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Sample records for a-t mutated atm

  1. Screening for ATM Mutations in an African-American Population to Identify a Predictor of Breast Cancer Susceptibility

    DTIC Science & Technology

    2006-07-01

    ATM genetic variant identified affects radiosensitivity and levels of the protein encoded by the ATM gene for each mutation examined. 15. SUBJECT...women without breast cancer. An additional objective is to determine the functional impact upon the protein encoded by the ATM gene for each mutation ...each ATM variant identified affects radiosensitivity and levels of the protein encoded by the ATM gene for mutations identified. Body STATEMENT

  2. A Novel Method to Screen for Dominant Negative ATM Mutations in Familial Breast Cancer

    DTIC Science & Technology

    2005-04-01

    carry dominant negative mutation in ATM due to natural variation amongst LCLs. Microarrays have been performed to determine differences in gene expression... genes that are altered in their expression in ATMmutation carriers. The validation of this data in carriers of different ATM mutation indicated that the...heterozygous carriers of T727 1 G mutation display a gene expression phenotype that appears identical to carriers of protein truncating mutations in

  3. ATM Mutations and the Development of Severe Radiation-Induced Morbidity Following Radiotherapy for Breast Cancer

    DTIC Science & Technology

    2005-07-01

    repair of radiation-induced damage. Furthermore, cells possessing a mutated copy of this gene are more radiosensitive than cells from individuals with...AD Award Number: DAMD17-02-1-0503 TITLE: ATM Mutations and the Development of Severe Radiation-Induced Morbidity Following Radiotherapy for Breast...2005 Annual 1 Jul 2004 - 30 Jun 2005 4. TITLE AND SUBTITLE 5a. CONTRACT NUMBER ATM Mutations and the Development of Severe Radiation-Induced Morbidity

  4. ATM Mutations and the Development of Severe Radiation-Induced Morbidity Following Radiotherapy for Breast Cancer

    DTIC Science & Technology

    2006-07-01

    patients who are carriers of an alteration in this gene . This project is innovative as it represents the first study to use the powerful DHPLC mutation ...development of adverse responses to radiotherapy (5-6). The first gene to have received significant attention was the mutated in ataxia telangiectasia (AT...Group and Concannon PJ. 2003. Designing and implementing quality control for multi-center screening of mutations in the ATM gene among women with

  5. Ataxia telangiectasia mutated (ATM) interacts with p400 ATPase for an efficient DNA damage response.

    PubMed

    Smith, Rebecca J; Savoian, Matthew S; Weber, Lauren E; Park, Jeong Hyeon

    2016-11-04

    Ataxia telangiectasia mutated (ATM) and TRRAP proteins belong to the phosphatidylinositol 3-kinase-related kinase family and are involved in DNA damage repair and chromatin remodeling. ATM is a checkpoint kinase that is recruited to sites of DNA double-strand breaks where it phosphorylates a diverse range of proteins that are part of the chromatin and DNA repair machinery. As an integral subunit of the TRRAP-TIP60 complexes, p400 ATPase is a chromatin remodeler that is also targeted to DNA double-strand break sites. While it is understood that DNA binding transcriptional activators recruit p400 ATPase into a regulatory region of the promoter, how p400 recognises and moves to DNA double-strand break sites is far less clear. Here we investigate a possibility whether ATM serves as a shuttle to deliver p400 to break sites. Our data indicate that p400 co-immunoprecipitates with ATM independently of DNA damage state and that the N-terminal domain of p400 is vital for this interaction. Heterologous expression studies using Sf9 cells revealed that the ATM-p400 complex can be reconstituted without other mammalian bridging proteins. Overexpression of ATM-interacting p400 regions in U2OS cells induced dominant negative effects including the inhibition of both DNA damage repair and cell proliferation. Consistent with the dominant negative effect, the stable expression of an N-terminal p400 fragment showed a decrease in the association of p400 with ATM, but did not alter the association of p400 with TRRAP. Taken together, our findings suggest that a protein-protein interaction between ATM and p400 ATPase occurs independently of DNA damage and contributes to efficient DNA damage response and repair.

  6. Almost 2% of Spanish breast cancer families are associated to germline pathogenic mutations in the ATM gene.

    PubMed

    Tavera-Tapia, A; Pérez-Cabornero, L; Macías, J A; Ceballos, M I; Roncador, G; de la Hoya, M; Barroso, A; Felipe-Ponce, V; Serrano-Blanch, R; Hinojo, C; Miramar-Gallart, M D; Urioste, M; Caldés, T; Santillan-Garzón, S; Benitez, J; Osorio, A

    2017-02-01

    There is still a considerable percentage of hereditary breast and ovarian cancer (HBOC) cases not explained by BRCA1 and BRCA2 genes. In this report, next-generation sequencing (NGS) techniques were applied to identify novel variants and/or genes involved in HBOC susceptibility. Using whole exome sequencing, we identified a novel germline mutation in the moderate-risk gene ATM (c.5441delT; p.Leu1814Trpfs*14) in a family negative for mutations in BRCA1/2 (BRCAX). A case-control association study was performed to establish its prevalence in Spanish population, in a series of 1477 BRCAX families and 589 controls further screened, and NGS panels were used for ATM mutational screening in a cohort of 392 HBOC Spanish BRCAX families and 350 patients affected with diseases not related to breast cancer. Although the interrogated mutation was not prevalent in case-control association study, a comprehensive mutational analysis of the ATM gene revealed 1.78% prevalence of mutations in the ATM gene in HBOC and 1.94% in breast cancer-only BRCAX families in Spanish population, where data about ATM mutations were very limited. ATM mutation prevalence in Spanish population highlights the importance of considering ATM pathogenic variants linked to breast cancer susceptibility.

  7. Tele-ultrasound using ATM over a T-1 satellite connection

    NASA Astrophysics Data System (ADS)

    Williamson, Morgan P.; Suitor, Charles T.; de Treville, Robert E.; Freckleton, Michael W.; Kinsey, Van; Goeringer, Fred; Lyche, David K.; Hunter, Bruce; Jennings, Neal E.; Shelton, Philip D.; Marcy, Jon; Poore, Tom; North, Jack

    1996-04-01

    In September 1995 the United States military conducted a demonstration project to provide live ultrasound video and diagnostic DICOM still images using GTE's asynchronous transfer mode (ATM) technologies over an Orion T-1 satellite link. Still images were frame-grabbed from a Diasonics ultrasound and sent to the ALI Wide Area Network system. A group of diagnostic images was then sent in DICOM 3.0 format over a virtual ethernet satellite link from Chantilly, Virginia to Dayton, Ohio. These images came across a DICOM gateway into the Medical Diagnostic Imaging Support (MDIS) System. Live video from the ultrasound was also routed through a CLI Radiance VTC over the satellite to a VTC in Ohio. The video bandwidth was progressively narrowed with two radiologists determining the minimal acceptable bandwidth for detecting test objects in a phantom. The radiologists accepted live video ultrasound at bandwidths as low as 384 kbps from the hands of an experienced ultrasonographer located hundreds of miles away. DICOM still images were sent uncompressed and were of acceptable image quality when viewed on the MDIS system. The technology demonstrated holds great promise for both deployed U.S. Military Forces and civil uses of remote radiology. Detailed network drawings and videotapes of the ultrasound examinations at the remote site are provided.

  8. The impact of an early truncating founder ATM mutation on immunoglobulins, specific antibodies and lymphocyte populations in ataxia-telangiectasia patients and their parents

    PubMed Central

    STRAY-PEDERSEN, A; JÓNSSON, T; HEIBERG, A; LINDMAN, C R; WIDING, E; AABERGE, I S; BORRESEN-DALE, A L; ABRAHAMSEN, T G

    2004-01-01

    Eleven Norwegian patients (aged 2–33 years, seven males and four females) with Ataxia-telangiectasia (A-T) and their parents were investigated. Five of the patients were homozygous for the same ATM mutation, 3245delATCinsTGAT, a Norwegian founder mutation. They had the lowest IgG2 levels; mean (95% confidence interval) 0·23 (0·05–0·41) g/l versus 0·91 (0·58–1·26) g/l in the other patients (P = 0·002). Among the 11 A-T patients, six had IgG2 deficiency, six had IgA deficiency (three in combination with IgG2 deficiency) and seven had low/undetectable IgE values. All patients had very low levels of antibodies to Streptococcus pneumoniae 0·9 (0·4–1·4) U/ml, while normal levels were found in their parents 11·1 (8·7–13·4) U/ml (P < 0·001). A positive linear relationship between pneumococcal antibodies and IgG2 (r = 0·85, P = 0·001) was found in the patients. Six of 11 had diphtheria antibodies and 7 of 11 tetanus antibodies after childhood vaccinations, while 4 of 7 Hemophilus influenzae type b (Hib) vaccinated patients had protective antibodies. Ten patients had low B cell (CD19+) counts, while six had low T cell (CD3+) counts. Of the T cell subpopulations, 11 had low CD4+ cell counts, six had reduced CD8+ cell counts, and four had an increased portion of double negative (CD3+/CD4-/CD8-) gamma delta T cells. Of the 22 parents (aged 23–64 years) 12 were heterozygous for the ATM founder mutation. Abnormalities in immunoglobulin levels and/or lymphocyte subpopulations were also observed in these carriers, with no correlation to a special ATM genotype. PMID:15196260

  9. A pharmacological screen for compounds that rescue the developmental lethality of a Drosophila ATM mutant

    PubMed Central

    Rimkus, Stacey A.

    2018-01-01

    Ataxia-telangiectasia (A-T) is a neurodegenerative disease caused by mutation of the A-T mutated (ATM) gene. ATM encodes a protein kinase that is activated by DNA damage and phosphorylates many proteins, including those involved in DNA repair, cell cycle control, and apoptosis. Characteristic biological and molecular functions of ATM observed in mammals are conserved in Drosophila melanogaster. As an example, conditional loss-of-function ATM alleles in flies cause progressive neurodegeneration through activation of the innate immune response. However, unlike in mammals, null alleles of ATM in flies cause lethality during development. With the goals of understanding biological and molecular roles of ATM in a whole animal and identifying candidate therapeutics for A-T, we performed a screen of 2400 compounds, including FDA-approved drugs, natural products, and bioactive compounds, for modifiers of the developmental lethality caused by a temperature-sensitive ATM allele (ATM8) that has reduced kinase activity at non-permissive temperatures. Ten compounds reproducibly suppressed the developmental lethality of ATM8 flies, including Ronnel, which is an organophosphate. Ronnel and other suppressor compounds are known to cause mitochondrial dysfunction or to inhibit the enzyme acetylcholinesterase, which controls the levels of the neurotransmitter acetylcholine, suggesting that detrimental consequences of reduced ATM kinase activity can be rescued by inhibiting the function of mitochondria or increasing acetylcholine levels. We carried out further studies of Ronnel because, unlike the other compounds that suppressed the developmental lethality of homozygous ATM8 flies, Ronnel was toxic to the development of heterozygous ATM8 flies. Ronnel did not affect the innate immune response of ATM8 flies, and it further increased the already high levels of DNA damage in brains of ATM8 flies, but its effects were not harmful to the lifespan of rescued ATM8 flies. These results provide

  10. Quantitative Phosphoproteomics of the Ataxia Telangiectasia-Mutated (ATM) and Ataxia Telangiectasia-Mutated and Rad3-related (ATR) Dependent DNA Damage Response in Arabidopsis thaliana*

    PubMed Central

    Roitinger, Elisabeth; Hofer, Manuel; Köcher, Thomas; Pichler, Peter; Novatchkova, Maria; Yang, Jianhua; Schlögelhofer, Peter; Mechtler, Karl

    2015-01-01

    The reversible phosphorylation of proteins on serine, threonine, and tyrosine residues is an important biological regulatory mechanism. In the context of genome integrity, signaling cascades driven by phosphorylation are crucial for the coordination and regulation of DNA repair. The two serine/threonine protein kinases ataxia telangiectasia-mutated (ATM) and Ataxia telangiectasia-mutated and Rad3-related (ATR) are key factors in this process, each specific for different kinds of DNA lesions. They are conserved across eukaryotes, mediating the activation of cell-cycle checkpoints, chromatin modifications, and regulation of DNA repair proteins. We designed a novel mass spectrometry-based phosphoproteomics approach to study DNA damage repair in Arabidopsis thaliana. The protocol combines filter aided sample preparation, immobilized metal affinity chromatography, metal oxide affinity chromatography, and strong cation exchange chromatography for phosphopeptide generation, enrichment, and separation. Isobaric labeling employing iTRAQ (isobaric tags for relative and absolute quantitation) was used for profiling the phosphoproteome of atm atr double mutants and wild type plants under either regular growth conditions or challenged by irradiation. A total of 10,831 proteins were identified and 15,445 unique phosphopeptides were quantified, containing 134 up- and 38 down-regulated ATM/ATR dependent phosphopeptides. We identified known and novel ATM/ATR targets such as LIG4 and MRE11 (needed for resistance against ionizing radiation), PIE1 and SDG26 (implicated in chromatin remodeling), PCNA1, WAPL, and PDS5 (implicated in DNA replication), and ASK1 and HTA10 (involved in meiosis). PMID:25561503

  11. Loss of ATM kinase activity leads to embryonic lethality in mice.

    PubMed

    Daniel, Jeremy A; Pellegrini, Manuela; Lee, Baeck-Seung; Guo, Zhi; Filsuf, Darius; Belkina, Natalya V; You, Zhongsheng; Paull, Tanya T; Sleckman, Barry P; Feigenbaum, Lionel; Nussenzweig, André

    2012-08-06

    Ataxia telangiectasia (A-T) mutated (ATM) is a key deoxyribonucleic acid (DNA) damage signaling kinase that regulates DNA repair, cell cycle checkpoints, and apoptosis. The majority of patients with A-T, a cancer-prone neurodegenerative disease, present with null mutations in Atm. To determine whether the functions of ATM are mediated solely by its kinase activity, we generated two mouse models containing single, catalytically inactivating point mutations in Atm. In this paper, we show that, in contrast to Atm-null mice, both D2899A and Q2740P mutations cause early embryonic lethality in mice, without displaying dominant-negative interfering activity. Using conditional deletion, we find that the D2899A mutation in adult mice behaves largely similar to Atm-null cells but shows greater deficiency in homologous recombination (HR) as measured by hypersensitivity to poly (adenosine diphosphate-ribose) polymerase inhibition and increased genomic instability. These results may explain why missense mutations with no detectable kinase activity are rarely found in patients with classical A-T. We propose that ATM kinase-inactive missense mutations, unless otherwise compensated for, interfere with HR during embryogenesis.

  12. Loss of ATM kinase activity leads to embryonic lethality in mice

    PubMed Central

    Pellegrini, Manuela; Lee, Baeck-Seung; Guo, Zhi; Filsuf, Darius; Belkina, Natalya V.; You, Zhongsheng; Paull, Tanya T.; Sleckman, Barry P.; Feigenbaum, Lionel

    2012-01-01

    Ataxia telangiectasia (A-T) mutated (ATM) is a key deoxyribonucleic acid (DNA) damage signaling kinase that regulates DNA repair, cell cycle checkpoints, and apoptosis. The majority of patients with A-T, a cancer-prone neurodegenerative disease, present with null mutations in Atm. To determine whether the functions of ATM are mediated solely by its kinase activity, we generated two mouse models containing single, catalytically inactivating point mutations in Atm. In this paper, we show that, in contrast to Atm-null mice, both D2899A and Q2740P mutations cause early embryonic lethality in mice, without displaying dominant-negative interfering activity. Using conditional deletion, we find that the D2899A mutation in adult mice behaves largely similar to Atm-null cells but shows greater deficiency in homologous recombination (HR) as measured by hypersensitivity to poly (adenosine diphosphate-ribose) polymerase inhibition and increased genomic instability. These results may explain why missense mutations with no detectable kinase activity are rarely found in patients with classical A-T. We propose that ATM kinase-inactive missense mutations, unless otherwise compensated for, interfere with HR during embryogenesis. PMID:22869595

  13. Germline Mutations in ATM and BRCA1/2 Distinguish Risk for Lethal and Indolent Prostate Cancer and are Associated with Early Age at Death

    PubMed Central

    Na, Rong; Zheng, S. Lilly; Han, Misop; Yu, Hongjie; Jiang, Deke; Shah, Sameep; Ewing, Charles M.; Zhang, Liti; Novakovic, Kristian; Petkewicz, Jacqueline; Gulukota, Kamalakar; Helseth, Donald L.; Quinn, Margo; Humphries, Elizabeth; Wiley, Kathleen E.; Isaacs, Sarah D.; Wu, Yishuo; Liu, Xu; Zhang, Ning; Wang, Chi-Hsiung; Khandekar, Janardan; Hulick, Peter J.; Shevrin, Daniel H.; Cooney, Kathleen A.; Shen, Zhoujun; Partin, Alan W.; Carter, H. Ballentine; Carducci, Michael A.; Eisenberger, Mario A.; Denmeade, Sam R.; McGuire, Michael; Walsh, Patrick C.; Helfand, Brian T.; Brendler, Charles B.; Ding, Qiang; Xu, Jianfeng; Isaacs, William B.

    2017-01-01

    Background Germline mutations in BRCA1/2 and ATM have been associated with prostate cancer (PCa) risk. Objective To directly assess whether germline mutations in these three genes distinguish lethal from indolent PCa and whether they confer any effect on age at death. Design, setting, and participants A retrospective case-case study of 313 patients who died of PCa and 486 patients with low-risk localized PCa of European, African, and Chinese descent. Germline DNA of each of the 799 patients was sequenced for these three genes. Outcome measurements and statistical analysis Mutation carrier rates and their effect on lethal PCa were analyzed using the Fisher’s exact test and Cox regression analysis, respectively. Results and limitations The combined BRCA1/2 and ATM mutation carrier rate was significantly higher in lethal PCa patients (6.07%) than localized PCa patients (1.44%), p = 0.0007. The rate also differed significantly among lethal PCa patients as a function of age at death (10.00%, 9.08%, 8.33%, 4.94%, and 2.97% in patients who died ≤60 yr, 61–65 yr, 66–70 yr, 71–75 yr, and over 75 yr, respectively, p = 0.046) and time to death after diagnosis (12.26%, 4.76%, and 0.98% in patients who died ≤5 yr, 6–10 yr, and > 10 yr after a PCa diagnosis, respectively, p = 0.0006). Survival analysis in the entire cohort revealed mutation carriers remained an independent predictor of lethal PCa after adjusting for race and age, prostate-specific antigen, and Gleason score at the time of diagnosis (hazard ratio = 2.13, 95% confidence interval: 1.24–3.66, p = 0.004). A limitation of this study is that other DNA repair genes were not analyzed. Conclusions Mutation status of BRCA1/2 and ATM distinguishes risk for lethal and indolent PCa and is associated with earlier age at death and shorter survival time. Patient summary Prostate cancer patients with inherited mutations in BRCA1/2 and ATM are more likely to die of prostate cancer and do so at an earlier age. PMID

  14. Morbidity and mortality from ataxia-telangiectasia are associated with ATM genotype.

    PubMed

    Micol, Romain; Ben Slama, Lilia; Suarez, Felipe; Le Mignot, Loïc; Beauté, Julien; Mahlaoui, Nizar; Dubois d'Enghien, Catherine; Laugé, Anthony; Hall, Janet; Couturier, Jérôme; Vallée, Louis; Delobel, Bruno; Rivier, François; Nguyen, Karine; Billette de Villemeur, Thierry; Stephan, Jean-Louis; Bordigoni, Pierre; Bertrand, Yves; Aladjidi, Nathalie; Pedespan, Jean-Michel; Thomas, Caroline; Pellier, Isabelle; Koenig, Michel; Hermine, Olivier; Picard, Capucine; Moshous, Despina; Neven, Bénédicte; Lanternier, Fanny; Blanche, Stéphane; Tardieu, Marc; Debré, Marianne; Fischer, Alain; Stoppa-Lyonnet, Dominique

    2011-08-01

    Ataxia-telangiectasia (A-T) is a rare genetic disease caused by germline biallelic mutations in the ataxia-telangiectasia mutated gene (ATM) that result in partial or complete loss of ATM expression or activity. The course of the disease is characterized by neurologic manifestations, infections, and cancers. We studied A-T progression and investigated whether manifestations were associated with the ATM genotype. We performed a retrospective cohort study in France of 240 patients with A-T born from 1954 to 2005 and analyzed ATM mutations in 184 patients, along with neurologic manifestations, infections, and cancers. Among patients with A-T, the Kaplan-Meier 20-year survival rate was 53.4%; the prognosis for these patients has not changed since 1954. Life expectancy was lower among patients with mutations in ATM that caused total loss of expression or function of the gene product (null mutations) compared with that seen in patients with hypomorphic mutations because of earlier onset of cancer (mainly hematologic malignancies). Cancer (hazard ratio, 2.7; 95% CI, 1.6-4.5) and respiratory tract infections (hazard ratio, 2.3; 95% CI, 1.4-3.8) were independently associated with mortality. Cancer (hazard ratio, 5.8; 95% CI, 2.9-11.6) was a major risk factor for mortality among patients with null mutations, whereas respiratory tract infections (hazard ratio, 4.1; 95% CI, 1.8-9.1) were the leading cause of death among patients with hypomorphic mutations. Morbidity and mortality among patients with A-T are associated with ATM genotype. This information could improve our prognostic ability and lead to adapted therapeutic strategies. Copyright © 2011 American Academy of Allergy, Asthma & Immunology. Published by Mosby, Inc. All rights reserved.

