01

The myeloproliferative neoplasms (MPNs) are a particularly useful model for studying mutation accumulation in neoplastic and the mechanisms of the molecular cells, understanding underlying defects our current This review summarizes acquisition. present their in patients with an MPN, and the effects of mutations targeting Janus kinase 2 (JAK2)-mediated intracellular signaling on DNA damage, and on the elimination of mutation-bearing cells by programmed cell death. Moreover, we discuss findings that suggest that the acquisition of disease-initiating mutations in hematopoietic stem cells of some MPN patients may be the consequence of an inherent genomic instability that was not previously appreciated. PMID:22641564

Transverse electron-scale instability in relativistic shear flows.

PubMed

Alves, E P; Grismayer, T; Fonseca, R A; Silva, L O

2015-08-01

Electron-scale surface waves are shown to be unstable in the transverse plane of a sheared flow in an initially unmagnetized collisionless plasma, not captured by (magneto)hydrodynamics. It is found that these unstable modes have a higher growth rate than the closely related electron-scale Kelvin-Helmholtz instability in relativistic shears. Multidimensional particle-in-cell simulations verify the analytic results and further reveal the emergence of mushroomlike electron density structures in the nonlinear phase of the instability, similar to those observed in the Rayleigh Taylor instability despite the great disparity in scales and different underlying physics. This transverse electron-scale instability may play an important role in relativistic and supersonic sheared flow scenarios, which are stable at the (magneto)hydrodynamic level. Macroscopic (≫c/ωpe) fields are shown to be generated by this microscopic shear instability, which are relevant for particle acceleration, radiation emission, and to seed magnetohydrodynamic processes at long time scales.

Electrostatic and magnetic instabilities in the transition layer of a collisionless weakly relativistic pair shock

NASA Astrophysics Data System (ADS)

Dieckmann, M. E.; Bret, A.

2018-01-01

Energetic electromagnetic emissions by astrophysical jets like those that are launched during the collapse of a massive star and trigger gamma-ray bursts are partially attributed to relativistic internal shocks. The shocks are mediated in the collisionless plasma of such jets by the filamentation instability of counterstreaming particle beams. The filamentation instability grows fastest only if the beams move at a relativistic relative speed. We model here with a particle-in-cell simulation, the collision of two cold pair clouds at the speed c/2 (c: speed of light). We demonstrate that the two-stream instability outgrows the filamentation instability for this speed and is thus responsible for the shock formation. The incomplete thermalization of the upstream plasma by its quasi-electrostatic waves allows other instabilities to grow. A shock transition layer forms, in which a filamentation instability modulates the plasma far upstream of the shock. The inflowing upstream plasma is progressively heated by a two-stream instability closer to the shock and compressed to the expected downstream density by the Weibel instability. The strong magnetic field due to the latter is confined to a layer 10 electron skin depths wide.

Effect of Gsk3 inhibitor CHIR99021 on aneuploidy levels in rat embryonic stem cells.

PubMed

Bock, Anagha S; Leigh, Nathan D; Bryda, Elizabeth C

2014-06-01

Germline competent embryonic stem (ES) cells can serve as a tool to create genetically engineered rat strains used to elucidate gene function or provide disease models. In optimum culture conditions, ES cells are able to retain their pluripotent state. The type of components present and their concentration in ES cell culture media greatly influences characteristics of ES cells including the ability to maintain the cells in a pluripotent state. We routinely use 2i media containing inhibitors CHIR99021 and PD0325901 to culture rat ES cells. CHIR99021 specifically inhibits the Gsk3β pathway. We have found that the vendor source of CHIR99021 has a measurable influence on the level of aneuploidy seen over time as rat ES cells are passaged. Karyotyping of three different rat ES cell lines passaged multiple times showed increased aneuploidy when CHIR99021 from source B was used. Mass spectrometry analysis of this inhibitor showed the presence of unexpected synthetic small molecules, which might directly or indirectly cause increases in chromosome instability. Identifying these molecules could further understanding of their influence on chromosome stability and indicate how to improve synthesis of this media component to prevent deleterious effects in culture.

Telomere dysfunction and cell survival: roles for distinctTIN2-containing complexes

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

Kim, Sahn-Ho; Davalos, Albert R.; Heo, Seok-Jin

Telomeres are maintained by three DNA binding proteins, TRF1, TRF2 and POT1, and several associated factors. One factor, TIN2, binds TRF1 and TRF2 directly and POT1 indirectly. These and two other proteins form a soluble complex that may be the core telomere-maintenance complex. It is not clear whether subcomplexes exist or function in vivo. Here, we provide evidence for two TIN2 subcomplexes with distinct functions in human cells. TIN2 ablation by RNA interference caused telomere uncapping and p53-independent cell death in all cells tested. However, we isolated two TIN2 complexes from cell lysates, each selectively sensitive to a TIN2 mutantmore » (TIN2-13, TIN2-15C). In cells with wild-type p53 function, TIN2-15C was more potent than TIN2-13 in causing telomere uncapping and eventual growth arrest. In cells lacking p53 function, TIN215C more than TIN2-13 caused genomic instability and cell death. Thus, TIN2 subcomplexes likely have distinct functions in telomere maintenance, and may provide selective targets for eliminating cells with mutant p53.« less

Buccal Micronucleus Cytome Assay in Sickle Cell Disease

PubMed Central

Naga, Mallika Bokka Sri Satya; Gour, Shreya; Nallagutta, Nalini; Velidandla, Surekha; Manikya, Sangameshwar

2016-01-01

Introduction Sickle Cell Anaemia (SCA) is a commonly inherited blood disorder preceded by episodes of pain, chronic haemolytic anaemia and severe infections. The underlying phenomenon which causes this disease is the point mutation in the haemoglobin beta gene (Hbβ) found on chromosome 11 p. Increased oxidative stress leads to DNA damage. DNA damage occurring in such conditions can be studied by the buccal micronucleus cytome assay, which is a minimally invasive method for studying chromosomal instability, cell death and regenerative potential of human buccal tissue. Aim To evaluate genomic instability in patients with sickle cell disease by buccal micronucleus cytome assay. Materials and Methods The study included 40 sickle cell anemia patients (Group A) and 40 age and sex matched controls (Group B). Buccal swabs were collected and stained with Papanicolaou (PAP). Number of cells with micronucleus, binuclei, nuclear bud, pyknosis and karyolysis were counted in two groups as parameters for the evaluation of genome stability. Results All the analysis was done using t-test. A p-value of <0.001 was considered statistically significant. There was a statistically significant increase in micronuclei number in SCA patients when compared with controls. Karyolytic (un-nucleated) cell number in Group A was more than to those of the controls. Conclusion The results might suggest that patients with sickle cell anaemia have genome instability which is represented by the presence of micronuclei in the somatic cells. Presence of apoptotic cells might only indicate the bodily damage to the tissue as a result of the disease. PMID:27504413

Buccal Micronucleus Cytome Assay in Sickle Cell Disease.

PubMed

Naga, Mallika Bokka Sri Satya; Gour, Shreya; Nallagutta, Nalini; Ealla, Kranti Kiran Reddy; Velidandla, Surekha; Manikya, Sangameshwar

2016-06-01

Sickle Cell Anaemia (SCA) is a commonly inherited blood disorder preceded by episodes of pain, chronic haemolytic anaemia and severe infections. The underlying phenomenon which causes this disease is the point mutation in the haemoglobin beta gene (Hbβ) found on chromosome 11 p. Increased oxidative stress leads to DNA damage. DNA damage occurring in such conditions can be studied by the buccal micronucleus cytome assay, which is a minimally invasive method for studying chromosomal instability, cell death and regenerative potential of human buccal tissue. To evaluate genomic instability in patients with sickle cell disease by buccal micronucleus cytome assay. The study included 40 sickle cell anemia patients (Group A) and 40 age and sex matched controls (Group B). Buccal swabs were collected and stained with Papanicolaou (PAP). Number of cells with micronucleus, binuclei, nuclear bud, pyknosis and karyolysis were counted in two groups as parameters for the evaluation of genome stability. All the analysis was done using t-test. A p-value of <0.001 was considered statistically significant. There was a statistically significant increase in micronuclei number in SCA patients when compared with controls. Karyolytic (un-nucleated) cell number in Group A was more than to those of the controls. The results might suggest that patients with sickle cell anaemia have genome instability which is represented by the presence of micronuclei in the somatic cells. Presence of apoptotic cells might only indicate the bodily damage to the tissue as a result of the disease.

Magnetic control of magnetohydrodynamic instabilities in tokamaks

DOE PAGES

Strait, Edward J.

2014-11-24

Externally applied, non-axisymmetric magnetic fields form the basis of several relatively simple and direct methods to control magnetohydrodynamic (MHD) instabilities in a tokamak, and most present and planned tokamaks now include a set of non-axisymmetric control coils for application of fields with low toroidal mode numbers. Non-axisymmetric applied fields are routinely used to compensate small asymmetries ( δB/B ~ 10 -3 to 10 -4) of the nominally axisymmetric field, which otherwise can lead to instabilities through braking of plasma rotation and through direct stimulus of tearing modes or kink modes. This compensation may be feedback-controlled, based on the magnetic responsemore » of the plasma to the external fields. Non-axisymmetric fields are used for direct magnetic stabilization of the resistive wall mode — a kink instability with a growth rate slow enough that feedback control is practical. Saturated magnetic islands are also manipulated directly with non-axisymmetric fields, in order to unlock them from the wall and spin them to aid stabilization, or position them for suppression by localized current drive. Several recent scientific advances form the foundation of these developments in the control of instabilities. Most fundamental is the understanding that stable kink modes play a crucial role in the coupling of non-axisymmetric fields to the plasma, determining which field configurations couple most strongly, how the coupling depends on plasma conditions, and whether external asymmetries are amplified by the plasma. A major advance for the physics of high-beta plasmas ( β = plasma pressure/magnetic field pressure) has been the understanding that drift-kinetic resonances can stabilize the resistive wall mode at pressures well above the ideal-MHD stability limit, but also that such discharges can be very sensitive to external asymmetries. The common physics of stable kink modes has brought significant unification to the topics of static error fields at low beta and resistive wall modes at high beta. Furthermore, these and other scientific advances, and their application to control of MHD instabilities, will be reviewed with emphasis on the most recent results and their applicability to ITER.« less

Atmospheric Characteristics of Cool Season Intermittent Precipitation Near Portland, Oregon

NASA Astrophysics Data System (ADS)

Cunningham, Jeffrey Glenn

Pacific Northwest cool season precipitation is often described as mostly stratiform (i.e. steady and continuous). While most regional precipitation is stratiform in terms of area and duration, embedded convective cells within stratiform precipitation occur frequently enough to warrant study. Embedded cells locally increase rain rate, total precipitation, and streamflow discharge and hence raise the risk of flooding, landslides, and debris flows. Analysis of vertically pointing radar data near Portland, Oregon for three cool seasons (2005 to 2008) indicates that fallstreaks in the snow layer, locally enhanced precipitation regions a few kilometers in size indicated in radar reflectivity data above the 0° C altitude, are nearly ubiquitous on days with significant rainfall accumulation and large areas of precipitation. The observed fallstreaks in snow enhance rainfall immediately below the snow fallstreak. Compared to stratiform periods, embedded convective periods include higher Doppler vertical velocity values and higher variability in velocities especially in the snow layer. The combination of these findings points to generating cells within the snow layer and the seeder-feeder mechanism as important sources of surface precipitation variability for periods of embedded convective cells within stratiform precipitation. The primary goal of this study was to determine the sources of instability typically associated with convective cells embedded within stratiform precipitation for Pacific Northwest cool season storms. Storm periods occurring over six cool seasons (2002 to 2008, totaling 1923 hours) of operational radar data (KRTX) and 166 upper air soundings (KSLE) are analyzed. A new method was employed to objectively determine the degree of precipitation intermittency in sequences of radar scans. The resulting continuum of intermittency values was grouped into four categories: mostly convective precipitation, mostly stratiform precipitation, embedded convective cells within stratiform precipitation, and other. Atmospheric soundings during periods with embedded convective cells within stratiform precipitation are more likely to have convective available potential energy (CAPE) than soundings during periods of mostly stratiform precipitation. Specifically, most unstable parcel CAPE (MUCAPE) > 0 J kg-1 occurs 2.8 more frequently during embedded periods than for mostly stratiform periods. Over 90% of embedded periods have MUCAPE > 0 J kg-1 or at least two 500 meter layers of potential instability. In contrast to the near surface based instability most commonly associated with the mostly convective precipitation, embedded convection is elevated. The median most unstable parcel height of origin for embedded convective periods is 2.5 km compared to 0.5 km for mostly convective periods. Although this present research did not deal directly with orographic precipitation enhancement, it does address synoptic and mesoscale precipitation processes that frequently occur near terrain in the Pacific Northwest. The exclusion of the seeder-feeder mechanism as a mode of cellularity for orographic precipitation in recent work is inconsistent with the observations presented here and inconsistent with much of the pre-2000 literature, which show the seeder-feeder mechanism directly modulating surface rain rate with or without terrain present. Numerical models, whether operational or idealized, need to represent the seeder-feeder process in order to accurately simulate precipitation variability at small spatial scales (less than < 5-10 km) and temporal scales (< 3 hours) within the warm sector of Pacific Northwest extratropical cyclones.

Interplay between protons and electrons in a firehose-unstable plasma: Particle-in-cell simulations

NASA Astrophysics Data System (ADS)

Bourdin, Philippe-A.; Maneva, Yana

2017-04-01

Kinetic plasma instabilities originating from unstable, non-Maxwellian shapes of the velocity distribution functions serve as internal degrees of freedom in plasma dynamics, and play an important role near solar current sheets and in solar wind plasmas. In the presence of strong temperature anisotropy (different thermal spreads in the velocity space with respect to the mean magnetic field), plasmas are unstable either to the firehose mode or to the mirror mode in the case of predominant parallel and perpendicular temperatures, respectively. The growth rates of these instabilities and their thresholds depend on plasma properties, such as the temperature anisotropy and the plasma beta. The physics of the temperature anisotropy-driven instabilities becomes even more diverse for various shapes of velocity distribution functions and the particle species of interest. Recent studies based on a linear instability analysis show an interplay in the firehose instability between protons and electrons when the both types of particle species are prone to unstable velocity distribution functions and their instability thresholds. In this work we perform for the first time 3D nonlinear PIC (particle-in-cell) numerical simulations to test for the linear-theory prediction of the simultaneous proton-electron firehose instability. The simulation setup allows us not only to evaluate the growth rate of each firehose instability, but also to track its nonlinear evolution and the related wave-particle interactions such as the pitch-angle scattering or saturation effects. The specialty of our simulation is that the magnetic and electric fields have a low numerical noise level by setting a sufficiently large number of super-particles into the simulation box and enhancing the statistical significance of the velocity distribution functions. We use the iPIC3D code with fully periodic boundaries under various conditions of the electron-to-proton mass ratio, which gives insight into the instability interplay at the intermediate electron-proton and on the scaling of our results towards more realistic particle settings.

Coalescence of two current loops with a kink instability simulated by a three-dimensional electromagnetic particle code

NASA Technical Reports Server (NTRS)

Nishikawa, K.-I.; Sakai, J.-I.; Zhao, Jie; Neubert, T.; Buneman, Oscar

1994-01-01

We have studied the dynamics of a coalescence of current loops using three-dimensional electromagnetic (EM) particle simulation code. Our focus is the investigation of such kinetic processes as energy trasnfer, heating particles, and electromagnetic emissions associated with a current loop coalescence which cannot be studied by MHD simulations. First, the two loops undergo a pinching oscillation due to a pressure imbalance between the inside and outside of the current loop. During the pinching oscillation, a kinetic kink instability is excited and electrons in the loops are heated perpendicularly to an ambient magnetic field. Next, the two current loops collide and coalesce, while at the same time a helical structure grows further. Subsequently, the perturbed current, which is due to these helically bunched electrons, can drive a whistler instability. It should be noted in this case that the whistler wave is excited by the kinetic kink instability and not a beam instability. After the coalescence of two helical loops, tilting motions can be observed in the direction of left-hand rotation, and the helical structure will relax resulting in strong plasma heating mostly in the direction perpendicular to the ambient magnetic field. It is also shown that high-frequency electromagnetic waves can be emitted from the region where the two loops coalesce and propagate strongly in the direction of the electron drift velocity. These processes may be important in understanding heating mechansims for coronal loops as well as radio wave emission mechanisms from active regions of solar plasmas.

Analysis of the common deletions in the mitochondrial DNA is a sensitive biomarker detecting direct and non-targeted cellular effects of low dose ionizing radiation.

PubMed

Schilling-Tóth, Boglárka; Sándor, Nikolett; Kis, Eniko; Kadhim, Munira; Sáfrány, Géza; Hegyesi, Hargita

2011-11-01

One of the key issues of current radiation research is the biological effect of low doses. Unfortunately, low dose science is hampered by the unavailability of easily performable, reliable and sensitive quantitative biomarkers suitable detecting low frequency alterations in irradiated cells. We applied a quantitative real time polymerase chain reaction (qRT-PCR) based protocol detecting common deletions (CD) in the mitochondrial genome to assess direct and non-targeted effects of radiation in human fibroblasts. In directly irradiated (IR) cells CD increased with dose and was higher in radiosensitive cells. Investigating conditioned medium-mediated bystander effects we demonstrated that low and high (0.1 and 2Gy) doses induced similar levels of bystander responses and found individual differences in human fibroblasts. The bystander response was not related to the radiosensitivity of the cells. The importance of signal sending donor and signal receiving target cells was investigated by placing conditioned medium from a bystander response positive cell line (F11-hTERT) to bystander negative cells (S1-hTERT) and vice versa. The data indicated that signal sending cells are more important in the medium-mediated bystander effect than recipients. Finally, we followed long term effects in immortalized radiation sensitive (S1-hTERT) and normal (F11-hTERT) fibroblasts up to 63 days after IR. In F11-hTERT cells CD level was increased until 35 days after IR then reduced back to control level by day 49. In S1-hTERT cells the increased CD level was also normalized by day 42, however a second wave of increased CD incidence appeared by day 49 which was maintained up to day 63 after IR. This second CD wave might be the indication of radiation-induced instability in the mitochondrial genome of S1-hTERT cells. The data demonstrated that measuring CD in mtDNA by qRT-PCR is a reliable and sensitive biomarker to estimate radiation-induced direct and non-targeted effects. Copyright © 2011 Elsevier B.V. All rights reserved.

Three dimensional instabilities of an electron scale current sheet in collisionless magnetic reconnection

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

Jain, Neeraj; Büchner, Jörg; Max Planck Institute for Solar System Research, Justus-Von-Liebig-Weg-3, Göttingen

In collisionless magnetic reconnection, electron current sheets (ECS) with thickness of the order of an electron inertial length form embedded inside ion current sheets with thickness of the order of an ion inertial length. These ECS's are susceptible to a variety of instabilities which have the potential to affect the reconnection rate and/or the structure of reconnection. We carry out a three dimensional linear eigen mode stability analysis of electron shear flow driven instabilities of an electron scale current sheet using an electron-magnetohydrodynamic plasma model. The linear growth rate of the fastest unstable mode was found to drop with themore » thickness of the ECS. We show how the nature of the instability depends on the thickness of the ECS. As long as the half-thickness of the ECS is close to the electron inertial length, the fastest instability is that of a translational symmetric two-dimensional (no variations along flow direction) tearing mode. For an ECS half thickness sufficiently larger or smaller than the electron inertial length, the fastest mode is not a tearing mode any more and may have finite variations along the flow direction. Therefore, the generation of plasmoids in a nonlinear evolution of ECS is likely only when the half-thickness is close to an electron inertial length.« less

Improving the Stability of Metal Halide Perovskite Materials and Light-Emitting Diodes.

PubMed

Cho, Himchan; Kim, Young-Hoon; Wolf, Christoph; Lee, Hyeon-Dong; Lee, Tae-Woo

2018-01-25

Metal halide perovskites (MHPs) have numerous advantages as light emitters such as high photoluminescence quantum efficiency with a direct bandgap, very narrow emission linewidth, high charge-carrier mobility, low energetic disorder, solution processability, simple color tuning, and low material cost. Based on these advantages, MHPs have recently shown unprecedented radical progress (maximum current efficiency from 0.3 to 42.9 cd A -1 ) in the field of light-emitting diodes. However, perovskite light-emitting diodes (PeLEDs) suffer from intrinsic instability of MHP materials and instability arising from the operation of the PeLEDs. Recently, many researchers have devoted efforts to overcome these instabilities. Here, the origins of the instability in PeLEDs are reviewed by categorizing it into two types: instability of (i) the MHP materials and (ii) the constituent layers and interfaces in PeLED devices. Then, the strategies to improve the stability of MHP materials and PeLEDs are critically reviewed, such as A-site cation engineering, Ruddlesden-Popper phase, suppression of ion migration with additives and blocking layers, fabrication of uniform bulk polycrystalline MHP layers, and fabrication of stable MHP nanoparticles. Based on this review of recent advances, future research directions and an outlook of PeLEDs for display applications are suggested. © 2018 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

A minimization principle for the description of modes associated with finite-time instabilities

PubMed Central

Babaee, H.

2016-01-01

We introduce a minimization formulation for the determination of a finite-dimensional, time-dependent, orthonormal basis that captures directions of the phase space associated with transient instabilities. While these instabilities have finite lifetime, they can play a crucial role either by altering the system dynamics through the activation of other instabilities or by creating sudden nonlinear energy transfers that lead to extreme responses. However, their essentially transient character makes their description a particularly challenging task. We develop a minimization framework that focuses on the optimal approximation of the system dynamics in the neighbourhood of the system state. This minimization formulation results in differential equations that evolve a time-dependent basis so that it optimally approximates the most unstable directions. We demonstrate the capability of the method for two families of problems: (i) linear systems, including the advection–diffusion operator in a strongly non-normal regime as well as the Orr–Sommerfeld/Squire operator, and (ii) nonlinear problems, including a low-dimensional system with transient instabilities and the vertical jet in cross-flow. We demonstrate that the time-dependent subspace captures the strongly transient non-normal energy growth (in the short-time regime), while for longer times the modes capture the expected asymptotic behaviour. PMID:27118900

The role of helplessness as mediator between neurological disability, emotional instability, experienced fatigue and depression in patients with multiple sclerosis.

PubMed

van der Werf, S P; Evers, A; Jongen, P J H; Bleijenberg, G

2003-02-01

The aim of this study was to test, in patients with multiple sclerosis (MS), whether the concept of helplessness might improve the understanding of the relationship between disease severity (neurological impairment) and personality characteristics (emotional instability) on one hand, and depressive mood and fatigue severity on the other hand. Data pertain to 89 patients with a definite diagnosis of MS (Expanded Disability Status Scale [EDSS] ratings: 1-8). Helplessness, fatigue severity, depressive mood and emotional instability were rated with validated questionnaires. Model testing revealed that more neurological impairment and more emotional instability were associated with more helplessness, while higher levels of helplessness were associated with more fatigue and depressive mood. The initially observed direct relationship between EDSS and fatigue disappeared. Emotional instability also had a direct significant relationship with depressive mood, and depressive mood had only a small relationship with fatigue severity. The results indicated that helplessness affected both depressive mood and fatigue severity and that fatigue was not merely a symptom of depressive mood. The correlation between neurological impairment and fatigue severity was largely explained by the mediating effect of helplessness. These findings suggest that MS patients troubled by disabling fatigue might benefit from a psychological intervention targeting unfavourable illness cognitions.

Instability and associated roll structure of Marangoni convection in high Prandtl number liquid bridge with large aspect ratio

NASA Astrophysics Data System (ADS)

Yano, T.; Nishino, K.; Kawamura, H.; Ueno, I.; Matsumoto, S.

2015-02-01

This paper reports the experimental results on the instability and associated roll structures (RSs) of Marangoni convection in liquid bridges formed under the microgravity environment on the International Space Station. The geometry of interest is high aspect ratio (AR = height/diameter ≥ 1.0) liquid bridges of high Prandtl number fluids (Pr = 67 and 207) suspended between coaxial disks heated differentially. The unsteady flow field and associated RSs were revealed with the three-dimensional particle tracking velocimetry. It is found that the flow field after the onset of instability exhibits oscillations with azimuthal mode number m = 1 and associated RSs traveling in the axial direction. The RSs travel in the same direction as the surface flow (co-flow direction) for 1.00 ≤ AR ≤ 1.25 while they travel in the opposite direction (counter-flow direction) for AR ≥ 1.50, thus showing the change of traveling directions with AR. This traveling direction for AR ≥ 1.50 is reversed to the co-flow direction when the temperature difference between the disks is increased to the condition far beyond the critical one. This change of traveling directions is accompanied by the increase of the oscillation frequency. The characteristics of the RSs for AR ≥ 1.50, such as the azimuthal mode of oscillation, the dimensionless oscillation frequency, and the traveling direction, are in reasonable agreement with those of the previous sounding rocket experiment for AR = 2.50 and those of the linear stability analysis of an infinite liquid bridge.