  15. ATM kinase inhibition in glial cells activates the innate immune response and causes neurodegeneration in Drosophila.

    PubMed

    Petersen, Andrew J; Rimkus, Stacey A; Wassarman, David A

    2012-03-13

    To investigate the mechanistic basis for central nervous system (CNS) neurodegeneration in the disease ataxia-telangiectasia (A-T), we analyzed flies mutant for the causative gene A-T mutated (ATM). ATM encodes a protein kinase that functions to monitor the genomic integrity of cells and control cell cycle, DNA repair, and apoptosis programs. Mutation of the C-terminal amino acid in Drosophila ATM inhibited the kinase activity and caused neuron and glial cell death in the adult brain and a reduction in mobility and longevity. These data indicate that reduced ATM kinase activity is sufficient to cause neurodegeneration in A-T. ATM kinase mutant flies also had elevated expression of innate immune response genes in glial cells. ATM knockdown in glial cells, but not neurons, was sufficient to cause neuron and glial cell death, a reduction in mobility and longevity, and elevated expression of innate immune response genes in glial cells, indicating that a non-cell-autonomous mechanism contributes to neurodegeneration in A-T. Taken together, these data suggest that early-onset CNS neurodegeneration in A-T is similar to late-onset CNS neurodegeneration in diseases such as Alzheimer's in which uncontrolled inflammatory response mediated by glial cells drives neurodegeneration.

  16. Iron loading and oxidative stress in the Atm-/- mouse liver.

    PubMed

    McDonald, Cameron J; Ostini, Lesa; Wallace, Daniel F; John, Abraham N; Watters, Dianne J; Subramaniam, V Nathan

    2011-04-01

    Ataxia-Telangiectasia (A-T) is an autosomal recessive disorder resulting in a myriad of abnormalities, including progressive neurodegeneration and cancer predisposition. At the cellular level, A-T is a disease of chronic oxidative stress (OS) causing damage to proteins, lipids, and DNA. OS is contributed to by pro-oxidative transition metals such as iron that catalyze the conversion of weakly reactive oxygen species to highly reactive hydroxyl radicals. Iron-associated OS has been linked to neurodegeneration in Alzheimer's and Parkinson's diseases and development of lymphoid tumors (which afflict ∼30% of A-T patients). To investigate iron regulation in A-T, iron indexes, regulatory genes, and OS markers were studied in livers of wild-type and Ataxia telangiectasia mutated (Atm) null mice on control or high-iron diets. Atm(-/-) mice had increased serum iron, hepatic iron, and ferritin and significantly higher Hepcidin compared with wild-type mice. When challenged with the high-iron diet, Bmp6 and Hfe expression was significantly increased. Atm(-/-) mice had increased protein tyrosine nitration and significantly higher Heme Oxygenase (decycling) 1 levels that were substantially increased by a high-iron diet. Ferroportin gene expression was significantly increased; however, protein levels were unchanged. We demonstrate that Atm(-/-) mice have a propensity to accumulate iron that is associated with a significant increase in hepatic OS. The iron-induced increase in hepcidin peptide in turn suppresses ferroportin protein levels, thus nullifying the upregulation of mRNA expression in response to increased OS. Our results suggest that increased iron status may contribute to the chronic OS seen in A-T patients and development of disease pathology.

  17. Assessment of targeted and non-targeted responses in cells deficient in ATM function following exposure to low and high dose X-rays.

    PubMed

    Kiuru, Anne; Kämäräinen, Meerit; Heinävaara, Sirpa; Pylkäs, Katri; Chapman, Kim; Koivistoinen, Armi; Parviainen, Teuvo; Winqvist, Robert; Kadhim, Munira; Launonen, Virpi; Lindholm, Carita

    2014-01-01

    Radiation sensitivity at low and high dose exposure to X-rays was investigated by means of chromosomal aberration (CA) analysis in heterozygous ATM mutation carrier and A-T patient (biallelic ATM mutation) lymphoblastoid cell lines (LCLs). Targeted and non-targeted responses to acutely delivered irradiation were examined by applying a co-culture system that enables study of both directly irradiated cells and medium-mediated bystander effects in the same experimental setting. No indication of radiation hypersensitivity was observed at doses of 0.01 Gy or 0.1 Gy for the ATM mutation carrier LCL. The A-T patient cells also did not show low-dose response. There was significant increase in unstable CA yields for both ATM mutation carrier and A-T LCLs at 1 and 2 Gy, the A-T cells displaying more distinct dose dependency. Both chromosome and chromatid type aberrations were induced at an increased rate in the irradiated A-T cells, whereas for ATM carrier cells, only unstable chromosomal aberrations were increased above the level observed in the wild type cell line. No bystander effect could be demonstrated in any of the cell lines or doses applied. Characteristics typical for the A-T cell line were detected, i.e., high baseline frequency of CA that increased with dose. In addition, dose-dependent loss of cell viability was observed. In conclusion, CA analysis did not demonstrate low-dose (≤100 mGy) radiosensitivity in ATM mutation carrier cells or A-T patient cells. However, both cell lines showed increased radiosensitivity at high dose exposure.

  18. Targeted disruption of Ataxia-telangiectasia mutated gene in miniature pigs by somatic cell nuclear transfer

    SciTech Connect

    Kim, Young June; Ahn, Kwang Sung; Kim, Minjeong

    2014-10-03

    Highlights: • ATM gene-targeted pigs were produced by somatic cell nuclear transfer. • A novel large animal model for ataxia telangiectasia was developed. • The new model may provide an alternative to the mouse model. - Abstract: Ataxia telangiectasia (A-T) is a recessive autosomal disorder associated with pleiotropic phenotypes, including progressive cerebellar degeneration, gonad atrophy, and growth retardation. Even though A-T is known to be caused by the mutations in the Ataxia telangiectasia mutated (ATM) gene, the correlation between abnormal cellular physiology caused by ATM mutations and the multiple symptoms of A-T disease has not been clearly determined. None ofmore » the existing ATM mouse models properly reflects the extent to which neurological degeneration occurs in human. In an attempt to provide a large animal model for A-T, we produced gene-targeted pigs with mutations in the ATM gene by somatic cell nuclear transfer. The disrupted allele in the ATM gene of cloned piglets was confirmed via PCR and Southern blot analysis. The ATM gene-targeted pigs generated in the present study may provide an alternative to the current mouse model for the study of mechanisms underlying A-T disorder and for the development of new therapies.« less

  19. ATM technology and beyond

    NASA Technical Reports Server (NTRS)

    Cheung, Nim K.

    1993-01-01

    Networks based on Asynchronous Transfer Mode (ATM) are expected to provide cost-effective and ubiquitous infrastructure to support broadband and multimedia services. In this paper, we give an overview of the ATM standards and its associated physical layer transport technologies. We use the experimental HIPPI-ATM-SONET (HAS) interface in the Nectar Gigabit Testbed to illustrate how one can use the SONET/ATM public network to provide transport for bursty gigabit applications.

  20. ATM CMG/EPEA

    NASA Technical Reports Server (NTRS)

    Abramowitz, R.; Kovek, J.; Teimer, W.; Haddad, S. P.

    1975-01-01

    The Apollo Telescope mount double gimballed control moment gyro ATM CMG is described. Photographs of the CMG and its subassemblies are presented along with a functional block diagram of the CMG subsystem. Analog processing electronics for ATM vehicle pointing control and ATM experiment package pointing control are also described.

  1. p38 MAPK-Mediated Bmi-1 Down-Regulation and Defective Proliferation in ATM-Deficient Neural Stem Cells Can Be Restored by Akt Activation

    PubMed Central

    Kim, Jeesun; Hwangbo, Jeon; Wong, Paul K. Y.

    2011-01-01

    A-T (ataxia telangiectasia) is a genetic disease caused by a mutation in the Atm (A-T mutated) gene that leads to neurodegeneration. Despite an increase in the numbers of studies in this area in recent years, the mechanisms underlying neurodegeneration in human A-T are still poorly understood. Previous studies demonstrated that neural stem cells (NSCs) isolated from the subventricular zone (SVZ) of Atm -/- mouse brains show defective self-renewal and proliferation, which is accompanied by activation of chronic p38 mitogen-activated protein kinase (MAPK) and a lower level of the polycomb protein Bmi-1. However, the mechanism underlying Bmi-1 down-regulation and its relevance to defective proliferation in Atm-/- NSCs remained unclear. Here, we show that over-expression of Bmi-1 increases self-renewal and proliferation of Atm-/- NSCs to normal, indicating that defective proliferation in Atm-/- NSCs is a consequence of down-regulation of Bmi-1. We also demonstrate that epidermal growth factor (EGF)-induced Akt phosphorylation renders Bmi-1 resistant to the proteasomal degradation, leading to its stabilization and accumulation in the nucleus. However, inhibition of the Akt-dependent Bmi-1 stabilizing process by p38 MAPK signaling reduces the levels of Bmi-1. Treatment of the Atm-/- NSCs with a specific p38 MAPK inhibitor SB203580 extended Bmi-1 posttranscriptional turnover and H2A ubiquitination in Atm-/- NSCs. Our observations demonstrate the molecular basis underlying the impairment of self-renewal and proliferation in Atm-/- NSCs through the p38 MAPK-Akt-Bmi-1-p21 signaling pathway. PMID:21305053

  2. ATM impacts IGF-1 signaling in skeletal muscle

    PubMed Central

    Ching, James Kain; Luebbert, Stephen H.; Collins, Roy L.; Zhang, Zhihong; Marupudi, Nandhini; Banerjee, Sankha; Hurd, Robin D.; Ralston, Lyle; Fisher, Jonathan S.

    2012-01-01

    Reports that ataxia telangiectasia mutated (ATM) is required for full activation of Akt raise the hypothesis that ATM plays a role in IGF-1 signaling through the Akt/mTOR pathway. Differentiated C2C12 cells harboring either ATM-targeting shRNA or non-targeting shRNA and myotubes from a C2C12 lineage previously exposed to empty vector lentivirus were incubated in the presence or absence of 10 nM IGF-1 followed by western blot analysis. Parallel experiments were performed in isolated soleus muscles from mice expressing only one functional ATM allele (ATM+/−) compared to muscles from wild-type (ATM+/+) mice. IGF-1 increased phosphorylation of Akt S473, Akt T308, and p70 S6 kinase (S6K) in myotubes expressing non-targeting shRNA and in empty vector controls, but the IGF-1 effects were significantly reduced in myotubes with shRNA-mediated ATM knockdown. Likewise, IGF-1-stimulated phosphorylation of Akt S473, Akt T308, mTOR, and S6K was lower in isolated soleus muscles from ATM+/− mice compared to muscles from ATM+/+ mice. The ATM inhibitor KU55933 prevented stimulation of S6K phosphorylation in C2C12 myotubes exposed to IGF-1, suggesting that decreased IGF-1 action is not limited to chronic conditions of decreased ATM function. Stimulation of IRS-1 tyrosine 612 phosphorylation by IGF-1 was unaffected by ATM deficiency, though IGF-1 phosphatidylinositol 3-kinase activity tended to be lower in muscle from ATM haploinsufficient mice compared to wild type muscle. The data suggest that ATM is a modulator of IGF-1 signaling downstream of IRS-1 in skeletal muscle. PMID:22941977

  3. Pms2 and uracil-DNA glycosylases act jointly in the mismatch repair pathway to generate Ig gene mutations at A-T base pairs.

    PubMed

    Girelli Zubani, Giulia; Zivojnovic, Marija; De Smet, Annie; Albagli-Curiel, Olivier; Huetz, François; Weill, Jean-Claude; Reynaud, Claude-Agnès; Storck, Sébastien

    2017-04-03

    During somatic hypermutation (SHM) of immunoglobulin genes, uracils introduced by activation-induced cytidine deaminase are processed by uracil-DNA glycosylase (UNG) and mismatch repair (MMR) pathways to generate mutations at G-C and A-T base pairs, respectively. Paradoxically, the MMR-nicking complex Pms2/Mlh1 is apparently dispensable for A-T mutagenesis. Thus, how detection of U:G mismatches is translated into the single-strand nick required for error-prone synthesis is an open question. One model proposed that UNG could cooperate with MMR by excising a second uracil in the vicinity of the U:G mismatch, but it failed to explain the low impact of UNG inactivation on A-T mutagenesis. In this study, we show that uracils generated in the G1 phase in B cells can generate equal proportions of A-T and G-C mutations, which suggests that UNG and MMR can operate within the same time frame during SHM. Furthermore, we show that Ung -/- Pms2 -/- mice display a 50% reduction in mutations at A-T base pairs and that most remaining mutations at A-T bases depend on two additional uracil glycosylases, thymine-DNA glycosylase and SMUG1. These results demonstrate that Pms2/Mlh1 and multiple uracil glycosylases act jointly, each one with a distinct strand bias, to enlarge the immunoglobulin gene mutation spectrum from G-C to A-T bases. © 2017 Girelli Zubani et al.

  4. Dominant mutations confer resistance to the immunosuppressant, rapamycin, in variants of a T cell lymphoma.

    PubMed

    Dumont, F J; Staruch, M J; Grammer, T; Blenis, J; Kastner, C A; Rupprecht, K M

    1995-06-01

    Rapamycin (RAP) disrupts signaling events implicated in cytokine-dependent proliferation of lymphocytes and other cells. This action is known to involve the formation of molecular complexes between the drug and intracellular binding proteins, termed FKBPs. However, the biochemical target(s) for the effector RAP-FKBP complexes remain uncharacterized. As an approach to explore the mechanism of action of RAP, we have isolated three independent sets of somatic mutants of the YAC-1 murine T cell line with markedly reduced sensitivity to the drug's inhibitory effects on proliferation and on IL-1-induced IFN-gamma production. These mutants were still fully sensitive to FK-506, an immunosuppressant structurally related to RAP whose mode of action also involves an interaction with FKBPs. Furthermore, the 12-kDa FKBP, FKBP12, was detectable in immunoblots from cytosolic extracts and eluates from RAP-affinity matrix in the mutants as in wild-type cells, suggesting that the resistance to RAP in the mutants is not due to a lack of FKBP12 expression. Cell fusion experiments were conducted to further define the nature of the alterations imparting RAP resistance in these mutants. Clones deficient in either thymidine kinase or hypoxanthine-guanine phosphoribosyltransferase, suitable as fusion partners for aminopterin-based selection of hybrids were generated from the wild-type or mutant lines. In most instances, the hybrids derived from the fusion between RAP-sensitive clones and RAP-resistant clones exhibited a RAP-resistant phenotype. Similar results were obtained with hybrids between RAP-resistant YAC-1 clones and the RAP-sensitive EL-4 cell line. Therefore, the mutations that confer resistance to RAP in the present system are dominant. Altogether, our observations are consistent with a model where pharmacologically relevant targets for the RAP-FKBP complex, rather than FKBP, might be altered in the mutants such that the inactivation of these targets by the effector complex is

  5. Mode of ATM-dependent suppression of chromosome translocation

    SciTech Connect

    Yamauchi, Motohiro, E-mail: motoyama@nagasaki-u.ac.jp; Suzuki, Keiji; Oka, Yasuyoshi

    2011-12-09

    Highlights: Black-Right-Pointing-Pointer We addressed how ATM suppresses frequency of chromosome translocation. Black-Right-Pointing-Pointer We found ATM/p53-dependent G1 checkpoint suppresses translocation frequency. Black-Right-Pointing-Pointer We found ATM and DNA-PKcs function in a common pathway to suppress translocation. -- Abstract: It is well documented that deficiency in ataxia telangiectasia mutated (ATM) protein leads to elevated frequency of chromosome translocation, however, it remains poorly understood how ATM suppresses translocation frequency. In the present study, we addressed the mechanism of ATM-dependent suppression of translocation frequency. To know frequency of translocation events in a whole genome at once, we performed centromere/telomere FISH and scored dicentric chromosomes, becausemore » dicentric and translocation occur with equal frequency and by identical mechanism. By centromere/telomere FISH analysis, we confirmed that chemical inhibition or RNAi-mediated knockdown of ATM causes 2 to 2.5-fold increase in dicentric frequency at first mitosis after 2 Gy of gamma-irradiation in G0/G1. The FISH analysis revealed that ATM/p53-dependent G1 checkpoint suppresses dicentric frequency, since RNAi-mediated knockdown of p53 elevated dicentric frequency by 1.5-fold. We found ATM also suppresses dicentric occurrence independently of its checkpoint role, as ATM inhibitor showed additional effect on dicentric frequency in the context of p53 depletion and Chk1/2 inactivation. Epistasis analysis using chemical inhibitors revealed that ATM kinase functions in the same pathway that requires kinase activity of DNA-dependent protein kinase catalytic subunit (DNA-PKcs) to suppress dicentric frequency. From the results in the present study, we conclude that ATM minimizes translocation frequency through its commitment to G1 checkpoint and DNA double-strand break repair pathway that requires kinase activity of DNA-PKcs.« less

  6. Regulation of Hyphal Morphogenesis and the DNA Damage Response by the Aspergillus nidulans ATM Homolog AtmA

    PubMed Central

    Malavazi, Iran; Semighini, Camile P.; von Zeska Kress, Marcia Regina; Harris, Steven D.; Goldman, Gustavo H.

    2006-01-01

    Ataxia telangiectasia (A-T) is an inherited disorder characterized by progressive loss of motor function and susceptibility to cancer. The most prominent clinical feature observed in A-T patients is the degeneration of Purkinje motor neurons. Numerous studies have emphasized the role of the affected gene product, ATM, in the regulation of the DNA damage response. However, in Purkinje cells, the bulk of ATM localizes to the cytoplasm and may play a role in vesicle trafficking. The nature of this function, and its involvement in the pathology underlying A-T, remain unknown. Here we characterize the homolog of ATM (AtmA) in the filamentous fungus Aspergillus nidulans. In addition to its expected role in the DNA damage response, we find that AtmA is also required for polarized hyphal growth. We demonstrate that an atmA mutant fails to generate a stable axis of hyphal polarity. Notably, cytoplasmic microtubules display aberrant cortical interactions at the hyphal tip. Our results suggest that AtmA regulates the function and/or localization of landmark proteins required for the formation of a polarity axis. We propose that a similar function may contribute to the establishment of neuronal polarity. PMID:16415361

  7. Direct Activation of ATM by Resveratrol under Oxidizing Conditions

    PubMed Central

    Myler, Logan R.; Zheng, Suting; Paull, Tanya T.

    2014-01-01

    Resveratrol has been widely reported to reduce cancer progression in model systems and to selectively induce cell death in transformed cell lines. Many enzymes have been reported to respond to resveratrol in mammalian cells, including the Ataxia-Telangiectasia Mutated (ATM) protein kinase that acts in DNA damage recognition, signaling, and repair. Here we investigate the responses of ATM to resveratrol exposure in normal and transformed human cell lines and find that ATM autophosphorylation and substrate phosphorylation is stimulated by resveratrol in a manner that is promoted by reactive oxygen species (ROS). We observe direct stimulatory effects of resveratrol on purified ATM in vitro and find that the catalytic efficiency of the kinase on a model substrate is increased by resveratrol. In the purified system we also observe a requirement for oxidation, as the effect of resveratrol on ATM signaling is substantially reduced by agents that prevent disulfide bond formation in ATM. These results demonstrate that resveratrol effects on ATM are direct, and suggest a mechanism by which the oxidizing environment of transformed cells promotes ATM activity and blocks cell proliferation. PMID:24933654

  8. Scalable ATM encryption

    SciTech Connect

    NONE

    1995-04-01

    In order to provide needed security assurances for traffic carried in Asynchronous Transfer Mode (ATM) networks, methods of protecting the integrity and privacy of traffic must be employed. Cryptographic methods can be used to assure authenticity and privacy, but are hard to scale and the incorporation of these methods into computer networks can severely impact functionality, reliability, and performance. To study these trade-offs, a research prototype encryptor/decryptor is under development. This prototype is to demonstrate the viability of implementing certain encryption techniques in high speed networks by processing Asynchronous Transfer Mode (ATM) cells in a SONET OC-3 payload. This papermore » describes the objectives and design trade-offs intended to be investigated with the prototype. User requirements for high performance computing and communication have driven Sandia to do work in the areas of functionality, reliability, security, and performance of high speed communication networks. Adherence to standards (including emerging standards) achieves greater functionality of high speed computer networks by providing wide interoperability of applications, network hardware, and network software.« less

  9. Structure of the intact ATM/Tel1 kinase

    PubMed Central

    Wang, Xuejuan; Chu, Huanyu; Lv, Mengjuan; Zhang, Zhihui; Qiu, Shuwan; Liu, Haiyan; Shen, Xuetong; Wang, Weiwu; Cai, Gang

    2016-01-01

    The ataxia-telangiectasia mutated (ATM) protein is an apical kinase that orchestrates the multifaceted DNA-damage response. Normally, ATM kinase is in an inactive, homodimer form and is transformed into monomers upon activation. Besides a conserved kinase domain at the C terminus, ATM contains three other structural modules, referred to as FAT, FATC and N-terminal helical solenoid. Here we report the first cryo-EM structure of ATM kinase, which is an intact homodimeric ATM/Tel1 from Schizosaccharomyces pombe. We show that two monomers directly contact head-to-head through the FAT and kinase domains. The tandem N-terminal helical solenoid tightly packs against the FAT and kinase domains. The structure suggests that ATM/Tel1 dimer interface and the consecutive HEAT repeats inhibit the binding of kinase substrates and regulators by steric hindrance. Our study provides a structural framework for understanding the mechanisms of ATM/Tel1 regulation as well as the development of new therapeutic agents. PMID:27229179

  10. Structure of the intact ATM/Tel1 kinase

    NASA Astrophysics Data System (ADS)

    Wang, Xuejuan; Chu, Huanyu; Lv, Mengjuan; Zhang, Zhihui; Qiu, Shuwan; Liu, Haiyan; Shen, Xuetong; Wang, Weiwu; Cai, Gang

    2016-05-01

    The ataxia-telangiectasia mutated (ATM) protein is an apical kinase that orchestrates the multifaceted DNA-damage response. Normally, ATM kinase is in an inactive, homodimer form and is transformed into monomers upon activation. Besides a conserved kinase domain at the C terminus, ATM contains three other structural modules, referred to as FAT, FATC and N-terminal helical solenoid. Here we report the first cryo-EM structure of ATM kinase, which is an intact homodimeric ATM/Tel1 from Schizosaccharomyces pombe. We show that two monomers directly contact head-to-head through the FAT and kinase domains. The tandem N-terminal helical solenoid tightly packs against the FAT and kinase domains. The structure suggests that ATM/Tel1 dimer interface and the consecutive HEAT repeats inhibit the binding of kinase substrates and regulators by steric hindrance. Our study provides a structural framework for understanding the mechanisms of ATM/Tel1 regulation as well as the development of new therapeutic agents.

  11. An HTRF® Assay for the Protein Kinase ATM.

    PubMed

    Adams, Phillip; Clark, Jonathan; Hawdon, Simon; Hill, Jennifer; Plater, Andrew

    2017-01-01

    Ataxia telangiectasia mutated (ATM) is a serine/threonine kinase that plays a key role in the regulation of DNA damage pathways and checkpoint arrest. In recent years, there has been growing interest in ATM as a therapeutic target due to its association with cancer cell survival following genotoxic stress such as radio- and chemotherapy. Large-scale targeted drug screening campaigns have been hampered, however, by technical issues associated with the production of sufficient quantities of purified ATM and the availability of a suitable high-throughput assay. Using a purified, functionally active recombinant ATM and one of its physiological substrates, p53, we have developed an in vitro FRET-based activity assay that is suitable for high-throughput drug screening.

  12. Satellite Communications for ATM

    NASA Technical Reports Server (NTRS)

    Shamma, Mohammed A.

    2003-01-01

    This presentation is an overview on Satellite Communication for the Aeronautical Telecommunication Management (ATM) research. Satellite Communications are being considered by the FAA and NASA as a possible alternative to the present and future ground systems supporting Air Traffic Communications. The international Civil Aviation Organization (ICAO) have in place Standards and Recommended Practices (SARPS) for the Aeronautical Mobile Satellite Services (AMSS) which is mainly derived from the pre-existing Inmarsat service that has been in service since the 1980s. The Working Group A of the Aeronautical Mobile Communication Panel of ICAO has also been investigating SARPS for what is called the Next Generation Satellite Service (NGSS) which conforms less to the Inmarsat based architecture and explores wider options in terms of satellite architectures. Several designs are being proposed by Firms such as Boeing, ESA, NASA that are geared toward full or secondary usage of satellite communications for ATM. Satellite communications for ATM can serve several purposes ranging from primary usage where ground services would play a minimal backup role, to an integrated solution where it will be used to cover services, or areas that are less likely to be supported by the proposed and existing ground infrastructure. Such Integrated roles can include usage of satellite communications for oceanic and remote land areas for example. It also can include relieving the capacity of the ground network by providing broadcast based services of Traffic Information Services messages (TIS-B), or Flight Information Services (FIS-B) which can take a significant portion of the ground system capacity. Additionally, satellite communication can play a backup role to support any needs for ground replacement, or additional needed capacity even after the new digital systems are in place. The additional bandwidth that can be provided via satellite communications can also open the door for many new

  13. Autosomal Dominant Retinal Dystrophies Caused by a Founder Splice Site Mutation, c.828+3A>T, in PRPH2 and Protein Haplotypes in trans as Modifiers.

    PubMed

    Shankar, Suma P; Hughbanks-Wheaton, Dianna K; Birch, David G; Sullivan, Lori S; Conneely, Karen N; Bowne, Sara J; Stone, Edwin M; Daiger, Stephen P

    2016-02-01

    We determined the phenotypic variation, disease progression, and potential modifiers of autosomal dominant retinal dystrophies caused by a splice site founder mutation, c.828+3A>T, in the PRPH2 gene. A total of 62 individuals (19 families) harboring the PRPH2 c.828+3A>T mutation, had phenotype analysis by fundus appearance, electrophysiology, and visual fields. The PRPH2 haplotypes in trans were sequenced for potential modifying variants and generalized estimating equations (GEE) used for statistical analysis. Several distinct phenotypes caused by the PRPH2 c.828+3A>T mutation were observed and fell into two clinical categories: Group I (N = 44) with mild pattern dystrophies (PD) and Group II (N = 18) with more severe cone-rod dystrophy (CRD), retinitis pigmentosa (RP), and central areolar chorioretinal dystrophy (CACD). The PRPH2 Gln304-Lys310-Asp338 protein haplotype in trans was found in Group I only (29.6% vs. 0%), whereas the Glu304-Lys310-Gly338 haplotype was predominant in Group II (94.4% vs. 70.4%). Generalized estimating equations analysis for PD versus the CRD/CACD/RP phenotypes in individuals over 43 years alone with the PRPH2 haplotypes in trans and age as predictors, adjusted for correlation within families, confirmed a significant effect of haplotype on severity (P = 0.03) with an estimated odds ratio of 7.16 (95% confidence interval [CI] = [2.8, 18.4]). The PRPH2 c.828+3A>T mutation results in multiple distinct phenotypes likely modified by protein haplotypes in trans; the odds of having the CACD/RP-like phenotype (versus the PD phenotype) are 7.16 times greater with a Glu304-Lys310-Gly338 haplotype in trans. Further functional studies of the modifying haplotypes in trans and PRPH2 splice variants may offer therapeutic targets.

  14. ATM CMG bearing failure analysis

    NASA Technical Reports Server (NTRS)

    1975-01-01

    The cause or causes for the failure of ATM CMG S/N 5 (Skylab 1) and the anomalies associated with ATM CMG S/N 6 (Skylab 2) were investigated. Skylab telemetry data were reviewed and presented in the form of parameter distributions. The theory that the problems were caused by marginal bearing lubrication was studied along with the effects of orbital conditions on lubricants. Bearing tests were performed to investigate the effect of lubricant or lack of lubricant in the ATM CMG bearings and the dispersion and migration of the lubricant. The vacuum and weightless conditions of space were simulated in the bearing tests. Analysis of the results of the tests conducted points to inadequate lubrication as the predominant factor causing the failure of ATM CMG S/N 5 (Skylab 1) and the anomalies associated with ATM CMG S/N 6 (Skylab 2).

  15. TCP over native ATM (TONA)

    NASA Astrophysics Data System (ADS)

    Grilo, Antonio M.; Nunes, Mario S.

    1998-09-01

    This paper presents an approach for carrying Internet transport PDUs directly over AAL5, discarding IP. The main advantage is an overhead reduction that can significantly impact upstream Internet traffic performance in asymmetric access network technologies such as HFC and ADSL. The TONA model proposed in the paper considers ATM to be at network layer-3, and tries to combine the best solutions given by previous models. Removal of the IP layer and the use of TCP over native ATM were achieved in a way that maximizes comparability with current standards and existent Internet applications, and allows the use of TCP by ATM applications.

  16. Increased A:T-->C:G mutations in the mutT strain upon 8-hydroxy-dGTP treatment: direct evidence for MutT involvement in the prevention of mutations by oxidized dGTP.

    PubMed

    Kamiya, Hiroyuki; Ishiguro, Chieko; Harashima, Hideyoshi

    2004-09-01

    The Escherichia coli MutT protein hydrolyzes 8-hydroxy-dGTP (8-OH-dGTP) in vitro, and mutT gene deficiencies cause increased spontaneous A:T-->C:G mutations. However, no direct evidence exists for enhanced mutagenicity of 8-OH-dGTP in mutT cells. In this study, 8-OH-dGTP was introduced into wild type and mutT E. coli cells, and mutations of a chromosomal gene were monitored. 8-OH-dGTP induced mutations of the rpoB gene, the degree of the mutation induction in the mutT strain being approximately 6-fold higher than that in the wild type strain. On the other hand, 2-hydroxy-dATP, which is not a substrate of the MutT protein, increased the mutation to similar degrees in the two strains. These results constitute the first evidence that the MutT protein suppresses mutation by 8-OH-dGTP in vivo.

  17. ATM localization and gene expression in the adult mouse eye.

    PubMed

    Leemput, Julia; Masson, Christel; Bigot, Karine; Errachid, Abdelmounaim; Dansault, Anouk; Provost, Alexandra; Gadin, Stéphanie; Aoufouchi, Said; Menasche, Maurice; Abitbol, Marc

    2009-01-01

    High levels of metabolism and oxygen consumption in most adult murine ocular compartments, combined with exposure to light and ultraviolet (UV) radiation, are major sources of oxidative stress, causing DNA damage in ocular cells. Of all mammalian body cells, photoreceptor cells consume the largest amount of oxygen and generate the highest levels of oxidative damage. The accumulation of such damage throughout life is a major factor of aging tissues. Several multiprotein complexes have recently been identified as the major sensors and mediators involved in the maintenance of DNA integrity. The activity of these complexes initially seemed to be restricted to dividing cells, given their ultimate role in major cell cycle checkpoints. However, it was later established that they are also active in post-mitotic cells. Recent findings demonstrate that the DNA damage response (DDR) is essential for the development, maintenance, and normal functioning of the adult central nervous system. One major molecular factor in the DDR is the protein, ataxia telangiectasia mutated (ATM). It is required for the rapid induction of cellular responses to DNA double-strand breaks. These cytotoxic DNA lesions may be caused by oxidative damage. To understand how ATM prevents oxidative stress and participates in the maintenance of genomic integrity and cell viability of the adult retina, we determined the ATM expression patterns and studied its localization in the adult mouse eye. Atm gene expression was analyzed by RT-PCR experiments and its localization by in situ hybridization on adult mouse ocular and cerebellar tissue sections. ATM protein expression was determined by western blot analysis of proteins homogenates extracted from several mouse tissues and its localization by immunohistochemistry experiments performed on adult mouse ocular and cerebellar tissue sections. In addition, subcellular localization was realized by confocal microscopy imaging of ocular tissue sections, with a special

  18. ATM localization and gene expression in the adult mouse eye

    PubMed Central

    Leemput, Julia; Masson, Christel; Bigot, Karine; Errachid, Abdelmounaim; Dansault, Anouk; Provost, Alexandra; Gadin, Stéphanie; Aoufouchi, Said; Menasche, Maurice

    2009-01-01

    Purpose High levels of metabolism and oxygen consumption in most adult murine ocular compartments, combined with exposure to light and ultraviolet (UV) radiation, are major sources of oxidative stress, causing DNA damage in ocular cells. Of all mammalian body cells, photoreceptor cells consume the largest amount of oxygen and generate the highest levels of oxidative damage. The accumulation of such damage throughout life is a major factor of aging tissues. Several multiprotein complexes have recently been identified as the major sensors and mediators involved in the maintenance of DNA integrity. The activity of these complexes initially seemed to be restricted to dividing cells, given their ultimate role in major cell cycle checkpoints. However, it was later established that they are also active in post-mitotic cells. Recent findings demonstrate that the DNA damage response (DDR) is essential for the development, maintenance, and normal functioning of the adult central nervous system. One major molecular factor in the DDR is the protein, ataxia telangiectasia mutated (ATM). It is required for the rapid induction of cellular responses to DNA double-strand breaks. These cytotoxic DNA lesions may be caused by oxidative damage. To understand how ATM prevents oxidative stress and participates in the maintenance of genomic integrity and cell viability of the adult retina, we determined the ATM expression patterns and studied its localization in the adult mouse eye. Methods Atm gene expression was analyzed by RT–PCR experiments and its localization by in situ hybridization on adult mouse ocular and cerebellar tissue sections. ATM protein expression was determined by western blot analysis of proteins homogenates extracted from several mouse tissues and its localization by immunohistochemistry experiments performed on adult mouse ocular and cerebellar tissue sections. In addition, subcellular localization was realized by confocal microscopy imaging of ocular tissue

  19. Downregulation of ATM Gene and Protein Expression in Canine Mammary Tumors.

    PubMed

    Raposo-Ferreira, T M M; Bueno, R C; Terra, E M; Avante, M L; Tinucci-Costa, M; Carvalho, M; Cassali, G D; Linde, S D; Rogatto, S R; Laufer-Amorim, R

    2016-11-01

    The ataxia telangiectasia mutated (ATM) gene encodes a protein associated with DNA damage repair and maintenance of genomic integrity. In women, ATM transcript and protein downregulation have been reported in sporadic breast carcinomas, and the absence of ATM protein expression has been associated with poor prognosis. The aim of this study was to evaluate ATM gene and protein expression in canine mammary tumors and their association with clinical outcome. ATM gene and protein expression was evaluated by reverse transcription-quantitative polymerase chain reaction and immunohistochemistry, respectively, in normal mammary gland samples (n = 10), benign mammary tumors (n = 11), nonmetastatic mammary carcinomas (n = 19), and metastatic mammary carcinomas (n = 11). Lower ATM transcript levels were detected in benign mammary tumors and carcinomas compared with normal mammary glands (P = .011). Similarly, lower ATM protein expression was observed in benign tumors (P = .0003), nonmetastatic mammary carcinomas (P < .0001), and the primary sites of metastatic carcinomas (P < .0001) compared with normal mammary glands. No significant differences in ATM gene or protein levels were detected among benign tumors and nonmetastatic and metastatic mammary carcinomas (P > .05). The levels of ATM gene or protein expression were not significantly associated with clinical and pathological features or with survival. Similar to human breast cancer, the data in this study suggest that ATM gene and protein downregulation is involved in canine mammary gland tumorigenesis. © The Author(s) 2016.

  20. Mitochondria are required for ATM activation by extranuclear oxidative stress in cultured human hepatoblastoma cell line Hep G2 cells

    SciTech Connect

    Morita, Akinori, E-mail: morita@tokushima-u.ac.jp; Department of Radiological Science, Institute of Health Biosciences, The University of Tokushima Graduate School, Tokushima 770-8509; Tanimoto, Keiji

    2014-01-24

    Highlights: • Oxidative ATM activation can occur in the absence of nuclear DNA damage response. • The oxidized Hep G2 cells were subjected to subcellular fractionation. • The obtained results suggest that the ATM activation occurs in mitochondria. • ATM failed to respond to oxidative stress in mitochondria-depleted Hep G2 cells. • Mitochondria are required for the oxidative activation of ATM. - Abstract: Ataxia–telangiectasia mutated (ATM) is a serine/threonine protein kinase that plays a central role in DNA damage response (DDR). A recent study reported that oxidized ATM can be active in the absence of DDR. However, the issue ofmore » where ATM is activated by oxidative stress remains unclear. Regarding the localization of ATM, two possible locations, namely, mitochondria and peroxisomes are possible. We report herein that ATM can be activated when exposed to hydrogen peroxide without inducing nuclear DDR in Hep G2 cells, and the oxidized cells could be subjected to subcellular fractionation. The first detergent-based fractionation experiment revealed that active, phosphorylated ATM was located in the second fraction, which also contained both mitochondria and peroxisomes. An alternative fractionation method involving homogenization and differential centrifugation, which permits the light membrane fraction containing peroxisomes to be produced, but not mitochondria, revealed that the light membrane fraction contained only traces of ATM. In contrast, the heavy membrane fraction, which mainly contained mitochondrial components, was enriched in ATM and active ATM, suggesting that the oxidative activation of ATM occurs in mitochondria and not in peroxisomes. In Rho 0-Hep G2 cells, which lack mitochondrial DNA and functional mitochondria, ATM failed to respond to hydrogen peroxide, indicating that mitochondria are required for the oxidative activation of ATM. These findings strongly suggest that ATM can be activated in response to oxidative stress in

  1. Variable phenotypic expressivity in a Swiss family with autosomal dominant retinitis pigmentosa due to a T494M mutation in the PRPF3 gene.