Fanconi anemia and the cell cycle: new perspectives on aneuploidy

PubMed Central

2014-01-01

Fanconi anemia (FA) is a complex heterogenic disorder of genomic instability, bone marrow failure, cancer predisposition, and congenital malformations. The FA signaling network orchestrates the DNA damage recognition and repair in interphase as well as proper execution of mitosis. Loss of FA signaling causes chromosome instability by weakening the spindle assembly checkpoint, disrupting centrosome maintenance, disturbing resolution of ultrafine anaphase bridges, and dysregulating cytokinesis. Thus, the FA genes function as guardians of genome stability throughout the cell cycle. This review discusses recent advances in diagnosis and clinical management of Fanconi anemia and presents the new insights into the origins of genomic instability in FA. These new discoveries may facilitate the development of rational therapeutic strategies for FA and for FA-deficient malignancies in the general population. PMID:24765528

Direct experimental evidence of ion-ion co-stream instability excited in the sheath-presheath of Ar +He two-ion species plasma

NASA Astrophysics Data System (ADS)

Kella, Vara Prasad; Ghosh, Joydeep; Chattopadhyay, Prabal; Sharma, Devendra; Saxena, Yogesh

2017-10-01

Recent experimental measurements of ion flow speeds near the sheath edge of two-ion species plasma shows that, the ions reach the sheath edge with common sound speed other than their individual Bohm speeds at nearly equal ion concentrations. Baalrud et al., explain these results on the basis of ion-ion two-stream instability enhanced collisional friction between the ions. Some authors stipulate the existence of the instability indirectly, by measuring the ion flow speeds near the sheath edge. In these experiments, the instability is directly observed from the floating potential fluctuations from Langmuir probe placed near the sheath edge and from grid in Ar +He plasma. The frequency spectra shows broad band peaks with central frequency in the range 150-200 kHz. The intensity of the instability maximizes in the plasma produced with approximately equal ion concentrations of both the ion species. The frequency and amplitude of the peak decreases as the He+ to Ar+ concentration ratio decreases from unity. The phase velocity of the wave is measured as 11 +/-2 km/s and identified to be twice the ion-sound speed in the bulk ( 6.3 km/s), which is good agreement with earlier results of IAWs. The measured wave number and frequencies are compared with the theoretical dispersion relations. These observations confirm the existence of ion-ion co-stream instability in sheath-presheath of two-ion species plasma.

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.

The investigation of flow instabilities on a rotating disk with curvature in the radial direction

NASA Technical Reports Server (NTRS)

Intemann, P. A.; Clarkson, M. H.

1982-01-01

The major objective is to explore any visible differences of the flow field with wall curvature of the test body, including possible interaction between Taylor-Gortler instabilities present along concave walls and the inflexional instabilities investigated here. An experimental study was conducted with emphasis placed on making visual observations and recording photographically the flow instabilities present under three different rotating bodies: a flat disk, a concave paraboloid, and a convex paraboloid. The data collected for the three test bodies lead to the conclusion that the wall curvature of the concave and convex paraboloids did not alter the observed flow field significantly from that observed on the flat disk.

Elimination of a Photovoltaic Induced Fast Instability in Photorefractive Iron-doped Lithium Niobate Crystals

NASA Astrophysics Data System (ADS)

Evans, D. R.; Saleh, M. A.; Allen, A. S.; Pottenger, T. P.; Bunning, T. J.; Guha, S.; Basun, S. A.; Cook, G.

2002-03-01

An instability on the order of 10 ns is observed while writing volume gratings in bulk crystals of iron-doped lithium niobate using contra-directional two-beam coupling along the c-axis. This instability is attributed to the quasi-breakdown of the uniform component of the photovoltaic field [1], which affects the uniform electric field formed inside the crystal causing a change in the refractive index through the electro-optic effect. A method to eliminate this instability by coating the z-surfaces of the crystal with a transparent conductive coating will be presented. [1] A. Krumins, Z. Chen, and T. Shiosaki, Opt. Comm. 117 (1995) 147-150.

Flow-driven instabilities during pattern formation of Dictyostelium discoideum

NASA Astrophysics Data System (ADS)

Gholami, A.; Steinbock, O.; Zykov, V.; Bodenschatz, E.

2015-06-01

The slime mold Dictyostelium discoideum is a well known model system for the study of biological pattern formation. In the natural environment, aggregating populations of starving Dictyostelium discoideum cells may experience fluid flows that can profoundly change the underlying wave generation process. Here we study the effect of advection on the pattern formation in a colony of homogeneously distributed Dictyostelium discoideum cells described by the standard Martiel-Goldbeter model. The external flow advects the signaling molecule cyclic adenosine monophosphate (cAMP) downstream, while the chemotactic cells attached to the solid substrate are not transported with the flow. The evolution of small perturbations in cAMP concentrations is studied analytically in the linear regime and by corresponding numerical simulations. We show that flow can significantly influence the dynamics of the system and lead to a flow-driven instability that initiate downstream traveling cAMP waves. We also show that boundary conditions have a significant effect on the observed patterns and can lead to a new kind of instability.

Analysis of Affective Instability in Ecological Momentary Assessment: Indices Using Successive Difference and Group Comparison via Multilevel Modeling

ERIC Educational Resources Information Center

Jahng, Seungmin; Wood, Phillip K.; Trull, Timothy J.

2008-01-01

Temporal instability of affect is a defining characteristic of psychological disorders such as borderline personality disorder (BPD) and mood cycling disorders. Ecological momentary assessment (EMA) enables researchers to directly assess such frequent and extreme fluctuations over time. The authors examined 4 operationalizations of such temporal…

The Impact of Accurate Distances on UV Spectroscopy of White Dwarfs and Cataclysmic Variables

DTIC Science & Technology

2009-01-01

evolution. Four instability strips in the HR diagram are associated with planetary nebulae nuclei (PNN) and white dwarfs (WDs). The rst instability...strip occurs during the high luminosity planetary nebula phase. The second is during the pre- WD stars of the PG 1159 spectral type, which are direct

Correction of both spontaneous and DEB-induced chromosome instability in Fanconi anemia FA-C cells by FACC cDNA

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

Stavropoulos, D.J.; Tomkins, D.J.; Allingham-Hawkins, D.J.

1994-09-01

Cells from all four Fanconi anemia complementation groups show hypersensitivity to cell-killing by mitomycin C (MMC), diepoxybutane (DEB) and other DNA cross-linking agents, and increased spontaneous and DEB-induced chromosome aberrations (CA). The extent of these phenotypes varies between lymphoblastoid cell lines from different complementation groups. Our data showed that the difference in MMC hypersensitivity and DEB-CA was not always coupled. While 230N (FA-B) had higher DEB-induced CA/cell than 536N (FA-C) (7.42 vs. 4.46 respectively), that latter was much more sensitive to cell-killing by MMC (dose at 10% survival, D{sub 10}: 5.2 vs. 1.2 ng/ml respectively). Strathdes et al. (1992) clonedmore » a cDNA Fanconi anemia complementation group C (FACC) which complemented the hypersensitivity to MMC and DEB cell-killing of FA-C cells (536N) but not cells from the other three complementation groups. The present study was initiated to determine whether chromosome instability in 536N is also complemented by the FACC (FAC3) cDNA. The pREP4-FAC3 vector was transfected into 536N and transfectants selected with hygromycin B. The DEB D{sub 10} of 536N (1.0 {mu}M) was corrected to the control level (16.2 {mu}M for 3TO) by FACC (15.1 {mu}M for 536N-FACC), as previously demonstrated. Chromosome instability (cab, cse, ctb, cte) was determined without and with 0.1 {mu}g/ml DEB treatment. Spontaneous CA of 536N (0.30 aberrations/cell) was corrected to the control level (0.04 for 3TO) by FACC (0.06 for 536N-FACC). Similarly, the DEB-induced CA was corrected (2.74 for 536N vs. 0.06 and 0.02 for 3TO and 536N-FACC respectively). Thus, at least for FA complementation group C, hypersensitivity to cell-killing and chromosome instability are not dissociated and are most likely caused by the same gene defect.« less

Impact of drag reducing polymers on the onset of instability in a pipe with reverse flow

NASA Astrophysics Data System (ADS)

Shashank, H. J.; Sreenivas, K. R.

2014-11-01

The objective of this study is to understand the mechanism by which drag reducing polymer (DRP) additives modify turbulent flow, so as to reduce turbulent drag. Reverse flow in a pipe occurs when the fluid close to the wall moves in an opposite direction to that of the core fluid. Reverse flow is established by using a piston-cylinder mechanism, the programmed motion of which imparts a known impulse to the fluid. When the piston is stopped at the end of the stroke, fluid inertia makes the core of the flow to continue in the same direction. In order to conserve mass, reverse flow is established close to the wall. An inflection point is thus formed, leading to flow instability above a critical Reynolds number. Dye and streak flow visualization experiments are performed to highlight the impact of DRP additives (polyethylene oxide, PEO, dissolved in water). The time of onset of the instability and the wavelength of the observed instability are studied in systems with and without DRP additives. This study will provide further insight into the phenomenon of turbulent polymer drag reduction.

Turbulent mixing noise from supersonic jets

NASA Technical Reports Server (NTRS)

Tam, Christopher K. W.; Chen, Ping

1994-01-01

There is now a substantial body of theoretical and experimental evidence that the dominant part of the turbulent noise of supersonic jets is generated directly by the large turbulence structures/instability waves of the jet flow. Earlier, Tam and Burton provided a description of the physical mechanism by which supersonically traveling instability waves can generate sound efficiently. They used the method of matched asymptotic expansions to construct an instability wave solution which is valid in the far field. The present work is an extension of the theory of Tam and Burton. It is argued that the instability wave spectrum of the jet may be regarded as generated by stochastic white noise excitation at the nozzle lip region. The reason why the excitation has white noise characteristics is that near the nozzle lip region the flow in the jet mixing layer has no intrinsic length and time scales. The present stochastic wave model theory of supersonic jet noise contains a single unknown multiplicative constant. Comparisons between the calculated noise directivities at selected Strouhal numbers and experimental measurements of a Mach 2 jet at different jet temperatures have been carried out. Favorable agreements are found.

The slow collisional E×B ion drift characterized as the major instability mechanism of a poorly magnetized plasma column with an inward-directed radial electric field

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

Pierre, Thiéry

2016-04-15

The low-frequency instability of a cylindrical poorly magnetized plasma with an inward-directed radial electric field is studied changing the gas pressure and the ion cyclotron frequency. The unstable frequency always decreases when the gas pressure is increased indicating collisional effects. At a fixed pressure, the unstable frequency increases with the magnetic field when the B-field is low and decreases at larger magnetic field strength. We find that the transition between these two regimes is obtained when the ion cyclotron frequency equals the ion-neutrals collision frequency. This is in agreement with the theory of the slow-ion drift instability induced by themore » collisional slowing of the electric ion drift [A. Simon, Phys. Fluids 6, 382 (1963)].« less

The effect of different unstable footwear constructions on centre of pressure motion during standing.

PubMed

Plom, W; Strike, S C; Taylor, M J D

2014-06-01

The aim of this study was to test the effect different unstable footwear constructions have on centre of pressure motion when standing. Sixteen young female volunteers were tested in five conditions, three unstable footwear (Reebok Easy-Tone, FitFlop and Skechers Shape-Ups), a standard shoe and barefoot in a randomised order. Double and single leg balance on a force plate was assessed via centre of pressure excursions and displacements in each condition. For double leg and single leg standing centre of pressure excursions in the anterior-posterior direction were significantly increased wearing Skechers Shape-Ups compared to barefoot and the standard shoe. For the Reebok Easy Tone during single leg standing excursions in the anterior-posterior direction were significantly greater compared to the barefoot condition. Cumulative displacement of the centre of pressure in medial-lateral direction increased significantly during single leg standing when wearing Skechers Shape-Ups compared to barefoot and standard shoe as well as for Reebok Easy Tone vs. barefoot. It would appear from these quiet standing results that the manner of the construction of instability shoes effects the CoP movement which is associated with induced instability. Greater CoP excursion occurred in the A-P direction while the cumulative displacements were greater in the M-L direction for those shoes with the rounded sole and soft foam and those with airpods. The shoe construction with altered density foam did not induce any change in the CoP movement, during quite standing, which tends to suggest that it is not effective at inducing balance. Not all instability shoes are effective in altering the overall instability of the wearer. Copyright © 2014 Elsevier B.V. All rights reserved.

Development and Reliability Testing of the FEDS System for Classifying Glenohumeral Instability

PubMed Central

Kuhn, John E.; Helmer, Tara T.; Dunn, Warren R.; Throckmorton V, Thomas W.

2010-01-01

Background Classification systems for glenohumeral instability (GHI) are opinion based, not validated, and poorly defined. This study is designed to methodologically develop and test a GHI classification system. Methods: Classification System Development A systematic literature review identified 18 systems for classifying GHI. The frequency characteristics used was recorded. Additionally 31 members of the American Shoulder and Elbow Surgeons responded to a survey to identify features important to characterize GHI. Frequency, Etiology, Direction, and Severity (FEDS), were found to be most important. Frequency was defined as solitary (one episode), occasional (2–5x/year), or frequent (>5x/year). Etiology was defined as traumatic or atraumatic. Direction referred to the primary direction of instability (anterior, posterior, or inferior). Severity was defined as either subluxation or dislocation. Methods: Reliability Testing Fifty GHI patients completed a questionnaire at their initial visit. One of six sports medicine fellowship trained physicians completed a similar questionnaire after examining the patient. Patients returned after two weeks and were examined by the original physician and two other physicians. Inter- and intra-rater agreement for the FEDS classification system was calculated. Results Agreement between patients and physicians was lowest for frequency (39%; k=0.130) and highest for direction (82%; k=0.636). Physician intra-rater agreement was 84– 97% for the individual FEDS characteristics (k=0.69 to 0.87)). Physician inter-rater agreement ranged from 82–90% (k=0.44 to 0.76). Conclusions The FEDS system has content validity and is highly reliable for classifying GHI. Physical examination using provocative testing to determine the primary direction of instability produces very high levels of inter- and intra-rater agreement. Level of evidence Level II, Development of Diagnostic Criteria with Consecutive Series of Patients, Diagnosis Study. PMID:21277809

Incompressible Modes Excited by Supersonic Shear in Boundary Layers: Acoustic CFS Instability

NASA Astrophysics Data System (ADS)

Belyaev, Mikhail A.

2017-02-01

We present an instability for exciting incompressible modes (e.g., gravity or Rossby modes) at the surface of a star accreting through a boundary layer. The instability excites a stellar mode by sourcing an acoustic wave in the disk at the boundary layer, which carries a flux of energy and angular momentum with the opposite sign as the energy and angular momentum density of the stellar mode. We call this instability the acoustic Chandrasekhar-Friedman-Schutz (CFS) instability, because of the direct analogy to the CFS instability for exciting modes on a rotating star by emission of energy in the form of gravitational waves. However, the acoustic CFS instability differs from its gravitational wave counterpart in that the fluid medium in which the acoustic wave propagates (I.e., the accretion disk) typically rotates faster than the star in which the incompressible mode is sourced. For this reason, the instability can operate even for a non-rotating star in the presence of an accretion disk. We discuss applications of our results to high-frequency quasi-periodic oscillations in accreting black hole and neutron star systems and dwarf nova oscillations in cataclysmic variables.

Incompressible Modes Excited by Supersonic Shear in Boundary Layers: Acoustic CFS Instability

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

Belyaev, Mikhail A., E-mail: mbelyaev@berkeley.edu

We present an instability for exciting incompressible modes (e.g., gravity or Rossby modes) at the surface of a star accreting through a boundary layer. The instability excites a stellar mode by sourcing an acoustic wave in the disk at the boundary layer, which carries a flux of energy and angular momentum with the opposite sign as the energy and angular momentum density of the stellar mode. We call this instability the acoustic Chandrasekhar–Friedman–Schutz (CFS) instability, because of the direct analogy to the CFS instability for exciting modes on a rotating star by emission of energy in the form of gravitationalmore » waves. However, the acoustic CFS instability differs from its gravitational wave counterpart in that the fluid medium in which the acoustic wave propagates (i.e., the accretion disk) typically rotates faster than the star in which the incompressible mode is sourced. For this reason, the instability can operate even for a non-rotating star in the presence of an accretion disk. We discuss applications of our results to high-frequency quasi-periodic oscillations in accreting black hole and neutron star systems and dwarf nova oscillations in cataclysmic variables.« less

Kinetic-MHD simulations of gyroresonance instability driven by CR pressure anisotropy

NASA Astrophysics Data System (ADS)

Lebiga, O.; Santos-Lima, R.; Yan, H.

2018-05-01

The transport of cosmic rays (CRs) is crucial for the understanding of almost all high-energy phenomena. Both pre-existing large-scale magnetohydrodynamic (MHD) turbulence and locally generated turbulence through plasma instabilities are important for the CR propagation in astrophysical media. The potential role of the resonant instability triggered by CR pressure anisotropy to regulate the parallel spatial diffusion of low-energy CRs (≲100 GeV) in the interstellar and intracluster medium of galaxies has been shown in previous theoretical works. This work aims to study the gyroresonance instability via direct numerical simulations, in order to access quantitatively the wave-particle scattering rates. For this, we employ a 1D PIC-MHD code to follow the growth and saturation of the gyroresonance instability. We extract from the simulations the pitch-angle diffusion coefficient Dμμ produced by the instability during the linear and saturation phases, and a very good agreement (within a factor of 3) is found with the values predicted by the quasi-linear theory (QLT). Our results support the applicability of the QLT for modelling the scattering of low-energy CRs by the gyroresonance instability in the complex interplay between this instability and the large-scale MHD turbulence.

Particle acceleration magnetic field generation, and emission in Relativistic pair jets

NASA Technical Reports Server (NTRS)

Nishikawa, K.-I.; Ramirez-Ruiz, E.; Hardee, P.; Hededal, C.; Kouveliotou, C.; Fishman, G. J.

2005-01-01

Plasma waves and their associated instabilities (e.g., the Buneman instability, two-streaming instability, and the Weibel instability) are responsible for particle acceleration in relativistic pair jets. Using a 3-D relativistic electromagnetic particle (REMP) code, we have investigated particle acceleration associated with a relativistic pair jet propagating through a pair plasma. Simulations show that the Weibel instability created in the collisionless shock accelerates particles perpendicular and parallel to the jet propagation direction. Simulation results show that this instability generates and amplifies highly nonuniform, small-scale magnetic fields, which contribute to the electron's transverse deflection behind the jet head. The "jitter' I radiation from deflected electrons can have different properties than synchrotron radiation which is calculated in a uniform magnetic field. This jitter radiation may be important to understanding the complex time evolution and/or spectral structure in gamma-ray bursts, relativistic jets, and supernova remnants. The growth rate of the Weibel instability and the resulting particle acceleration depend on the magnetic field strength and orientation, and on the initial particle distribution function. In this presentation we explore some of the dependencies of the Weibel instability and resulting particle acceleration on the magnetic field strength and orientation, and the particle distribution function.

Magnetorotational dynamo action in the shearing box

NASA Astrophysics Data System (ADS)

Walker, Justin; Boldyrev, Stanislav

2017-09-01

Magnetic dynamo action caused by the magnetorotational instability is studied in the shearing-box approximation with no imposed net magnetic flux. Consistent with recent studies, the dynamo action is found to be sensitive to the aspect ratio of the box: it is much easier to obtain in tall boxes (stretched in the direction normal to the disc plane) than in long boxes (stretched in the radial direction). Our direct numerical simulations indicate that the dynamo is possible in both cases, given a large enough magnetic Reynolds number. To explain the relatively larger effort required to obtain the dynamo action in a long box, we propose that the turbulent eddies caused by the instability most efficiently fold and mix the magnetic field lines in the radial direction. As a result, in the long box the scale of the generated strong azimuthal (stream-wise directed) magnetic field is always comparable to the scale of the turbulent eddies. In contrast, in the tall box the azimuthal magnetic flux spreads in the vertical direction over a distance exceeding the scale of the turbulent eddies. As a result, different vertical sections of the tall box are permeated by large-scale non-zero azimuthal magnetic fluxes, facilitating the instability. In agreement with this picture, the cases when the dynamo is efficient are characterized by a strong intermittency of the local azimuthal magnetic fluxes.

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.

Particle Acceleration, Magnetic Field Generation, and Emission in Relativistic Pair Jets

NASA Technical Reports Server (NTRS)

Nishikawa, K.-I.; Ramirez-Ruiz, E.; Hardee, P.; Hededal, C.; Mizuno, Y.

2005-01-01

Shock acceleration is a ubiquitous phenomenon in astrophysical plasmas. Plasma waves and their associated instabilities (e.g., the Buneman instability, two-streaming instability, and the Weibel instability) created by relativistic pair jets are responsible for particle (electron, positron, and ion) acceleration. Using a 3-D relativistic electromagnetic particle (REMP) code, we have investigated particle acceleration associated with a relativistic jet propagating through an ambient plasma with and without initial magnetic fields. The growth rates of the Weibel instability depends on the distribution of pair jets. Simulations show that the Weibel instability created in the collisionless shock accelerates particles perpendicular and parallel to the jet propagation direction. The simulation results show that this instability is responsible for generating and amplifying highly nonuniform, small-scale magnetic fields, which contribute to the electron's transverse deflection behind the jet head. The "jitter" radiation from deflected electrons has different properties than synchrotron radiation which is calculated in a uniform magnetic field. This jitter radiation may be important to understanding the complex time evolution and/or spectral structure in gamma-ray bursts, relativistic jets, and supernova remnants.

Vortex formation and instability in the left ventricle

NASA Astrophysics Data System (ADS)

Le, Trung Bao; Sotiropoulos, Fotis; Coffey, Dane; Keefe, Daniel

2012-09-01

We study the formation of the mitral vortex ring during early diastolic filling in a patient-specific left ventricle (LV) using direct numerical simulation. The geometry of the left ventricle is reconstructed from Magnetic Resonance Imaging (MRI) data of a healthy human subject. The left ventricular kinematics is modeled via a cell-based activation methodology, which is inspired by cardiac electro-physiology and yields physiologic LV wall motion. In the fluid dynamics videos, we describe in detail the three-dimensional structure of the mitral vortex ring, which is formed during early diastolic filling. The ring starts to deform as it propagates toward the apex of the heart and becomes inclined. The trailing secondary vortex tubes are formed as the result of interaction between the vortex ring and the LV wall. These vortex tubes wrap around the circumference and begin to interact with and destabilize the mitral vortex ring. At the end of diastole, the vortex ring impinges on the LV wall and the large-scale intraventricular flow rotates in clockwise direction. We show for the first time that the mitral vortex ring evolution is dominated by a number of vortex-vortex and vortex-wall interactions, including lateral straining and deformation of vortex ring, the interaction of two vortex tubes with unequal strengths, helicity polarization of vortex tubes and twisting instabilities of the vortex cores.

Turbulence in Three-Dimensional Simulations of Magnetopause Reconnection

NASA Astrophysics Data System (ADS)

Price, L.; Swisdak, M.; Drake, J. F.; Burch, J. L.; Cassak, P. A.; Ergun, R. E.

2017-11-01

We present detailed analysis of the turbulence observed in three-dimensional particle-in-cell simulations of magnetic reconnection at the magnetopause. The parameters are representative of an electron diffusion region encounter of the Magnetospheric Multiscale (MMS) mission. The turbulence is found to develop around both the magnetic X line and separatrices, is electromagnetic in nature, is characterized by a wave vector k given by kρe˜(meTe/miTi)0.25 with ρe the electron Larmor radius, and appears to have the ion pressure gradient as its source of free energy. Taken together, these results suggest the instability is a variant of the lower hybrid drift instability. The turbulence produces electric field fluctuations in the out-of-plane direction (the direction of the reconnection electric field) with an amplitude of around ±10 mV/m, which is much greater than the reconnection electric field of around 0.1 mV/m. Such large values of the out-of-plane electric field have been identified in the MMS data. The turbulence in the simulations controls the scale lengths of the density profile and current layers in asymmetric reconnection, driving them closer to √{ρeρi} than the ρe or de scalings seen in 2-D reconnection simulations, and produces significant anomalous resistivity and viscosity in the electron diffusion region.

Kinetic suppression of microtubule dynamic instability by griseofulvin: Implications for its possible use in the treatment of cancer

PubMed Central

Panda, Dulal; Rathinasamy, K.; Santra, Manas K.; Wilson, Leslie

2005-01-01

The antifungal drug griseofulvin inhibits mitosis strongly in fungal cells and weakly in mammalian cells by affecting mitotic spindle microtubule (MT) function. Griseofulvin also blocks cell-cycle progression at G2/M and induces apoptosis in human tumor cell lines. Despite extensive study, the mechanism by which the drug inhibits mitosis in human cells remains unclear. Here, we analyzed the ability of griseofulvin to inhibit cell proliferation and mitosis and to affect MT polymerization and organization in HeLa cells together with its ability to affect MT polymerization and dynamic instability in vitro. Griseofulvin inhibited cell-cycle progression at prometaphase/anaphase of mitosis in parallel with its ability to inhibit cell proliferation. At its mitotic IC50 of 20 μM, spindles in blocked cells displayed nearly normal quantities of MTs and MT organization similar to spindles blocked by more powerful MT-targeted drugs. Similar to previously published data, we found that very high concentrations of griseofulvin (>100 μM) were required to inhibit MT polymerization in vitro. However, much lower drug concentrations (1–20 μM) strongly suppressed the dynamic instability behavior of the MTs. We suggest that the primary mechanism by which griseofulvin inhibits mitosis in human cells is by suppressing spindle MT dynamics in a manner qualitatively similar to that of much more powerful antimitotic drugs, including the vinca alkaloids and the taxanes. In view of griseofulvin's lack of significant toxicity in humans, we further suggest that it could be useful as an adjuvant in combination with more powerful drugs for the treatment of cancer. PMID:15985553

Biology of telomeres: importance in etiology of esophageal cancer and as therapeutic target.

PubMed

Pal, Jagannath; Gold, Jason S; Munshi, Nikhil C; Shammas, Masood A

2013-12-01

The purpose of this review is to highlight the importance of telomeres, the mechanisms implicated in their maintenance, and their role in the etiology as well as the treatment of human esophageal cancer. We will also discuss the role of telomeres in the maintenance and preservation of genomic integrity, the consequences of telomere dysfunction, and the various factors that may affect telomere health in esophageal tissue predisposing it to oncogenesis. There has been growing evidence that telomeres, which can be affected by various intrinsic and extrinsic factors, contribute to genomic instability, oncogenesis, as well as proliferation of cancer cells. Telomeres are the protective DNA-protein complexes at chromosome ends. Telomeric DNA undergoes progressive shortening with age leading to cellular senescence and/or apoptosis. If senescence/apoptosis is prevented as a consequence of specific genomic changes, continued proliferation leads to very short (ie, dysfunctional) telomeres that can potentially cause genomic instability, thus, increasing the risk for activation of telomere maintenance mechanisms and oncogenesis. Like many other cancers, esophageal cancer cells have short telomeres and elevated telomerase, the enzyme that maintains telomeres in most cancer cells. Homologous recombination, which is implicated in the alternate pathway of telomere elongation, is also elevated in Barrett's-associated esophageal adenocarcinoma. Evidence from our laboratory indicates that both telomerase and homologous recombination contribute to telomere maintenance, DNA repair, and the ongoing survival of esophageal cancer cells. This indicates that telomere maintenance mechanisms may potentially be targeted to make esophageal cancer cells static. The rate at which telomeres in healthy cells shorten is determined by a number of intrinsic and extrinsic factors, including those associated with lifestyle. Avoidance of factors that may directly or indirectly injure esophageal tissue including its telomeric and other genomic DNA can not only reduce the risk of development of esophageal cancer but may also have positive impact on overall health and lifespan. Copyright © 2013 Mosby, Inc. All rights reserved.