    PubMed

    Vaclavik, Veronika; Gaillard, Marie-Claire; Tiab, L; Schorderet, Daniel F; Munier, Francis L

    2010-03-19

    To characterize the clinical, psychophysical, and electrophysiological phenotypes in a five-generation Swiss family with dominantly inherited retinitis pigmentosa caused by a T494M mutation in the Precursor mRNA-Processing factor 3 (PRPF3) gene, and to relate the phenotype to the underlying genetic mutation. Eleven affected patients were ascertained for phenotypic and genotypic characterization. Ophthalmologic evaluations included color vision testing, Goldmann perimetry, and digital fundus photography. Some patients had autofluorescence imaging, Optical Coherence Tomography, and ISCEV-standard full-field electroretinography. All affected patients had genetic testing. The age of onset of night blindness and the severity of the progression of the disease varied between members of the family. Some patients reported early onset of night blindness at age three, with subsequent severe deterioration of visual acuity, which was 0.4 in the best eye after their fifties. The second group of patients had a later onset of night blindness, in the mid-twenties, with a milder disease progression and a visual acuity of 0.8 at age 70. Fundus autofluorescence imaging and electrophysiological and visual field abnormalities also showed some degree of varying phenotypes. The autofluorescence imaging showed a large high-density ring bilaterally. Myopia (range: -0.75 to -8) was found in 10/11 affected subjects. Fundus findings showed areas of atrophy along the arcades. A T494M change was found in exon 11 of the PRPF3 gene. The change segregates with the disease in the family. A mutation in the PRPF3 gene is rare compared to other genes causing autosomal dominant retinitis pigmentosa (ADRP). Although a T494M change has been reported, the family in our study is the first with variable expressivity. Mutations in the PRPF3 gene can cause a variable ADRP phenotype, unlike in the previously described Danish, English, and Japanese families. Our report, based on one of the largest affected

  2. A T42A Ran mutation: differential interactions with effectors and regulators, and defect in nuclear protein import.

    PubMed

    Murphy, G A; Moore, M S; Drivas, G; Pérez de la Ossa, P; Villamarin, A; D'Eustachio, P; Rush, M G

    1997-12-01

    Ran, the small, predominantly nuclear GTPase, has been implicated in the regulation of a variety of cellular processes including cell cycle progression, nuclear-cytoplasmic trafficking of RNA and protein, nuclear structure, and DNA synthesis. It is not known whether Ran functions directly in each process or whether many of its roles may be secondary to a direct role in only one, for example, nuclear protein import. To identify biochemical links between Ran and its functional target(s), we have generated and examined the properties of a putative Ran effector mutation, T42A-Ran. T42A-Ran binds guanine nucleotides as well as wild-type Ran and responds as well as wild-type Ran to GTP or GDP exchange stimulated by the Ran-specific guanine nucleotide exchange factor, RCC1. T42A-Ran.GDP also retains the ability to bind p10/NTF2, a component of the nuclear import pathway. In contrast to wild-type Ran, T42A-Ran.GTP binds very weakly or not detectably to three proposed Ran effectors, Ran-binding protein 1 (RanBP1), Ran-binding protein 2 (RanBP2, a nucleoporin), and karyopherin beta (a component of the nuclear protein import pathway), and is not stimulated to hydrolyze bound GTP by Ran GTPase-activating protein, RanGAP1. Also in contrast to wild-type Ran, T42A-Ran does not stimulate nuclear protein import in a digitonin permeabilized cell assay and also inhibits wild-type Ran function in this system. However, the T42A mutation does not block the docking of karyophilic substrates at the nuclear pore. These properties of T42A-Ran are consistent with its classification as an effector mutant and define the exposed region of Ran containing the mutation as a probable effector loop.

  3. ATM promotes apoptosis and suppresses tumorigenesis in response to Myc

    NASA Astrophysics Data System (ADS)

    Pusapati, Raju V.; Rounbehler, Robert J.; Hong, Sungki; Powers, John T.; Yan, Mingshan; Kiguchi, Kaoru; McArthur, Mark J.; Wong, Paul K.; Johnson, David G.

    2006-01-01

    Overexpression of the c-myc oncogene contributes to the development of a significant number of human cancers. In response to deregulated Myc activity, the p53 tumor suppressor is activated to promote apoptosis and inhibit tumor formation. Here we demonstrate that p53 induction in response to Myc overexpression requires the ataxia-telangiectasia mutated (ATM) kinase, a major regulator of the cellular response to DNA double-strand breaks. In a transgenic mouse model overexpressing Myc in squamous epithelial tissues, inactivation of Atm suppresses apoptosis and accelerates tumorigenesis. Deregulated Myc expression induces DNA damage in primary transgenic keratinocytes and the formation of H2AX and phospho-SMC1 foci in transgenic tissue. These findings suggest that Myc overexpression causes DNA damage in vivo and that the ATM-dependent response to this damage is critical for p53 activation, apoptosis, and the suppression of tumor development. p53 | DNA damage

  4. Homeostatic regulation of meiotic DSB formation by ATM/ATR

    SciTech Connect

    Cooper, Tim J.; Wardell, Kayleigh; Garcia, Valerie

    2014-11-15

    Ataxia–telangiectasia mutated (ATM) and RAD3-related (ATR) are widely known as being central players in the mitotic DNA damage response (DDR), mounting responses to DNA double-strand breaks (DSBs) and single-stranded DNA (ssDNA) respectively. The DDR signalling cascade couples cell cycle control to damage-sensing and repair processes in order to prevent untimely cell cycle progression while damage still persists [1]. Both ATM/ATR are, however, also emerging as essential factors in the process of meiosis; a specialised cell cycle programme responsible for the formation of haploid gametes via two sequential nuclear divisions. Central to achieving accurate meiotic chromosome segregation is the introduction ofmore » numerous DSBs spread across the genome by the evolutionarily conserved enzyme, Spo11. This review seeks to explore and address how cells utilise ATM/ATR pathways to regulate Spo11-DSB formation, establish DSB homeostasis and ensure meiosis is completed unperturbed.« less

  5. Gigabit ATM: another technical mistake?

    NASA Astrophysics Data System (ADS)

    Christ, Paul

    1998-09-01

    Once upon a time, or more precisely during February 1988 at the CCITT Seoul plenary, and definitely arriving as a revolution, ATM hit the hard-core B-ISDN circuit-switching gang. Initiated by the Telecoms' camp, but, surprisingly, soon to be pushed by computer minded people, ATM's generic technological history is somewhat richer than single-sided stories. Here are two classical elements of that history: Firstly, together with X.25, ATM suffers from the connection versus datagram dichotomy, well known for more than twenty years. Secondly, and lesser known, ATM's use of cells in support of the 'I' of B-ISDN was questioned from the very beginning by the packet switching camp. Furthermore, in this context, there are two other essential elements to be considered: Firstly, the exponential growth of the Internet and later intranets, using Internet technology, sparked by the success of the Web and the WINTEL alliance, resulted in a corresponding demand for both aggregate and end-system network bandwidth. Secondly, servers, historically restricted to the exclusive club of HIPPI-equipped supercomputers, suddenly become ordinary high-end PCs with 64-bit wide PCI busses -- definitely aiming at the Gigabit. Here, if your aim is for Gigabit ATM with 5000-transactions per second classical supercomputers, a 65K ATM MTU -- as implemented by Cray -- might be okay. Following Clark and others, another part of the story is the adoption and redefinition, by the IETF, of the Telecoms' notion of 'Integrated Services' and QoS mechanisms. The quest for low-delay IP packet forwarding, perhaps possible over ATM cut-throughs, has resulted in the switching versus/or integrated-with-routing movement. However, a blow for ATM may be the recent results concerning fast routing table lookup algorithms. This, by making Gigabit routing possible using ordinary Pentium processors may eventually render the much prophesized ATM switching performance unnecessary. Recently, with the rise of Gigabit Ethernet

  6. Structures of closed and open conformations of dimeric human ATM

    PubMed Central

    Baretić, Domagoj; Pollard, Hannah K.; Fisher, David I.; Johnson, Christopher M.; Santhanam, Balaji; Truman, Caroline M.; Kouba, Tomas; Fersht, Alan R.; Phillips, Christopher; Williams, Roger L.

    2017-01-01

    ATM (ataxia-telangiectasia mutated) is a phosphatidylinositol 3-kinase–related protein kinase (PIKK) best known for its role in DNA damage response. ATM also functions in oxidative stress response, insulin signaling, and neurogenesis. Our electron cryomicroscopy (cryo-EM) suggests that human ATM is in a dynamic equilibrium between closed and open dimers. In the closed state, the PIKK regulatory domain blocks the peptide substrate–binding site, suggesting that this conformation may represent an inactive or basally active enzyme. The active site is held in this closed conformation by interaction with a long helical hairpin in the TRD3 (tetratricopeptide repeats domain 3) domain of the symmetry-related molecule. The open dimer has two protomers with only a limited contact interface, and it lacks the intermolecular interactions that block the peptide-binding site in the closed dimer. This suggests that the open conformation may be more active. The ATM structure shows the detailed topology of the regulator-interacting N-terminal helical solenoid. The ATM conformational dynamics shown by the structures represent an important step in understanding the enzyme regulation. PMID:28508083

  7. Premeiotic germ cell defect in seminiferous tubules of Atm-null testis

    SciTech Connect

    Takubo, Keiyo; Hirao, Atsushi; Core Research for Evolutional Science and Technology

    2006-12-29

    Lifelong spermatogenesis is maintained by coordinated sequential processes including self-renewal of stem cells, proliferation of spermatogonial cells, meiotic division, and spermiogenesis. It has been shown that ataxia telangiectasia-mutated (ATM) is required for meiotic division of the seminiferous tubules. Here, we show that, in addition to its role in meiosis, ATM has a pivotal role in premeiotic germ cell maintenance. ATM is activated in premeiotic spermatogonial cells and the Atm-null testis shows progressive degeneration. In Atm-null testicular cells, differing from bone marrow cells of Atm-null mice, reactive oxygen species-mediated p16{sup Ink4a} activation does not occur in Atm-null premeiotic germ cells, whichmore » suggests the involvement of different signaling pathways from bone marrow defects. Although Atm-null bone marrow undergoes p16{sup Ink4a}-mediated cellular senescence program, Atm-null premeiotic germ cells exhibited cell cycle arrest and apoptotic elimination of premeiotic germ cells, which is different from p16{sup Ink4a}-mediated senescence.« less

  8. ATM Inhibition Potentiates Death of Androgen Receptor-inactivated Prostate Cancer Cells with Telomere Dysfunction

    PubMed Central

    Reddy, Vidyavathi; Wu, Min; Ciavattone, Nicholas; McKenty, Nathan; Menon, Mani; Barrack, Evelyn R.; Reddy, G. Prem-Veer; Kim, Sahn-Ho

    2015-01-01

    Androgen receptor (AR) plays a role in maintaining telomere stability in prostate cancer cells, as AR inactivation induces telomere dysfunction within 3 h. Since telomere dysfunction in other systems is known to activate ATM (ataxia telangiectasia mutated)-mediated DNA damage response (DDR) signaling pathways, we investigated the role of ATM-mediated DDR signaling in AR-inactivated prostate cancer cells. Indeed, the induction of telomere dysfunction in cells treated with AR-antagonists (Casodex or MDV3100) or AR-siRNA was associated with a dramatic increase in phosphorylation (activation) of ATM and its downstream effector Chk2 and the presenceof phosphorylated ATM at telomeres, indicating activation of DDR signaling at telomeres. Moreover, Casodex washout led to the reversal of telomere dysfunction, indicating repair of damaged telomeres. ATM inhibitor blocked ATM phosphorylation, induced PARP cleavage, abrogated cell cycle checkpoint activation and attenuated the formation of γH2AX foci at telomeres in AR-inactivated cells, suggesting that ATM inhibitor induces apoptosis in AR-inactivated cells by blocking the repair of damaged DNA at telomeres. Finally, colony formation assay revealed a dramatic decrease in the survival of cells co-treated with Casodex and ATM inhibitor as compared with those treated with either Casodex or ATM inhibitor alone. These observations indicate that inhibitors of DDR signaling pathways may offer a unique opportunity to enhance the potency of AR-targeted therapies for the treatment of androgen-sensitive as well as castration-resistant prostate cancer. PMID:26336104

  9. ATM Heterozygosity and the Development of Radiation-Induced Erectile Dysfunction and Urinary Morbidity Following Radiotherapy for Prostate Cancer

    DTIC Science & Technology

    2005-02-01

    of the ATM gene for germline mutations. If a correlation is found between radiosensitivity and ATM heterozygosity, this would indicate that possession...Community Health Outcomes, Behavioral Medicine, and Ethical Issues in Clinical Research. Also the PI, while at Mount Sinai, will make significant progress in...treatment morbidity and the potential for a genetic basis must be considered. The purpose of this study is to investigate whether the ATM gene plays a role

  10. ATM gene alterations in chronic lymphocytic leukemia patients induce a distinct gene expression profile and predict disease progression

    PubMed Central

    Guarini, Anna; Marinelli, Marilisa; Tavolaro, Simona; Bellacchio, Emanuele; Magliozzi, Monia; Chiaretti, Sabina; De Propris, Maria Stefania; Peragine, Nadia; Santangelo, Simona; Paoloni, Francesca; Nanni, Mauro; Del Giudice, Ilaria; Mauro, Francesca Romana; Torrente, Isabella; Foà, Robin

    2012-01-01

    Background The genetic characterization of chronic lymphocytic leukemia cells correlates with the behavior, progression and response to treatment of the disease. Design and Methods Our aim was to investigate the role of ATM gene alterations, their biological consequences and their value in predicting disease progression. The ATM gene was analyzed by denaturing high performance liquid chromatography and multiplex ligation probe amplification in a series of patients at diagnosis. The results were correlated with immunoglobulin gene mutations, cytogenetic abnormalities, ZAP-70 and CD38 expression, TP53 mutations, gene expression profile and treatment-free interval. Results Mutational screening of the ATM gene identified point mutations in 8/57 cases (14%). Multiplex ligation probe amplification analysis identified six patients with 11q deletion: all of them had at least 20% of deleted cells, analyzed by fluorescent in situ hybridization. Overall, ATM point mutations and deletions were detected in 14/57 (24.6%) cases at presentation, representing the most common unfavorable genetic anomalies in chronic lymphocytic leukemia, also in stage A patients. Patients with deleted or mutated ATM had a significantly shorter treatment-free interval compared to patients without ATM alterations. ATM-mutated cases had a peculiar gene expression profile characterized by the deregulation of genes involved in apoptosis and DNA repair. Finally, definition of the structure of the ATM-mutated protein led to a hypothesis that functional abnormalities are responsible for the unfavorable clinical course of patients carrying these point mutations. Conclusions ATM alterations are present at diagnosis in about 25% of individuals with chronic lymphocytic leukemia; these alterations are associated with a peculiar gene expression pattern and a shorter treatment-free interval. PMID:21993670

  11. Critical Involvement of the ATM-Dependent DNA Damage Response in the Apoptotic Demise of HIV-1-Elicited Syncytia

    PubMed Central

    Bourouba, Mehdi; Subra, Frédéric; Gros, Laurent; Séror, Claire; Manic, Gwenola; Rosselli, Filippo; Amendola, Alessandra; Masdehors, Peggy; Chessa, Luciana; Novelli, Giuseppe; Ojcius, David M.; Siwicki, Jan Konrad; Chechlinska, Magdalena; Auclair, Christian; Regueiro, José R.; de Thé, Hugues; Gougeon, Marie-Lise; Piacentini, Mauro; Kroemer, Guido

    2008-01-01

    DNA damage can activate the oncosuppressor protein ataxia telangiectasia mutated (ATM), which phosphorylates the histone H2AX within characteristic DNA damage foci. Here, we show that ATM undergoes an activating phosphorylation in syncytia elicited by the envelope glycoprotein complex (Env) of human immunodeficiency virus-1 (HIV-1) in vitro. This was accompanied by aggregation of ATM in discrete nuclear foci that also contained phospho-histone H2AX. DNA damage foci containing phosphorylated ATM and H2AX were detectable in syncytia present in the brain or lymph nodes from patients with HIV-1 infection, as well as in a fraction of blood leukocytes, correlating with viral status. Knockdown of ATM or of its obligate activating factor NBS1 (Nijmegen breakage syndrome 1 protein), as well as pharmacological inhibition of ATM with KU-55933, inhibited H2AX phosphorylation and prevented Env-elicited syncytia from undergoing apoptosis. ATM was found indispensable for the activation of MAP kinase p38, which catalyzes the activating phosphorylation of p53 on serine 46, thereby causing p53 dependent apoptosis. Both wild type HIV-1 and an HIV-1 mutant lacking integrase activity induced syncytial apoptosis, which could be suppressed by inhibiting ATM. HIV-1-infected T lymphoblasts from patients with inactivating ATM or NBS1 mutations also exhibited reduced syncytial apoptosis. Altogether these results indicate that apoptosis induced by a fusogenic HIV-1 Env follows a pro-apoptotic pathway involving the sequential activation of ATM, p38MAPK and p53. PMID:18560558

  12. [Progress of the ATM Crew

    NASA Technical Reports Server (NTRS)

    2003-01-01

    Activities for each of the following programs are discussed in separate sections for the bimonthly reporting period: Airborne Oceanographic Lidar (AOL); Airborne Topographic Mapper (ATM); Other Mission Support Activities, including modeling activities, EAARL activities, and the Scanning Radar Altimeter (SAR); Tropical Rain Measuring Mission (TRMM). The tasks undertaken for each program are discussed in the pertinent section of the report.

  13. NPP ATMS Snowfall Rate Product

    NASA Technical Reports Server (NTRS)

    Meng, Huan; Ferraro, Ralph; Kongoli, Cezar; Wang, Nai-Yu; Dong, Jun; Zavodsky, Bradley; Yan, Banghua

    2015-01-01

    Passive microwave measurements at certain high frequencies are sensitive to the scattering effect of snow particles and can be utilized to retrieve snowfall properties. Some of the microwave sensors with snowfall sensitive channels are Advanced Microwave Sounding Unit (AMSU), Microwave Humidity Sounder (MHS) and Advance Technology Microwave Sounder (ATMS). ATMS is the follow-on sensor to AMSU and MHS. Currently, an AMSU and MHS based land snowfall rate (SFR) product is running operationally at NOAA/NESDIS. Based on the AMSU/MHS SFR, an ATMS SFR algorithm has been developed recently. The algorithm performs retrieval in three steps: snowfall detection, retrieval of cloud properties, and estimation of snow particle terminal velocity and snowfall rate. The snowfall detection component utilizes principal component analysis and a logistic regression model. The model employs a combination of temperature and water vapor sounding channels to detect the scattering signal from falling snow and derive the probability of snowfall (Kongoli et al., 2015). In addition, a set of NWP model based filters is also employed to improve the accuracy of snowfall detection. Cloud properties are retrieved using an inversion method with an iteration algorithm and a two-stream radiative transfer model (Yan et al., 2008). A method developed by Heymsfield and Westbrook (2010) is adopted to calculate snow particle terminal velocity. Finally, snowfall rate is computed by numerically solving a complex integral. NCEP CMORPH analysis has shown that integration of ATMS SFR has improved the performance of CMORPH-Snow. The ATMS SFR product is also being assessed at several NWS Weather Forecast Offices for its usefulness in weather forecast.

  14. An ergonomics evaluation of certain ATM dimensions.

    PubMed

    Al-Saleh, Khalid; Bendak, Salaheddine

    2013-01-01

    Although millions of automatic teller machines (ATMs) are currently used all over the world, users of ATMs still have usability problems including inappropriate user-ATM interaction, display problems and others. Many developed countries already have standards in place for ATMs. However, this is not the case in many other countries. This paper aims to assess certain dimensions of ATM machines and their suitability for users in Middle Eastern countries using anthropometric measurements of the user population taking Saudi Arabia as a case study. Dimensions of all ATMs used in Saudi Arabia were measured and compared with recommended dimensions based on anthropometric measurements of the user population. Results show that there is a mismatch between the dimensions of ATMs used in Saudi Arabia and the recommended dimensions based on the user population. Practical recommendations are given as to improve the usability of ATMs in Saudi Arabia and other Middle Eastern countries.

  15. Coexistence of a T118M PMP22 missense mutation and chromosome 17 (17p11.2-p12) deletion

    PubMed Central

    Jerath, Nivedita U.; Kamholz, John; Grider, Tiffany; Harper, Amy; Swenson, Andrea; Shy, Michael E.

    2015-01-01

    We describe a 6-year-old girl with a T118M PMP22 mutation and heterozygous deletion of PMP22 on chromosome 17 (17p11.2-p12) resulting in a severe sensorimotor polyneuropathy. Methods Case Report Results Foot pain, cavovarus feet, tibialis anterior atrophy, absent reflexes, and inability to walk were found at age 6. Nerve conduction studies showed evidence of a sensorimotor polyneuropathy and compressive mononeuropathies of bilateral median nerves at the wrist and ulnar nerves at the elbow. Genetic testing revealed a deletion of a PMP22 allele and T118M PMP22 mutation in the remaining allele. Conclusions The severe presentation of sensory motor polyneuropathy and HNPP in this patient is likely a consequence of both decreased expression of PMP22 causing features consistent with HNPP, and unopposed expression of the T118M mutant form of PMP22 that is relatively benign in the heterozygous state. The T118M mutant form of PMP22 can be disease-modifying in the appropriate circumstances. PMID:26012543

  16. Phenotypic Analysis of ATM Protein Kinase in DNA Double-Strand Break Formation and Repair.

    PubMed

    Mian, Elisabeth; Wiesmüller, Lisa

    2017-01-01

    Ataxia telangiectasia mutated (ATM) encodes a serine/threonine protein kinase, which is involved in various regulatory processes in mammalian cells. Its best-known role is apical activation of the DNA damage response following generation of DNA double-strand breaks (DSBs). When DSBs appear, sensor and mediator proteins are recruited, activating transducers such as ATM, which in turn relay a widespread signal to a multitude of downstream effectors. ATM mutation causes Ataxia telangiectasia (AT), whereby the disease phenotype shows differing characteristics depending on the underlying ATM mutation. However, all phenotypes share progressive neurodegeneration and marked predisposition to malignancies at the organismal level and sensitivity to ionizing radiation and chromosome aberrations at the cellular level. Expression and localization of the ATM protein can be determined via western blotting and immunofluorescence microscopy; however, detection of subtle alterations such as resulting from amino acid exchanges rather than truncating mutations requires functional testing. Previous studies on the role of ATM in DSB repair, which connects with radiosensitivity and chromosomal stability, gave at first sight contradictory results. To systematically explore the effects of clinically relevant ATM mutations on DSB repair, we engaged a series of lymphoblastoid cell lines (LCLs) derived from AT patients and controls. To examine DSB repair both in a quantitative and qualitative manners, we used an EGFP-based assay comprising different substrates for distinct DSB repair mechanisms. In this way, we demonstrated that particular signaling defects caused by individual ATM mutations led to specific DSB repair phenotypes. To explore the impact of ATM on carcinogenic chromosomal aberrations, we monitored chromosomal breakage at a breakpoint cluster region hotspot within the MLL gene that has been associated with therapy-related leukemia. PCR-based MLL-breakage analysis of HeLa cells

  17. Running TCP/IP over ATM Networks.

    ERIC Educational Resources Information Center

    Witt, Michael

    1995-01-01

    Discusses Internet protocol (IP) and subnets and describes how IP may operate over asynchronous transfer mode (ATM). Topics include TCP (transmission control protocol), ATM cells and adaptation layers, a basic architectural model for IP over ATM, address resolution, mapping IP to a subnet technology, and connection management strategy. (LRW)

  18. Defining ATM-Independent Functions of the Mre11 Complex with a Novel Mouse Model.

    PubMed

    Balestrini, Alessia; Nicolas, Laura; Yang-Lott, Katherine; Guryanova, Olga A; Levine, Ross L; Bassing, Craig H; Chaudhuri, Jayanta; Petrini, John H J

    2016-02-01

    The Mre11 complex (Mre11, Rad50, and Nbs1) occupies a central node of the DNA damage response (DDR) network and is required for ATM activation in response to DNA damage. Hypomorphic alleles of MRE11 and NBS1 confer embryonic lethality in ATM-deficient mice, indicating that the complex exerts ATM-independent functions that are essential when ATM is absent. To delineate those functions, a conditional ATM allele (ATM(flox)) was crossed to hypomorphic NBS1 mutants (Nbs1(ΔB/ΔB) mice). Nbs1(ΔB/ΔB) Atm(-/-) hematopoietic cells derived by crossing to vav(cre) were viable in vivo. Nbs1(ΔB/ΔB) Atm(-/-) (VAV) mice exhibited a pronounced defect in double-strand break repair and completely penetrant early onset lymphomagenesis. In addition to repair defects observed, fragile site instability was noted, indicating that the Mre11 complex promotes genome stability upon replication stress in vivo. The data suggest combined influences of the Mre11 complex on DNA repair, as well as the responses to DNA damage and DNA replication stress. A novel mouse model was developed, by combining a vav(cre)-inducible ATM knockout mouse with an NBS1 hypomorphic mutation, to analyze ATM-independent functions of the Mre11 complex in vivo. These data show that the DNA repair, rather than DDR signaling functions of the complex, is acutely required in the context of ATM deficiency to suppress genome instability and lymphomagenesis. ©2015 American Association for Cancer Research.

  19. MANS and ATM: evolution, interconnection, and interworking

    NASA Astrophysics Data System (ADS)

    Sara, Lini; Cuthbert, Laurie; Pitts, Jonathan

    1993-10-01

    This paper, based on work within RACE project R1022 -- `Technology for ATD,' places the evolution of MANs towards ATM within the overall context of ATM introduction and evolution. Beginning with a major motivating factor, the need for LAN to LAN interconnection, a likely evolution of MANs is described, from first introduction, through interconnection via the ATM cross connect network, to the provision of connectionless data service over the ATM network. The introduction and evolution of ATM in general is then considered. This begins with a review of basic introductory approaches (substitution, island, overlay) and how they can be applied. An overview of the main customer groupings and their likely service requirements is provided as a precursor to discussing how fiber will be used in the access network for both business and residential customers. The paper concludes with an assessment of how MAN evolution towards ATM fits within the overall context of ATM introduction and the provision of broadband services.

  20. Lyn tyrosine kinase promotes silencing of ATM-dependent checkpoint signaling during recovery from DNA double-strand breaks

    SciTech Connect

    Fukumoto, Yasunori, E-mail: fukumoto@faculty.chiba-u.jp; Kuki, Kazumasa; Morii, Mariko

    2014-09-26

    Highlights: • Inhibition of Src family kinases decreased γ-H2AX signal. • Inhibition of Src family increased ATM-dependent phosphorylation of Chk2 and Kap1. • shRNA-mediated knockdown of Lyn increased phosphorylation of Kap1 by ATM. • Ectopic expression of Src family kinase suppressed ATM-mediated Kap1 phosphorylation. • Src is involved in upstream signaling for inactivation of ATM signaling. - Abstract: DNA damage activates the DNA damage checkpoint and the DNA repair machinery. After initial activation of DNA damage responses, cells recover to their original states through completion of DNA repair and termination of checkpoint signaling. Currently, little is known about the processmore » by which cells recover from the DNA damage checkpoint, a process called checkpoint recovery. Here, we show that Src family kinases promote inactivation of ataxia telangiectasia mutated (ATM)-dependent checkpoint signaling during recovery from DNA double-strand breaks. Inhibition of Src activity increased ATM-dependent phosphorylation of Chk2 and Kap1. Src inhibition increased ATM signaling both in G2 phase and during asynchronous growth. shRNA knockdown of Lyn increased ATM signaling. Src-dependent nuclear tyrosine phosphorylation suppressed ATM-mediated Kap1 phosphorylation. These results suggest that Src family kinases are involved in upstream signaling that leads to inactivation of the ATM-dependent DNA damage checkpoint.« less

  1. Genetic Interactions of the Aspergillus nidulans atmAATM Homolog With Different Components of the DNA Damage Response Pathway

    PubMed Central

    Malavazi, Iran; Lima, Joel Fernandes; de Castro, Patrícia Alves; Savoldi, Marcela; de Souza Goldman, Maria Helena; Goldman, Gustavo Henrique

    2008-01-01

    Ataxia telangiectasia mutated (ATM) is a phosphatidyl-3-kinase-related protein kinase that functions as a central regulator of the DNA damage response in eukaryotic cells. In humans, mutations in ATM cause the devastating neurodegenerative disease ataxia telangiectasia. Previously, we characterized the homolog of ATM (AtmA) in the filamentous fungus Aspergillus nidulans. In addition to its expected role in the DNA damage response, we found that AtmA is also required for polarized hyphal growth. Here, we extended these studies by investigating which components of the DNA damage response pathway are interacting with AtmA. The AtmAATM loss of function caused synthetic lethality when combined with mutation in UvsBATR. Our results suggest that AtmA and UvsB are interacting and they are probably partially redundant in terms of DNA damage sensing and/or repairing and polar growth. We identified and inactivated A. nidulans chkACHK1 and chkBCHK2 genes. These genes are also redundantly involved in A. nidulans DNA damage response. We constructed several combinations of double mutants for ΔatmA, ΔuvsB, ΔchkA, and ΔchkB. We observed a complex genetic relationship with these mutations during the DNA replication checkpoint and DNA damage response. Finally, we observed epistatic and synergistic interactions between AtmA, and bimEAPC1, ankAWEE1 and the cdc2-related kinase npkA, at S-phase checkpoint and in response to DNA-damaging agents. PMID:18245360

  2. DNA damage checkpoint kinase ATM regulates germination and maintains genome stability in seeds.

    PubMed

    Waterworth, Wanda M; Footitt, Steven; Bray, Clifford M; Finch-Savage, William E; West, Christopher E

    2016-08-23

    Genome integrity is crucial for cellular survival and the faithful transmission of genetic information. The eukaryotic cellular response to DNA damage is orchestrated by the DNA damage checkpoint kinases ATAXIA TELANGIECTASIA MUTATED (ATM) and ATM AND RAD3-RELATED (ATR). Here we identify important physiological roles for these sensor kinases in control of seed germination. We demonstrate that double-strand breaks (DSBs) are rate-limiting for germination. We identify that desiccation tolerant seeds exhibit a striking transcriptional DSB damage response during germination, indicative of high levels of genotoxic stress, which is induced following maturation drying and quiescence. Mutant atr and atm seeds are highly resistant to aging, establishing ATM and ATR as determinants of seed viability. In response to aging, ATM delays germination, whereas atm mutant seeds germinate with extensive chromosomal abnormalities. This identifies ATM as a major factor that controls germination in aged seeds, integrating progression through germination with surveillance of genome integrity. Mechanistically, ATM functions through control of DNA replication in imbibing seeds. ATM signaling is mediated by transcriptional control of the cell cycle inhibitor SIAMESE-RELATED 5, an essential factor required for the aging-induced delay to germination. In the soil seed bank, seeds exhibit increased transcript levels of ATM and ATR, with changes in dormancy and germination potential modulated by environmental signals, including temperature and soil moisture. Collectively, our findings reveal physiological functions for these sensor kinases in linking genome integrity to germination, thereby influencing seed quality, crucial for plant survival in the natural environment and sustainable crop production.

  3. DNA damage checkpoint kinase ATM regulates germination and maintains genome stability in seeds

    PubMed Central

    Waterworth, Wanda M.; Footitt, Steven; Bray, Clifford M.; Finch-Savage, William E.; West, Christopher E.

    2016-01-01

    Genome integrity is crucial for cellular survival and the faithful transmission of genetic information. The eukaryotic cellular response to DNA damage is orchestrated by the DNA damage checkpoint kinases ATAXIA TELANGIECTASIA MUTATED (ATM) and ATM AND RAD3-RELATED (ATR). Here we identify important physiological roles for these sensor kinases in control of seed germination. We demonstrate that double-strand breaks (DSBs) are rate-limiting for germination. We identify that desiccation tolerant seeds exhibit a striking transcriptional DSB damage response during germination, indicative of high levels of genotoxic stress, which is induced following maturation drying and quiescence. Mutant atr and atm seeds are highly resistant to aging, establishing ATM and ATR as determinants of seed viability. In response to aging, ATM delays germination, whereas atm mutant seeds germinate with extensive chromosomal abnormalities. This identifies ATM as a major factor that controls germination in aged seeds, integrating progression through germination with surveillance of genome integrity. Mechanistically, ATM functions through control of DNA replication in imbibing seeds. ATM signaling is mediated by transcriptional control of the cell cycle inhibitor SIAMESE-RELATED 5, an essential factor required for the aging-induced delay to germination. In the soil seed bank, seeds exhibit increased transcript levels of ATM and ATR, with changes in dormancy and germination potential modulated by environmental signals, including temperature and soil moisture. Collectively, our findings reveal physiological functions for these sensor kinases in linking genome integrity to germination, thereby influencing seed quality, crucial for plant survival in the natural environment and sustainable crop production. PMID:27503884

  4. Constitutive phosphorylation of ATM in lymphoblastoid cell lines from patients with ICF syndrome without downstream kinase activity.

    PubMed

    Goldstine, Jimena V; Nahas, Shareef; Gamo, Kristin; Gartler, Stanley M; Hansen, R Scott; Roelfsema, Jeroen H; Gatti, Richard A; Marahrens, York

    2006-04-08

    Double strand DNA breaks in the genome lead to the activation of the ataxia-telangiectasia mutated (ATM) kinase in a process that requires ATM autophosphorylation at serine-1981. ATM autophosphorylation only occurs if ATM is previously acetylated by Tip60. The activated ATM kinase phosphorylates proteins involved in arresting the cell cycle, including p53, and in repairing the DNA breaks. Chloroquine treatment and other manipulations that produce chromatin defects in the absence of detectable double strand breaks also trigger ATM phosphorylation and the phosphorylation of p53 in primary human fibroblasts, while other downstream substrates of ATM that are involved in the repair of DNA double strand breaks remain unphosphorylated. This raises the issue of whether ATM is constitutively activated in patients with genetic diseases that display chromatin defects. We examined lymphoblastoid cell lines (LCLs) generated from patients with different types of chromatin disorders: Immunodeficiency, Centromeric instability, Facial anomalies (ICF) syndrome, Coffin Lowry syndrome, Rubinstein Taybi syndrome and Fascioscapulohumeral Muscular Dystrophy. We show that ATM is phosphorylated on serine-1981 in LCLs derived from ICF patients but not from the other syndromes. The phosphorylated ATM in ICF cells did not phosphorylate the downstream targets NBS1, SMC1 and H2AX, all of which require the presence of double strand breaks. We demonstrate that ICF cells respond normally to ionizing radiation, ruling out the possibility that genetic deficiency in ICF cells renders activated ATM incapable of phosphorylating its downstream substrates. Surprisingly, p53 was also not phosphorylated in ICF cells or in chloroquine-treated wild type LCLs. In this regard the response to chromatin-altering agents differs between primary fibroblasts and LCLs. Our findings indicate that although phosphorylation at serine-1981 is essential in the activation of the ATM kinase, serine-1981 phosphorylation is

  5. Usage parameter control in ATM-PON

    NASA Astrophysics Data System (ADS)

    Wang, Zhili; Chen, Xue; Ye, Peida

    2001-10-01

    ATM Passive optical network (ATM-PON) is a kind of low-cost access network for resident and small-business users while Usage Parameter Control (UPC) is an important traffic control function in such networks. The basic traffic control function in an ATM network is the combination of UPC, network parameter control (NPC) and connection access control (CAC). As the entrance of an ATM network, an ATM- PON must have the function of UPC to check it the cell streams entering the network comply with the traffic contract negotiated between the user and the network during the connection setup. In this paper the UPC parameters negotiation methods in ATM-PONs are introduced, and the control algorithms and their realization are also discussed with the necessary simulation results.

  6. Activation of ATM by DNA Damaging Agents

    DTIC Science & Technology

    2004-09-01

    independent accumulation of p53 protein reductase inhibitor [83], ATM-independent phosphorylation on serine 15 [83], Phosphorylation on serine 46 and...on serine 15 [94], No phosphorylation on serine 15 [95] Sodium chromate (chromium(VL)) DNA-cross-links Stimulation of kinase activity [96] ATM...cytochrome P450 reductase and NAD(P)H (30). To evaluate a possible role for ROS in doxonibicin-mediated effects on p53, ATM-proficient BT cells were

  7. A new hemoglobin variant: Hb Meylan [β73(E17)Asp → Phe; HBB: c.220G>T; c.221A>T] with a double base mutation at the same codon.

    PubMed

    Renoux, Céline; Feray, Cécile; Joly, Philippe; Zanella-Cleon, Isabelle; Garcia, Caroline; Lacan, Philippe; Couprie, Nicole; Francina, Alain

    2015-01-01

    We report a new β-globin chain variant: Hb Meylan [β73(E17)Asp → Phe; HBB: c.220G>T; c.221A>T]. The new variant results from a double nucleotide mutation at the same codon. The possible molecular mechanisms are discussed.

  8. Expression and clinical significance of ATM and PUMA gene in patients with colorectal cancer.

    PubMed

    Xiong, Hui; Zhang, Jiangnan

    2017-12-01

    The expression of ataxia-telangiectasia mutated (ATM) and p53 upregulated modulator of apoptosis (PUMA) genes in patients with colorectal cancer were investigated, to explore the correlation between the expression of ATM and PUMA and tumor development, to evaluate the clinical significance of ATM and PUMA in the treatment of colorectal cancer. Quantitative real-time PCR was used to detect the expression of ATM and PUMA in tumor tissue and adjacent healthy tissue of 67 patients with colorectal cancer and in normal colorectal tissue of 33 patients with colorectal polyps at mRNA level. The expression level of ATM mRNA in colorectal cancer tissues was significantly higher than that in normal mucosa tissues and adjacent non-cancerous tissue (P≤0.05), while no significant differences in expression level of ATM mRNA were found between normal mucosa tissues and adjacent noncancerous tissue (P=0.07). There was a negative correlation between the expression of ATM mRNA and the degree of differentiation of colorectal cancer (r= -0.312, P=0.013), while expression level of ATM mRNA was not significantly correlated with the age, sex, tumor invasion, lymph node metastasis or clinical stage (P>0.05). Expression levels of PUMA mRNA in colorectal cancer tissues, adjacent noncancerous tissue and normal tissues were 0.68±0.07, 0.88±0.04 and 1.76±0.06, respectively. Expression level of PUMA mRNA in colorectal cancer tissues and adjacent noncancerous tissue was significantly lower than that in normal colorectal tissues (P<0.05). The results showed that ATM mRNA is expressed abnormally in colorectal cancer tissues. Expression of PUMA gene in colorectal carcinoma is downregulated, and is negatively correlated with the occurrence of cancer.

  9. Buffer Management Simulation in ATM Networks

    NASA Technical Reports Server (NTRS)

    Yaprak, E.; Xiao, Y.; Chronopoulos, A.; Chow, E.; Anneberg, L.

    1998-01-01

    This paper presents a simulation of a new dynamic buffer allocation management scheme in ATM networks. To achieve this objective, an algorithm that detects congestion and updates the dynamic buffer allocation scheme was developed for the OPNET simulation package via the creation of a new ATM module.

  10. Satellite ATM Networks: Architectures and Guidelines Developed

    NASA Technical Reports Server (NTRS)

    vonDeak, Thomas C.; Yegendu, Ferit

    1999-01-01

    An important element of satellite-supported asynchronous transfer mode (ATM) networking will involve support for the routing and rerouting of active connections. Work published under the auspices of the Telecommunications Industry Association (http://www.tiaonline.org), describes basic architectures and routing protocol issues for satellite ATM (SATATM) networks. The architectures and issues identified will serve as a basis for further development of technical specifications for these SATATM networks. Three ATM network architectures for bent pipe satellites and three ATM network architectures for satellites with onboard ATM switches were developed. The architectures differ from one another in terms of required level of mobility, supported data rates, supported terrestrial interfaces, and onboard processing and switching requirements. The documentation addresses low-, middle-, and geosynchronous-Earth-orbit satellite configurations. The satellite environment may require real-time routing to support the mobility of end devices and nodes of the ATM network itself. This requires the network to be able to reroute active circuits in real time. In addition to supporting mobility, rerouting can also be used to (1) optimize network routing, (2) respond to changing quality-of-service requirements, and (3) provide a fault tolerance mechanism. Traffic management and control functions are necessary in ATM to ensure that the quality-of-service requirements associated with each connection are not violated and also to provide flow and congestion control functions. Functions related to traffic management were identified and described. Most of these traffic management functions will be supported by on-ground ATM switches, but in a hybrid terrestrial-satellite ATM network, some of the traffic management functions may have to be supported by the onboard satellite ATM switch. Future work is planned to examine the tradeoffs of placing traffic management functions onboard a satellite as

  11. Multifunctional Role of ATM/Tel1 Kinase in Genome Stability: From the DNA Damage Response to Telomere Maintenance

    PubMed Central

    2014-01-01

    The mammalian protein kinase ataxia telangiectasia mutated (ATM) is a key regulator of the DNA double-strand-break response and belongs to the evolutionary conserved phosphatidylinositol-3-kinase-related protein kinases. ATM deficiency causes ataxia telangiectasia (AT), a genetic disorder that is characterized by premature aging, cerebellar neuropathy, immunodeficiency, and predisposition to cancer. AT cells show defects in the DNA damage-response pathway, cell-cycle control, and telomere maintenance and length regulation. Likewise, in Saccharomyces cerevisiae, haploid strains defective in the TEL1 gene, the ATM ortholog, show chromosomal aberrations and short telomeres. In this review, we outline the complex role of ATM/Tel1 in maintaining genomic stability through its control of numerous aspects of cellular survival. In particular, we describe how ATM/Tel1 participates in the signal transduction pathways elicited by DNA damage and in telomere homeostasis and its importance as a barrier to cancer development. PMID:25247188

  12. MSFC institutional area network and ATM technology

    NASA Technical Reports Server (NTRS)

    Amin, Ashok T.