Hydrodynamic simulations of long-scale-length plasmas for two-plasmon-decay planar-target experiments on the NIF

NASA Astrophysics Data System (ADS)

Solodov, A. A.; Rosenberg, M. J.; Myatt, J. F.; Epstein, R.; Regan, S. P.; Seka, W.; Shaw, J.; Hohenberger, M.; Bates, J. W.; Moody, J. D.; Ralph, J. E.; Turnbull, D. P.; Barrios, M. A.

2016-05-01

The two-plasmon-decay (TPD) instability can be detrimental for direct-drive inertial confinement fusion because it generates high-energy electrons that can preheat the target, thereby reducing target performance. Hydrodynamic simulations to design a new experimental platform to investigate TPD and other laser-plasma instabilities relevant to direct-drive-ignition implosions at the National Ignition Facility are presented. The proposed experiments utilize planar plastic targets with an embedded Mo layer to characterize generation of hot electrons through Mo Kα fluorescence and hard x-ray emission. Different laser-irradiation geometries approximate conditions near both the equator and the pole of a polar-direct-drive implosion.

Identification, expansion and characterization of cancer cells with stem cell properties from head and neck squamous cell carcinomas

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

Kaseb, Hatem O.; Department of Clinical Pathology, National Cancer Institute; Fohrer-Ting, Helene

Head and neck squamous cell carcinoma (HNSCC) is a major public health concern. Recent data indicate the presence of cancer stem cells (CSC) in many solid tumors, including HNSCC. Here, we assessed the stem cell (SC) characteristics, including cell surface markers, radioresistance, chromosomal instability, and in vivo tumorigenic capacity of CSC isolated from HNSCC patient specimens. We show that spheroid enrichment of CSC from early and short-term HNSCC cell cultures was associated with increased expression of CD44, CD133, SOX2 and BMI1 compared with normal oral epithelial cells. On immunophenotyping, five of 12 SC/CSC markers were homogenously expressed in all tumormore » cultures, while one of 12 was negative, four of 12 showed variable expression, and two of the 12 were expressed heterogeneously. We showed that irradiated CSCs survived and retained their self-renewal capacity across different ionizing radiation (IR) regimens. Fluorescence in situ hybridization (FISH) analyses of parental and clonally-derived tumor cells revealed different chromosome copy numbers from cell to cell, suggesting the presence of chromosomal instability in HNSCC CSC. Further, our in vitro and in vivo mouse engraftment studies suggest that CD44+/CD66− is a promising, consistent biomarker combination for HNSCC CSC. Overall, our findings add further evidence to the proposed role of HNSCC CSCs in therapeutic resistance. - Highlights: • Spheroid enrichment selects cancer stem cells (CSC) from head & neck tumors (HNSCC). • Compared to normal epithelial cells, isolated CSC express increased SC/CSC markers. • Isolated CSC display enhanced radioresistance, clonogenicity and tumorigenicity. • HNSCC CSC express chromosomal instability. • CD44+/CD66− is a promising, consistent biomarker for HNSCC CSC.« less

Crawling and turning in a minimal reaction-diffusion cell motility model: Coupling cell shape and biochemistry

NASA Astrophysics Data System (ADS)

Camley, Brian A.; Zhao, Yanxiang; Li, Bo; Levine, Herbert; Rappel, Wouter-Jan

2017-01-01

We study a minimal model of a crawling eukaryotic cell with a chemical polarity controlled by a reaction-diffusion mechanism describing Rho GTPase dynamics. The size, shape, and speed of the cell emerge from the combination of the chemical polarity, which controls the locations where actin polymerization occurs, and the physical properties of the cell, including its membrane tension. We find in our model both highly persistent trajectories, in which the cell crawls in a straight line, and turning trajectories, where the cell transitions from crawling in a line to crawling in a circle. We discuss the controlling variables for this turning instability and argue that turning arises from a coupling between the reaction-diffusion mechanism and the shape of the cell. This emphasizes the surprising features that can arise from simple links between cell mechanics and biochemistry. Our results suggest that similar instabilities may be present in a broad class of biochemical descriptions of cell polarity.

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.

[Shoulder instability].

PubMed

Sailer, J; Imhof, H

2004-06-01

Shoulder instability is a common clinical feature leading to recurrent pain and limited range of motion within the glenohumeral joint. Instability can be due a single traumatic event, general joint laxity or repeated episodes of microtrauma. Differentiation between traumatic and atraumatic forms of shoulder instability requires careful history and a systemic clinical examination. Shoulder laxity has to be differentiated from true instability followed by the clinical assessment of direction and degree of glenohumeral translation. Conventional radiography and CT are used for the diagnosis of bony lesions. MR imaging and MR arthrography help in the detection of soft tissue affection, especially of the glenoid labrum and the capsuloligamentous complex. The most common lesion involving the labrum is the anterior labral tear, associated with capsuloperiostal stripping (Bankart lesion). A number of variants of the Bankart lesion have been described, such as ALPSA, SLAP or HAGL lesions. The purpose of this review is to highlight different forms of shoulder instability and its associated radiological findings with a focus on MR imaging.

Fast Transverse Instability and Electron Cloud Measurements in Fermilab Recycler

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

Eldred, Jeffery; Adamson, Philip; Capista, David

2015-03-01

A new transverse instability is observed that may limit the proton intensity in the Fermilab Recycler. The instability is fast, leading to a beam-abort loss within two hundred turns. The instability primarily affects the first high-intensity batch from the Fermilab Booster in each Recycler cycle. This paper analyzes the dynamical features of the destabilized beam. The instability excites a horizontal betatron oscillation which couples into the vertical motion and also causes transverse emittance growth. This paper describes the feasibility of electron cloud as the mechanism for this instability and presents the first measurements of the electron cloud in the Fermilabmore » Recycler. Direct measurements of the electron cloud are made using a retarding field analyzer (RFA) newly installed in the Fermilab Recycler. Indirect measurements of the electron cloud are made by propagating a microwave carrier signal through the beampipe and analyzing the phase modulation of the signal. The maximum betatron amplitude growth and the maximum electron cloud signal occur during minimums of the bunch length oscillation.« less

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

Kaothekar, Sachin, E-mail: sackaothekar@gmail.com

I have studied the effects of finite electron inertia, finite ion Larmor radius (FLR) corrections, and radiative heat-loss function on the thermal instability of an infinite homogeneous, viscous plasma incorporating the effect of thermal conductivity for star formation in interstellar medium (ISM). A general dispersion relation is derived using the normal mode analysis method with the help of relevant linearized perturbation equations of the problem. The wave propagation is discussed for longitudinal and transverse directions to the external magnetic field and the conditions of modified thermal instabilities and stabilities are discussed in different cases. We find that the thermal instabilitymore » criterion is get modified into radiative instability criterion by inclusion of radiative heat-loss functions with thermal conductivity. The viscosity of medium removes the effect of FLR corrections from the condition of radiative instability. Numerical calculation shows stabilizing effect of heat-loss function, viscosity and FLR corrections, and destabilizing effect of finite electron inertia on the thermal instability. Results carried out in this paper shows that stars are formed in interstellar medium mainly due to thermal instability.« less

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.

Laboratory and theoretical models of planetary-scale instabilities and waves

NASA Technical Reports Server (NTRS)

Hart, John E.; Toomre, Juri

1991-01-01

Meteorologists and planetary astronomers interested in large-scale planetary and solar circulations recognize the importance of rotation and stratification in determining the character of these flows. The two outstanding problems of interest are: (1) the origins and nature of chaos in baroclinically unstable flows; and (2) the physical mechanisms responsible for high speed zonal winds and banding on the giant planets. The methods used to study these problems, and the insights gained, are useful in more general atmospheric and climate dynamic settings. Because the planetary curvature or beta-effect is crucial in the large scale nonlinear dynamics, the motions of rotating convecting liquids in spherical shells were studied using electrohydrodynamic polarization forces to generate radial gravity and centrally directed buoyancy forces in the laboratory. The Geophysical Fluid Flow Cell (GFFC) experiments performed on Spacelab 3 in 1985 were analyzed. The interpretation and extension of these results have led to the construction of efficient numerical models of rotating convection with an aim to understand the possible generation of zonal banding on Jupiter and the fate of banana cells in rapidly rotating convection as the heating is made strongly supercritical. Efforts to pose baroclinic wave experiments for future space missions using a modified version of the 1985 instrument have led us to develop theoretical and numerical models of baroclinic instability. Some surprising properties of both these models were discovered.

Molecular evolution of colorectal cancer: from multistep carcinogenesis to the big bang.

PubMed

Amaro, Adriana; Chiara, Silvana; Pfeffer, Ulrich

2016-03-01

Colorectal cancer is characterized by exquisite genomic instability either in the form of microsatellite instability or chromosomal instability. Microsatellite instability is the result of mutation of mismatch repair genes or their silencing through promoter methylation as a consequence of the CpG island methylator phenotype. The molecular causes of chromosomal instability are less well characterized. Genomic instability and field cancerization lead to a high degree of intratumoral heterogeneity and determine the formation of cancer stem cells and epithelial-mesenchymal transition mediated by the TGF-β and APC pathways. Recent analyses using integrated genomics reveal different phases of colorectal cancer evolution. An initial phase of genomic instability that yields many clones with different mutations (big bang) is followed by an important, previously not detected phase of cancer evolution that consists in the stabilization of several clones and a relatively flat outgrowth. The big bang model can best explain the coexistence of several stable clones and is compatible with the fact that the analysis of the bulk of the primary tumor yields prognostic information.

Regulation of microtubule dynamic instability by the carboxy-terminal tail of β-tubulin

PubMed Central

Fees, Colby P; Moore, Jeffrey K

2018-01-01

Dynamic instability is an intrinsic property of microtubules; however, we do not understand what domains of αβ-tubulins regulate this activity or how these regulate microtubule networks in cells. Here, we define a role for the negatively charged carboxy-terminal tail (CTT) domain of β-tubulin in regulating dynamic instability. By combining in vitro studies with purified mammalian tubulin and in vivo studies with tubulin mutants in budding yeast, we demonstrate that β-tubulin CTT inhibits microtubule stability and regulates the structure and stability of microtubule plus ends. Tubulin that lacks β-tubulin CTT polymerizes faster and depolymerizes slower in vitro and forms microtubules that are more prone to catastrophe. The ends of these microtubules exhibit a more blunted morphology and rapidly switch to disassembly after tubulin depletion. In addition, we show that β-tubulin CTT is required for magnesium cations to promote depolymerization. We propose that β-tubulin CTT regulates the assembly of stable microtubule ends and provides a tunable mechanism to coordinate dynamic instability with ionic strength in the cell.

Mutagenesis of diploid mammalian genes by gene entrapment

PubMed Central

Lin, Qing; Donahue, Sarah L.; Moore-Jarrett, Tracy; Cao, Shang; Osipovich, Anna B.; Ruley, H. Earl

2006-01-01

The present study describes a genome-wide method for biallelic mutagenesis in mammalian cells. Novel poly(A) gene trap vectors, which contain features for direct cloning vector–cell fusion transcripts and for post-entrapment genome engineering, were used to generate a library of 979 mutant ES cells. The entrapment mutations generally disrupted gene expression and were readily transmitted through the germline, establishing the library as a resource for constructing mutant mice. Cells homozygous for most entrapment loci could be isolated by selecting for enhanced expression of an inserted neomycin-resistance gene that resulted from losses of heterozygosity (LOH). The frequencies of LOH measured at 37 sites in the genome ranged from 1.3 × 10−5 to 1.2 × 10−4 per cell and increased with increasing distance from the centromere, implicating mitotic recombination in the process. The ease and efficiency of obtaining homozygous mutations will (i) facilitate genetic studies of gene function in cultured cells, (ii) permit genome-wide studies of recombination events that result in LOH and mediate a type of chromosomal instability important in carcinogenesis, and (iii) provide new strategies for phenotype-driven mutagenesis screens in mammalian cells. PMID:17062627

Elimination of numerical Cherenkov instability in flowing-plasma particle-in-cell simulations by using Galilean coordinates

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

Lehe, Remi; Kirchen, Manuel; Godfrey, Brendan B.

Particle-in-cell (PIC) simulations of relativistic flowing plasmas are of key interest to several fields of physics (including, e.g., laser-wakefield acceleration, when viewed in a Lorentz-boosted frame) but remain sometimes infeasible due to the well-known numerical Cherenkov instability (NCI). In this article, we show that, for a plasma drifting at a uniform relativistic velocity, the NCI can be eliminated by simply integrating the PIC equations in Galilean coordinates that follow the plasma (also sometimes known as comoving coordinates) within a spectral analytical framework. The elimination of the NCI is verified empirically and confirmed by a theoretical analysis of the instability. Moreover,more » it is shown that this method is applicable both to Cartesian geometry and to cylindrical geometry with azimuthal Fourier decomposition.« less

Elimination of numerical Cherenkov instability in flowing-plasma particle-in-cell simulations by using Galilean coordinates

DOE PAGES

Lehe, Remi; Kirchen, Manuel; Godfrey, Brendan B.; ...

2016-11-14

Particle-in-cell (PIC) simulations of relativistic flowing plasmas are of key interest to several fields of physics (including, e.g., laser-wakefield acceleration, when viewed in a Lorentz-boosted frame) but remain sometimes infeasible due to the well-known numerical Cherenkov instability (NCI). In this article, we show that, for a plasma drifting at a uniform relativistic velocity, the NCI can be eliminated by simply integrating the PIC equations in Galilean coordinates that follow the plasma (also sometimes known as comoving coordinates) within a spectral analytical framework. The elimination of the NCI is verified empirically and confirmed by a theoretical analysis of the instability. Moreover,more » it is shown that this method is applicable both to Cartesian geometry and to cylindrical geometry with azimuthal Fourier decomposition.« less

ER stress and genomic instability induced by gamma radiation in mice primary cultured glial cells.

PubMed

Chatterjee, Jit; Nairy, Rajesha K; Langhnoja, Jaldeep; Tripathi, Ashutosh; Patil, Rajashekhar K; Pillai, Prakash P; Mustak, Mohammed S

2018-06-01

Ionizing radiation induces various pathophysiological conditions by altering central nervous system (CNS) homeostasis, leading to neurodegenerative diseases. However, the potential effect of ionizing radiation response on cellular physiology in glial cells is unclear. In the present study, micronucleus test, comet assay, and RT-PCR were performed to investigate the potential effect of gamma radiation in cultured oligodendrocytes and astrocytes with respect to genomic instability, Endoplasmic Reticulum (ER) stress, and inflammation. Further, we studied the effect of alteration in ER stress specific gene expression in cortex post whole body radiation in mice. Results showed that exposure of gamma radiation of 2Gy in-vitro cultured astrocytes and oligodendrocytes and 7Gy in-vivo induced ER stress and Inflammation along with profuse DNA damage and Chromosomal abnormality. Additionally, we observed downregulation of myelin basic protein levels in cultured oligodendrocytes exposed to radiation. The present data suggests that ER stress and pro inflammatory cytokines serve as the major players in inducing glial cell dysfunction post gamma irradiation along with induction of genomic instability. Taken together, these results indicate that ER stress, DNA damage, and inflammatory pathways may be critical events leading to glial cell dysfunction and subsequent cell death following exposure to ionizing radiation.

Characteristics of genomic instability in clones of TK6 human lymphoblasts surviving exposure to 56Fe ions

NASA Technical Reports Server (NTRS)

Evans, Helen H.; Horng, Min-Fen; Ricanati, Marlene; Diaz-Insua, Mireya; Jordan, Robert; Schwartz, Jeffrey L.

2002-01-01

Genomic instability in the human lymphoblast cell line TK6 was studied in clones surviving 36 generations after exposure to accelerated 56Fe ions. Clones were assayed for 20 characteristics, including chromosome aberrations, plating efficiency, apoptosis, cell cycle distribution, response to a second irradiation, and mutant frequency at two loci. The primary effect of the 56Fe-ion exposure on the surviving clones was a significant increase in the frequency of unstable chromosome aberrations compared to the very low spontaneous frequency, along with an increase in the phenotypic complexity of the unstable clones. The radiation-induced increase in the frequency of unstable chromosome aberrations was much greater than that observed previously in clones of the related cell line, WTK1, which in comparison to the TK6 cell line expresses an increased radiation resistance, a mutant TP53 protein, and an increased frequency of spontaneous unstable chromosome aberrations. The characteristics of the unstable clones of the two cell lines also differed. Most of the TK6 clones surviving exposure to 56Fe ions showed unstable cytogenetic abnormalities, while the phenotype of the WTK1 clones was more diverse. The results underscore the importance of genotype in the characteristics of instability after radiation exposure.

Chronic exposure to the cytolethal distending toxins of Gram-negative bacteria promotes genomic instability and altered DNA damage response

PubMed Central

Guidi, Riccardo; Guerra, Lina; Levi, Laura; Stenerlöw, Bo; Fox, James G.; Josenhans, Christine; Masucci, Maria G.; Frisan, Teresa

2014-01-01

Summary Epidemiological evidence links chronic bacterial infections to the increased incidence of certain types of cancer but the molecular mechanisms by which bacteria contribute to tumour initiation and progression are still poorly characterized. Here we show that chronic exposure to the genotoxin cytolethal distending toxin (CDT) of Gram-negative bacteria promotes genomic instability and acquisition of phenotypic properties of malignancy in fibroblasts and colon epithelial cells. Cells grown for more than 30 weeks in the presence of sublethal doses of CDT showed increased mutation frequency, and accumulation of chromatin and chromosomal aberrations in the absence of significant alterations of cell cycle distribution, decreased viability or senescence. Cell survival was dependent on sustained activity of the p38 MAP kinase. The ongoing genomic instability was associated with impaired activation of the DNA damage response and failure to efficiently activate cell cycle checkpoints upon exposure to genotoxic stress. Independently selected sublines showed enhanced anchorage-independent growth as assessed by the formation of colonies in semisolid agarose. These findings support the notion that chronic infection by CDT-producing bacteria may promote malignant transformation, and point to the impairment of cellular control mechanisms associated with the detection and repair of DNA damage as critical events in the process. PMID:22998585

Instabilities of geared couplings: Theory and practice

NASA Technical Reports Server (NTRS)

Kirk, R. G.; Mondy, R. E.; Murphy, R. C.

1982-01-01

The use of couplings for high speed turbocompressors or pumps is essential to transmit power from the driver. Typical couplings are either of the lubricated gear or dry diaphragm type design. Gear couplings have been the standard design for many years and recent advances in power and speed requirements have pushed the standard design criteria to the limit. Recent test stand and field data on continuous lube gear type couplings have forced a closer examination of design tolerances and concepts to avoid operational instabilities. Two types of mechanical instabilities are reviewed in this paper: (1) entrapped fluid, and (2) gear mesh instability resulting in spacer throw-out onset. Test stand results of these types of instabilities and other directly related problems are presented together with criteria for proper coupling design to avoid these conditions. An additional test case discussed shows the importance of proper material selection and processing and what can happen to an otherwise good design.

Designing cylindrical implosion experiments on NIF to study deceleration phase of Rayleigh-Taylor

NASA Astrophysics Data System (ADS)

Vazirani, N.; Kline, J. L.; Loomis, E.; Sauppe, J. P.; Palaniyappan, S.; Flippo, K.; Srinivasan, B.; Malka, E.; Bose, A.; Shvarts, D.

2017-10-01

The Rayleigh-Taylor (RT) hydrodynamic instability occurs when a lower density fluid pushes on a higher density fluid. This occurs in inertial confinement fusion (ICF) implosions at each of the capsule interfaces during the initial acceleration and the deceleration as it stagnates. The RT instabilities mix capsule material into the fusion fuel degrading the Deuterium-Tritium reactivity and ultimately play a key role in limiting target performance. While significant effort has focused on understanding RT at the outer capsule surface, little work has gone into understanding the inner surface RT instability growth during the deceleration phase. Direct measurements of the RT instability are difficult to make at high convergence in a spherical implosion. Here we present the design of a cylindrical implosion system for the National Ignition Facility for studying deceleration phase RT. We will discuss the experimental design, the estimated instability growth, and our outstanding concerns.

Radiation Effects on the Thermodiffusive Instability of Premixed Flames on a Cylindrical Porous Flame Holder

NASA Astrophysics Data System (ADS)

Du, Minglong; Yang, Lijun

2017-10-01

A linear analysis method was used to investigate the mechanics of radiation heat loss and mass transfer in the porous wall of premixed annular flames and their effect on thermodiffusive instability. The dispersion relation between the disturbance wave growth rate and wavenumber was calculated numerically. Results showed that radiation heat loss elevated the annular flame slightly away from the porous wall. In the annular flame with small Lewis numbers, radiation heat loss changed the thermodiffusive instability from a pulsating to a cellular state, while for the large Lewis numbers, only the pulsating instability was represented. Increasing radiation heat loss and the radius of the porous wall enhanced the instability of the annular flames. Heat losses decreased with the continued increase in thickness of the porous wall and the decrease in porosity. Annular flames with long-wave mode along the angular direction were more unstable than the shortwave mode.

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.

A cryostat device for liquid nitrogen convection experiments

NASA Astrophysics Data System (ADS)

Dubois, Charles; Duchesne, Alexis; Caps, Herve

2015-11-01

When a horizontal layer of expansible fluid heated from below is submitted to a large vertical temperature gradient, one can observe convective cells. This phenomenon is the so-called Rayleigh-Bénard instability. In the literature, this instability is mainly studied when the entire bottom surface of a container heats the liquid. Under these conditions, the development of regularly spaced convective cells in the liquid bulk is observed. Cooling applications led us to consider this instability in a different geometry, namely a resistor immersed in a bath of cold liquid. We present here experiments conducted with liquid nitrogen. For this purpose, we developed a cryostat in order to be able to perform Particle Image Velocimetry. We obtained 2D maps of the flow and observed, as expected, two Rayleigh-Bénard convective cells around the heater. We particularly investigated the vertical velocity in the central column between the two cells. We compared these data to results we obtained with silicone oil and water in the same geometry. We derived theoretical law from classical models applied to the proposed geometry and found a good agreement with our experimental data. This project has been financially supported by ARC SuperCool contract of the University of Liege.

Effect of electron thermal anisotropy on the kinetic cross-field streaming instability

NASA Technical Reports Server (NTRS)

Tsai, S. T.; Tanaka, M.; Gaffey, J. D., Jr.; Wu, C. S.; Da Jornada, E. H.; Ziebell, L. F.

1984-01-01

The investigation of the kinetic cross-field streaming instability, motivated by the research of collisionless shock waves and previously studied by Wu et al. (1983), is discussed more fully. Since in the ramp region of a quasi-perpendicular shock electrons can be preferentially heated in the direction transverse to the ambient magnetic field, it is both desirable and necessary to include the effect of the thermal anisotropy on the instability associated with a shock. It is found that Te-perpendicular greater than Te-parallel can significantly enhance the peak growth rate of the cross-field streaming instability when the electron beta is sufficiently high. Furthermore, the present analysis also improves the analytical and numerical solutions previously obtained.

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

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.

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.

Magneto-Rayleigh-Taylor instability driven by a rotating magnetic field

NASA Astrophysics Data System (ADS)

Duan, Shuchao; Xie, Weiping; Cao, Jintao; Li, Ding

2018-04-01

In this paper, we analyze theoretically the magneto-Rayleigh-Taylor instability driven by a rotating magnetic field. Slab configurations of finite thickness are treated both with and without using the Wenzel-Kramers-Brillouin approximation. Regardless of the slab thickness, the directional rotation of the driving magnetic field contributes to suppressing these instabilities. The two factors of the finite thickness and directional rotation of the magnetic field cooperate to enhance suppression, with the finite thickness playing a role only when the orientation of the magnetic field is time varying. The suppression becomes stronger as the driving magnetic field rotates faster, and all modes are suppressed, in contrast to the case of a non-rotating magnetic field, for which the vertical mode cannot be suppressed. This implies that the dynamically alternate configuration of a Theta-pinch and a Z-pinch may be applicable to the concept of Theta-Z liner inertial fusion.

Flapping dynamics of a thin liquid sheet

NASA Astrophysics Data System (ADS)

Vadivukkarasan, M.; Kumaran, Dhivyaraja; Panchagnula, Mahesh; Multi-phase flow physics Group Team

2017-11-01

We attempt to delineate and describe the complete evolution of a thin soap film when air is blown through a nozzle in the normal direction. The sequence of events and its intrinsic dynamics are captured using high speed imaging. By careful observation, it was observed that multiple mechanisms occur in the same system and each event is triggered by an independent mechanism. The events include (a) flapping of a liquid sheet and pinching of the bubble, (b) onset of rupture on the liquid sheet, (c) formation of ligaments and (d) ejection of drops. From this study, it is shown that these events are predominantly governed by Kelvin-Helmholtz instability, Taylor - Culick law, Rayleigh-Taylor instability and capillary instability, respectively. The present experiments can be considered as an extension to the previous studies on soap films as well as thin flapping sheets which has direct relevance to coaxial atomizers used in aircraft applications.

Blobs and drift wave dynamics

DOE PAGES

Zhang, Yanzeng; Krasheninnikov, S. I.

2017-09-29

The modified Hasegawa-Mima equation retaining all nonlinearities is investigated from the point of view of the formation of blobs. The linear analysis shows that the amplitude of the drift wave packet propagating in the direction of decreasing background plasma density increases and eventually saturates due to nonlinear effects. Nonlinear modification of the time averaged plasma density profile results in the formation of large amplitude modes locked in the radial direction, but still propagating in the poloidal direction, which resembles the experimentally observed chain of blobs propagating in the poloidal direction. Such specific density profiles, causing the locking of drift waves,more » could form naturally at the edge of tokamak due to a neutral ionization source. Thus, locked modes can grow in situ due to plasma instabilities, e.g., caused by finite resistivity. Furthermore, the modulation instability (in the poloidal direction) of these locked modes can result in a blob-like burst of plasma density.« less

Flow-driven waves and sink-driven oscillations during aggregation of Dictyostelium discoideum

NASA Astrophysics Data System (ADS)

Gholami, Azam; Zykov, Vladimir; Steinbock, Oliver; Bodenschatz, Eberhard

The slime mold Dictyostelium discoideum (D.d) is a well-known model system for the study of biological pattern formation. Under starvation, D.d. cells aggregate chemotactically towards cAMP signals emitted periodically from an aggregation center. In the natural environment, D.d cells may experience fluid flows that can profoundly change the underlying wave generation process. We investigate spatial-temporal dynamics of a uniformly distributed population of D.d. cells in a flow-through narrow microfluidic channel with a cell-free inlet area. We show that flow can significantly influence the dynamics of the system and lead to a flow- driven instability that initiate downstream traveling cAMP waves. We also show that cell-free boundary regions have a significant effect on the observed patterns and can lead to a new kind of instability. Since there are no cells in the inlet to produce cAMP, the points in the vicinity of the inlet lose cAMP due to advection or diffusion and gain only a little from the upstream of the channel (inlet). In other words, there is a large negative flux of cAMP in the neighborhood close to the inlet, which can be considered as a sink. This negative flux close to the inlet drives a new kind of instability called sink-driven oscillations. Financial support of the MaxSynBio Consortium is acknowledged.

Interacting tilt and kink instabilities in repelling current channels

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

Keppens, R.; Porth, O.; Xia, C., E-mail: rony.keppens@wis.kuleuven.be

2014-11-01

We present a numerical study in resistive magnetohydrodynamics (MHD) where the initial equilibrium configuration contains adjacent, oppositely directed, parallel current channels. Since oppositely directed current channels repel, the equilibrium is liable to an ideal magnetohydrodynamic tilt instability. This tilt evolution, previously studied in planar settings, involves two magnetic islands or flux ropes, which on Alfvénic timescales undergo a combined rotation and separation. This in turn leads to the creation of (near) singular current layers, posing severe challenges to numerical approaches. Using our open-source grid-adaptive MPI-AMRVAC software, we revisit the planar evolution case in compressible MHD, as well as its extensionmore » to two-and-a-half-dimensional (2.5D) and full three-dimensional (3D) scenarios. As long as the third dimension can be ignored, pure tilt evolutions result that are hardly affected by out of plane magnetic field components. In all 2.5D runs, our simulations do show secondary tearing type disruptions throughout the near singular current sheets in the far nonlinear saturation regime. In full 3D runs, both current channels can be liable to additional ideal kink deformations. We discuss the effects of having both tilt and kink instabilities acting simultaneously in the violent, reconnection-dominated evolution. In 3D, both the tilt and the kink instabilities can be stabilized by tension forces. As a concrete space plasma application, we argue that interacting tilt-kink instabilities in repelling current channels provide a novel route to initiate solar coronal mass ejections, distinctly different from the currently favored pure kink or torus instability routes.« less

Acceleration of plasma electrons by intense nonrelativistic ion and electron beams propagating in background plasma due to two-stream instability

NASA Astrophysics Data System (ADS)

Kaganovich, Igor D.

2015-11-01

In this paper we study the effects of the two-stream instability on the propagation of intense nonrelativistic ion and electron beams in background plasma. Development of the two-stream instability between the beam ions and plasma electrons leads to beam breakup, a slowing down of the beam particles, acceleration of the plasma particles, and transfer of the beam energy to the plasma particles and wave excitations. Making use of the particle-in-cell codes EDIPIC and LSP, and analytic theory we have simulated the effects of the two-stream instability on beam propagation over a wide range of beam and plasma parameters. Because of the two-stream instability the plasma electrons can be accelerated to velocities as high as twice the beam velocity. The resulting return current of the accelerated electrons may completely change the structure of the beam self - magnetic field, thereby changing its effect on the beam from focusing to defocusing. Therefore, previous theories of beam self-electromagnetic fields that did not take into account the effects of the two-stream instability must be significantly modified. This effect can be observed on the National Drift Compression Experiment-II (NDCX-II) facility by measuring the spot size of the extracted beamlet propagating through several meters of plasma. Particle-in-cell, fluid simulations, and analytical theory also reveal the rich complexity of beam- plasma interaction phenomena: intermittency and multiple regimes of the two-stream instability in dc discharges; band structure of the growth rate of the two-stream instability of an electron beam propagating in a bounded plasma and repeated acceleration of electrons in a finite system. In collaboration with E. Tokluoglu, D. Sydorenko, E. A. Startsev, J. Carlsson, and R. C. Davidson. Research supported by the U.S. Department of Energy.

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

NASA Technical Reports Server (NTRS)

Morgan, William F.

2002-01-01

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

Screech tones from free and ducted supersonic jets

NASA Technical Reports Server (NTRS)

Tam, C. K. W.; Ahuja, K. K.; Jones, R. R., III

1993-01-01

The dependence of the instability wave spectrum on azimuthal mode number, the jet to ambient gas temperature ratio, and the jet Mach number is studied. It is shown that the switch of the dominant screech mode (axisymmetric to helical/flapping) as Mach number increases is due to the switch in dominance of the corresponding mode of instability waves. Super-resonance can occur when the feedback loop is powered by the most amplified instability wave. It is suggested that the large amplitude pressure fluctuations and tone in the test cells are generated by super-resonance.

Nonlinear evolution of three-dimensional instabilities of thin and thick electron scale current sheets: Plasmoid formation and current filamentation

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

Jain, Neeraj; Büchner, Jörg; Max Planck Institute for Solar System Research, Justus-Von-Liebig-Weg-3, Göttingen

Nonlinear evolution of three dimensional electron shear flow instabilities of an electron current sheet (ECS) is studied using electron-magnetohydrodynamic simulations. The dependence of the evolution on current sheet thickness is examined. For thin current sheets (half thickness =d{sub e}=c/ω{sub pe}), tearing mode instability dominates. In its nonlinear evolution, it leads to the formation of oblique current channels. Magnetic field lines form 3-D magnetic spirals. Even in the absence of initial guide field, the out-of-reconnection-plane magnetic field generated by the tearing instability itself may play the role of guide field in the growth of secondary finite-guide-field instabilities. For thicker current sheetsmore » (half thickness ∼5 d{sub e}), both tearing and non-tearing modes grow. Due to the non-tearing mode, current sheet becomes corrugated in the beginning of the evolution. In this case, tearing mode lets the magnetic field reconnect in the corrugated ECS. Later thick ECS develops filamentary structures and turbulence in which reconnection occurs. This evolution of thick ECS provides an example of reconnection in self-generated turbulence. The power spectra for both the thin and thick current sheets are anisotropic with respect to the electron flow direction. The cascade towards shorter scales occurs preferentially in the direction perpendicular to the electron flow.« less

MULTICOMPONENT THEORY OF BUOYANCY INSTABILITIES IN ASTROPHYSICAL PLASMA OBJECTS: THE CASE OF MAGNETIC FIELD PERPENDICULAR TO GRAVITY

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

Nekrasov, Anatoly K.; Shadmehri, Mohsen, E-mail: anatoli.nekrassov@t-online.d, E-mail: mshadmehri@thphys.nuim.i

2010-12-01

We develop a general theory of buoyancy instabilities in the electron-ion plasma with the electron heat flux based not upon magnetohydrodynamic (MHD) equations, but using a multicomponent plasma approach in which the momentum equation is solved for each species. We investigate the geometry in which the background magnetic field is perpendicular to the gravity and stratification. General expressions for the perturbed velocities are given without any simplifications. Collisions between electrons and ions are taken into account in the momentum equations in a general form, permitting us to consider both weakly and strongly collisional objects. However, the electron heat flux ismore » assumed to be directed along the magnetic field, which implies a weakly collisional case. Using simplifications justified for an investigation of buoyancy instabilities with electron thermal flux, we derive simple dispersion relations for both collisionless and collisional cases for arbitrary directions of the wave vector. Our dispersion relations considerably differ from that obtained in the MHD framework and conditions of instability are similar to Schwarzschild's criterion. This difference is connected with simplified assumptions used in the MHD analysis of buoyancy instabilities and with the role of the longitudinal electric field perturbation which is not captured by the ideal MHD equations. The results obtained can be applied to clusters of galaxies and other astrophysical objects.« less

Direct Simulation of Evolution and Control of Three-Dimensional Instabilities in Attachment-Line Boundary Layers

NASA Technical Reports Server (NTRS)

Joslin, Ronald D.

1995-01-01

The spatial evolution of three-dimensional disturbances in an attachment-line boundary layer is computed by direct numerical simulation of the unsteady, incompressible Navier-Stokes equations. Disturbances are introduced into the boundary layer by harmonic sources that involve unsteady suction and blowing through the wall. Various harmonic- source generators are implemented on or near the attachment line, and the disturbance evolutions are compared. Previous two-dimensional simulation results and nonparallel theory are compared with the present results. The three-dimensional simulation results for disturbances with quasi-two-dimensional features indicate growth rates of only a few percent larger than pure two-dimensional results; however, the results are close enough to enable the use of the more computationally efficient, two-dimensional approach. However, true three-dimensional disturbances are more likely in practice and are more stable than two-dimensional disturbances. Disturbances generated off (but near) the attachment line spread both away from and toward the attachment line as they evolve. The evolution pattern is comparable to wave packets in at-plate boundary-layer flows. Suction stabilizes the quasi-two-dimensional attachment-line instabilities, and blowing destabilizes these instabilities; these results qualitatively agree with the theory. Furthermore, suction stabilizes the disturbances that develop off the attachment line. Clearly, disturbances that are generated near the attachment line can supply energy to attachment-line instabilities, but suction can be used to stabilize these instabilities.

Brown adipogenesis of mouse embryonic stem cells in alginate microstrands

NASA Astrophysics Data System (ADS)

Unser, Andrea Mannarino

The ability of brown adipocytes (fat cells) to dissipate energy as heat shows great promise for the treatment of obesity and other metabolic disorders. Employing pluripotent stem cells, with an emphasis on directed differentiation, may overcome many issues currently associated with primary fat cell cultures. However, brown adipocytes are difficult to transplant in vivo due to the instability of fat, in terms of necrosis and neovascularization, once injected. Thus, 3D cell culture systems that have the potential to mimic adipogenic microenvironments are needed, not only to advance brown fat implantation, but also to better understand the role of brown adipocytes in treating obesity. To address this need, we created 3D "Brown-Fat-in-Microstrands" by microfluidic synthesis of alginate hydrogel microstrands that encapsulated cells and directly induced cell differentiation into brown adipocytes, using mouse embryonic stem cells (ESCs) as a model of pluripotent stem cells and brown preadipocytes as a positive control. The effect of hydrogel formation parameters on brown adipogenesis was studied, leading to the establishment of "Brown-Fat-in-Microstrands". Brown adipocyte differentiation within microstrands was confirmed by lipid droplet accumulation, immunocytochemistry and qPCR analysis of gene expression of brown adipocyte marker uncoupling protein 1 (UCP1) in addition to adipocyte marker expression. Compared to a 2D approach, 3D differentiated "Brown-Fat-in-Microstrands" exhibited higher level of brown adipocyte marker expression. The functional analysis of "Brown-Fat-in-Microstrands" was attempted by measuring the mitochondrial activity of ESC-differentiated brown adipocytes in 3D using Seahorse XF24 3 Extracellular Flux Analyzer. The ability to create "Brown-Fat-in-Microstrands" from pluripotent stem cells opens up a new arena to understanding brown adipogenesis and its implications in obesity and metabolic disorders.

Gravitational Effects on Flow Instability and Transition in Low Density Jets

NASA Technical Reports Server (NTRS)

Agrawal A. K.; Parthasarathy, K.; Pasumarthi, K.; Griffin, D. W.

2000-01-01

Recent experiments have shown that low-density gas jets injected into a high-density ambient gas undergo an instability mode, leading to highly-periodic oscillations in the flow-field for certain conditions. The transition from laminar to turbulent flow in these jets is abrupt, without the gradual change in scales. Even the fine scale turbulent structure repeats itself with extreme regularity from cycle to cycle. Similar observations were obtained in buoyancy-dominated and momentum-dominated jets characterized by the Richardson numbers, Ri = [gD(rho(sub a)-rho(sub j))/rho(sub j)U(sub j)(exp 2) ] where g is the gravitational acceleration, D is the jet diameter, rho(sub a) and rho(sub a) are, respectively, the free-stream and jet densities, and U(sub j) is the mean jet exit velocity. At high Richardson numbers, the instability is presumably caused by buoyancy since the flow-oscillation frequency (f) or the Strouhal number, St = [fD/U(sub j)] scales with Ri. In momentum-dominated jets, however, the Strouhal number of the oscillating flow is relatively independent of the Ri. In this case, a local absolute instability is predicted in the potential core of low-density jets with S [= rho(sub j)/rho(sub a)] < 0.7, which agrees qualitatively with experiments. Although the instability in gas jets of high Richardson numbers is attributed to buoyancy, direct physical evidence has not been acquired in experiments. If the instability is indeed caused by buoyancy, the near-field flow structure of the jet will change significantly when the buoyancy is removed, for example, in the microgravity environment. Thus, quantitative data on the spatial and temporal evolutions of the instability, length and time scale of the oscillating mode and its effects on the mean flow and breakdown of the potential core are needed in normal and microgravity to delineate gravitational effects in buoyant jets. In momentum dominated low-density jets, the instability is speculated to originate in the potential core. However, experiments have not succeeded in identifying the direct physical cause of the instability. For example, the theory predicts an oscillating mode for S<0.62 in the limit of zero momentum thickness, which contradicts with the experimental findings of Kyle and Sreenivasan. The analyses of momentum-dominated jets neglect buoyancy effects because of the small Richardson number. Although this assumption is appropriate in the potential core, the gravitational effects are important in the annular region surrounding the jet, where the density and velocity gradients are large. This reasoning provides basis for the hypothesis that the instability in low Richardosn number jets studied by Kyle and Sreenivasan and Monkewitz et al. is caused by buoyancy. The striking similarity in characteristics of the instability and virtually the identical conclusions reached by Subbarao and Cantwell in buoyant (Ri>0.5) helium jets on one hand and by Kyle and Sreenivasan in momentum-dominated (Ri<1x10(exp -3)) helium jets on the other support this hypothesis. However, quantitative experiments in normal and microgravity are necessary to obtain direct physical evidence of buoyancy effects on the flow instability and structure of momentum-dominated low-density jets. The primary objective of this new research project is to quantify how buoyancy affects the flow instability and structure in the near field of low-density jets. The flow will be described by the spatial and temporal evolutions of the instability, length and time scales of the oscillating mode, and the mean and fluctuating concentration fields. To meet this objective, concentration measurements will be obtained across the whole field using quantitative Rainbow Schlieren Deflectometry, providing spatial resolution of 0.1mm and temporal resolution of 0.017s to 1ms. The experimental effort will be supplemented with linear stability analysis of low-density jets by considering buoyancy. The first objective of this research is to investigate the effects of gravity on the flow instability and structure of low-density jets. The flow instability in these jets has been attributed to buoyancy. By removing buoyancy in our experiments, we seek to obtain the direct physical evidence of the instability mechanism. In the absence of the instability, the flow structure will undergo a significant change. We seek to quantify these changes by mapping the flow field (in terms of the concentration profiles) of these jets at non-buoyant conditions. Such information is presently lacking in the existing literature. The second objective of this research is to determine if the instability in momentum-driven, low-density jets is caused by buoyancy. At these conditions, the buoyancy effects are commonly ignored because of the small Richardson based on global parameters. By eliminating buoyancy in our experiments, globally as well as locally, we seek to examine the possibility that the instability mechanism in self-excited, buoyant or momentum-driven jets is the same. To meet this objective, we would quantify the jet flow in normal and microgravity, while systematically decreasing the Richardson number from buoyancy-driven to momentum driven flow regime. The third objective of this research is to perform a linear stability analysis of low-density gas jets by including the gravitational effects. The flow oscillations in these jets are attributed to an absolute instability, whereby the disturbance grows exponentially at the site to ultimately contaminate the entire flow field. We seek to study the characteristics of both convective and absolute instabilities and demarcate the boundary between them.

Tumors overexpressing RNF168 show altered DNA repair and responses to genotoxic treatments, genomic instability and resistance to proteotoxic stress.

PubMed

Chroma, K; Mistrik, M; Moudry, P; Gursky, J; Liptay, M; Strauss, R; Skrott, Z; Vrtel, R; Bartkova, J; Kramara, J; Bartek, J

2017-04-27

Chromatin DNA damage response (DDR) is orchestrated by the E3 ubiquitin ligase ring finger protein 168 (RNF168), resulting in ubiquitin-dependent recruitment of DDR factors and tumor suppressors breast cancer 1 (BRCA1) and p53 binding protein 1 (53BP1). This ubiquitin signaling regulates pathway choice for repair of DNA double-strand breaks (DSB), toxic lesions whose frequency increases during tumorigenesis. Recruitment of 53BP1 curbs DNA end resection, thereby limiting homologous recombination (HR) and directing DSB repair toward error-prone non-homologous end joining (NHEJ). Under cancer-associated ubiquitin starvation conditions reflecting endogenous or treatment-evoked proteotoxic stress, the ubiquitin-dependent accrual of 53BP1 and BRCA1 at the DNA damage sites is attenuated or lost. Challenging this current paradigm, here we identified diverse human cancer cell lines that display 53BP1 recruitment to DSB sites even under proteasome inhibitor-induced proteotoxic stress, that is, under substantial depletion of free ubiquitin. We show that central to this unexpected phenotype is overabundance of RNF168 that enables more efficient exploitation of the residual-free ubiquitin. Cells with elevated RNF168 are more resistant to combined treatment by ionizing radiation and proteasome inhibition, suggesting that such aberrant RNF168-mediated signaling might reflect adaptation to chronic proteotoxic and genotoxic stresses experienced by tumor cells. Moreover, the overabundant RNF168 and the ensuing unorthodox recruitment patterns of 53BP1, RIF1 and REV7 (monitored on laser micro-irradiation-induced DNA damage) shift the DSB repair balance from HR toward NHEJ, a scenario accompanied by enhanced chromosomal instability/micronuclei formation and sensitivity under replication stress-inducing treatments with camptothecin or poly(ADP-ribose) polymerase (PARP) inhibitor. Overall, our data suggest that the deregulated RNF168/53BP1 pathway could promote tumorigenesis by selecting for a more robust, better stress-adapted cancer cell phenotype, through altered DNA repair, fueling genomic instability and tumor heterogeneity. Apart from providing insights into cancer (patho)biology, the elevated RNF168, documented here also by immunohistochemistry on human clinical tumor specimens, may impact responses to standard-of-care and some emerging targeted cancer therapies.

Phase separation and emergent structures in an active nematic fluid.

PubMed

Putzig, Elias; Baskaran, Aparna

2014-10-01

We consider a phenomenological continuum theory for an active nematic fluid and show that there exists a universal, model-independent instability which renders the homogeneous nematic state unstable to order fluctuations. Using numerical and analytic tools we show that, in the vicinity of a critical point, this instability leads to a phase-separated state in which the ordered regions form bands in which the direction of nematic order is perpendicular to the direction of the density gradient. We argue that the underlying mechanism that leads to this phase separation is a universal feature of active fluids of different symmetries.

Towards multi-field D-brane inflation in a warped throat

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

Chen, Heng-Yu; Gong, Jinn-Ouk; Koyama, Kazuya

2010-11-01

We study the inflationary dynamics in a model of slow-roll inflation in warped throat. Inflation is realized by the motion of a D-brane along the radial direction of the throat, and at later stages instabilities develop in the angular directions. We closely investigate both the single field potential relevant for the slow-roll phase, and the full multi-field one including the angular modes which becomes important at later stages. We study the main features of the instability process, discussing its possible consequences and identifying the vacua towards which the angular modes are driven.

The effect of a crosslinking chemical reaction on pattern formation in viscous fingering of miscible fluids in a Hele-Shaw cell.

PubMed

Bunton, Patrick H; Tullier, Michael P; Meiburg, Eckart; Pojman, John A

2017-10-01

Viscous fingering can occur in fluid motion whenever a high mobility fluid displaces a low mobility fluid in a Darcy type flow. When the mobility difference is primarily attributable to viscosity (e.g., flow between the two horizontal plates of a Hele-Shaw cell), viscous fingering (VF) occurs, which is sometimes termed the Saffman-Taylor instability. Alternatively, in the presence of differences in density in a gravity field, buoyancy-driven convection can occur. These instabilities have been studied for decades, in part because of their many applications in pollutant dispersal, ocean currents, enhanced petroleum recovery, and so on. More recent interest has emerged regarding the effects of chemical reactions on fingering instabilities. As chemical reactions change the key flow parameters (densities, viscosities, and concentrations), they may have either a destabilizing or stabilizing effect on the flow. Hence, new flow patterns can emerge; moreover, one can then hope to gain some control over flow instabilities through reaction rates, flow rates, and reaction products. We report effects of chemical reactions on VF in a Hele-Shaw cell for a reactive step-growth cross-linking polymerization system. The cross-linked reaction product results in a non-monotonic viscosity profile at the interface, which affects flow stability. Furthermore, three-dimensional internal flows influence the long-term pattern that results.

APC/C Dysfunction Limits Excessive Cancer Chromosomal Instability

PubMed Central

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

2017-01-01

Intercellular heterogeneity, exacerbated by chromosomal instability (CIN), fosters tumor heterogeneity and drug resistance. However, extreme CIN correlates with improved cancer outcome, suggesting that karyotypic diversity required to adapt to selection pressures might be balanced in tumors against the risk of excessive instability. Here, we used a functional genomics screen, genome editing, and pharmacologic approaches to identify CIN-survival factors in diploid cells. We find partial anaphase-promoting complex/cyclosome (APC/C) dysfunction lengthens mitosis, suppresses pharmacologically induced chromosome segregation errors, and reduces naturally occurring lagging chromosomes in cancer cell lines or following tetraploidization. APC/C impairment caused adaptation to MPS1 inhibitors, revealing a likely resistance mechanism to therapies targeting the spindle assembly checkpoint. Finally, CRISPR-mediated introduction of cancer somatic mutations in the APC/C subunit cancer driver gene CDC27 reduces chromosome segregation errors, whereas reversal of an APC/C subunit nonsense mutation increases CIN. Subtle variations in mitotic duration, determined by APC/C activity, influence the extent of CIN, allowing cancer cells to dynamically optimize fitness during tumor evolution. Significance We report a mechanism whereby cancers balance the evolutionary advantages associated with CIN against the fitness costs caused by excessive genome instability, providing insight into the consequence of CDC27 APC/C subunit driver mutations in cancer. Lengthening of mitosis through APC/C modulation may be a common mechanism of resistance to cancer therapeutics that increase chromosome segregation errors. PMID:28069571

The effect of a crosslinking chemical reaction on pattern formation in viscous fingering of miscible fluids in a Hele-Shaw cell

NASA Astrophysics Data System (ADS)

Bunton, Patrick H.; Tullier, Michael P.; Meiburg, Eckart; Pojman, John A.

2017-10-01

Viscous fingering can occur in fluid motion whenever a high mobility fluid displaces a low mobility fluid in a Darcy type flow. When the mobility difference is primarily attributable to viscosity (e.g., flow between the two horizontal plates of a Hele-Shaw cell), viscous fingering (VF) occurs, which is sometimes termed the Saffman-Taylor instability. Alternatively, in the presence of differences in density in a gravity field, buoyancy-driven convection can occur. These instabilities have been studied for decades, in part because of their many applications in pollutant dispersal, ocean currents, enhanced petroleum recovery, and so on. More recent interest has emerged regarding the effects of chemical reactions on fingering instabilities. As chemical reactions change the key flow parameters (densities, viscosities, and concentrations), they may have either a destabilizing or stabilizing effect on the flow. Hence, new flow patterns can emerge; moreover, one can then hope to gain some control over flow instabilities through reaction rates, flow rates, and reaction products. We report effects of chemical reactions on VF in a Hele-Shaw cell for a reactive step-growth cross-linking polymerization system. The cross-linked reaction product results in a non-monotonic viscosity profile at the interface, which affects flow stability. Furthermore, three-dimensional internal flows influence the long-term pattern that results.

Cell division patterns and chromosomal segregation defects in oral cancer stem cells.

PubMed

Kaseb, Hatem O; Lewis, Dale W; Saunders, William S; Gollin, Susanne M

2016-09-01

Oral squamous cell carcinoma (OSCC) is a serious public health problem caused primarily by smoking and alcohol consumption or human papillomavirus. The cancer stem cell (CSC) theory posits that CSCs show unique characteristics, including self-renewal and therapeutic resistance. Examining biomarkers and other features of CSCs is critical to better understanding their biology. To this end, the results show that cellular SOX2 immunostaining correlates with other CSC biomarkers in OSCC cell lines and marks the rare CSC population. To assess whether CSC division patterns are symmetrical, resulting in two CSC, or asymmetrical, leading to one CSC and one cancer cell, cell size and fluorescence intensity of mitotic cells stained with SOX2 were analyzed. Asymmetrical SOX2 distribution in ≈25% of the mitoses analyzed was detected. Chromosomal instability, some of which is caused by chromosome segregation defects (CSDs), is a feature of cancer cells that leads to altered gene copy numbers. We compare chromosomal instability (as measured by CSDs) between CSCs (SOX2+) and non-CSCs (SOX2-) from the same OSCC cell lines. CSDs were more common in non-CSCs (SOX2-) than CSCs (SOX2+) and in symmetrical CSC (SOX2+) mitotic pairs than asymmetrical CSC (SOX2+/SOX2-) mitotic pairs. CSCs showed fewer and different types of CSDs after ionizing radiation treatment than non-CSCs. Overall, these data are the first to demonstrate both symmetrical and asymmetrical cell divisions with CSDs in OSCC CSC. Further, the results suggest that CSCs may undergo altered behavior, including therapeutic resistance as a result of chromosomal instability due to chromosome segregation defects. © 2016 Wiley Periodicals, Inc. © 2016 Wiley Periodicals, Inc.