    1994-01-01

    The New Institutional Area Network (NEWIAN) at Marshall supports over 5000 end users with access to 26 file servers providing work presentation services. It is comprised of some 150 Ethernet LAN's interconnected by bridges/routers which are in turn connected to servers over two dual FDDI rings. The network supports various higher level protocols such as IP, IPX, AppleTalk (AT), and DECNet. At present IPX and AT protocols packets are routed, and IP protocol packets are bridged; however, work is in progress to route all IP packets. The impact of routing IP packets on network operation is examined. Broadband Integrated Services Data Network (BISDN), presently at various stages of development, is intended to provide voice, video, and data transfer services over a single network. BISDN will use asynchronous transfer mode (ATM) as a data transfer technique which provides for transmission, multiplexing, switching, and relaying of small size data units called cells. Limited ATM Wide Area Network (WAN) services are offered by Wiltel, AT&T, Sprint, and others. NASA is testing a pilot ATM WAN with a view to provide Program Support Communication Network services using ATM. ATM supports wide range of data rates and quality of service requirements. It is expected that ATM switches will penetrate campus networks as well. However, presently products in these areas are at various stages of development and standards are not yet complete. We examine development of ATM to help assess its role in the evolution of NEWIAN.

  13. The tumor suppressor, TAX1BP2, is a novel substrate of ATM kinase.

    PubMed

    Lai, W L; Hung, W Y; Ching, Y P

    2014-11-06

    DNA damage repair response is a crucial process for cancer prevention. One of the key regulators of this process is ataxia telangiectasia mutated (ATM) kinase, which modulates the p53 level by direct and indirect phosphorylation. Recent data showed that ATM also localizes at the centrosome, but the function remains elusive. TAX1BP2 was initially identified as a novel centrosomal protein that interacts directly with the human T-cell leukemia virus type 1 (HTLV-1)-encoded oncoprotein, Tax, and inhibits centrosome overduplication. Subsequently, TAX1BP2 was found to be a tumor suppressor in hepatocellular carcinoma, and accumulation of TAX1BP2 was observed upon chemotherapeutic drug treatment. Here, we provide evidence that TAX1BP2 is a direct phosphorylation substrate of ATM. The protein level of TAX1BP2 is significantly upregulated in response to DNA damaging agents. Serine-922 of TAX1BP2 is the phosphorylation site of ATM, and such phosphorylation modulates the protein stability, ubiquitination and tumor suppressor activity of TAX1BP2. Taken together, we demonstrate for the first time that TAX1BP2 is a novel effector of ATM in DNA damage response and delineated a new mechanism by which ATM stabilizes the tumor suppressor TAX1BP2.

  14. Mutation of ataxia-telangiectasia mutated is associated with dysfunctional glutathione homeostasis in cerebellar astroglia.

    PubMed

    Campbell, Andrew; Bushman, Jared; Munger, Joshua; Noble, Mark; Pröschel, Christoph; Mayer-Pröschel, Margot

    2016-02-01

    Astroglial dysfunction plays an important role in neurodegenerative diseases otherwise attributed to neuronal loss of function. Here we focus on the role of astroglia in ataxia-telangiectasia (A-T), a disease caused by mutations in the ataxia-telangiectasia mutated (ATM) gene. A hallmark of A-T pathology is progressive loss of cerebellar neurons, but the mechanisms that impact neuronal survival are unclear. We now provide a possible mechanism by which A-T astroglia affect the survival of cerebellar neurons. As astroglial functions are difficult to study in an in vivo setting, particularly in the cerebellum where these cells are intertwined with the far more numerous neurons, we conducted in vitro coculture experiments that allow for the generation and pharmacological manipulation of purified cell populations. Our analyses revealed that cerebellar astroglia isolated from Atm mutant mice show decreased expression of the cystine/glutamate exchanger subunit xCT, glutathione (GSH) reductase, and glutathione-S-transferase. We also found decreased levels of intercellular and secreted GSH in A-T astroglia. Metabolic labeling of l-cystine, the major precursor for GSH, revealed that a key component of the defect in A-T astroglia is an impaired ability to import this rate-limiting precursor for the production of GSH. This impairment resulted in suboptimal extracellular GSH supply, which in turn impaired survival of cerebellar neurons. We show that by circumventing the xCT-dependent import of L-cystine through addition of N-acetyl-L-cysteine (NAC) as an alternative cysteine source, we were able to restore GSH levels in A-T mutant astroglia providing a possible future avenue for targeted therapeutic intervention. © 2015 Wiley Periodicals, Inc.

  15. The checkpoint kinase ATM protects against stress-induced elevation of cyclin D1 and potential cell death in neurons.

    PubMed

    Hitomi, Masahiro; Stacey, Dennis W

    2010-06-01

    Quantitative cytometric studies show that cyclin D1 levels must decline during S phase for proper cell cycle progression, and that cyclin D1 decline follows phosphorylation induced by the checkpoint kinases ataxia telangiectasia mutated (ATM) and ATM and Rad3-related (ATR). ATM is mutated in ataxia telangiectasia (AT), a disease characterized by progressive neurodegeneration. Importantly, neurodegeneration in many cases has been linked to the increased expression of cyclin D1 in neurons leading to inappropriate cell cycle entry. These facts prompted us to test the possibility that ATM normally protects against neural degeneration by suppressing cyclin D1 levels, particularly following genotoxic stress. For this purpose, neural stem cells were induced to differentiate into mature neural cells, including neurons. ATM activity in these cultures was inhibited with a specific chemical inhibitor in the presence or absence of hydrogen peroxide treatment, and the effect on cyclin D1 expression was determined by quantitative, single cell cytometric analyses. As predicted, inhibition of ATM did promote elevation of cyclin D1 in differentiated neurons, particularly under conditions of oxidative stress. The survival of differentiated neurons and of neural stem cells was reduced by such treatments. These data support our suggestion that ATM functions to maintain low levels of cyclin D1 expression in differentiated neurons; and may provide important clues in understanding neural degeneration in general. Copyright 2010 International Society for Advancement of Cytometry.

  16. Drosophila atm/telomere fusion is required for telomeric localization of HP1 and telomere position effect.

    PubMed

    Oikemus, Sarah R; McGinnis, Nadine; Queiroz-Machado, Joana; Tukachinsky, Hanna; Takada, Saeko; Sunkel, Claudio E; Brodsky, Michael H

    2004-08-01

    Terminal deletions of Drosophila chromosomes can be stably protected from end-to-end fusion despite the absence of all telomere-associated sequences. The sequence-independent protection of these telomeres suggests that recognition of chromosome ends might contribute to the epigenetic protection of telomeres. In mammals, Ataxia Telangiectasia Mutated (ATM) is activated by DNA damage and acts through an unknown, telomerase-independent mechanism to regulate telomere length and protection. We demonstrate that the Drosophila homolog of ATM is encoded by the telomere fusion (tefu) gene. In the absence of ATM, telomere fusions occur even though telomere-specific Het-A sequences are still present. High levels of spontaneous apoptosis are observed in ATM-deficient tissues, indicating that telomere dysfunction induces apoptosis in Drosophila. Suppression of this apoptosis by p53 mutations suggests that loss of ATM activates apoptosis through a DNA damage-response mechanism. Loss of ATM reduces the levels of heterochromatin protein 1 (HP1) at telomeres and suppresses telomere position effect. We propose that recognition of chromosome ends by ATM prevents telomere fusion and apoptosis by recruiting chromatin-modifying complexes to telomeres.

  17. Drosophila atm/telomere fusion is required for telomeric localization of HP1 and telomere position effect

    PubMed Central

    Oikemus, Sarah R.; McGinnis, Nadine; Queiroz-Machado, Joana; Tukachinsky, Hanna; Takada, Saeko; Sunkel, Claudio E.; Brodsky, Michael H.

    2004-01-01

    Terminal deletions of Drosophila chromosomes can be stably protected from end-to-end fusion despite the absence of all telomere-associated sequences. The sequence-independent protection of these telomeres suggests that recognition of chromosome ends might contribute to the epigenetic protection of telomeres. In mammals, Ataxia Telangiectasia Mutated (ATM) is activated by DNA damage and acts through an unknown, telomerase-independent mechanism to regulate telomere length and protection. We demonstrate that the Drosophila homolog of ATM is encoded by the telomere fusion (tefu) gene. In the absence of ATM, telomere fusions occur even though telomere-specific Het-A sequences are still present. High levels of spontaneous apoptosis are observed in ATM-deficient tissues, indicating that telomere dysfunction induces apoptosis in Drosophila. Suppression of this apoptosis by p53 mutations suggests that loss of ATM activates apoptosis through a DNA damage-response mechanism. Loss of ATM reduces the levels of heterochromatin protein 1 (HP1) at telomeres and suppresses telomere position effect. We propose that recognition of chromosome ends by ATM prevents telomere fusion and apoptosis by recruiting chromatin-modifying complexes to telomeres. PMID:15256487

  18. ATM Card Cloning and Ethical Considerations.

    PubMed

    Kaur, Paramjit; Krishan, Kewal; Sharma, Suresh K; Kanchan, Tanuj

    2018-05-01

    With the advent of modern technology, the way society handles and performs monetary transactions has changed tremendously. The world is moving swiftly towards the digital arena. The use of Automated Teller Machine (ATM) cards (credit and debit) has led to a "cash-less society" and has fostered digital payments and purchases. In addition to this, the trust and reliance of the society upon these small pieces of plastic, having numbers engraved upon them, has increased immensely over the last two decades. In the past few years, the number of ATM fraud cases has increased exponentially. With the money of the people shifting towards the digital platform, ATM skimming has become a problem that has eventually led to a global outcry. The present review discusses the serious repercussions of ATM card cloning and the associated privacy, ethical and legal concerns. The preventive measures which need to be taken and adopted by the government authorities to mitigate the problem have also been discussed.

  19. Borman Expressway Atms Equipment Evaluation; Final Report

    DOT National Transportation Integrated Search

    1996-08-01

    AN ADVANCED TRAFFIC MANAGEMENT SYSTEM (ATMS) IS UNDER DEVELOPMENT IN NORTHERN INDIANA BY THE INDIANA DEPARTMENT OF TRANSPORTATION (INDOT) IN CONJUNCTION WITH HUGHES TRANSPORTATION MANAGEMENT SYSTEMS. THE STUDY AREA COMPRISES A SIXTEEN MILE SEGMENT OF...

  20. A T9G mutation in the prototype TATA-box TCACTATATATAG determines nucleosome formation and synergy with upstream activator sequences in plant promoters.

    PubMed

    Ranjan, Amol; Ansari, Suraiya A; Srivastava, Rakesh; Mantri, Shrikant; Asif, Mehar H; Sawant, Samir V; Tuli, Rakesh

    2009-12-01

    We had earlier reported that mutations to G and C at the seventh and eighth positions in the prototype TATA-box TCACTATATATAG inhibited light-dependent activation of transcription from the promoter. In this study, we characterized mutations at the ninth position of the prototype TATA-box. Substitution of T at the ninth position with G or C enhanced transcription from the promoter in transgenic tobacco (Nicotiana tabacum) plants. The effect of T9G/C mutations was not light dependent, although the 9G/C TATA-box showed synergy with the light-responsive element (lre). However, the 9G/C mutants in the presence of lre failed to respond to phytochromes, sugar, and calcium signaling, in contrast to the prototype TATA-box with lre. The 9G/C mutation shifted the point of initiation of transcription, and transcription activation was dependent upon the type of activating element present upstream. The synergy in activation was noticed with lre and legumin activators but not with rbcS, Pcec, and PR-1a activators. The 9G mutation resulted in a micrococcal nuclease-sensitive region over the TATA-box, suggesting a nucleosome-free region, in contrast to the prototype promoter, which had a distinct nucleosome on the TATA-box. Thus, the transcriptional augmentation with mutation at the ninth position might be because of the loss of a repressive nucleosomal structure on the TATA-box. In agreement with our findings, the promoters containing TATAGATA as identified by genome-wide analysis of Arabidopsis (Arabidopsis thaliana) are not tightly repressed.

  1. Asynchronous Transfer Mode (ATM) Switch Technology and Vendor Survey

    NASA Technical Reports Server (NTRS)

    Berry, Noemi

    1995-01-01

    Asynchronous Transfer Mode (ATM) switch and software features are described and compared in order to make switch comparisons meaningful. An ATM switch's performance cannot be measured solely based on its claimed switching capacity; traffic management and congestion control are emerging as the determining factors in an ATM network's ultimate throughput. Non-switch ATM products and experiences with actual installations of ATM networks are described. A compilation of select vendor offerings as of October 1994 is provided in chart form.

  2. An ATM-independent S-phase checkpoint response involves CHK1 pathway

    NASA Technical Reports Server (NTRS)

    Zhou, Xiang-Yang; Wang, Xiang; Hu, Baocheng; Guan, Jun; Iliakis, George; Wang, Ya

    2002-01-01

    After exposure to genotoxic stress, proliferating cells actively slow down the DNA replication through a S-phase checkpoint to provide time for repair. We report that in addition to the ataxia-telangiectasia mutated (ATM)-dependent pathway that controls the fast response, there is an ATM-independent pathway that controls the slow response to regulate the S-phase checkpoint after ionizing radiation in mammalian cells. The slow response of S-phase checkpoint, which is resistant to wortmannin, sensitive to caffeine and UCN-01, and related to cyclin-dependent kinase phosphorylation, is much stronger in CHK1 overexpressed cells, and it could be abolished by Chk1 antisense oligonucleotides. These results provide evidence that the ATM-independent slow response of S-phase checkpoint involves CHK1 pathway.

  3. Crystal structures of nucleotide-free and glutathione-bound mitochondrial ABC transporter Atm1.

    PubMed

    Srinivasan, Vasundara; Pierik, Antonio J; Lill, Roland

    2014-03-07

    The yeast mitochondrial ABC transporter Atm1, in concert with glutathione, functions in the export of a substrate required for cytosolic-nuclear iron-sulfur protein biogenesis and cellular iron regulation. Defects in the human ortholog ABCB7 cause the sideroblastic anemia XLSA/A. Here, we report the crystal structures of free and glutathione-bound Atm1 in inward-facing, open conformations at 3.06- and 3.38-angstrom resolution, respectively. The glutathione binding site includes a residue mutated in XLSA/A and is located close to the inner membrane surface in a large cavity. The two nucleotide-free adenosine 5'-triphosphate binding domains do not interact yet are kept in close vicinity through tight interaction of the two C-terminal α-helices of the Atm1 dimer. The resulting protein stabilization may be a common structural feature of all ABC exporters.

  4. Health ATMs in Saudi Arabia: A Perspective

    PubMed Central

    Aldosari, Bakheet

    2017-01-01

    Background: Health ATMs are terminals which are connected to a centrally located database storing patients’ electronic healthcare records (EHR). These machines are capable of collecting information in a far superior fashion than humans and are also able to rectify obsolete data in a manner that humans are generally not inclined to. Objectives: The main goal of this study is to assess the importance of adopting health ATMs in the Kingdom of Saudi Arabia (KSA), which can improve the confidence of patients, reward health self-management, and achieve positive health outcomes through their easy-to-use applications that are secure and accessible through various devices. Methods: Strength, Weakness, Opportunity, and Threat (SWOT) analysis was used to assess the efficiency of adopting health ATMs in KSA and reveal the said characteristics. Three focus groups assembled in the cities of Riyadh, Jeddah and Dammam during the period 2013-2014. The groups consisted of individuals experienced in the function of health ATMs. Results: It was found that the sector possessed a number of strengths that would help it in reaching the goals outlined therein, thereby achieving successful outcomes. Conclusions: Health ATMs could be a promising new advancement in the field of health if the project were to be planned and implemented correctly. Their benefits would consequently reach organizational and national levels. It is, therefore, crucial to educate the project managers about the benefits of learning from others as well as educating them about the needs and the requirements of the concerned organization. PMID:28883680

  5. Health ATMs in Saudi Arabia: A Perspective.

    PubMed

    Aldosari, Bakheet

    2017-06-01

    Health ATMs are terminals which are connected to a centrally located database storing patients' electronic healthcare records (EHR). These machines are capable of collecting information in a far superior fashion than humans and are also able to rectify obsolete data in a manner that humans are generally not inclined to. The main goal of this study is to assess the importance of adopting health ATMs in the Kingdom of Saudi Arabia (KSA), which can improve the confidence of patients, reward health self-management, and achieve positive health outcomes through their easy-to-use applications that are secure and accessible through various devices. Strength, Weakness, Opportunity, and Threat (SWOT) analysis was used to assess the efficiency of adopting health ATMs in KSA and reveal the said characteristics. Three focus groups assembled in the cities of Riyadh, Jeddah and Dammam during the period 2013-2014. The groups consisted of individuals experienced in the function of health ATMs. It was found that the sector possessed a number of strengths that would help it in reaching the goals outlined therein, thereby achieving successful outcomes. Health ATMs could be a promising new advancement in the field of health if the project were to be planned and implemented correctly. Their benefits would consequently reach organizational and national levels. It is, therefore, crucial to educate the project managers about the benefits of learning from others as well as educating them about the needs and the requirements of the concerned organization.

  6. Myc is required for activation of the ATM-dependent checkpoints in response to DNA damage.

    PubMed

    Guerra, Lina; Albihn, Ami; Tronnersjö, Susanna; Yan, Qinzi; Guidi, Riccardo; Stenerlöw, Bo; Sterzenbach, Torsten; Josenhans, Christine; Fox, James G; Schauer, David B; Thelestam, Monica; Larsson, Lars-Gunnar; Henriksson, Marie; Frisan, Teresa

    2010-01-27

    The MYC protein controls cellular functions such as differentiation, proliferation, and apoptosis. In response to genotoxic agents, cells overexpressing MYC undergo apoptosis. However, the MYC-regulated effectors acting upstream of the mitochondrial apoptotic pathway are still unknown. In this study, we demonstrate that expression of Myc is required to activate the Ataxia telangiectasia mutated (ATM)-dependent DNA damage checkpoint responses in rat cell lines exposed to ionizing radiation (IR) or the bacterial cytolethal distending toxin (CDT). Phosphorylation of the ATM kinase and its downstream effectors, such as histone H2AX, were impaired in the myc null cell line HO15.19, compared to the myc positive TGR-1 and HOmyc3 cells. Nuclear foci formation of the Nijmegen Breakage Syndrome (Nbs) 1 protein, essential for efficient ATM activation, was also reduced in absence of myc. Knock down of the endogenous levels of MYC by siRNA in the human cell line HCT116 resulted in decreased ATM and CHK2 phosphorylation in response to irradiation. Conversely, cell death induced by UV irradiation, known to activate the ATR-dependent checkpoint, was similar in all the cell lines, independently of the myc status. These data demonstrate that MYC contributes to the activation of the ATM-dependent checkpoint responses, leading to cell death in response to specific genotoxic stimuli.