Radionuclides in radiation-induced bystander effect; may it share in radionuclide therapy?

PubMed

Widel, M

2017-01-01

For many years in radiobiology and radiotherapy predominated the conviction that cellular DNA is the main target for ionizing radiation, however, the view has changed in the past 20 years. Nowadays, it is assumed that not only directed (targeted) radiation effect, but also an indirect (non-targeted) effect may contribute to the result of radiation treatment. Non-targeted effect is relatively well recognized after external beam irradiation in vitro and in vivo, and comprises such phenomena like radiation-induced bystander effect (RIBE), genomic instability, adaptive response and abscopal (out of field) effect. These stress-induced and molecular signaling mediated phenomena appear in non-targeted cells as variety responses resembling that observed in directly hit cells. Bystander effects can be both detrimental and beneficial in dependence on dose, dose-rate, cell type, genetic status and experimental condition. Less is known about radionuclide-induced non-targeted effects in radionuclide therapy, although, based on characteristics of the radionuclide radiation, on experiments in vitro utilizing classical and 3-D cell cultures, and preclinical study on animals it seems obvious that exposure to radionuclide is accompanied by various bystander effects, mostly damaging, less often protective. This review summarizes existing data on radionuclide induced bystander effects comprising radionuclides emitting beta- and alpha-particles and Auger electrons used in tumor radiotherapy and diagnostics. So far, separation of the direct effect of radionuclide decay from crossfire and bystander effects in clinical targeted radionuclide therapy is impossible because of the lack of methods to assess whether, and to what extent bystander effect is involved in human organism. Considerations on this topic are also included.

Measuring DNA Replication in Hypoxic Conditions.

PubMed

Foskolou, Iosifina P; Biasoli, Deborah; Olcina, Monica M; Hammond, Ester M

2016-01-01

It is imperative that dividing cells maintain replication fork integrity in order to prevent DNA damage and cell death. The investigation of DNA replication is of high importance as alterations in this process can lead to genomic instability, a known causative factor of tumor development. A simple, sensitive, and informative technique which enables the study of DNA replication, is the DNA fiber assay, an adaptation of which is described in this chapter. The DNA fiber method is a powerful tool, which allows the quantitative and qualitative analysis of DNA replication at the single molecule level. The sequential pulse labeling of live cells with two thymidine analogues and the subsequent detection with specific antibodies and fluorescence imaging allows direct examination of sites of DNA synthesis. In this chapter, we describe how this assay can be performed in conditions of low oxygen levels (hypoxia)-a physiologically relevant stress that occurs in most solid tumors. Moreover, we suggest ways on how to overcome the technical problems that arise while using the hypoxic chambers.

Insights into Cdc13 Dependent Telomere Length Regulation

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

M Mason; E Skordalakes

Cdc13 is a single stranded telomere binding protein that specifically localizes to the telomere ends of budding yeasts and is essential for cell viability. It caps the ends of chromosomes thus preventing chromosome end-to-end fusions and exonucleolytic degradation, events that could lead to genomic instability and senescence, the hallmark of aging. Cdc13 is also involved in telomere length regulation by recruiting or preventing access of telomerase to the telomeric overhang. Recruitment of telomerase to the telomeres for G-strand extension is required for continuous cell division, while preventing its access to the telomeres through capping the chromosome ends prevents mitotic eventsmore » that could lead to cell immortality, the hall mark of carcinogenesis. Cdc13 and its putative homologues human CTC1 and POT1 are therefore key to many biological processes directly associated with life extension and cancer prevention and can be viewed as an ideal target for cancer and age related therapies.« less

Rosa26-GFP Direct Repeat (RaDR-GFP) Mice Reveal Tissue- and Age-Dependence of Homologous Recombination in Mammals In Vivo

PubMed Central

Kay, Jennifer E.; Na, Li; Rowland, Elizabeth A.; Winther, Kelly E.; Chow, Danielle N.; Kimoto, Takafumi; Matsuguchi, Tetsuya; Jonnalagadda, Vidya S.; Maklakova, Vilena I.; Singh, Vijay R.; Wadduwage, Dushan N.; Rajapakse, Jagath; So, Peter T. C.; Collier, Lara S.; Engelward, Bevin P.

2014-01-01

Homologous recombination (HR) is critical for the repair of double strand breaks and broken replication forks. Although HR is mostly error free, inherent or environmental conditions that either suppress or induce HR cause genomic instability. Despite its importance in carcinogenesis, due to limitations in our ability to detect HR in vivo, little is known about HR in mammalian tissues. Here, we describe a mouse model in which a direct repeat HR substrate is targeted to the ubiquitously expressed Rosa26 locus. In the Rosa26 Direct Repeat-GFP (RaDR-GFP) mice, HR between two truncated EGFP expression cassettes can yield a fluorescent signal. In-house image analysis software provides a rapid method for quantifying recombination events within intact tissues, and the frequency of recombinant cells can be evaluated by flow cytometry. A comparison among 11 tissues shows that the frequency of recombinant cells varies by more than two orders of magnitude among tissues, wherein HR in the brain is the lowest. Additionally, de novo recombination events accumulate with age in the colon, showing that this mouse model can be used to study the impact of chronic exposures on genomic stability. Exposure to N-methyl-N-nitrosourea, an alkylating agent similar to the cancer chemotherapeutic temozolomide, shows that the colon, liver and pancreas are susceptible to DNA damage-induced HR. Finally, histological analysis of the underlying cell types reveals that pancreatic acinar cells and liver hepatocytes undergo HR and also that HR can be specifically detected in colonic somatic stem cells. Taken together, the RaDR-GFP mouse model provides new understanding of how tissue and age impact susceptibility to HR, and enables future studies of genetic, environmental and physiological factors that modulate HR in mammals. PMID:24901438

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

Enhancement of particle-induced viscous fingering in bidisperse suspensions

NASA Astrophysics Data System (ADS)

Xu, Feng; Lee, Sungyon

2017-11-01

The novel particle-induced fingering instability is observed when bidisperse particle suspensions displace air in a Hele-Shaw cell. Leading to the instability, we observe that larger particles consistently enrich the fluid-fluid interface at a faster rate than the small particles. This size-dependent enrichment of the interface leads to an earlier onset of the fingering instability for bidisperse suspensions, compared to their monodisperse counterpart. Careful experiments are carried out by either systematically varying the ratio of large to small particles at fixed total concentrations, or by changing the total concentrations while the large particle concentrations are held constant. Experimental results show that the presence of large particle causes the instability to occur at concentrations as much as 5% lower than the pure small particle case. We also discuss the physical mechanism that drives the enrichment and the subsequent instability based on the modified suspension balance model.

The nature of interfacial instabilities in liquid metal batteries in a vertical magnetic field

NASA Astrophysics Data System (ADS)

Molokov, S.

2018-02-01

The nature of instabilities in liquid metal batteries in the presence of a vertical magnetic field has been studied. The battery consists of two liquid metal layers, connected to the collectors, and a layer with an electrolyte inbetween. The closed geometry in the horizontal plane has been replaced by a half-plane to get a better insight into the problem. As in aluminium reduction cells the instability is generated at the electrically insulating sidewall of the battery. A travelling-wave solution has been obtained, which shows that there are two modes of the instability, fast and slow. Either of these modes may be most unstable depending on the values of various parameters, the most important of which are the well-known parameter of the instability, β, and the density of the electrolyte. For the intermediate range of the electrolyte density the medium-size batteries may be expected to be stable.

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.

Investigation of wheelchair instability during transport in large accessible transit vehicles.

PubMed

Salipur, Zdravko; Frost, Karen; Bertocci, Gina

2012-01-01

Large accessible transit vehicles (LATVs, fixed-route intracity buses), generally considered safe, may not be as safe for wheelchair-seated passengers. Transit provider practices vary regarding use of wheelchair tiedown and occupant restraint systems (WTORSs), while recent research suggests high levels of WTORS disuse and misuse. We sought to better understand wheelchair and wheelchair passenger instabilities related to WTORS disuse and misuse on LATVs. This article presents a retrospective review of 295 video surveillance records of wheelchair passenger trips on LATVs. Wheelchair trips involving disuse and misuse of WTORS were quantified and categorized based on WTORS configurations. Cases of wheelchair and wheelchair passenger instability were categorized based on severity, type, and direction. Three adverse events involving severe wheelchair and/or passenger instability were examined in greater detail. Results showed 20.3% of records involved wheelchair-related adverse events (95% minor instabilities, 5% severe instabilities). Scooters were most likely to be unstable, followed by manual and power wheelchairs. In most instability cases, no tiedowns were used to secure the wheelchair and no lap belt was used to restrain the wheelchair passenger properly. In many instances, the lap belt was misused in an attempt to secure the wheelchair, whereas the shoulder belt was never used.

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.

Filtering of non-linear instabilities

NASA Technical Reports Server (NTRS)

Khosla, P. K.; Rubin, S. G.

1978-01-01

For Courant numbers larger than one and cell Reynolds numbers larger than two, oscillations and in some cases instabilities are typically found with implicit numerical solutions of the fluid dynamics equations. This behavior has sometimes been associated with the loss of diagonal dominance of the coefficient matrix. It is shown that these problems can be related to the choice of the spatial differences, with the resulting instability related to aliasing or nonlinear interaction. Appropriate filtering can reduce the intensity of these oscillations and possibly eliminate the instability. These filtering procedures are equivalent to a weighted average of conservation and nonconservation differencing. The entire spectrum of filtered equations retains a three point character as well as second order spatial accuracy. Burgers equation was considered as a model.

Chromosomal instability induced by heavy ion irradiation

NASA Technical Reports Server (NTRS)

Limoli, C. L.; Ponnaiya, B.; Corcoran, J. J.; Giedzinski, E.; Morgan, W. F.

2000-01-01

PURPOSE: To establish the dose-response relationship for the induction of chromosomal instability in GM10115 cells exposed to high-energy iron ions (1 GeV/nucleon, mean LET 146 keV/microm) and gold ions (11 GeV/nucleon, mean LET 1450 keV/microm). Past work has established that sparsely ionizing X-rays can induce a long-lived destabilization of chromosomes in a dose-dependent manner at an incidence of approximately 3% per gray. The present investigation assesses the capacity of High-Z and High-energy (HZE) particles to elicit this same endpoint. MATERIALS AND METHODS: Clonal populations derived from single progenitor cells surviving heavy-ion irradiation were analyzed cytogenetically to identify those clones showing a persistent destablization of chromosomes. RESULTS: Dose-response data, with a particular emphasis at low dose (< 1.0 Gy), indicate a frequency of approximately 4% per gray for the induction of chromosomal instability in clones derived from single progenitor cells surviving exposure to iron ions. The induction of chromosomal instability by gold ions was, however, less responsive to applied dose, as the observed incidence of this phenotype varied from 0 to 10% over 1-8 Gy. Both iron and gold ions gave dose-dependent increases in the yield of chromosomal aberrations (both chromosome- and chromatid-type) measured at the first mitosis following irradiation, as well as shoulderless survival curves having D0=0.87 and 1.1 Gy respectively. CONCLUSIONS: Based on the present dose-response data, the relative biological effectiveness of iron ions is 1.3 for the induction of chromosomal instability, and this indicates that heavy ions are only slightly more efficient than X-rays at eliciting this delayed phenotype.

Steady dynein forces induce flutter instability and propagating waves in mathematical models of flagella

PubMed Central

Dutcher, S. K.

2016-01-01

Cilia and flagella are highly conserved organelles that beat rhythmically with propulsive, oscillatory waveforms. The mechanism that produces these autonomous oscillations remains a mystery. It is widely believed that dynein activity must be dynamically regulated (switched on and off, or modulated) on opposite sides of the axoneme to produce oscillations. A variety of regulation mechanisms have been proposed based on feedback from mechanical deformation to dynein force. In this paper, we show that a much simpler interaction between dynein and the passive components of the axoneme can produce coordinated, propulsive oscillations. Steady, distributed axial forces, acting in opposite directions on coupled beams in viscous fluid, lead to dynamic structural instability and oscillatory, wave-like motion. This ‘flutter’ instability is a dynamic analogue to the well-known static instability, buckling. Flutter also occurs in slender beams subjected to tangential axial loads, in aircraft wings exposed to steady air flow and in flexible pipes conveying fluid. By analysis of the flagellar equations of motion and simulation of structural models of flagella, we demonstrate that dynein does not need to switch direction or inactivate to produce autonomous, propulsive oscillations, but must simply pull steadily above a critical threshold force. PMID:27798276

PLASMA TURBULENCE AND KINETIC INSTABILITIES AT ION SCALES IN THE EXPANDING SOLAR WIND

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

Hellinger, Petr; Trávnícek, Pavel M.; Matteini, Lorenzo

The relationship between a decaying strong turbulence and kinetic instabilities in a slowly expanding plasma is investigated using two-dimensional (2D) hybrid expanding box simulations. We impose an initial ambient magnetic field perpendicular to the simulation box, and we start with a spectrum of large-scale, linearly polarized, random-phase Alfvénic fluctuations that have energy equipartition between kinetic and magnetic fluctuations and vanishing correlation between the two fields. A turbulent cascade rapidly develops; magnetic field fluctuations exhibit a power-law spectrum at large scales and a steeper spectrum at ion scales. The turbulent cascade leads to an overall anisotropic proton heating, protons are heatedmore » in the perpendicular direction, and, initially, also in the parallel direction. The imposed expansion leads to generation of a large parallel proton temperature anisotropy which is at later stages partly reduced by turbulence. The turbulent heating is not sufficient to overcome the expansion-driven perpendicular cooling and the system eventually drives the oblique firehose instability in a form of localized nonlinear wave packets which efficiently reduce the parallel temperature anisotropy. This work demonstrates that kinetic instabilities may coexist with strong plasma turbulence even in a constrained 2D regime.« less

Radiation-induced transgenerational instability.

PubMed

Dubrova, Yuri E

2003-10-13

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

Must is a Four Letter Word: The Role of Plasma Instabilities in the Intergalactic Magnetic Field Story

NASA Astrophysics Data System (ADS)

Broderick, Avery

2014-06-01

The detection of inverse Compton halos from cosmological TeV sources provide a direct means to constrain the putative intergalactic magnetic field. However, the converse may not be the case! The fate of the pairs generated by TeV gamma rays annihilating on the extragalactic background light is presently unclear, clouded by the possibility that cosmological scale plasma instabilities may dominate their energetic evolution. I will briefly motivate these plasma instabilities theoretically, summarize some empirical evidence that they may be occurring in practice, and assess their potential impact upon studies of intergalactic magnetic fields.

Instabilities and pattern formation on the pore scale

NASA Astrophysics Data System (ADS)

Juel, Anne

What links a baby's first breath to adhesive debonding, enhanced oil recovery, or even drop-on-demand devices? All these processes involve moving or expanding bubbles displacing fluid in a confined space, bounded by either rigid or elastic walls. In this talk, we show how spatial confinement may either induce or suppress interfacial instabilities and pattern formation in such flows. We demonstrate that a simple change in the bounding geometry can radically alter the behaviour of a fluid-displacing air finger both in rigid and elastic vessels. A rich array of propagation modes, including steady and oscillatory fingers, is uncovered when air displaces oil from axially uniform tubes that have local variations in flow resistance within their cross-sections. Moreover, we show that the experimentally observed states can all be captured by a two-dimensional depth-averaged model for bubble propagation through wide channels. Viscous fingering in Hele-Shaw cells is a classical and widely studied fluid-mechanical instability: when air is injected into the narrow, liquid-filled gap between parallel rigid plates, the axisymmetrically expanding air-liquid interface tends to be unstable to non-axisymmetric disturbances. We show how the introduction of wall elasticity (via the replacement of the upper bounding plate by an elastic membrane) can weaken or even suppress the fingering instability by allowing changes in cell confinement through the flow-induced deflection of the boundary. The presence of a deformable boundary also makes the system prone to additional solid-mechanical instabilities, and these wrinkling instabilities can in turn enhance viscous fingering. The financial support of EPSRC and the Leverhulme Trust is gratefully acknowledged.

Opposite Roles for p38MAPK-Driven Responses and Reactive Oxygen Species in the Persistence and Resolution of Radiation-Induced Genomic Instability

PubMed Central

Werner, Erica; Wang, Huichen; Doetsch, Paul W.

2014-01-01

We report the functional and temporal relationship between cellular phenotypes such as oxidative stress, p38MAPK-dependent responses and genomic instability persisting in the progeny of cells exposed to sparsely ionizing low-Linear Energy Transfer (LET) radiation such as X-rays or high-charge and high-energy (HZE) particle high-LET radiation such as 56Fe ions. We found that exposure to low and high-LET radiation increased reactive oxygen species (ROS) levels as a threshold-like response induced independently of radiation quality and dose. This response was sustained for two weeks, which is the period of time when genomic instability is evidenced by increased micronucleus formation frequency and DNA damage associated foci. Indicators for another persisting response sharing phenotypes with stress-induced senescence, including beta galactosidase induction, increased nuclear size, p38MAPK activation and IL-8 production, were induced in the absence of cell proliferation arrest during the first, but not the second week following exposure to high-LET radiation. This response was driven by a p38MAPK-dependent mechanism and was affected by radiation quality and dose. This stress response and elevation of ROS affected genomic instability by distinct pathways. Through interference with p38MAPK activity, we show that radiation-induced stress phenotypes promote genomic instability. In contrast, exposure to physiologically relevant doses of hydrogen peroxide or increasing endogenous ROS levels with a catalase inhibitor reduced the level of genomic instability. Our results implicate persistently elevated ROS following exposure to radiation as a factor contributing to genome stabilization. PMID:25271419

The prolyl isomerase FKBP25 regulates microtubule polymerization impacting cell cycle progression and genomic stability

PubMed Central

Dilworth, David; Gudavicius, Geoff; Xu, Xiaoxue; Boyce, Andrew K J; O’Sullivan, Connor; Serpa, Jason J; Bilenky, Misha; Petrochenko, Evgeniy V; Borchers, Christoph H; Hirst, Martin; Swayne, Leigh Anne; Howard, Perry; Nelson, Christopher J

2018-01-01

Abstract FK506 binding proteins (FKBPs) catalyze the interconversion of cis-trans proline conformers in proteins. Importantly, FK506 drugs have anti-cancer and neuroprotective properties, but the effectors and mechanisms underpinning these properties are not well understood because the cellular function(s) of most FKBP proteins are unclear. FKBP25 is a nuclear prolyl isomerase that interacts directly with nucleic acids and is associated with several DNA/RNA binding proteins. Here, we show the catalytic FKBP domain binds microtubules (MTs) directly to promote their polymerization and stabilize the MT network. Furthermore, FKBP25 associates with the mitotic spindle and regulates entry into mitosis. This interaction is important for mitotic spindle dynamics, as we observe increased chromosome instability in FKBP25 knockdown cells. Finally, we provide evidence that FKBP25 association with chromatin is cell-cycle regulated by Protein Kinase C phosphorylation. This disrupts FKBP25–DNA contacts during mitosis while maintaining its interaction with the spindle apparatus. Collectively, these data support a model where FKBP25 association with chromatin and MTs is carefully choreographed to ensure faithful genome duplication. Additionally, they highlight that FKBP25 is a MT-associated FK506 receptor and potential therapeutic target in MT-associated diseases. PMID:29361176

Characterization of the role of Fhit in maintenance of genomic integrity following low dose radiation, in vivo and in vitro

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

Ya Wang

2010-05-31

The major goal of this study is to determine the effects of the Fhit pathway on low dose ({le} 0.1 Gy) ionizing radiation (IR)-induced genetic instability. Reduction of Fhit protein expression is observed in most solid tumors particularly in those tumors resulting from exposure to environmental carcinogens. Therefore, characterization of the role of the Fhit-dependent pathway in preventing low dose IR-induced genetic instability will provide useful parameters for evaluating the low dose IR-induced risk of mutagenesis and carcinogenesis. We pursued 3 specific aims to study our hypothesis that the Fhit-dependent pathways maintain genomic integrity through adjusting checkpoint response and repairmore » genes expression following low dose IR. Aim 1: Determine whether Fhit interaction with RPA is necessary for Fhit to affect the cellular response to low dose IR. We combined the approaches of in vitro (GST pull-down and site-directed mutagenesis) and in vivo (observing the co-localization and immunoprecipitation of Fhit and RPA in Fhit knock out mouse cells transfected with mutant Fhit which has lost ability to interact with RPA in vitro). Aim 2: Determine the role of genes whose expression is affected by Fhit in low dose irradiated cells. We analyzed the distinct signature of gene expression in low dose irradiated Fhit-/- cells compared with Fhit+/+ cells by combining microarray, gene transfection and siRNA approaches. Aim 3: Determine the role of Fhit in genetic susceptibility to low dose IR in vivo. We compared the gene mutation frequency and the fragile site stability in the cells isolated from the Fhit+/+ and Fhit-/- mice at 1.5 years following low dose IR. These results determine the role of the Fhit-dependent pathway in maintaining genomic integrity in vitro and in vivo, which provide a basis for choosing surrogate markers in the Fhit-dependent pathway to evaluate low dose IR-induced risk of mutagenesis and carcinogenesis.« less

Suppression of Myc oncogenic activity by ribosomal protein haploinsufficiency

PubMed Central

Barna, Maria; Pusic, Aya; Zollo, Ornella; Costa, Maria; Kondrashov, Nadya; Rego, Eduardo; Rao, Pulivarthi H; Ruggero, Davide

2008-01-01

The Myc oncogene regulates the expression of multiple components of the protein synthetic machinery, including ribosomal proteins, initiation factors of translation, Pol III, and rDNA1,2. An outstanding question is whether and how increasing the cellular protein synthesis capacity can affect the multi-step process leading to cancer. We utilized ribosomal protein heterozygote mice as a genetic tool to restore increased protein synthesis in Eμ–Myc/+ transgenic mice to normal levels and show that in this context Myc's oncogenic potential is suppressed. Our findings demonstrate that the ability of Myc to increase protein synthesis directly augments cell size and is sufficient to accelerate cell cycle progression independently of known cell cycle targets transcriptionally regulated by Myc. In addition, when protein synthesis is restored to normal levels, Myc overexpressing precancerous cells are more efficiently eliminated by programmed cell death. Our findings reveal a novel paradigm that links increases in general protein synthesis rates downstream of an oncogenic signal to a specific molecular impairment in the modality of translation initiation employed to regulate the expression of selective mRNAs. We show that an aberrant increase in cap-dependent translation downstream Myc hyperactivation specifically impairs the translational switch to internal ribosomal entry site (IRES)-dependent translation required for accurate mitotic progression. Failure of this translational switch results in reduced mitotic-specific expression of the endogenous IRES-dependent form of Cdk11 (p58-PITSLRE)3-5, which leads to cytokinesis defects and is associated with increased centrosome numbers and genome instability in Eμ–Myc/+ mice. When accurate translational control is re-established in Eμ–Myc/+ mice, genome instability is suppressed. Our findings reveal how perturbations in translational control provide a highly specific outcome on gene expression, genome stability, and cancer initiation that have important implications for understanding the molecular mechanism of cancer formation at the post-genomic level. PMID:19011615

High-Voltage Breakdown Penalties for the Beam-Breakup Instability

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

Ekdahl, Carl August

2016-11-22

The strength of the dangerous beam breakup (BBU) instability in linear induction accelerators (LIAs) is determined by the transverse coupling impedance Z ⊥ of the induction cell cavity. For accelerating gap width w less than the beam pipe radius b, the transverse impedance is theoretically proportional to w/b, favoring narrow gaps to suppress BBU. On the other hand, cells with narrow gaps cannot support high accelerating gradients, because of electrical breakdown and shorting of the gap. Thus, there is an engineering trade-off between BBU growth and accelerating gradient, which must be considered for next generation LIAs now being designed. Inmore » this article this tradeoff is explored, using a simple pillbox cavity as an illustrative example. For this model, widening the gap to reduce the probability of breakdown increases BBU growth, unless higher magnetic focusing fields are used to further suppress the instability.« less

DNA replication stress as a hallmark of cancer.

PubMed

Macheret, Morgane; Halazonetis, Thanos D

2015-01-01

Human cancers share properties referred to as hallmarks, among which sustained proliferation, escape from apoptosis, and genomic instability are the most pervasive. The sustained proliferation hallmark can be explained by mutations in oncogenes and tumor suppressors that regulate cell growth, whereas the escape from apoptosis hallmark can be explained by mutations in the TP53, ATM, or MDM2 genes. A model to explain the presence of the three hallmarks listed above, as well as the patterns of genomic instability observed in human cancers, proposes that the genes driving cell proliferation induce DNA replication stress, which, in turn, generates genomic instability and selects for escape from apoptosis. Here, we review the data that support this model, as well as the mechanisms by which oncogenes induce replication stress. Further, we argue that DNA replication stress should be considered as a hallmark of cancer because it likely drives cancer development and is very prevalent.

Flow instabilities due to the interfacial formation of surfactant-fatty acid material in a Hele-Shaw cell

NASA Astrophysics Data System (ADS)

Niroobakhsh, Zahra; Litman, Matthew; Belmonte, Andrew

2017-11-01

We present an experimental study of pattern formation during the penetration of an aqueous surfactant solution into a liquid fatty acid in a Hele-Shaw cell. When a solution of the cationic surfactant cetylpyridinium chloride is injected into oleic acid, a wide variety of fingering patterns are observed as a function of surfactant concentration and flow rate, which are strikingly different than the classic Saffman-Taylor (ST) instability. We observe evidence of interfacial material forming between the two liquids, causing these instabilities. Moreover, the number of fingers decreases with increasing flow rate Q , while the average finger width increases with Q , both trends opposite to the ST case. Bulk rheology on related mixtures indicates a gel-like state. Comparison of experiments using other oils indicates the importance of pH and the carboxylic head group in the formation of the surfactant-fatty acid material.

Tumor Hypoxia and Genetic Alterations in Sporadic Cancers

PubMed Central

Koi, Minoru; Boland, C.R.

2011-01-01

The cancer genome contains many gene alterations. How cancer cells acquire these alterations is a matter for discussion. One hypothesis is that cancer cells obtain mutations in genome stability genes at an early stage of tumor development, which results in genetic instability and generates a gene pool that enhances cellular proliferation and survival. Another hypothesis puts its emphasis on the natural selection of gene mutations for fitness. Recent data for systematic cancer genome sequencing shows that mutations in stability genes are rare in human sporadic cancers. Instead, many “passenger” mutations that do not drive the carcinogenesis process have been found in the cancer genome. Both the hypotheses mentioned above fall short in explaining recent data. Recently, many studies demonstrate the role of the tumor microenvironment, especially hypoxia and reoxygenation, in genetic instability. In this review, literature will be presented which supports a third hypothesis, i.e. that hypoxia/re-oxygenation induces genetic instability. PMID:21272156

Neuroendocrine-type prostatic adenocarcinoma with microsatellite instability in a patient with lynch syndrome.

PubMed

Wagner, David G; Gatalica, Zoran; Lynch, Henry T; Kohl, Shane; Johansson, Sonny L; Lele, Subodh M

2010-12-01

Lynch syndrome is an autosomal-dominant cancer syndrome that can be identified with microsatellite instability molecular tests or immunohistochemical stains on pathologic material from patients who meet the Amsterdam Criteria II. The development of prostatic carcinoma in situ or invasive small cell carcinoma (SCC) of the prostate has not been previously reported in a patient with this syndrome. In this report, an 87-year-old White man with the Lynch syndrome had a prostate biopsy that revealed a mixed high-grade conventional adenocarcinoma and SCC of the prostate with high-grade prostatic intraepithelial neoplasia of the small cell neuroendocrine-type (HGPIN-NE), all showing MSH2 microsatellite instability and loss of MSH2 expression, a finding not previously published. These findings suggest that HGPIN-NE is a precursor of invasive SCC and also that prostatic SCC can develop in a patient with the Lynch syndrome.

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

Genomic instability in cancer: Teetering on the limit of tolerance

PubMed Central

Andor, Noemi; Maley, Carlo C.; Ji, Hanlee P.

2017-01-01

Cancer genomic instability contributes to the phenomenon of intratumoral genetic heterogeneity, provides the genetic diversity required for natural selection and enables the extensive phenotypic diversity that is frequently observed among patients. Genomic instability has previously been associated with poor prognosis. However, we have evidence that for solid tumors of epithelial origin, extreme levels of genomic instability, where more than 75% of the genome is subject to somatic copy number alterations, are associated with a potentially better prognosis compared to intermediate levels under this threshold. This has been observed in clonal subpopulations of larger size, especially when genomic instability is shared among a limited number of clones. We hypothesize that cancers with extreme levels of genomic instability may be teetering on the brink of a threshold where so much of their genome is adversely altered that cells rarely replicate successfully. Another possibility is that tumors with high levels of genomic instability are more immunogenic than other cancers with a less extensive burden of genetic aberrations. Regardless of the exact mechanism, but hinging on our ability to quantify how a tumor’s burden of genetic aberrations is distributed among coexisting clones – genomic instability has important therapeutic implications. Herein, we explore the possibility that a high genomic instability could be the basis for a tumor’s sensitivity to DNA damaging therapies. We primarily focus on studies of epithelial-derived solid tumors. PMID:28432052

Growth hormone is a cellular senescence target in pituitary and nonpituitary cells

PubMed Central

Chesnokova, Vera; Zhou, Cuiqi; Ben-Shlomo, Anat; Zonis, Svetlana; Tani, Yuji; Ren, Song-Guang; Melmed, Shlomo

2013-01-01

Premature proliferative arrest in benign or early-stage tumors induced by oncoproteins, chromosomal instability, or DNA damage is associated with p53/p21 activation, culminating in either senescence or apoptosis, depending on cell context. Growth hormone (GH) elicits direct peripheral metabolic actions as well as growth effects mediated by insulin-like growth factor 1 (IGF1). Locally produced peripheral tissue GH, in contrast to circulating pituitary-derived endocrine GH, has been proposed to be both proapoptotic and prooncogenic. Pituitary adenomas expressing and secreting GH are invariably benign and exhibit DNA damage and a senescent phenotype. We therefore tested effects of nutlin-induced p53-mediated senescence in rat and human pituitary cells. We show that DNA damage senescence induced by nutlin triggers the p53/p21 senescent pathway, with subsequent marked induction of intracellular pituitary GH in vitro. In contrast, GH is not induced in cells devoid of p53. Furthermore we show that p53 binds specific GH promoter motifs and enhances GH transcription and secretion in senescent pituitary adenoma cells and also in nonpituitary (human breast and colon) cells. In vivo, treatment with nutlin results in up-regulation of both p53 and GH in the pituitary gland, as well as increased GH expression in nonpituitary tissues (lung and liver). Intracrine GH acts in pituitary cells as an apoptosis switch for p53-mediated senescence, likely protecting the pituitary adenoma from progression to malignancy. Unlike in the pituitary, in nonpituitary cells GH exerts antiapoptotic properties. Thus, the results show that GH is a direct p53 transcriptional target and fulfills criteria as a p53 target gene. Induced GH is a readily measurable cell marker for p53-mediated cellular senescence. PMID:23940366

Smectic layer instabilities in liquid crystals.

PubMed

Dierking, Ingo; Mitov, Michel; Osipov, Mikhail A

2015-02-07

Scientists aspire to understand the underlying physics behind the formation of instabilities in soft matter and how to manipulate them for diverse investigations, while engineers aim to design materials that inhibit or impede the nucleation and growth of these instabilities in critical applications. The present paper reviews the field-induced rotational instabilities which may occur in chiral smectic liquid-crystalline layers when subjected to an asymmetric electric field. Such instabilities destroy the so-named bookshelf geometry (in which the smectic layers are normal to the cell surfaces) and have a detrimental effect on all applications of ferroelectric liquid crystals as optical materials. The transformation of the bookshelf geometry into horizontal chevron structures (in which each layer is in a V-shaped structure), and the reorientation dynamics of these chevrons, are discussed in details with respect to the electric field conditions, the material properties and the boundary conditions. Particular attention is given to the polymer-stabilisation of smectic phases as a way to forbid the occurrence of instabilities and the decline of related electro-optical performances. It is also shown which benefit may be gained from layer instabilities to enhance the alignment of the liquid-crystalline geometry in practical devices, such as optical recording by ferroelectric liquid crystals. Finally, the theoretical background of layer instabilities is given and discussed in relation to the experimental data.

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

The enemy within: Targeting host–parasite interaction for antileishmanial drug discovery

PubMed Central

Späth, Gerald F.; Rachidi, Najma; Prina, Eric

2017-01-01

The state of antileishmanial chemotherapy is strongly compromised by the emergence of drug-resistant Leishmania. The evolution of drug-resistant phenotypes has been linked to the parasites’ intrinsic genome instability, with frequent gene and chromosome amplifications causing fitness gains that are directly selected by environmental factors, including the presence of antileishmanial drugs. Thus, even though the unique eukaryotic biology of Leishmania and its dependence on parasite-specific virulence factors provide valid opportunities for chemotherapeutical intervention, all strategies that target the parasite in a direct fashion are likely prone to select for resistance. Here, we review the current state of antileishmanial chemotherapy and discuss the limitations of ongoing drug discovery efforts. We finally propose new strategies that target Leishmania viability indirectly via mechanisms of host–parasite interaction, including parasite-released ectokinases and host epigenetic regulation, which modulate host cell signaling and transcriptional regulation, respectively, to establish permissive conditions for intracellular Leishmania survival. PMID:28594938

The enemy within: Targeting host-parasite interaction for antileishmanial drug discovery.

PubMed

Lamotte, Suzanne; Späth, Gerald F; Rachidi, Najma; Prina, Eric

2017-06-01

The state of antileishmanial chemotherapy is strongly compromised by the emergence of drug-resistant Leishmania. The evolution of drug-resistant phenotypes has been linked to the parasites' intrinsic genome instability, with frequent gene and chromosome amplifications causing fitness gains that are directly selected by environmental factors, including the presence of antileishmanial drugs. Thus, even though the unique eukaryotic biology of Leishmania and its dependence on parasite-specific virulence factors provide valid opportunities for chemotherapeutical intervention, all strategies that target the parasite in a direct fashion are likely prone to select for resistance. Here, we review the current state of antileishmanial chemotherapy and discuss the limitations of ongoing drug discovery efforts. We finally propose new strategies that target Leishmania viability indirectly via mechanisms of host-parasite interaction, including parasite-released ectokinases and host epigenetic regulation, which modulate host cell signaling and transcriptional regulation, respectively, to establish permissive conditions for intracellular Leishmania survival.

Prolonged particulate chromate exposure does not inhibit homologous recombination repair in North Atlantic right whale (Eubalaena glacialis) lung cells.

PubMed

Browning, Cynthia L; Wise, Catherine F; Wise, John Pierce

2017-09-15

Chromosome instability is a common feature of cancers that forms due to the misrepair of DNA double strand breaks. Homologous recombination (HR) repair is a high fidelity DNA repair pathway that utilizes a homologous DNA sequence to accurately repair such damage and protect the genome. Prolonged exposure (>72h) to the human lung carcinogen, particulate hexavalent chromium (Cr(VI)), inhibits HR repair, resulting in increased chromosome instability in human cells. Comparative studies have shown acute Cr(VI) exposure induces less chromosome damage in whale cells than human cells, suggesting investigating the effect of this carcinogen in other species may inform efforts to prevent Cr(VI)-induced chromosome instability. Thus, the goal of this study was to determine the effect of prolonged Cr(VI) exposure on HR repair and clastogenesis in North Atlantic right whale (Eubalaena glacialis) lung cells. We show particulate Cr(VI) induces HR repair activity after both acute (24h) and prolonged (120h) exposure in North Atlantic right whale cells. Although the RAD51 response was lower following prolonged Cr(VI) exposure compared to acute exposure, the response was sufficient for HR repair to occur. In accordance with active HR repair, no increase in Cr(VI)-induced clastogenesis was observed with increased exposure time. These results suggest prolonged Cr(VI) exposure affects HR repair and genomic stability differently in whale and human lung cells. Future investigation of the differences in how human and whale cells respond to chemical carcinogens may provide valuable insight into mechanisms of preventing chemical carcinogenesis. Copyright © 2017. Published by Elsevier Inc.

DNS of Laminar-Turbulent Transition in Swept-Wing Boundary Layers

NASA Technical Reports Server (NTRS)

Duan, L.; Choudhari, M.; Li, F.

2014-01-01

Direct numerical simulation (DNS) is performed to examine laminar to turbulent transition due to high-frequency secondary instability of stationary crossflow vortices in a subsonic swept-wing boundary layer for a realistic natural-laminar-flow airfoil configuration. The secondary instability is introduced via inflow forcing and the mode selected for forcing corresponds to the most amplified secondary instability mode that, in this case, derives a majority of its growth from energy production mechanisms associated with the wall-normal shear of the stationary basic state. An inlet boundary condition is carefully designed to allow for accurate injection of instability wave modes and minimize acoustic reflections at numerical boundaries. Nonlinear parabolized stability equation (PSE) predictions compare well with the DNS in terms of modal amplitudes and modal shape during the strongly nonlinear phase of the secondary instability mode. During the transition process, the skin friction coefficient rises rather rapidly and the wall-shear distribution shows a sawtooth pattern that is analogous to the previously documented surface flow visualizations of transition due to stationary crossflow instability. Fully turbulent features are observed in the downstream region of the flow.

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.

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.

Antagonizing functions of BARD1 and its alternatively spliced variant BARD1δ in telomere stability.

PubMed

Pilyugin, Maxim; André, Pierre-Alain; Ratajska, Magdalena; Kuzniacka, Alina; Limon, Janusz; Tournier, Benjamin B; Colas, Julien; Laurent, Geoff; Irminger-Finger, Irmgard

2017-02-07

Previous reports have shown that expression of BARD1δ, a deletion-bearing isoform of BARD1, correlates with tumor aggressiveness and progression. We show that expression of BARD1δ induces cell cycle arrest in vitro and in vivo in non-malignant cells. We investigated the mechanism that leads to proliferation arrest and found that BARD1δ overexpression induced mitotic arrest with chromosome and telomere aberrations in cell cultures, in transgenic mice, and in cells from human breast and ovarian cancer patients with BARD1 mutations. BARD1δ binds more efficiently than BARD1 to telomere binding proteins and causes their depletion from telomeres, leading to telomere and chromosomal instability. While this induces cell cycle arrest, cancer cells lacking G2/M checkpoint controls might continue to proliferate despite the BARD1δ-induced chromosomal instability. These features of BARD1δ may make it a genome permutator and a driver of continuous uncontrolled proliferation of cancer cells.

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

PubMed

Shima, Naoko; Pederson, Kayla D

2017-08-01

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

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.

A powerful local shear instability in weakly magnetized disks. I - Linear analysis. II - Nonlinear evolution

NASA Technical Reports Server (NTRS)

Balbus, Steven A.; Hawley, John F.

1991-01-01

A broad class of astronomical accretion disks is presently shown to be dynamically unstable to axisymmetric disturbances in the presence of a weak magnetic field, an insight with consequently broad applicability to gaseous, differentially-rotating systems. In the first part of this work, a linear analysis is presented of the instability, which is local and extremely powerful; the maximum growth rate, which is of the order of the angular rotation velocity, is independent of the strength of the magnetic field. Fluid motions associated with the instability directly generate both poloidal and toroidal field components. In the second part of this investigation, the scaling relation between the instability's wavenumber and the Alfven velocity is demonstrated, and the independence of the maximum growth rate from magnetic field strength is confirmed.

Generation of capillary instabilities by external disturbances in a liquid jet. Ph.D. Thesis - State Univ. of N.Y.

NASA Technical Reports Server (NTRS)

Leib, S. J.

1985-01-01

The receptivity problem in a circular liquid jet is considered. A time harmonic axial pressure gradient is imposed on the steady, parallel flow of a jet of liquid emerging from a circular duct. Using a technique developed in plasma physics a casual solution to the forced problem is obtained over certain ranges of Weber number for a number of mean velocity profiles. This solution contains a term which grows exponentially in the downstream direction and can be identified with a capillary instability wave. Hence, it is found that the externally imposed disturbances can indeed trigger instability waves in a liquid jet. The amplitude of the instability wave generated relative to the amplitude of the forcing is computed numerically for a number of cases.

Generation of waves in the Venus mantle by the ion acoustic beam instability

NASA Technical Reports Server (NTRS)

Huba, J. D.

1993-01-01

The ion acoustic beam instability is suggested as a mechanism to produce wave turbulence observed in the Venus mantle at frequencies 100 Hz and 730 Hz. The plasma is assumed to consist of a stationary cold O(+) ion plasma and a flowing, shocked solar wind plasma. The O(+) ions appear as a beam relative to the flowing ionosheath plasma which provides the free energy to drive the instability. The plasma is driven unstable by inverse electron Landau damping of an ion acoustic wave associated with the cold ionospheric O(+) ions. The instability can directly generate the observed 100 Hz waves in the Venus mantle as well as the observed 730 Hz waves through the Doppler shift of the frequency caused by the satellite motion.

On radiating baroclinic instability of zonally varying flow

NASA Technical Reports Server (NTRS)

Finley, Catherine A.; Nathan, Terrence R.

1993-01-01

A quasi-geostrophic, two-layer, beta-plane model is used to study the baroclinic instability characteristics of a zonally inhomogeneous flow. It is assumed that the disturbance varied slowly in the cross-stream direction, and the stability problem was formulated as a 1D initial value problem. Emphasis is placed on determining how the vertically averaged wind, local maximum in vertical wind shear, and length of the locally supercritical region combine to yield local instabilities. Analysis of the local disturbance energetics reveals that, for slowly varying basic states, the baroclinic energy conversion predominates within the locally unstable region. Using calculations of the basic state tendencies, it is shown that the net effect of the local instabilities is to redistribute energy from the baroclinic to the barotropic component of the basic state flow.

Crosstalk between telomere maintenance and radiation effects: A key player in the process of radiation-induced carcinogenesis

PubMed Central

Shim, Grace; Ricoul, Michelle; Hempel, William M.; Azzam, Edouard I.; Sabatier, Laure

2014-01-01

It is well established that ionizing radiation induces chromosomal damage, both following direct radiation exposure and via non-targeted (bystander) effects, activating DNA damage repair pathways, of which the proteins are closely linked to telomeric proteins and telomere maintenance. Long-term propagation of this radiation-induced chromosomal damage during cell proliferation results in chromosomal instability. Many studies have shown the link between radiation exposure and radiation-induced changes in oxidative stress and DNA damage repair in both targeted and non-targeted cells. However, the effect of these factors on telomeres, long established as guardians of the genome, still remains to be clarified. In this review, we will focus on what is known about how telomeres are affected by exposure to low- and high-LET ionizing radiation and during proliferation, and will discuss how telomeres may be a key player in the process of radiation-induced carcinogenesis. PMID:24486376

Rb vapor-cell clock demonstration with a frequency-doubled telecom laser.

PubMed

Almat, Nil; Pellaton, Matthieu; Moreno, William; Gruet, Florian; Affolderbach, Christoph; Mileti, Gaetano

2018-06-01

We employ a recently developed laser system, based on a low-noise telecom laser emitting around 1.56 μm, to evaluate its impact on the performance of an Rb vapor-cell clock in a continuous-wave double-resonance scheme. The achieved short-term clock instability below 2.5·10 -13 ·τ -1/2 demonstrates, for the first time, the suitability of a frequency-doubled telecom laser for this specific application. We measure and study quantitatively the impact of laser amplitude and frequency noises and of the ac Stark shift, which limit the clock frequency stability on short timescales. We also report on the detailed noise budgets and demonstrate experimentally that, under certain conditions, the short-term stability of the clock operated with the low-noise telecom laser is improved by a factor of three compared to clock operation using the direct 780-nm laser.

What’s the Damage? The Impact of Pathogens on Pathways that Maintain Host Genome Integrity

PubMed Central

Weitzman, Matthew D.; Weitzman, Jonathan B.

2014-01-01

Maintaining genome integrity and transmission of intact genomes is critical for cellular, organismal, and species survival. Cells can detect damaged DNA, activate checkpoints, and either enable DNA repair or trigger apoptosis to eliminate the damaged cell. Aberrations in these mechanisms lead to somatic mutations and genetic instability, which are hallmarks of cancer. Considering the long history of host-microbe coevolution, an impact of microbial infection on host genome integrity is not unexpected, and emerging links between microbial infections and oncogenesis further reinforce this idea. In this review, we compare strategies employed by viruses, bacteria, and parasites to alter, subvert, or otherwise manipulate host DNA damage and repair pathways. We highlight how microbes contribute to tumorigenesis by directly inducing DNA damage, inactivating checkpoint controls, or manipulating repair processes. We also discuss indirect effects resulting from inflammatory responses, changes in cellular metabolism, nuclear architecture, and epigenome integrity, and the associated evolutionary tradeoffs. PMID:24629335

Equatorial dynamics in a 2 {1}/{2}- layer model

NASA Astrophysics Data System (ADS)

McCreary, Julian P.; Yu, Zuojun

A nonlinear, 2 {1}/{2}- layer model is used to study the dynamics of wind-driven equatorial ocean circulation, including the generation of mean flows and instabilities. The model allows water to entrain into, and detrain from, the upper layer, and as a consequence the temperatures of the two active layers can vary. The model ocean basin is rectangular, extends 100° zonally, and for most solutions has open boundaries at 15°S and 15°N. All solutions are forced by a switched-on wind field that is an idealized version of the Pacific trades: the wind is westward, uniform in the meridional direction (so it has no curl), located primarily in the central and eastern oceans, and in most cases it has an amplitude of 0.5 dyn cm -2. For reasonable choices of parameters, solutions adjust to have a realistic equatorial circulation with a westward surface jet, an eastward undercurrent, and with upwelling and cool sea surface temperature in the eastern ocean. Most of the meridional circulation (81% of the transport) is part of a closed tropical circulation cell, in which water upwells in the eastern, equatorial ocean and downwells elsewhere in the basin; the rest participates in a mid-latitude circulation cell with lower-layer water entering the basin and upper-layer water leaving it through the open boundaries. Three basic types of unstable disturbances are generated in the eastern ocean: two of them are antisymmetric about the equator, one being surface-trapped with a period of about 21 days (f 1), and the other predominantly a lower-layer oscillation with periods ranging from 35 to 53 days (f 2) that causes the undercurrent to meander; the third is symmetric with a period of about 28 days (f 0) and a structure like that of a first-meridional-mode Rossby wave. The amplitudes of the disturbances are sensitive to model parameters, and as parameter values are varied systematically solutions appear to follow variations of the quasi-periodic route to turbulence, one of the common transitions to chaotic behavior. Realistic mean flows develop only when detrainment and lower-layer cooling are present in the model physics, processes that are necessary for the generation of a tropical circulation cell: without detrainment, water accumulutes in the upper layer until entrainment ceases and the model adjusts to Sverdrup balance, which is a state of rest for a wind without curl; without cooling, the temperature of the lower layer slowly rises until it approaches that of the upper layer. The mean-momentum budget for the upper layer shows that the model's Reynolds-stress terms are not a significant part of the momentum balance, having a maximum amplitude only about 19% of the wind stress. In contrast, the mean-heat budget demonstrates that eddy heating warms the cold tongue significantly, with an amplitude as large as the heating through the surface. Interestingly, the time-averaged continuity equations indicate that the instabilities tend to increase the upward tilt of the upper-layer interface toward the equator. When layer temperatures are kept fixed only a weak version of disturbance f 1 develops, indicating that the equatorial temperature front is an important aspect of instability dynamics. In fact, a frontal instability does exist in the model; it involves the conversion of mean to eddy potential energy, but it is the mean energy associated with the variable upper-layer temperature field, rather than with tilted layer interfaces, as is the case for traditional baroclinic instability. Perturbation-energy budgets suggest that frontal, barotropic and Kelvin-Helmholtz instabilities are energy sources for the disturbances, whereas traditional baroclinic instability is an energy sink. The two, fastest growing, antisymmetric, unstable-wave solutions to a linearized version of the model correspond closely to disturbances f 1 and f 2 from the nonlinear model, and perturbation-energy budgets for these waves indicate that their energy sources are primarily frontal instability and lower-layer barotropic instability, respectively.

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

PubMed Central

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

2013-01-01

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

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.

Hydrodynamic Instabilities in High-Energy-Density Settings

NASA Astrophysics Data System (ADS)

Smalyuk, Vladimir

2016-10-01

Our understanding of hydrodynamic instabilities, such as the Rayleigh-Taylor (RT), Richtmyer-Meshkov (RM), and Kelvin-Helmholtz (KH) instabilities, in high-energy-density (HED) settings over past two decades has progressed enormously. The range of conditions where hydrodynamic instabilities are experimentally observed now includes direct and indirect drive inertial confinement fusion (ICF) where surprises continue to emerge, linear and nonlinear regimes, classical interfaces vs. stabilized ablation fronts, tenuous ideal plasmas vs. high density Fermi degenerate plasmas, bulk fluid interpenetration vs. mixing down to the atomic level, in the presence of magnetic fields and/or intense radiation, and in solid state plastic flow at high pressures and strain rates. Regimes in ICF can involve extreme conditions of matter with temperatures up to kilovolts, densities of a thousand times solid densities, and time scales of nanoseconds. On the other hand, scaled conditions can be generated that map to exploding stars (supernovae) with length and time scales of millions of kilometers and hours to days or even years of instability evolution, planetary formation dynamics involving solid-state plastic flow which severely modifies the RT growth and continues to challenge reliable theoretical descriptions. This review will look broadly at progress in probing and understanding hydrodynamic instabilities in these very diverse HED settings, and then will examine a few cases in more depth to illustrate the detailed science involved. Experimental results on large-scale HED facilities such as the Omega, Nike, Gekko, and Shenguang lasers will be reviewed and the latest developments at the National Ignition Facility (NIF) and Z machine will be covered. Finally, current overarching questions and challenges will be summarized to motivate research directions for future. This work was performed under the auspices of the U.S. Department of Energy by LLNL under Contract DE-AC52-07NA27344.

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.

Tectonic controlled submarine slidings and dewatering structures

NASA Astrophysics Data System (ADS)

Yamamoto, Y.; Hirono, T.; Takahashi, M.

2003-04-01

Geologic structures associated with mass movements processes such as slumping, sliding, and creeping can be the key to understanding the tectonic or geologic constraints in the time they were formed. Because they are sensitively reflected by the paleo-topography which must be associated with active tectonics. It must be very useful if the direction of paleo-slope instability is known easily in a wide area. We paid attentions to convolute lamination and flame structure which might be associated with dewatering and loading, respectively. Some recent researches report the possibility that well regulated flame structures might be formed in relation to paleo-slope instability. However, there is an alternative idea that they were reflection of heterogeneous loading associated with ripple marks on the sandy layers. This controversy has not been settled. Accordingly, to evaluate the reliability of the relationship between formation of such structures with well regulated arrays and paleo-slope instability, the Pliocene Chikura Group in the southern part of the Boso Peninsula, central Japan, was studied. The Chikura Group overlying the Miura Group, Miocene accretionary prism, is composed of trench-fill sediments in the lowermost and of trench-slope basin sediments in the upper. The Chikura Group was deposited on an east-west extended sedimentary basin during east-west trending folds and faults development. These indicate the direction of paleo-slope in the Chikura Group due north or south. Flame structures and convolute laminations were recognized over 60 sites in the Chikura Group. They have well-regulated planar arrays which extend almost east west, perpendicular to the direction of paleo-slope instability. Some examples of such structures and slump deposit were observed in the same outcrop. Vergence of these slump deposits were toward north or south, and ridges of flame structures and convolute laminations extend east-west. Experimental study of direct imaging of dewatering under shear stress regime by using X-ray CT and X-ray microscope shows similar arrays of dewatering paths. Water escapes through the foliation which might be a tension fracture caused by direct shear strain. The foliation has vertical trends to the applied shear stress and has high angle dippings with approximately 65 to 75 degrees to the direct shear plane. These field-based study and experiment indicate that well regulated flame structures and convolute laminations were formed by dewatering or mud liquidization by which water escapes through the tension fractures associated with shear stress corresponding to the paleo-slope instability. These structures are very important because we can identify easily the paleo-slope directions, direction of synsedimentary shear and also macro-scopic geologic constraints on tectonics around a study area.