  7. ATM regulates 3-Methylpurine-DNA glycosylase and promotes therapeutic resistance to alkylating agents

    PubMed Central

    Agnihotri, Sameer; Burrell, Kelly; Buczkowicz, Pawel; Remke, Marc; Golbourn, Brian; Chornenkyy, Yevgen; Gajadhar, Aaron; Fernandez, Nestor A.; Clarke, Ian D.; Barszczyk, Mark S.; Pajovic, Sanja; Ternamian, Christian; Head, Renee; Sabha, Nesrin; Sobol, Robert W.; Taylor, Michael D; Rutka, James T.; Jones, Chris; Dirks, Peter B.; Zadeh, Gelareh; Hawkins, Cynthia

    2014-01-01

    Alkylating agents are a frontline therapy for the treatment of several aggressive cancers including pediatric glioblastoma, a lethal tumor in children. Unfortunately, many tumors are resistant to this therapy. We sought to identify ways of sensitizing tumor cells to alkylating agents while leaving normal cells unharmed; increasing therapeutic response while minimizing toxicity. Using a siRNA screen targeting over 240 DNA damage response genes, we identified novel sensitizers to alkylating agents. In particular the base excision repair (BER) pathway, including 3-methylpurine-DNA glycosylase (MPG), as well as ataxia telangiectasia mutated (ATM) were identified in our screen. Interestingly, we identified MPG as a direct novel substrate of ATM. ATM-mediated phosphorylation of MPG was required for enhanced MPG function. Importantly, combined inhibition or loss of MPG and ATM resulted in increased alkylating agent-induced cytotoxicity in vitro and prolonged survival in vivo. The discovery of the ATM-MPG axis will lead to improved treatment of alkylating agent-resistant tumors. PMID:25100205

  8. ATM interface design issues for IP traffic over ATM/ADSL access networks

    NASA Astrophysics Data System (ADS)

    Buschmann, Jonathan E.; Pampolini, Matteo

    1999-01-01

    The combination of ATM and ADSL is fast becoming an attractive alternative for Internet access for home and small business. ADSL modems allow the use of the existing copper plant at speeds much higher than those afforded by traditional modem technologies. The use of ATM both enables the long-sought goal of an ATM end-to-end network, and allows, through the use of QOS guarantees, efficient use of the limited upstream bandwidth of ADSL. Although the client- server model, which typified classical Internet traffic and newer multimedia IP services, fits well an asymmetric network model, performance can be greatly impacted unless the interactions between ADSL, ATM, and Internet protocols are well understood an taken into account in the design of ATM interfaces. In this paper we investigate the potential limitations on performance in IP/ATM/ADSL networks and explain how, in our ATM interface designs, we have ameliorated these problems and optimized the use of IP services over such networks. We discuss the importance of 'traffic shaping', heretofore afforded little importance for IP traffic, and the impact of latency and asymmetric bandwidth of ADSL, on both traditional and multimedia IP services, in our implementations.

  9. ATM over hybrid fiber-coaxial cable networks: practical issues in deploying residential ATM services

    NASA Astrophysics Data System (ADS)

    Laubach, Mark

    1996-11-01

    Residential broadband access network technology based on asynchronous transfer modem (ATM) will soon reach commercial availability. The capabilities provided by ATM access network promise integrated services bandwidth available in excess of those provided by traditional twisted pair copper wire public telephone networks. ATM to the side of the home placed need quality of service capability closest to the subscriber allowing immediate support for Internet services and traditional voice telephony. Other services such as desktop video teleconferencing and enhanced server-based application support can be added as part of future evolution of the network. Additionally, advanced subscriber home networks can be supported easily. This paper presents an updated summary of the standardization efforts for the ATM over HFC definition work currently taking place in the ATM forum's residential broadband working group and the standards progress in the IEEE 802.14 cable TV media access control and physical protocol working group. This update is fundamental for establishing the foundation for delivering ATM-based integrated services via a cable TV network. An economic model for deploying multi-tiered services is presenting showing that a single-tier service is insufficient for a viable cable operator business. Finally, the use of an ATM based system lends itself well to various deployment scenarios of synchronous optical networks (SONET).

  10. Distinct roles of ATR and DNA-PKcs in triggering DNA damage responses in ATM-deficient cells

    PubMed Central

    Tomimatsu, Nozomi; Mukherjee, Bipasha; Burma, Sandeep

    2009-01-01

    The cellular response to DNA double-strand breaks involves direct activation of ataxia telangiectasia mutated (ATM) and indirect activation of ataxia telangiectasia and Rad3 related (ATR) in an ATM/Mre11/cell-cycle-dependent manner. Here, we report that the crucial checkpoint signalling proteins—p53, structural maintainance of chromosomes 1 (SMC1), p53 binding protein 1 (53BP1), checkpoint kinase (Chk)1 and Chk2—are phosphorylated rapidly by ATR in an ATM/Mre11/cell-cycle-independent manner, albeit at low levels. We observed the sequential recruitment of replication protein A (RPA) and ATR to the sites of DNA damage in ATM-deficient cells, which provides a mechanistic basis for the observed phosphorylations. The recruitment of ATR and consequent phosphorylations do not require Mre11 but are dependent on Exo1. We show that these low levels of phosphorylation are biologically important, as ATM-deficient cells enforce an early G2/M checkpoint that is ATR-dependent. ATR is also essential for the late G2 accumulation that is peculiar to irradiated ATM-deficient cells. Interestingly, phosphorylation of KRAB associated protein 1 (KAP-1), a protein involved in chromatin remodelling, is mediated by DNA-dependent protein kinase catalytic subunit (DNA-PKcs) in a spatio-temporal manner in addition to ATM. We posit that ATM substrates involved in cell-cycle checkpoint signalling can be minimally phosphorylated independently by ATR, while a small subset of proteins involved in chromatin remodelling are phosphorylated by DNA-PKcs in addition to ATM. PMID:19444312

  11. GNSS real time performance monitoring and CNS/ATM implementation

    DOT National Transportation Integrated Search

    2006-07-01

    The global transition to communications, navigation, surveillance / air traffic management (CNS/ATM) technology is moving forward at an increasing pace. A critical part of the CNS/ATM concept is the ability to monitor, analyze, and distribute aeronau...

  12. Early deployment of ATMS/ATIS for metropolitan Detroit

    DOT National Transportation Integrated Search

    1994-09-26

    The Michigan Department of Transportation (MDOT) is currently planning for the expansion of their current Advanced Traffic Management and Advanced Traveler Information Systems (ATMS and ATIS, respectively). Current ATMS and ATIS coverage include 3...

  13. ATM/cable arch and beam structural test program

    NASA Technical Reports Server (NTRS)

    Housley, J. A.

    1972-01-01

    The structural testing is described of an Apollo Telescope Mount (ATM) cable arch and beam assembly, using static loads to simulate the critical conditions expected during transportation and launch of the ATM. All test objectives were met. Stress and deflection data show that the assembly is structurally adequate for use in the ATM.

  14. Methods for detection of ataxia telangiectasia mutations

    DOEpatents

    Gatti, Richard A.

    2005-10-04

    The present invention is directed to a method of screening large, complex, polyexonic eukaryotic genes such as the ATM gene for mutations and polymorphisms by an improved version of single strand conformation polymorphism (SSCP) electrophoresis that allows electrophoresis of two or three amplified segments in a single lane. The present invention also is directed to new mutations and polymorphisms in the ATM gene that are useful in performing more accurate screening of human DNA samples for mutations and in distinguishing mutations from polymorphisms, thereby improving the efficiency of automated screening methods.

  15. Development of a high-content high-throughput screening assay for the discovery of ATM signaling inhibitors.

    PubMed

    Bardelle, Catherine; Boros, Joanna

    2012-08-01

    The genome is constantly exposed to DNA damage agents, leading up to as many as 1 million individual lesions per cell per day. Cells have developed a variety of DNA damage repair (DDR) mechanisms to respond to harmful effects of DNA damage. Failure to repair the damaged DNA causes genomic instability and, as a result, leads to cellular transformation. Indeed, deficiencies of DDR frequently occur in human cancers, thus providing a great opportunity for cancer therapy by developing anticancer agents that work by synthetic lethality-based mechanisms or enhancing the clinical efficacy of radiotherapy and existing chemotherapies. Ataxia-telangiectasia mutated (ATM) plays a key role in regulating the cellular response to DNA double-strand breaks. Ionizing radiation causes double-strand breaks and induces rapid ATM autophosphorylation on serine 1981 that initiates ATM kinase activity. Activation of ATM results in phosphorylation of many downstream targets that modulate numerous damage-response pathways, most notably cell-cycle checkpoints. We describe here the development and validation of a high-throughput imaging assay measuring levels of phospho-ATM Ser1981 in HT29 cells after exposure to ionizing radiation. We also examined activation of downstream ATM effectors and checked specificity of the endpoint using known inhibitors of DNA repair pathways.

  16. Eradication of Large Solid Tumors by Gene Therapy with a T-Cell Receptor Targeting a Single Cancer-Specific Point Mutation.

    PubMed

    Leisegang, Matthias; Engels, Boris; Schreiber, Karin; Yew, Poh Yin; Kiyotani, Kazuma; Idel, Christian; Arina, Ainhoa; Duraiswamy, Jaikumar; Weichselbaum, Ralph R; Uckert, Wolfgang; Nakamura, Yusuke; Schreiber, Hans

    2016-06-01

    Cancers usually contain multiple unique tumor-specific antigens produced by single amino acid substitutions (AAS) and encoded by somatic nonsynonymous single nucleotide substitutions. We determined whether adoptively transferred T cells can reject large, well-established solid tumors when engineered to express a single type of T-cell receptor (TCR) that is specific for a single AAS. By exome and RNA sequencing of an UV-induced tumor, we identified an AAS in p68 (mp68), a co-activator of p53. This AAS seemed to be an ideal tumor-specific neoepitope because it is encoded by a trunk mutation in the primary autochthonous cancer and binds with highest affinity to the MHC. A high-avidity mp68-specific TCR was used to genetically engineer T cells as well as to generate TCR-transgenic mice for adoptive therapy. When the neoepitope was expressed at high levels and by all cancer cells, their direct recognition sufficed to destroy intratumor vessels and eradicate large, long-established solid tumors. When the neoepitope was targeted as autochthonous antigen, T cells caused cancer regression followed by escape of antigen-negative variants. Escape could be thwarted by expressing the antigen at increased levels in all cancer cells or by combining T-cell therapy with local irradiation. Therapeutic efficacies of TCR-transduced and TCR-transgenic T cells were similar. Gene therapy with a single TCR targeting a single AAS can eradicate large established cancer, but a uniform expression and/or sufficient levels of the targeted neoepitope or additional therapy are required to overcome tumor escape. Clin Cancer Res; 22(11); 2734-43. ©2015 AACRSee related commentary by Liu, p. 2602. ©2015 American Association for Cancer Research.

  17. Early B-cell-specific inactivation of ATM synergizes with ectopic CyclinD1 expression to promote pre-germinal center B-cell lymphomas in mice.

    PubMed

    Yamamoto, K; Lee, B J; Li, C; Dubois, R L; Hobeika, E; Bhagat, G; Zha, S

    2015-06-01

    Ataxia telangiectasia-mutated (ATM) kinase is a master regulator of the DNA damage response. ATM is frequently inactivated in human B-cell non-Hodgkin lymphomas, including ~50% of mantle cell lymphomas (MCLs) characterized by ectopic expression of CyclinD1. Here we report that early and robust deletion of ATM in precursor/progenitor B cells causes cell autonomous, clonal mature B-cell lymphomas of both pre- and post-germinal center (GC) origins. Unexpectedly, naive B-cell-specific deletion of ATM is not sufficient to induce lymphomas in mice, highlighting the important tumor suppressor function of ATM in immature B cells. Although EμCyclinD1 is not sufficient to induce lymphomas, EμCyclinD1 accelerates the kinetics and increases the incidence of clonal lymphomas in ATM-deficient B-cells and skews the lymphomas toward pre-GC-derived small lymphocytic neoplasms, sharing morphological features of human MCL. This is in part due to CyclinD1-driven expansion of ATM-deficient naive B cells with genomic instability, which promotes the deletions of additional tumor suppressor genes (i.e. Trp53, Mll2, Rb1 and Cdkn2a). Together these findings define a synergistic function of ATM and CyclinD1 in pre-GC B-cell proliferation and lymphomagenesis and provide a prototypic animal model to study the pathogenesis of human MCL.

  18. Do Structural Missense Variants in the ATM Gene Found in Women With Breast Cancer Cause Breast Cancer in Knock-in Mouse Strains?

    DTIC Science & Technology

    2006-04-01

    W81XWH-05-1-0282 TITLE: Do Structural Missense Variants in the ATM Gene Found in Women with Breast Cancer Cause Breast Cancer in "Knock-in...5a. CONTRACT NUMBER Do Structural Missense Variants in the ATM Gene Found in Women with Breast Cancer Cause Breast Cancer in "Knock-in" Mouse...human cohort-specific missense mutations will develop breast cancer with dominant inheritance in a subset of animals. It also is hypothesized that

  19. Preservation of methane hydrate at 1 atm

    USGS Publications Warehouse

    Stern, L.A.; Circone, S.; Kirby, S.H.; Durham, W.B.

    2001-01-01

    A "pressure-release" method that enables reproducible bulk preservation of pure, porous, methane hydrate at conditions 50 to 75 K above its equilibrium T (193 K) at 1 atm is refined. The amount of hydrate preserved by this method appears to be greatly in excess of that reported in the previous citations, and is likely the result of a mechanism different from ice shielding.

  20. ATM Coastal Topography-Mississippi, 2001

    USGS Publications Warehouse

    Nayegandhi, Amar; Yates, Xan; Brock, John C.; Sallenger, A.H.; Klipp, Emily S.; Wright, C. Wayne

    2009-01-01

    These remotely sensed, geographically referenced elevation measurements of lidar-derived first-surface (FS) topography were produced collaboratively by the U.S. Geological Survey (USGS), Florida Integrated Science Center (FISC), St. Petersburg, FL, and the National Aeronautics and Space Administration (NASA), Wallops Flight Facility, VA. This project provides highly detailed and accurate datasets of the Mississippi coastline, from Lakeshore to Petit Bois Island, acquired September 9-10, 2001. The datasets are made available for use as a management tool to research scientists and natural-resource managers. An innovative scanning lidar instrument originally developed by NASA, and known as the Airborne Topographic Mapper (ATM), was used during data acquisition. The ATM system is a scanning lidar system that measures high-resolution topography of the land surface and incorporates a green-wavelength laser operating at pulse rates of 2 to 10 kilohertz. Measurements from the laser-ranging device are coupled with data acquired from inertial navigation system (INS) attitude sensors and differentially corrected global positioning system (GPS) receivers to measure topography of the surface at accuracies of +/-15 centimeters. The nominal ATM platform is a Twin Otter or P-3 Orion aircraft, but the instrument may be deployed on a range of light aircraft. Elevation measurements were collected over the survey area using the ATM system, and the resulting data were then processed using the Airborne Lidar Processing System (ALPS), a custom-built processing system developed in a NASA-USGS collaboration. ALPS supports the exploration and processing of lidar data in an interactive or batch mode. Modules for presurvey flight-line definition, flight-path plotting, lidar raster and waveform investigation, and digital camera image playback have been developed. Processing algorithms have been developed to extract the range to the first and last significant return within each waveform. ALPS

  1. ATM Coastal Topography-Alabama 2001

    USGS Publications Warehouse

    Nayegandhi, Amar; Yates, Xan; Brock, John C.; Sallenger, A.H.; Bonisteel, Jamie M.; Klipp, Emily S.; Wright, C. Wayne

    2009-01-01

    These remotely sensed, geographically referenced elevation measurements of Lidar-derived first surface (FS) topography were produced collaboratively by the U.S. Geological Survey (USGS), Florida Integrated Science Center (FISC), St. Petersburg, FL, and the National Aeronautics and Space Administration (NASA), Wallops Flight Facility, VA. This project provides highly detailed and accurate datasets of the Alabama coastline, acquired October 3-4, 2001. The datasets are made available for use as a management tool to research scientists and natural resource managers. An innovative scanning Lidar instrument originally developed by NASA, and known as the Airborne Topographic Mapper (ATM), was used during data acquisition. The ATM system is a scanning Lidar system that measures high-resolution topography of the land surface, and incorporates a green-wavelength laser operating at pulse rates of 2 to 10 kilohertz. Measurements from the laser ranging device are coupled with data acquired from inertial navigation system (INS) attitude sensors and differentially corrected global positioning system (GPS) receivers to measure topography of the surface at accuracies of +/-15 centimeters. The nominal ATM platform is a Twin Otter or P-3 Orion aircraft, but the instrument may be deployed on a range of light aircraft. Elevation measurements were collected over the survey area using the ATM system, and the resulting data were then processed using the Airborne Lidar Processing System (ALPS), a custom-built processing system developed in a NASA-USGS collaboration. ALPS supports the exploration and processing of Lidar data in an interactive or batch mode. Modules for pre-survey flight line definition, flight path plotting, Lidar raster and waveform investigation, and digital camera image playback have been developed. Processing algorithms have been developed to extract the range to the first and last significant return within each waveform. ALPS is routinely used to create maps that

  2. Experiences with the AEROnet/PSCN ATM Prototype

    NASA Technical Reports Server (NTRS)

    Kurak, Richard S.; Lisotta, Anthony J.; McCabe, James D.; Nothaft, Alfred E.; Russell, Kelly R.; Lasinski, T. A. (Technical Monitor)

    1995-01-01

    This paper discusses the experience gained by the AEROnet/PSCN networking team in deploying a prototype Asynchronous Transfer Mode (ATM) based network as part of the wide-area network for the Numerical Aerodynamic Simulation (NAS) Program at NASA Ames Research Center. The objectives of this prototype were to test concepts in using ATM over wide-area Internet Protocol (IP) networks and measure end-to-end system performance. This testbed showed that end-to-end ATM over a DS3 reaches approximately 80% of the throughput achieved from a FDDI to DS3 network. The 20% reduction in through-put can be attributed to the overhead associated with running ATM. As a result, we conclude that if the loss in capacity due to ATM overhead is balanced by the reduction in cost of ATM services, as compared to dedicated circuits, then ATM can be a viable alternative.

  3. Analysis of Chromosomal Aberrations after Low and High Dose Rate Gamma Irradiation in ATM or NBS Suppressed Human Fibroblast Cells

    NASA Technical Reports Server (NTRS)

    Hada, M.; Huff, J. L.; Patel, Z.; Pluth, J. M.; George, K. A.; Cucinotta, F. A.

    2009-01-01

    A detailed understanding of the biological effects of heavy nuclei is needed for space radiation protection and for cancer therapy. High-LET radiation produces more complex DNA lesions that may be non-repairable or that may require additional processing steps compared to endogenous DSBs, increasing the possibility of misrepair. Interplay between radiation sensitivity, dose, and radiation quality has not been studied extensively. Previously we studied chromosome aberrations induced by low- and high- LET radiation in several cell lines deficient in ATM (ataxia telangactasia mutated; product of the gene that is mutated in ataxia telangiectasia patients) or NBS (nibrin; product of the gene mutated in the Nijmegen breakage syndrome), and gliomablastoma cells that are proficient or lacking in DNA-dependent protein kinase (DNA-PK) activity. We found that the yields of both simple and complex chromosomal aberrations were significantly increased in the DSB repair defective cells compared to normal cells. The increased aberrations observed for the ATM and NBS defective lines was due to a significantly larger quadratic dose-response term compared to normal fibroblasts for both simple and complex aberrations, while the linear dose-response term was significantly higher in NBS cells only for simple exchanges. These results point to the importance of the functions of ATM and NBS in chromatin modifications that function to facilitate correct DSB repair and minimize aberration formation. To further understand the sensitivity differences that were observed in ATM and NBS deficient cells, in this study, chromosomal aberration analysis was performed in normal lung fibroblast cells treated with KU-55933, a specific ATM kinase inhibitor, or Mirin, an MRN complex inhibitor involved in activation of ATM. We are also testing siRNA knockdown of these proteins. Normal and ATM or NBS suppressed cells were irradiated with gamma-rays and chromosomes were collected with a premature chromosome

  4. Atm heterozygous mice are more sensitive to radiation-induced cataracts than are their wild-type counterparts

    NASA Technical Reports Server (NTRS)

    Worgul, Basil V.; Smilenov, Lubomir; Brenner, David J.; Junk, Anna; Zhou, Wei; Hall, Eric J.