A transition in the viscous fingering instability in miscible fluids

NASA Astrophysics Data System (ADS)

Videbaek, Thomas; Nagel, Sidney R.

2017-11-01

The viscous fingering instability in a quasi-two dimensional Hele-Shaw cell is an example of complex structure formation from benign initial conditions. When the invading fluid has the lesser viscosity, the interface between the two fluids is unstable to finger formation. Here, we study the instability between pairs of miscible fluids in a circular cell with fluid injected at its center. As the injection rate is decreased, diffusion will smooth out the discontinuity in the gap-averaged viscosity at the interface between the fluids. At high injection rates (i.e., high Péclet number, Pe), fingering is associated with three-dimensional structure within the gap between the confining plates. On lowering Pe, we find a sharp transition in the finger morphology at a critical value, Pec (ηi /ηo) 1 / 2 , with ηi (ηo) being the viscosity of the inner (outer) fluid; at this point, the width of the fingers jumps, the length of the fingers shrinks towards zero and the three-dimensional structure goes from half filling to fully filling the gap. Thus, by controlling the viscosity contrast at the interface, one can alter and even completely suppress the instability.

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

Specificity of Affective Instability in Patients With Borderline Personality Disorder Compared to Posttraumatic Stress Disorder, Bulimia Nervosa, and Healthy Controls

PubMed Central

Santangelo, Philip; Mussgay, Lutz; Sawitzki, Günther; Trull, Timothy J.; Reinhard, Iris; Steil, Regina; Klein, Christoph; Bohus, Martin; Ebner-Priemer, Ulrich W.

2014-01-01

Affective instability is a core feature of borderline personality disorder (BPD). The use of advanced assessment methodologies and appropriate statistical analyses has led to consistent findings that indicate a heightened instability in patients with BPD compared with healthy controls. However, few studies have investigated the specificity of affective instability among patients with BPD with regard to relevant clinical control groups. In this study, 43 patients with BPD, 28 patients with posttraumatic stress disorder (PTSD), 20 patients with bulimia nervosa (BN), and 28 healthy controls carried e-diaries for 24 hours and were prompted to rate their momentary affective states approximately every 15 minutes while awake. To quantify instability, we used 3 state-of-the-art indices: multilevel models for squared successive differences (SSDs), multilevel models for probability of acute changes (PACs), and aggregated point-by-point changes (APPCs). Patients with BPD displayed heightened affective instability for emotional valence and distress compared with healthy controls, regardless of the specific instability indices. These results directly replicate earlier studies. However, affective instability did not seem to be specific to patients with BPD. With regard to SSDs, PACs, and APPCs, patients with PTSD or BN showed a similar heightened instability of affect (emotional valence and distress) to that of patients with BPD. Our results give raise to the discussion if affective instability is a transdiagnostic or a disorder-specific mechanism. Current evidence cannot answer this question, but investigating psychopathological mechanisms in everyday life across disorders is a promising approach to enhance validity and specificity of mental health diagnoses. PMID:24661176

A study of directional instability during mitotic chromosome movement

NASA Astrophysics Data System (ADS)

Joglekar, Ajit P.

Mitotic chromosome movements are responsible for the correct segregation of duplicated chromosomes into the daughter cells. Errors in this process are known to play a role in some of the serious diseases such as cancer, and the little understood process of aging. A thorough comprehension of the physical basis of this process is therefore necessary. An intriguing aspect of chromosome movements during mitosis is "directional instability": runs with approximately constant speed punctuated by abrupt reversal in direction of motion. I have constructed a mechanistic model that views chromosome movement as a result of interplay between poleward and antipoleward or polar ejection forces (PEF) on a chromosome; and microtubule (MT) depolymerization-coupled movement of the chromosome. Computer simulations based on this model using a single set of parameters accurately and quantitatively predict: the force, character, speed, and duration of chromosome movements, oscillations of chromosomes associated with only one spindle pole, the larger force during anaphase, the effect of MT-depolymerizing drugs on chromosome movements, and the decreased turnover of kinetochore-MTs during anaphase. The model also predicts how chromosome behavior should respond to perturbations of the PEF. These predictions could be unequivocally tested if it were possible to destroy structures smaller than the light resolution limit with minimal collateral damage. To address these requirements, I developed a methodology for ultrahigh resolution microsurgery with tightly-focused, ultrafast lasers pulses. This entailed an in-depth study of optical breakdown in dielectrics. Characterization of the single pulse damage in test dielectric materials ranging from silicon and glass to cell walls and membranes has shown that in the target regions where the laser intensity exceeds critical intensity, optical breakdown proceeds by tunneling ionization followed by a runaway avalanche ionization that ends with the ionization of all the valence electrons. Highly reproducible features on the nanometer size-scale indicate that the valence electron density is the central factor determining the critical intensity, implying that high precision can be maintained in a wide range of solids. Along with the new understanding optical breakdown, this technique will find potential applications in diverse fields ranging from MEMS fabrication to nano-fluidics, as well as cellular nanosurgery.

New Insights into the Instability of Discharge Products in Na-O2 Batteries.

PubMed

Landa-Medrano, Imanol; Pinedo, Ricardo; Bi, Xuanxuan; Ruiz de Larramendi, Idoia; Lezama, Luis; Janek, Jürgen; Amine, Khalil; Lu, Jun; Rojo, Teófilo

2016-08-10

Sodium-oxygen batteries currently stimulate extensive research due to their high theoretical energy density and improved operational stability when compared to lithium-oxygen batteries. Cell stability, however, needs to be demonstrated also under resting conditions before future implementation of these batteries. In this work we analyze the effect of resting periods on the stability of the sodium superoxide (NaO2) discharge product. The instability of NaO2 in the cell environment is demonstrated leading to the evolution of oxygen during the resting period and the decrease of the cell efficiency. In addition, migration of the superoxide anion (O2(-)) in the electrolyte is observed and demonstrated to be an important factor affecting Coulombic efficiency.

New Insights into the Instability of Discharge Products in Na–O 2 Batteries

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

Landa-Medrano, Imanol; Pinedo, Ricardo; Bi, Xuanxuan

2016-08-10

Sodium–oxygen batteries currently stimulate extensive research due to their high theoretical energy density and improved operational stability when compared to lithium–oxygen batteries. Cell stability, however, needs to be demonstrated also under resting conditions before future implementation of these batteries. In this work we analyze the effect of resting periods on the stability of the sodium superoxide (NaO 2) discharge product. The instability of NaO 2 in the cell environment is demonstrated leading to the evolution of oxygen during the resting period and the decrease of the cell efficiency. In addition, migration of the superoxide anion (O2–) in the electrolyte ismore » observed and demonstrated to be an important factor affecting Coulombic efficiency.« less

Patellofemoral instability in children: T2 relaxation times of the patellar cartilage in patients with and without patellofemoral instability and correlation with morphological grading of cartilage damage.

PubMed

Kang, Chang Ho; Kim, Hee Kyung; Shiraj, Sahar; Anton, Christopher; Kim, Dong Hoon; Horn, Paul S

2016-07-01

Patellofemoral instability is one of the most common causes of cartilage damage in teenagers. To quantitatively evaluate the patellar cartilage in patients with patellofemoral instability using T2 relaxation time maps (T2 maps), compare the values to those in patients without patellofemoral instability and correlate them with morphological grades in patients with patellofemoral instability. Fifty-three patients with patellofemoral instability (mean age: 15.9 ± 2.4 years) and 53 age- and gender-matched patients without patellofemoral instability were included. Knee MR with axial T2 map was performed. Mean T2 relaxation times were obtained at the medial, central and lateral zones of the patellar cartilage and compared between the two groups. In the patellofemoral instability group, morphological grading of the patellar cartilage (0-4) was performed and correlated with T2 relaxation times. Mean T2 relaxation times were significantly longer in the group with patellofemoral instability as compared to those of the control group across the patellar cartilage (Student's t-test, P<0.05) with the longest time at the central area. Positive correlation was seen between mean T2 relaxation time and morphological grading (Pearson correlation coefficiency, P<0.001). T2 increased with severity of morphological grading from 0 to 3 (mixed model, P<0.001), but no statistical difference was seen between grades 3 and 4. In patellofemoral instability, patellar cartilage damage occurs across the entire cartilage with the highest T2 values at the apex. T2 relaxation times directly reflect the severity in low-grade cartilage damage, which implies an important role for T2 maps in differentiating between normal and low-grade cartilage damage.

Near-limit flame structures at low Lewis number

NASA Technical Reports Server (NTRS)

Ronney, Paul D.

1990-01-01

The characteristics of premixed gas flames in mixtures with low Lewis numbers near flammability limits were studied experimentally using a low-gravity environment to reduce buoyant convection. The behavior of such flames was found to be dominated by diffusive-thermal instabilities. For sufficiently reactive mixtures, cellular structures resulting from these instabilities were observed and found to spawn new cells in regular patterns. For less reactive mixtures, cells formed shortly after ignition but did not spawn new cells; instead these cells evolved into a flame structure composed of stationary, apparently stable spherical flamelets. Experimental observations are found to be in qualitative agreement with elementary analytical models based on the interaction of heat release due to chemical reaction, differential diffusion of thermal energy and mass, flame front curvature, and volumetric heat losses due to gas and/or soot radiation.

A study of the propagation, dynamics, and extinguishment of cellular flames using microgravity techniques

NASA Technical Reports Server (NTRS)

Ronney, Paul D.

1989-01-01

The characteristics of premixed gas flames in mixtures with low Lewis numbers, free of natural convection effects, were investigated and found to be dominated by diffusive-thermal instabilities. For sufficiently reactive mixtures, cellular structures resulting from these instabilities were observed and found to spawn new cells in regular patterns. For less reactive mixtures, cells formed shortly after ignition but did not spawn new cells; instead these cells evolved into a flame structure composed of stationary, apparently stable spherical flamelets. As a result of these phenomena, well-defined flammability limits were not observed. The experimental results are found to be in qualitative agreement with a simple analytical model based on the interaction of heat release due to chemical reaction, differential diffusion of thermal energy and mass, flame front curvature, and heat losses due to gas radiation.

Mitochondria regulate DNA damage and genomic instability induced by high LET radiation

NASA Astrophysics Data System (ADS)

Zhang, Bo; Davidson, Mercy M.; Hei, Tom K.

2014-04-01

High linear energy transfer (LET) radiation including α particles and heavy ions is the major type of radiation found in space and is considered a potential health risk for astronauts. Even though the chance that these high LET particles traversing through the cytoplasm of cells is higher than that through the nuclei, the contribution of targeted cytoplasmic irradiation to the induction of genomic instability and other chromosomal damages induced by high LET radiation is not known. In the present study, we investigated whether mitochondria are the potential cytoplasmic target of high LET radiation in mediating cellular damage using a mitochondrial DNA (mtDNA) depleted (ρ0) human small airway epithelial (SAE) cell model and a precision charged particle microbeam with a beam width of merely one micron. Targeted cytoplasmic irradiation by high LET α particles induced DNA oxidative damage and double strand breaks in wild type ρ+ SAE cells. Furthermore, there was a significant increase in autophagy and micronuclei, which is an indication of genomic instability, together with the activation of nuclear factor kappa-B (NF-κB) and mitochondrial inducible nitric oxide synthase (iNOS) signaling pathways in ρ+ SAE cells. In contrast, ρ0 SAE cells exhibited a significantly lower response to these same endpoints examined after cytoplasmic irradiation with high LET α particles. The results indicate that mitochondria are essential in mediating cytoplasmic radiation induced genotoxic damage in mammalian cells. Furthermore, the findings may shed some light in the design of countermeasures for space radiation.

Difference in postural control between patients with functional and mechanical ankle instability.

PubMed

Chen, Henry; Li, Hong-Yun; Zhang, Jian; Hua, Ying-Hui; Chen, Shi-Yi

2014-10-01

Lateral ankle sprain is one of the most common injuries. Since the structural and pathological differences in mechanical ankle instability (MAI) and functional ankle instability (FAI) may not be the same, it may be better to treat these as separate groups. The purpose of this study was to compare the difference in postural sway between MAI and FAI in patients with chronic ankle instability (CAI). Twenty-six patients with CAI and 14 healthy control participants were included in the study. The CAI patients were subdivided into MAI (15 patients) and FAI (11 patients) groups. Patients who were diagnosed with lateral ankle ligaments rupture by magnetic resonance imaging and ultrasonography were assigned to the MAI group. All participants performed single-limb postural sway tests 3 times on each leg with eyes closed and open. The average distances from the mean center of pressure position in the mediolateral and anteroposterior directions were recorded and compared among the 3 groups. The unstable ankles in the MAI group showed significantly greater postural sway in the anterior, posterior, and medial directions compared with those in the control group with eyes closed. With eyes open, significantly greater postural sway was found in the anterior direction. In the FAI group, no difference was found in postural sway compared with those in the control group. The MAI group showed significantly greater postural sway in the anterior direction compared with the FAI group with eyes closed and open. No significant difference in postural sway was found between the unstable and stable ankles in the MAI or FAI groups, with or without vision. Patients with MAI have deficits in postural control, especially in anterior-posterior directions. However, no difference was found in postural sway in patients with FAI compared with healthy people. As MAI patients suffer from deficits in postural control, balance training should be applied in those patients. In addition, special training should also include the contralateral side after a unilateral ankle ligament injured. © The Author(s) 2014.

Self-gravitational instability of dense degenerate viscous anisotropic plasma with rotation

NASA Astrophysics Data System (ADS)

Sharma, Prerana; Patidar, Archana

2017-12-01

The influence of finite Larmor radius correction, tensor viscosity and uniform rotation on self-gravitational and firehose instabilities is discussed in the framework of the quantum magnetohydrodynamic and Chew-Goldberger-Low (CGL) fluid models. The general dispersion relation is obtained for transverse and longitudinal modes of propagation. In both the modes of propagation the dispersion relation is further analysed with respect to the direction of the rotational axis. In the analytical discussion the axis of rotation is considered in parallel and in the perpendicular direction to the magnetic field. (i) In the transverse mode of propagation, when rotation is parallel to the direction of the magnetic field, the Jeans instability criterion is affected by the rotation, finite Larmor radius (FLR) and quantum parameter but remains unaffected due to the presence of tensor viscosity. The calculated critical Jeans masses for rotating and non-rotating dense degenerate plasma systems are \\odot $ and \\odot $ respectively. It is clear that the presence of rotation enhances the threshold mass of the considered system. (ii) In the case of longitudinal mode of propagation when rotation is parallel to the direction of the magnetic field, Alfvén and viscous self-gravitating modes are obtained. The Alfvén mode is modified by FLR corrections and rotation. The analytical as well as graphical results show that the presence of FLR and rotation play significant roles in stabilizing the growth rate of the firehose instability by suppressing the parallel anisotropic pressure. The viscous self-gravitating mode is significantly affected by tensor viscosity, anisotropic pressure and the quantum parameter while it remains free from rotation and FLR corrections. When the direction of rotation is perpendicular to the magnetic field, the rotation of the considered system coupled the Alfvén and viscous self-gravitating modes to each other. The finding of the present work is applicable to strongly magnetized dense degenerate plasma.

Two-dimensional Nonlinear Simulations of Temperature-anisotropy Instabilities with a Proton-alpha Drift

NASA Astrophysics Data System (ADS)

Markovskii, S. A.; Chandran, Benjamin D. G.; Vasquez, Bernard J.

2018-04-01

We present two-dimensional hybrid simulations of proton-cyclotron and mirror instabilities in a proton-alpha plasma with particle-in-cell ions and a neutralizing electron fluid. The instabilities are driven by the protons with temperature perpendicular to the background magnetic field larger than the parallel temperature. The alpha particles with initially isotropic temperature have a nonzero drift speed with respect to the protons. The minor ions are known to influence the relative effect of the proton-cyclotron and mirror instabilities. In this paper, we show that the mirror mode can dominate the power spectrum at the nonlinear stage even if its linear growth rate is significantly lower than that of the proton-cyclotron mode. The proton-cyclotron instability combined with the alpha-proton drift is a possible cause of the nonzero magnetic helicity observed in the solar wind for fluctuations propagating nearly parallel to the magnetic field. Our simulations generally confirm this concept but reveal a complex helicity spectrum that is not anticipated from the linear theory of the instability.

Droplet formation at the non-equilibrium water/water (w/w) interface

NASA Astrophysics Data System (ADS)

Chao, Youchuang; Mak, Sze Yi; Kong, Tiantian; Ding, Zijing; Shum, Ho Cheung

2017-11-01

The interfacial instability at liquid-liquid interfaces has been intensively studied in recent years due to their important role in nature and technology. Among them, two classic instabilities are Rayleigh-Taylor (RT) and double diffusive (DD) instabilities, which are practically relevant to many industrial processes, such as geologic CO2 sequestration. Most experimental and theoretical works have focused on RT or DD instability in binary systems. However, the study of such instability in complex systems, such as non-equilibrium ternary systems that involves mass-transfer-induced phase separation, has received less attention. Here, by using a ternary system known as the aqueous two-phase system (ATPS), we investigate experimentally the behavior of non-equilibrium water/water (w/w) interfaces in a vertically orientated Hele-Shaw cell. We observe that an array of fingers emerge at the w/w interface, and then break into droplets. We explore the instability using different concentrations of two aqueous phases. Our experimental findings are expected to inspire the mass production of all-aqueous emulsions in a simple setup.

Viscous Analysis of Pulsating Hydrodynamic Instability and Thermal Coupling Liquid-Propellant Combustion

NASA Technical Reports Server (NTRS)

Margolis, Stephen B.; Sacksteder, Kurt (Technical Monitor)

2000-01-01

A pulsating form of hydrodynamic instability has recently been shown to arise during liquid-propellant deflagration in those parameter regimes where the pressure-dependent burning rate is characterized by a negative pressure sensitivity. This type of instability can coexist with the classical cellular, or Landau form of hydrodynamic instability, with the occurrence of either dependent on whether the pressure sensitivity is sufficiently large or small in magnitude. For the inviscid problem, it has been shown that, when the burning rate is realistically allowed to depend on temperature as well as pressure, sufficiently large values of the temperature sensitivity relative to the pressure sensitivity causes like pulsating form of hydrodynamic instability to become dominant. In that regime, steady, planar burning becomes intrinsically unstable to pulsating disturbances whose wave numbers are sufficiently small. This analysis is extended to the fully viscous case, where it is shown that although viscosity is stabilizing for intermediate and larger wave number perturbations, the intrinsic pulsating instability for small wave numbers remains. Under these conditions, liquid-propellant combustion is predicted to be characterized by large unsteady cells along the liquid/gas interface.

Non-thermal electron distribution functions through 3D magnetic reconnection instabilities in the solar wind

NASA Astrophysics Data System (ADS)

Alejandro Munoz Sepulveda, Patricio; Buechner, Joerg

2017-04-01

The effects of kinetic instabilities on the solar wind electron velocity distribution functions (eVDFs) are mostly well understood under local homogeneous and stationary conditions. But the solar wind also contains current sheets, which affect the local properties of instabilities, turbulence and thus the observed non-maxwellian features in the eVDFs. Those processes are vastly unexplored. Therefore, we aim to investigate the influence of self-consistently generated turbulence via electron-scale instabilities in reconnecting current sheets on the formation of suprathermal features in the eVDFs. For this sake, we carry out 3D fully-kinetic Particle-in-Cell code numerical simulations of force free current sheets with a guide magnetic field. We find extended tails, anisotropic plateaus and non-gyrotropic features in the eVDFs, correlated with the locations and time where micro-turbulence is enhanced in the current sheet due to current-aligned streaming instabilities. We also discuss the influence of the plasma parameters, such as the ion to electron temperature ratio, on the excitation of current sheet instabilities and their effect on the properties of the eVDFs.

3D electrostatic gyrokinetic electron and fully kinetic ion simulation of lower-hybrid drift instability of Harris current sheet

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

Wang, Zhenyu; Lin, Yu; Wang, Xueyi

The eigenmode stability properties of three-dimensional lower-hybrid-drift-instabilities (LHDI) in a Harris current sheet with a small but finite guide magnetic field have been systematically studied by employing the gyrokinetic electron and fully kinetic ion (GeFi) particle-in-cell (PIC) simulation model with a realistic ion-to-electron mass ratio m i/m e. In contrast to the fully kinetic PIC simulation scheme, the fast electron cyclotron motion and plasma oscillations are systematically removed in the GeFi model, and hence one can employ the realistic m i/m e. The GeFi simulations are benchmarked against and show excellent agreement with both the fully kinetic PIC simulation and the analytical eigenmode theory. Our studies indicate that, for small wavenumbers, ky, along the current direction, the most unstable eigenmodes are peaked at the location wheremore » $$\\vec{k}$$• $$\\vec{B}$$ =0, consistent with previous analytical and simulation studies. Here, $$\\vec{B}$$ is the equilibrium magnetic field and $$\\vec{k}$$ is the wavevector perpendicular to the nonuniformity direction. As ky increases, however, the most unstable eigenmodes are found to be peaked at $$\\vec{k}$$ •$$\\vec{B}$$ ≠0. Additionally, the simulation results indicate that varying m i/m e, the current sheet width, and the guide magnetic field can affect the stability of LHDI. Simulations with the varying mass ratio confirm the lower hybrid frequency and wave number scalings.« less

3D electrostatic gyrokinetic electron and fully kinetic ion simulation of lower-hybrid drift instability of Harris current sheet

DOE PAGES

Wang, Zhenyu; Lin, Yu; Wang, Xueyi; ...

2016-07-07

The eigenmode stability properties of three-dimensional lower-hybrid-drift-instabilities (LHDI) in a Harris current sheet with a small but finite guide magnetic field have been systematically studied by employing the gyrokinetic electron and fully kinetic ion (GeFi) particle-in-cell (PIC) simulation model with a realistic ion-to-electron mass ratio m i/m e. In contrast to the fully kinetic PIC simulation scheme, the fast electron cyclotron motion and plasma oscillations are systematically removed in the GeFi model, and hence one can employ the realistic m i/m e. The GeFi simulations are benchmarked against and show excellent agreement with both the fully kinetic PIC simulation and the analytical eigenmode theory. Our studies indicate that, for small wavenumbers, ky, along the current direction, the most unstable eigenmodes are peaked at the location wheremore » $$\\vec{k}$$• $$\\vec{B}$$ =0, consistent with previous analytical and simulation studies. Here, $$\\vec{B}$$ is the equilibrium magnetic field and $$\\vec{k}$$ is the wavevector perpendicular to the nonuniformity direction. As ky increases, however, the most unstable eigenmodes are found to be peaked at $$\\vec{k}$$ •$$\\vec{B}$$ ≠0. Additionally, the simulation results indicate that varying m i/m e, the current sheet width, and the guide magnetic field can affect the stability of LHDI. Simulations with the varying mass ratio confirm the lower hybrid frequency and wave number scalings.« less

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

Casner, A.; Masse, L.; Delorme, B.

Understanding and mitigating hydrodynamic instabilities and the fuel mix are the key elements for achieving ignition in Inertial Confinement Fusion. Cryogenic indirect-drive implosions on the National Ignition Facility have evidenced that the ablative Rayleigh-Taylor Instability (RTI) is a driver of the hot spot mix. This motivates the switch to a more flexible higher adiabat implosion design [O. A. Hurricane et al., Phys. Plasmas 21, 056313 (2014)]. The shell instability is also the main candidate for performance degradation in low-adiabat direct drive cryogenic implosions [Goncharov et al., Phys. Plasmas 21, 056315 (2014)]. This paper reviews recent results acquired in planar experimentsmore » performed on the OMEGA laser facility and devoted to the modeling and mitigation of hydrodynamic instabilities at the ablation front. In application to the indirect-drive scheme, we describe results obtained with a specific ablator composition such as the laminated ablator or a graded-dopant emulator. In application to the direct drive scheme, we discuss experiments devoted to the study of laser imprinted perturbations with special phase plates. The simulations of the Richtmyer-Meshkov phase reversal during the shock transit phase are challenging, and of crucial interest because this phase sets the seed of the RTI growth. Recent works were dedicated to increasing the accuracy of measurements of the phase inversion. We conclude by presenting a novel imprint mitigation mechanism based on the use of underdense foams. Lastly, the foams induce laser smoothing by parametric instabilities thus reducing the laser imprint on the CH foil.« less

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

Casner, A., E-mail: alexis.casner@cea.fr; Masse, L.; Huser, G.

Understanding and mitigating hydrodynamic instabilities and the fuel mix are the key elements for achieving ignition in Inertial Confinement Fusion. Cryogenic indirect-drive implosions on the National Ignition Facility have evidenced that the ablative Rayleigh-Taylor Instability (RTI) is a driver of the hot spot mix. This motivates the switch to a more flexible higher adiabat implosion design [O. A. Hurricane et al., Phys. Plasmas 21, 056313 (2014)]. The shell instability is also the main candidate for performance degradation in low-adiabat direct drive cryogenic implosions [Goncharov et al., Phys. Plasmas 21, 056315 (2014)]. This paper reviews recent results acquired in planar experimentsmore » performed on the OMEGA laser facility and devoted to the modeling and mitigation of hydrodynamic instabilities at the ablation front. In application to the indirect-drive scheme, we describe results obtained with a specific ablator composition such as the laminated ablator or a graded-dopant emulator. In application to the direct drive scheme, we discuss experiments devoted to the study of laser imprinted perturbations with special phase plates. The simulations of the Richtmyer-Meshkov phase reversal during the shock transit phase are challenging, and of crucial interest because this phase sets the seed of the RTI growth. Recent works were dedicated to increasing the accuracy of measurements of the phase inversion. We conclude by presenting a novel imprint mitigation mechanism based on the use of underdense foams. The foams induce laser smoothing by parametric instabilities thus reducing the laser imprint on the CH foil.« less

Mechanics modelling of fern cavitation catapult

NASA Astrophysics Data System (ADS)

Kang, Jingtian; Li, Kai; Tan, Huifeng; Wang, Changguo; Cai, Shengqiang

2017-12-01

Cavitation is often regarded as a failure mode in soft materials. An intriguing phenomenon has been recently discovered that fern sporangium can take advantage of drying-induced cavitation instability in annulus cells to disperse spores at an extraordinarily high acceleration. Briefly, the decrease of environmental humidity causes continuous bending of the sporangium and growth of cavities inside the annulus cells, with the elastic energy accumulated in sporangium walls. When the humidity is lower than a critical value, the cavities suddenly expand dramatically inside the cells, causing a quick release of the elastic energy stored in the annular structure. As a result, like a catapult, the sporangium snaps back and ejects the seeds at a high speed. Motivated by the observation, in this article, we study cavitation instability in a similar structure as the sporangium. To simplify the problem, in our model, the mechanics of cells in the sporangium are described by the polymer gel model, while the sporangium wall is modelled as a hyperelastic material. When the environmental humidity is lower than a critical value, through energetic analyses, we can predict the cavitation catapult phenomenon using the model. We hope that our study in this article can provide useful insights into the bio-inspired design of structures which can take advantage of cavitation instability in soft materials.

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.

Acoustic far-field of shroud-lip-scattered instability modes of supersonic co-flowing jets

NASA Astrophysics Data System (ADS)

Samanta, Arnab; Freund, Jonathan B.

2013-11-01

We consider the acoustic radiation of instability modes in dual-stream jets, with the inner nozzle buried within the outer shroud, particularly the upstream scattering into acoustic modes that occurs at the shroud lip. For supersonic core jets, several families of instability waves are possible, beyond the regular Kelvin-Helmholtz (K-H) mode, with very different modal shapes and propagation characteristics, which are candidates for changing the sound character of very high-speed jets. The co-axial shear layers are modeled as vortex sheets, with the Wiener-Hopf method used to compute these modes coupled with an asymptotic solution for the far-field radiation. A broadband mode spectra as well as single propagating modes are considered as incident and scattered waves. The resulting far-field directivity patterns are quantified, to show the efficiency of some of these radiation mechanisms, particularly in the upstream direction, which is not directly affected by the Mach-wave-like sound that is radiated from these modes irrespective of any scattering surface. A full Kutta condition, which provides the usual boundary condition at the shroud lip, is altered to examine how vortex shedding, perhaps controllable at the lip, affects the radiated sound.

Stability of miscible displacements across stratified porous media

NASA Astrophysics Data System (ADS)

Shariati, Maryam; Yortsos, Yanis C.

2001-08-01

We consider the stability of miscible displacements across stratified porous media, where the heterogeneity is along the direction of displacement. Asymptotic results for long and short wavelengths are derived. It is found that heterogeneity has a long-wave effect on the instability, which, in the absence of gravity, becomes nontrivial when the viscosity profiles are nonmonotonic. In the latter case, profiles with end-point viscosities, predicted to be stable using the Saffman-Taylor criterion, can become unstable, if the permeability contrast in the direction of displacement is sufficiently large. Conversely, profiles with end-point viscosities predicted to be unstable, can become stable, if the permeability decrease in the direction of displacement is sufficiently large. Analogous results are found in the presence of gravity, but without the nonmonotonic restriction on the viscosity profile. The increase or decrease in the propensity for instability as the permeability increases or decreases, respectively, reflects the variation of the two different components of the effective fluid mobility. While permeability remains frozen in space, viscosity varies following the concentration field. Thus, the condition for instability does not solely depend on the overall fluid mobility, as in the case of displacements in homogeneous media, but it is additionally dependent on the permeability variation.

Inelastic Strain and Damage in Surface Instability Tests

NASA Astrophysics Data System (ADS)

Kao, Chu-Shu; Tarokh, Ali; Biolzi, Luigi; Labuz, Joseph F.

2016-02-01

Spalling near a free surface in laboratory experiments on two sandstones was characterized using acoustic emission and digital image correlation. A surface instability apparatus was used to reproduce a state of plane strain near a free surface in a modeled semi-infinite medium subjected to far-field compressive stress. Comparison between AE locations and crack trajectory mapped after the test showed good consistency. Digital image correlation was used to find the displacements in directions parallel (axial direction) and perpendicular (lateral direction) to the free surface at various stages of loading. At a load ratio, LR = current load/peak load, of approximately 30 %, elastic deformation was measured. At 70-80 % LR, the free-face effect started to appear in the displacement contours, especially for the lateral displacement measurements. As the axial compressive stress increased close to peak, extensional lateral strain started to show concentrations associated with localized damage. Continuum damage mechanics was used to describe damage evolution in the surface instability test, and it was shown that a critical value of extensional inelastic strain, on the order of -10-3 for the virgin sandstones, may provide an indicator for determining the onset of surface spalling.

Direct measurement of the image displacement instability in a linear induction accelerator

NASA Astrophysics Data System (ADS)

Burris-Mog, T. J.; Ekdahl, C. A.; Moir, D. C.

2017-06-01

The image displacement instability (IDI) has been measured on the 20 MeV Axis I of the dual axis radiographic hydrodynamic test facility and compared to theory. A 0.23 kA electron beam was accelerated across 64 gaps in a low solenoid focusing field, and the position of the beam centroid was measured to 34.3 meters downstream from the cathode. One beam dynamics code was used to model the IDI from first principles, while another code characterized the effects of the resistive wall instability and the beam break-up (BBU) instability. Although the BBU instability was not found to influence the IDI, it appears that the IDI influences the BBU. Because the BBU theory does not fully account for the dependence on beam position for coupling to cavity transverse magnetic modes, the effect of the IDI is missing from the BBU theory. This becomes of particular concern to users of linear induction accelerators operating in or near low magnetic guide fields tunes.

Direct measurement of the image displacement instability in a linear induction accelerator

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

Burris-Mog, T. J.; Ekdahl, C. A.; Moir, D. C.

The image displacement instability (IDI) has been measured on the 20 MeV Axis I of the dual axis radiographic hydrodynamic test facility and compared to theory. A 0.23 kA electron beam was accelerated across 64 gaps in a low solenoid focusing field, and the position of the beam centroid was measured to 34.3 meters downstream from the cathode. One beam dynamics code was used to model the IDI from first principles, while another code characterized the effects of the resistive wall instability and the beam break-up (BBU) instability. Although the BBU instability was not found to influence the IDI, itmore » appears that the IDI influences the BBU. Because the BBU theory does not fully account for the dependence on beam position for coupling to cavity transverse magnetic modes, the effect of the IDI is missing from the BBU theory. Finally, this becomes of particular concern to users of linear induction accelerators operating in or near low magnetic guide fields tunes.« less

Direct measurement of the image displacement instability in a linear induction accelerator

DOE PAGES

Burris-Mog, T. J.; Ekdahl, C. A.; Moir, D. C.

2017-06-19

The image displacement instability (IDI) has been measured on the 20 MeV Axis I of the dual axis radiographic hydrodynamic test facility and compared to theory. A 0.23 kA electron beam was accelerated across 64 gaps in a low solenoid focusing field, and the position of the beam centroid was measured to 34.3 meters downstream from the cathode. One beam dynamics code was used to model the IDI from first principles, while another code characterized the effects of the resistive wall instability and the beam break-up (BBU) instability. Although the BBU instability was not found to influence the IDI, itmore » appears that the IDI influences the BBU. Because the BBU theory does not fully account for the dependence on beam position for coupling to cavity transverse magnetic modes, the effect of the IDI is missing from the BBU theory. Finally, this becomes of particular concern to users of linear induction accelerators operating in or near low magnetic guide fields tunes.« less

Lunate fractures and associated radiocarpal and midcarpal instabilities: a systematic review.

PubMed

Shunmugam, Meenalochani; Phadnis, Joideep; Watts, Amy; Bain, Gregory I

2018-01-01

The aim of this study was to analyse lunate fractures and any associated osseo-ligamentous injuries. A systematic review identified 34 cases. We identified carpal instabilities at the radiocarpal and midcarpal joints in volar and dorsal directions. Radiocarpal instabilities (10/34) were usually dorsoradial (8/10), with a transverse lunate fracture, best seen on a coronal image. Midcarpal instabilities (24/34) were usually volar (14/18), with a volar lunate shear fracture, best seen on a sagittal image. Instabilities were sub-classified into non-displaced, subluxated and dislocated. Associated fractures of the scaphoid and the radial and ulnar styloid processes were common. Lunate fractures without subluxation or dislocation had good outcomes with cast immobilization or fixation of associated fractures. Lunate fracture-subluxations are unstable injuries that are best managed with fixation of the carpal fractures. Lunate fracture-dislocations are complex injuries, requiring stabilization of the lunate, associated fractures and ligament injuries; complications are common and acute or delayed salvage procedures may be required.

Coping Mediates the Association Between Marital Instability and Depression, but Not Marital Satisfaction and Depression

PubMed Central

Fink, Brandi C.; Shapiro, Alyson F.

2014-01-01

The association between marital discord and depression is well established. Marital discord is hypothesized to be a stressful life event that would evoke one’s efforts to cope with it. In an effort to further understand the nature of this association, the current study investigated coping as a mediating variable between marital dissatisfaction and depression and between marital instability and depression. Both marital dissatisfaction and instability, reflecting orthogonal dimensions of marital discord, were included in the model examined to elucidate a more complete picture of marital functioning. Structural Equation Modeling analyses revealed that coping mediated the association between marital instability and depression, but not marital dissatisfaction and depression, suggesting that coping traditionally considered adaptive for individuals in the context of controllable stressors may not be adaptive in the context of couple relationship instability. The findings also have implications for interventions focusing on decreasing maladaptive coping strategies in couples presenting for marital therapy or depression in addition to efforts directed at improving marital quality. PMID:25032063

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

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

Marchetti, Francesco; Wyrobek, Andrew J.

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

Aging impairs double-strand break repair by homologous recombination in Drosophila germ cells.

PubMed

Delabaere, Laetitia; Ertl, Henry A; Massey, Dashiell J; Hofley, Carolyn M; Sohail, Faraz; Bienenstock, Elisa J; Sebastian, Hans; Chiolo, Irene; LaRocque, Jeannine R

2017-04-01

Aging is characterized by genome instability, which contributes to cancer formation and cell lethality leading to organismal decline. The high levels of DNA double-strand breaks (DSBs) observed in old cells and premature aging syndromes are likely a primary source of genome instability, but the underlying cause of their formation is still unclear. DSBs might result from higher levels of damage or repair defects emerging with advancing age, but repair pathways in old organisms are still poorly understood. Here, we show that premeiotic germline cells of young and old flies have distinct differences in their ability to repair DSBs by the error-free pathway homologous recombination (HR). Repair of DSBs induced by either ionizing radiation (IR) or the endonuclease I-SceI is markedly defective in older flies. This correlates with a remarkable reduction in HR repair measured with the DR-white DSB repair reporter assay. Strikingly, most of this repair defect is already present at 8 days of age. Finally, HR defects correlate with increased expression of early HR components and increased recruitment of Rad51 to damage in older organisms. Thus, we propose that the defect in the HR pathway for germ cells in older flies occurs following Rad51 recruitment. These data reveal that DSB repair defects arise early in the aging process and suggest that HR deficiencies are a leading cause of genome instability in germ cells of older animals. © 2016 The Authors. Aging Cell published by the Anatomical Society and John Wiley & Sons Ltd.

Biological instability in a chlorinated drinking water distribution network.

PubMed

Nescerecka, Alina; Rubulis, Janis; Vital, Marius; Juhna, Talis; Hammes, Frederik

2014-01-01

The purpose of a drinking water distribution system is to deliver drinking water to the consumer, preferably with the same quality as when it left the treatment plant. In this context, the maintenance of good microbiological quality is often referred to as biological stability, and the addition of sufficient chlorine residuals is regarded as one way to achieve this. The full-scale drinking water distribution system of Riga (Latvia) was investigated with respect to biological stability in chlorinated drinking water. Flow cytometric (FCM) intact cell concentrations, intracellular adenosine tri-phosphate (ATP), heterotrophic plate counts and residual chlorine measurements were performed to evaluate the drinking water quality and stability at 49 sampling points throughout the distribution network. Cell viability methods were compared and the importance of extracellular ATP measurements was examined as well. FCM intact cell concentrations varied from 5×10(3) cells mL(-1) to 4.66×10(5) cells mL(-1) in the network. While this parameter did not exceed 2.1×10(4) cells mL(-1) in the effluent from any water treatment plant, 50% of all the network samples contained more than 1.06×10(5) cells mL(-1). This indisputably demonstrates biological instability in this particular drinking water distribution system, which was ascribed to a loss of disinfectant residuals and concomitant bacterial growth. The study highlights the potential of using cultivation-independent methods for the assessment of chlorinated water samples. In addition, it underlines the complexity of full-scale drinking water distribution systems, and the resulting challenges to establish the causes of biological instability.

Biological Instability in a Chlorinated Drinking Water Distribution Network

PubMed Central

Nescerecka, Alina; Rubulis, Janis; Vital, Marius; Juhna, Talis; Hammes, Frederik

2014-01-01

The purpose of a drinking water distribution system is to deliver drinking water to the consumer, preferably with the same quality as when it left the treatment plant. In this context, the maintenance of good microbiological quality is often referred to as biological stability, and the addition of sufficient chlorine residuals is regarded as one way to achieve this. The full-scale drinking water distribution system of Riga (Latvia) was investigated with respect to biological stability in chlorinated drinking water. Flow cytometric (FCM) intact cell concentrations, intracellular adenosine tri-phosphate (ATP), heterotrophic plate counts and residual chlorine measurements were performed to evaluate the drinking water quality and stability at 49 sampling points throughout the distribution network. Cell viability methods were compared and the importance of extracellular ATP measurements was examined as well. FCM intact cell concentrations varied from 5×103 cells mL−1 to 4.66×105 cells mL−1 in the network. While this parameter did not exceed 2.1×104 cells mL−1 in the effluent from any water treatment plant, 50% of all the network samples contained more than 1.06×105 cells mL−1. This indisputably demonstrates biological instability in this particular drinking water distribution system, which was ascribed to a loss of disinfectant residuals and concomitant bacterial growth. The study highlights the potential of using cultivation-independent methods for the assessment of chlorinated water samples. In addition, it underlines the complexity of full-scale drinking water distribution systems, and the resulting challenges to establish the causes of biological instability. PMID:24796923

TC Mps1 12, a novel Mps1 inhibitor, suppresses the growth of hepatocellular carcinoma cells via the accumulation of chromosomal instability.

PubMed

Choi, Minji; Min, Yoo Hong; Pyo, Jaehyuk; Lee, Chang-Woo; Jang, Chang-Young; Kim, Ja-Eun

2017-06-01

Chromosomal instability is not only a hallmark of cancer but also an attractive therapeutic target. A diverse set of mitotic kinases maintains chromosomal stability. One of these is monopolar spindle 1 (Mps1, also known as TTK), which is essential for chromosome alignment and for the spindle assembly checkpoint (SAC). Pharmacological inhibition of Mps1 has been suggested as a cancer therapeutic; however, despite the existence of a novel Mps1 inhibitor, TC Mps1 12, no such studies have been performed. The effects of TC Mps1 12 on cell viability, chromosome alignment, centrosome number, mitotic duration, apoptosis and SAC were determined in hepatocellular carcinoma (HCC) cells. In addition, the association of Mps1 expression with the overall survival of HCC patients was analysed. Treatment of human HCC cells with TC Mps1 12 led to chromosome misalignment and missegregation, and disorganization of centrosomes. Even in the presence of these errors, TC Mps1 12-treated cells overrode the SAC, resulting in a shortened mitotic duration and mitotic slippage. This mitotic catastrophe triggered apoptosis and, finally, inhibited the growth of HCC cells. In addition, the expression of the Mps1-encoding TTK gene was associated with poor overall survival of HCC patients. TC Mps1 12 results in the accumulation of chromosomal instabilities and mitotic catastrophe in HCC cells. Overall, these data demonstrate that the inhibition of Mps1 kinase using TC Mps1 12 is a promising therapeutic approach for liver cancer. © 2017 The British Pharmacological Society.

Activation of the ALT pathway for telomere maintenance can affect other sequences in the human genome.

PubMed

Jeyapalan, Jennie N; Varley, Helen; Foxon, Jenny L; Pollock, Raphael E; Jeffreys, Alec J; Henson, Jeremy D; Reddel, Roger R; Royle, Nicola J

2005-07-01

Immortal human cells maintain telomere length by the expression of telomerase or through the alternative lengthening of telomeres (ALT). The ALT mechanism involves a recombination-like process that allows the rapid elongation of shortened telomeres. However, it is not known whether activation of the ALT pathway affects other sequences in the genome. To address this we have investigated, in ALT-expressing cell lines and tumours, the stability of tandem repeat sequences known to mutate via homologous recombination in the human germline. We have shown extraordinary somatic instability in the human minisatellite MS32 (D1S8) in ALT-expressing (ALT+) but not in normal or telomerase-expressing cell lines. The MS32 mutation frequency varied across 15 ALT+ cell lines and was on average 55-fold greater than in ALT- cell lines. The MS32 minisatellite was also highly unstable in three of eight ALT+ soft tissue sarcomas, indicating that somatic destabilization occurs in vivo. The MS32 mutation rates estimated for two ALT+ cell lines were similar to that seen in the germline. However, the internal structures of ALT and germline mutant alleles are very different, indicating differences in the underlying mutation mechanisms. Five other hypervariable minisatellites did not show elevated instability in ALT-expressing cell lines, indicating that minisatellite destabilization is not universal. The elevation of MS32 instability upon activation of the ALT pathway and telomere length maintenance suggests there is overlap between the underlying processes that may be tractable through analysis of the D1S8 locus.

Prostate Cancer Cell Telomere Length Variability and Stromal Cell Telomere Length as Prognostic Markers for Metastasis and Death

PubMed Central

Heaphy, Christopher M.; Yoon, Ghil Suk; Peskoe, Sarah B.; Joshu, Corinne E.; Lee, Thomas K.; Giovannucci, Edward; Mucci, Lorelei A.; Kenfield, Stacey A.; Stampfer, Meir J.; Hicks, Jessica L.; De Marzo, Angelo M.; Platz, Elizabeth A.; Meeker, Alan K.

2013-01-01

Current prognostic indicators are imperfect predictors of outcome in men with clinicallylocalized prostate cancer. Thus, tissue-based markers are urgently needed to improve treatment and surveillance decision-making. Given that shortened telomeres enhance chromosomal instability and such instability is a hallmark of metastatic lesions, we hypothesized that alterations in telomere length in the primary cancer would predict risk of progression to metastasis and prostate cancer death. To test this hypothesis, we conducted a prospective cohort study of 596 surgically treated men who participated in the ongoing Health Professionals Follow-up Study. Men who had the combination of more variable telomere length among prostate cancer cells (cell-to-cell) and shorter telomere length in prostate cancer-associated stromal cells were substantially more likely to progress to metastasis or die of their prostate cancer. These findings point to the translational potential of this telomere biomarker for prognostication and risk stratification for individualized therapeutic and surveillance strategies. PMID:23779129

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.

Activation of BRCA1/BRCA2-Associated Helicase BACH1 Is Required for Timely Progression through S Phase▿

PubMed Central

Kumaraswamy, Easwari; Shiekhattar, Ramin

2007-01-01

BACH1 (also known as FANCJ and BRIP1) is a DNA helicase that directly interacts with the C-terminal BRCT repeat of the breast cancer susceptibility protein BRCA1. Previous biochemical and functional analyses have suggested a role for the BACH1 homolog in Caenorhabditis elegans during DNA replication. Here, we report the association of BACH1 with a distinct BRCA1/BRCA2-containing complex during the S phase of the cell cycle. Depletion of BACH1 or BRCA1 using small interfering RNAs results in delayed entry into the S phase of the cell cycle. Such timely progression through S phase requires the helicase activity of BACH1. Importantly, cells expressing a dominant negative mutation in BACH1 that results in a defective helicase displayed increased activation of DNA damage checkpoints and genomic instability. BACH1 helicase is silenced during the G1 phase of the cell cycle and is activated through a dephosphorylation event as cells enter S phase. These results point to a critical role for BACH1 helicase activity not only in the timely progression through the S phase but also in maintaining genomic stability. PMID:17664283

Deletion of TAK1 in the Myeloid Lineage Results in the Spontaneous Development of Myelomonocytic Leukemia in Mice

PubMed Central

Lamothe, Betty; Lai, YunJu; Hur, Lana; Orozco, Natalia Martin; Wang, Jing; Campos, Alejandro D.; Xie, Min; Schneider, Michael D.; Lockworth, Cynthia R.; Jakacky, Jared; Tran, Diep; Ho, Michael; Dawud, Sity; Dong, Chen; Lin, Hui-Kuan; Hu, Peter; Estrov, Zeev; Bueso-Ramos, Carlos E.; Darnay, Bryant G.

2012-01-01

Previous studies of the conditional ablation of TGF-β activated kinase 1 (TAK1) in mice indicate that TAK1 has an obligatory role in the survival and/or development of hematopoietic stem cells, B cells, T cells, hepatocytes, intestinal epithelial cells, keratinocytes, and various tissues, primarily because of these cells’ increased apoptotic sensitivity, and have implicated TAK1 as a critical regulator of the NF-κB and stress kinase pathways and thus a key intermediary in cellular survival. Contrary to this understanding of TAK1’s role, we report a mouse model in which TAK1 deletion in the myeloid compartment that evoked a clonal myelomonocytic cell expansion, splenomegaly, multi-organ infiltration, genomic instability, and aggressive, fatal myelomonocytic leukemia. Unlike in previous reports, simultaneous deletion of TNF receptor 1 (TNFR1) failed to rescue this severe phenotype. We found that the features of the disease in our mouse model resemble those of human chronic myelomonocytic leukemia (CMML) in its transformation to acute myeloid leukemia (AML). Consequently, we found TAK1 deletion in 13 of 30 AML patients (43%), thus providing direct genetic evidence of TAK1’s role in leukemogenesis. PMID:23251462

Chromosome Aberrations in Cells Infected with Bovine Papillomavirus: Comparing Cutaneous Papilloma, Esophagus Papilloma, and Urinary Bladder Lesion Cells

PubMed Central

Campos, S. R. C.; Melo, T. C.; Assaf, S.; Araldi, R. P.; Mazzuchelli-de-Souza, J.; Sircili, M. P.; Carvalho, R. F.; Roperto, F.; Beçak, W.; Stocco, R. C.

2013-01-01

The majority of malignant cells present genetic instability with chromosome number changes plus segmental defects: these changes involve intact chromosomes and breakage-induced alterations. Some pathways of chromosomal instability have been proposed as random breakage, telomere fusion, and centromere fission. Chromosome alterations in tumor cells have been described in animal models and in vitro experiments. One important question is about possible discrepancies between animal models, in vitro studies, and the real events in cancer cells in vivo. Papillomaviruses are relevant agents in oncogenic processes related to action on host genome. Recently, many reports have discussed the presence of virus DNA in peripheral blood, in humans and in animals infected by papillomaviruses. The meaning of this event is of controversy: possible product of apoptosis occurring in cancer cells, metastasized cancer cells, or active DNA sequences circulating in bloodstream. This study compares chromosome aberrations detected in bovine cells, in peripheral blood cells, and in BPV lesion cells: the literature is poor in this type of study. Comparing chromosome aberrations described in the different cells, a common mechanism in their origin, can be suggested. Furthermore blood cells can be evaluated as an effective way of virus transmission. PMID:24298391

On the structure of the two-stream instability–complex G-Hamiltonian structure and Krein collisions between positive- and negative-action modes

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

Zhang, Ruili; Liu, Jian; Xiao, Jianyuan

2016-07-15

The two-stream instability is probably the most important elementary example of collective instabilities in plasma physics and beam-plasma systems. For a warm plasma with two charged particle species, the instability diagram of the two-stream instability based on a 1D warm-fluid model exhibits an interesting band structure that has not been explained. We show that the band structure for this instability is the consequence of the Hamiltonian nature of the warm two-fluid system. Interestingly, the Hamiltonian nature manifests as a complex G-Hamiltonian structure in wave-number space, which directly determines the instability diagram. Specifically, it is shown that the boundaries between themore » stable and unstable regions are locations for Krein collisions between eigenmodes with different Krein signatures. In terms of physics, this rigorously implies that the system is destabilized when a positive-action mode resonates with a negative-action mode, and that this is the only mechanism by which the system can be destabilized. It is anticipated that this physical mechanism of destabilization is valid for other collective instabilities in conservative systems in plasma physics, accelerator physics, and fluid dynamics systems, which admit infinite-dimensional Hamiltonian structures.« less

Stationary Crossflow Breakdown due to Mixed Mode Spectra of Secondary Instabilities

NASA Technical Reports Server (NTRS)

Li, Fei; Choudhari, Meelan M.; Duan, Lian

2016-01-01

Numerical simulations are used to study laminar breakdown characteristics associated with stationary crossflow instability in the boundary-layer flow over a subsonic swept-wing configuration. Previous work involving the linear and nonlinear development of individual, fundamental modes of secondary instability waves is extended by considering the role of more complex, yet controlled, spectra of the secondary instability modes. Direct numerical simulations target a mixed mode transition scenario involving the simultaneous presence of Y and Z modes of secondary instability. For the initial amplitudes investigated in this paper, the Y modes are found to play an insignificant role during the onset of transition, in spite of achieving rather large, O(5%), amplitudes of RMS velocity fluctuation prior to transition. Analysis of the numerical simulations shows that this rather surprising finding can be attributed to the fact that the Y modes are concentrated near the top of the crossflow vortex and exert relatively small influence on the Z modes that reside closer to the surface and can lead to transition via nonlinear spreading that does not involve interactions with the Y mode. Finally, secondary instability calculations reveal that subharmonic modes of secondary instability have substantially lower growth rates than those of the fundamental modes, and hence, are less likely to play an important role during the breakdown process involving complex initial spectra.

White-light parametric instabilities in plasmas.

PubMed

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

2007-06-08

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