    2002-01-01

    It is important to know whether the human population includes genetically predisposed radiosensitive subsets. In vitro studies have shown that cells from individuals homozygous for ataxia telangiectasia (A-T) are much more radiosensitive than cells from unaffected individuals. Although cells heterozygous for the ATM gene (ATM(+/-)) may be slightly more radiosensitive in vitro, it remained to be determined whether the greater susceptibility of ATM(+/-) cells translates into an increased sensitivity for late effects in vivo, though there is a suggestion that radiotherapy patients that are heterozygous for the ATM gene may be more at risk of developing late normal tissue damage. We chose cataractogenesis in the lens as a means to assay for the effects of ATM deficiency in a late-responding tissue. One eye of wild-type, Atm heterozygous and homozygous knockout mice was exposed to 0.5-, 1.0-, 2.0-, or 4.0-Gy x rays. The animals were followed weekly for cataract development by conventional slit-lamp biomicroscopy. Cataract development in the animals of all three groups was strongly dependent on dose. The lenses of homozygous mice were the first to opacify at any given dose. Most important in the present context is that cataracts appeared earlier in the heterozygous versus wild-type animals. The data suggest that ATM heterozygotes in the human population may also be radiosensitive. This may influence the choice of individuals destined to be exposed to higher than normal doses of radiation, such as astronauts, and may also suggest that radiotherapy patients who are ATM heterozygotes could be predisposed to increased late normal tissue damage.

  5. ATM Quality of Service Tests for Digitized Video Using ATM Over Satellite: Laboratory Tests

    NASA Technical Reports Server (NTRS)

    Ivancic, William D.; Brooks, David E.; Frantz, Brian D.

    1997-01-01

    A digitized video application was used to help determine minimum quality of service parameters for asynchronous transfer mode (ATM) over satellite. For these tests, binomially distributed and other errors were digitally inserted in an intermediate frequency link via a satellite modem and a commercial gaussian noise generator. In this paper, the relation- ship between the ATM cell error and cell loss parameter specifications is discussed with regard to this application. In addition, the video-encoding algorithms, test configurations, and results are presented in detail.

  6. ATP-driven Rad50 conformations regulate DNA tethering, end resection, and ATM checkpoint signaling

    PubMed Central

    Deshpande, Rajashree A; Williams, Gareth J; Limbo, Oliver; Williams, R Scott; Kuhnlein, Jeff; Lee, Ji-Hoon; Classen, Scott; Guenther, Grant; Russell, Paul; Tainer, John A; Paull, Tanya T

    2014-01-01

    The Mre11-Rad50 complex is highly conserved, yet the mechanisms by which Rad50 ATP-driven states regulate the sensing, processing and signaling of DNA double-strand breaks are largely unknown. Here we design structure-based mutations in Pyrococcus furiosus Rad50 to alter protein core plasticity and residues undergoing ATP-driven movements within the catalytic domains. With this strategy we identify Rad50 separation-of-function mutants that either promote or destabilize the ATP-bound state. Crystal structures, X-ray scattering, biochemical assays, and functional analyses of mutant PfRad50 complexes show that the ATP-induced ‘closed’ conformation promotes DNA end binding and end tethering, while hydrolysis-induced opening is essential for DNA resection. Reducing the stability of the ATP-bound state impairs DNA repair and Tel1 (ATM) checkpoint signaling in Schizosaccharomyces pombe, double-strand break resection in Saccharomyces cerevisiae, and ATM activation by human Mre11-Rad50-Nbs1 in vitro, supporting the generality of the P. furiosus Rad50 structure-based mutational analyses. These collective results suggest that ATP-dependent Rad50 conformations switch the Mre11-Rad50 complex between DNA tethering, ATM signaling, and 5′ strand resection, revealing molecular mechanisms regulating responses to DNA double-strand breaks. PMID:24493214

  7. A novel manganese-dependent ATM-p53 signaling pathway is selectively impaired in patient-based neuroprogenitor and murine striatal models of Huntington's disease

    PubMed Central

    Tidball, Andrew M.; Bryan, Miles R.; Uhouse, Michael A.; Kumar, Kevin K.; Aboud, Asad A.; Feist, Jack E.; Ess, Kevin C.; Neely, M. Diana; Aschner, Michael; Bowman, Aaron B.

    2015-01-01

    The essential micronutrient manganese is enriched in brain, especially in the basal ganglia. We sought to identify neuronal signaling pathways responsive to neurologically relevant manganese levels, as previous data suggested that alterations in striatal manganese handling occur in Huntington's disease (HD) models. We found that p53 phosphorylation at serine 15 is the most responsive cell signaling event to manganese exposure (of 18 tested) in human neuroprogenitors and a mouse striatal cell line. Manganese-dependent activation of p53 was severely diminished in HD cells. Inhibitors of ataxia telangiectasia mutated (ATM) kinase decreased manganese-dependent phosphorylation of p53. Likewise, analysis of ATM autophosphorylation and additional ATM kinase targets, H2AX and CHK2, support a role for ATM in the activation of p53 by manganese and that a defect in this process occurs in HD. Furthermore, the deficit in Mn-dependent activation of ATM kinase in HD neuroprogenitors was highly selective, as DNA damage and oxidative injury, canonical activators of ATM, did not show similar deficits. We assessed cellular manganese handling to test for correlations with the ATM-p53 pathway, and we observed reduced Mn accumulation in HD human neuroprogenitors and HD mouse striatal cells at manganese exposures associated with altered p53 activation. To determine if this phenotype contributes to the deficit in manganese-dependent ATM activation, we used pharmacological manipulation to equalize manganese levels between HD and control mouse striatal cells and rescued the ATM-p53 signaling deficit. Collectively, our data demonstrate selective alterations in manganese biology in cellular models of HD manifest in ATM-p53 signaling. PMID:25489053

  8. Activation of the phosphorylation of ATM contributes to radioresistance of glioma stem cells.

    PubMed

    Zhou, Wei; Sun, Mao; Li, Guang-Hui; Wu, Yong-Zhong; Wang, Ying; Jin, Fu; Zhang, Yun-Yun; Yang, Li; Wang, Dong-Lin

    2013-10-01

    Ionizing radiation (IR) is currently the most efficient therapy available for malignant glioma. Unfortunately, this strategy is palliative due to the characteristics of radioresistance of malignant glioma. The aim of our study was to compare glioma stem cells (GSCs) with glioma cells (GCs) to determine whether GSCs are responsible for the radioresistance phenotype and to elucidate whether cell cycle checkpoint proteins are responsible for the radioresistance of GSCs. In this study, CD133 (a marker of brain cancer stem cells) and nestin were co-expressed in GSCs isolated from GCs. The percent of CD133+ cells in GSCs and GCs were >80 and <2%, respectively. Significantly more GSCs survived following 2, 4, 6 and 8 Gy IR than GCs. IR kills cancer cells primarily through DNA double-strand breaks (DSBs). The neutral comet assay is often used to intuitively show the level of DSBs. Significantly fewer GSCs showed DNA damage than GCs following 2 Gy IR. This demonstrated that GSCs are more resistant to in vitro radiation than GCs. Furthermore, activated ataxia telangiectasia mutated (ATM) is essential for the activation of downstream effector kinases, such as checkpoint kinase 2 (Chk2) and p53 which mainly contribute to the proper regulation of IR-induced arrest in the G1 phase. DNA damage induced by IR potently initiated activation of phosphorylation of the ATM, p53 and Chk2 checkpoint proteins. Activation of the phosphorylation of these checkpoint proteins was significantly higher in the GSCs compared to GCs. We found that inhibition of ATM activation induced cell cycle checkpoint defects and increased the rate of apoptosis of GSCs following IR. Our results suggest that GSCs were more resistant to radiation compared to GCs due to high expression of phosphorylated cell cycle checkpoint proteins, and inhibition of ATM could significantly reduce the radioresistance of GSCs and GCs. ATM may represent a source of radioresistance in GSCs and a target of improved radiosensitivity

  9. ATMS Snowfall Rate Product and Its Applications

    NASA Astrophysics Data System (ADS)

    Meng, H.; Kongoli, C.; Dong, J.; Wang, N. Y.; Ferraro, R. R.; Zavodsky, B.; Banghua Yan, B.

    2015-12-01

    A snowfall rate (SFR) algorithm has been developed for the Advanced Technology Microwave Sounder (ATMS) aboard S-NPP and future JPSS satellites. The product is based on the NOAA/NESDIS operational Microwave Humidity Sounder (MHS) SFR but with several key advancements. The algorithm has benefited from continuous development to improve accuracy and snowfall detection efficiency. The enhancements also expand the applicable temperature range for the algorithm and allow significantly more snowfall to be detected than the operational SFR. Another major improvement is the drastically reduced product latency by using Direct Broadcast (DB) data. The new developments have also been implemented in the MHS SFR to ensure product consistency across satellites. Currently, there are five satellites that carry either ATMS or MHS: S-NPP, NOAA-18/-19 and Metop-A/-B. The combined satellites deliver up to ten SFR estimates a day at any location over land in mid-latitudes. The product provides much needed winter precipitation estimates for applications such as weather forecasting and hydrology. Both ATMS and MHS SFR serve as input to a global precipitation analysis product, the NOAA/NCEP CMORPH-Snow. SFR is the sole satellite-based snowfall estimates in the blended product. In addition, ATMS and MHS SFR was assessed at several NWS Weather Forecast Offices (WFOs) and NESDIS/Satellite Analysis Branch (SAB) for its operational values in winter 2015. This is a joint effort among NASA/SPoRT, NOAA/NESDIS, University of Maryland/CICS, and the WFOs. The feedback from the assessment indicated that SFR provides useful information for snowfall forecast. It is especially valuable for areas with poor radar coverage and ground observations. The feedback also identified some limitations of the product such as inadequate detection of shallow snowfall. The algorithm developers will continue to improve product quality as well as developing SFR for new microwave sensors and over ocean in a project

  10. Traffic Management in ATM Networks Over Satellite Links

    NASA Technical Reports Server (NTRS)

    Goyal, Rohit; Jain, Raj; Goyal, Mukul; Fahmy, Sonia; Vandalore, Bobby; vonDeak, Thomas

    1999-01-01

    This report presents a survey of the traffic management Issues in the design and implementation of satellite Asynchronous Transfer Mode (ATM) networks. The report focuses on the efficient transport of Transmission Control Protocol (TCP) traffic over satellite ATM. First, a reference satellite ATM network architecture is presented along with an overview of the service categories available in ATM networks. A delay model for satellite networks and the major components of delay and delay variation are described. A survey of design options for TCP over Unspecified Bit Rate (UBR), Guaranteed Frame Rate (GFR) and Available Bit Rate (ABR) services in ATM is presented. The main focus is on traffic management issues. Several recommendations on the design options for efficiently carrying data services over satellite ATM networks are presented. Most of the results are based on experiments performed on Geosynchronous (GEO) latencies. Some results for Low Earth Orbits (LEO) and Medium Earth Orbit (MEO) latencies are also provided.

  11. Preliminary experiences with telemedicine, multimedia, and ATM

    NASA Astrophysics Data System (ADS)

    Cabral, James E., Jr.; Deforge, Christian; Kim, Yongmin

    1996-04-01

    With the goal of eventually increasing the quality of medical care, especially in remote areas, we have developed a system for telemedicine research based on a combination of ATM networking and a high-speed DSP board based on the Texas Instruments TMS320C80. The purpose of the system is to give health care providers at remote locations the ability to consult with specialists using a combination of video, audio, and externally-acquired images. The system can also be used for education purposes to support bi-directional video/audio communications for grand round lectures, classes, and case conferences. In order to maximize the utilization of the available transmission medium (ranging from land-based copper and fiber optic cable to satellite link) while providing the best possible video and audio quality, the compression performed by the system is adaptable to a wide variety of bandwidths. After about two years of experience with telemedicine in a research environment, we have some preliminary findings to report regarding the performance of a telemedicine application combining ATM and programmable multimedia processors in PC environments.

  12. Meiotic telomere distribution and Sertoli cell nuclear architecture are altered in Atm- and Atm-p53-deficient mice.

    PubMed

    Scherthan, H; Jerratsch, M; Dhar, S; Wang, Y A; Goff, S P; Pandita, T K

    2000-10-01

    The ataxia telangiectasia mutant (ATM) protein is an intrinsic part of the cell cycle machinery that surveys genomic integrity and responses to genotoxic insult. Individuals with ataxia telangiectasia as well as Atm(-/-) mice are predisposed to cancer and are infertile due to spermatogenesis disruption during first meiotic prophase. Atm(-/-) spermatocytes frequently display aberrant synapsis and clustered telomeres (bouquet topology). Here, we used telomere fluorescent in situ hybridization and immunofluorescence (IF) staining of SCP3 and testes-specific histone H1 (H1t) to spermatocytes of Atm- and Atm-p53-deficient mice and investigated whether gonadal atrophy in Atm-null mice is associated with stalling of telomere motility in meiotic prophase. SCP3-H1t IF revealed that most Atm(-/-) p53(-/-) spermatocytes degenerated during late zygotene, while a few progressed to pachytene and diplotene and some even beyond metaphase II, as indicated by the presence of a few round spermatids. In Atm(-/-) p53(-/-) meiosis, the frequency of spermatocytes I with bouquet topology was elevated 72-fold. Bouquet spermatocytes with clustered telomeres were generally void of H1t signals, while mid-late pachytene and diplotene Atm(-/-) p53(-/-) spermatocytes displayed expression of H1t and showed telomeres dispersed over the nuclear periphery. Thus, it appears that meiotic telomere movements occur independently of ATM signaling. Atm inactivation more likely leads to accumulation of spermatocytes I with bouquet topology by slowing progression through initial stages of first meiotic prophase and an ensuing arrest and demise of spermatocytes I. Sertoli cells (SECs), which contribute to faithful spermatogenesis, in the Atm mutants were found to frequently display numerous heterochromatin and telomere clusters-a nuclear topology which resembles that of immature SECs. However, Atm(-/-) SECs exhibited a mature vimentin and cytokeratin 8 intermediate filament expression signature. Upon IF with

  13. Integrated network management framework for ATM-over-ADSL service

    NASA Astrophysics Data System (ADS)

    Hong, Won-Kyu; Yoon, Sung-Sook; Hong, Seong-Ik; Kim, Dong-Il; Jung, Mun-Jo; Song, Joong-Goo

    2001-11-01

    In this paper, we describe an integrated network management system for ATM over ADSL service provisioning. There are two distinct networks of ATM and Internet. Most of routers in Internet connected with WDM. The Network Access Server (NAS) in the Internet provides the Internet access service for the ATM over ADSL subscriber. The ATM network takes the roles of backbone network for the pure ATM PVC and SVC services and the access network for the ATM over ADSL service. In order to define the generic network model that can be commonly applicable for the backbone network for pure ATM service and the access network for ATM over ADSL service taking into account the scalability, we suggest two fragments of the topological fragment and connectivity fragment to maximize the scalability in accordance with the ITU-T G.805 layering and partitioning concepts and the RM-ODP information viewpoint. In addition, we propose the distributed computational model of the ATM over ADSL network management system using the RM-ODP computational viewpoint and TMN functional decomposition of FCAPS taking into account the functional distribution and the modularity. Lastly, we describe the scenario for providing the integrated ADSL service.

  14. ATM and KAT5 safeguard replicating chromatin against formaldehyde damage

    PubMed Central

    Ortega-Atienza, Sara; Wong, Victor C.; DeLoughery, Zachary; Luczak, Michal W.; Zhitkovich, Anatoly

    2016-01-01

    Many carcinogens damage both DNA and protein constituents of chromatin, and it is unclear how cells respond to this compound injury. We examined activation of the main DNA damage-responsive kinase ATM and formation of DNA double-strand breaks (DSB) by formaldehyde (FA) that forms histone adducts and replication-blocking DNA-protein crosslinks (DPC). We found that low FA doses caused a strong and rapid activation of ATM signaling in human cells, which was ATR-independent and restricted to S-phase. High FA doses inactivated ATM via its covalent dimerization and formation of larger crosslinks. FA-induced ATM signaling showed higher CHK2 phosphorylation but much lower phospho-KAP1 relative to DSB inducers. Replication blockage by DPC did not produce damaged forks or detectable amounts of DSB during the main wave of ATM activation, which did not require MRE11. Chromatin-monitoring KAT5 (Tip60) acetyltransferase was responsible for acetylation and activation of ATM by FA. KAT5 and ATM were equally important for triggering of intra-S-phase checkpoint and ATM signaling promoted recovery of normal human cells after low-dose FA. Our results revealed a major role of the KAT5-ATM axis in protection of replicating chromatin against damage by the endogenous carcinogen FA. PMID:26420831

  15. Modest increased sensitivity to radiation oncogenesis in ATM heterozygous versus wild-type mammalian cells

    NASA Technical Reports Server (NTRS)

    Smilenov, L. B.; Brenner, D. J.; Hall, E. J.

    2001-01-01

    Subpopulations that are genetically predisposed to radiation-induced cancer could have significant public health consequences. Individuals homozygous for null mutations at the ataxia telangiectasia gene are indeed highly radiosensitive, but their numbers are very small. Ataxia Telangiectasia heterozygotes (1-2% of the population) have been associated with somewhat increased radiosensitivity for some end points, but none directly related to carcinogenesis. Here, intralitter comparisons between wild-type mouse embryo fibroblasts and mouse embryo fibroblasts carrying ataxia telangiectasia mutated (ATM) null mutation indicate that the heterozygous cells are more sensitive to radiation oncogenesis than their normal, litter-matched, counterparts. From these data we suggest that Ataxia Telangiectasia heterozygotes could indeed represent a societally-significant radiosensitive human subpopulation.

  16. Parametric analysis of ATM solar array.

    NASA Technical Reports Server (NTRS)

    Singh, B. K.; Adkisson, W. B.

    1973-01-01

    The paper discusses the methods used for the calculation of ATM solar array performance characteristics and provides the parametric analysis of solar panels used in SKYLAB. To predict the solar array performance under conditions other than test conditions, a mathematical model has been developed. Four computer programs have been used to convert the solar simulator test data to the parametric curves. The first performs module summations, the second determines average solar cell characteristics which will cause a mathematical model to generate a curve matching the test data, the third is a polynomial fit program which determines the polynomial equations for the solar cell characteristics versus temperature, and the fourth program uses the polynomial coefficients generated by the polynomial curve fit program to generate the parametric data.

  17. FPGA Based Reconfigurable ATM Switch Test Bed

    NASA Technical Reports Server (NTRS)

    Chu, Pong P.; Jones, Robert E.

    1998-01-01

    Various issues associated with "FPGA Based Reconfigurable ATM Switch Test Bed" are presented in viewgraph form. Specific topics include: 1) Network performance evaluation; 2) traditional approaches; 3) software simulation; 4) hardware emulation; 5) test bed highlights; 6) design environment; 7) test bed architecture; 8) abstract sheared-memory switch; 9) detailed switch diagram; 10) traffic generator; 11) data collection circuit and user interface; 12) initial results; and 13) the following conclusions: Advances in FPGA make hardware emulation feasible for performance evaluation, hardware emulation can provide several orders of magnitude speed-up over software simulation; due to the complexity of hardware synthesis process, development in emulation is much more difficult than simulation and requires knowledge in both networks and digital design.

  18. Is Increased Low-dose somatic Radiosensitivity Associated with Increased Transgenerational Germline Mutation

    SciTech Connect

    Brenner, David J.

    2008-10-02

    Using single-molecule polymerase chain reaction, the frequency of spontaneous and radiation-induced mutation at an expanded simple tandem repeat (ESTR) locus was studied in DNA samples extracted from sperm and bone marrow of Atm knockout (Atm+/–) heterozygous male mice. The frequency of spontaneous mutation in sperm and bone marrow in Atm+/– males did not significantly differ from that in wild-type BALB/c mice. Acute gamma-ray exposure did not affect ESTR mutation frequency in bone marrow and resulted in similar increases in sperm samples taken from Atm+/– and BALB/c males. Taken together, these results suggest that the Atm haploinsufficiency analyzed in our studymore » does not affect spontaneous and radiation-induced ESTR mutation frequency in mice.« less

  19. ATM test and integration. [Skylab Apollo Telescope Mount

    NASA Technical Reports Server (NTRS)

    Moore, J. W.; Mitchell, J. R.

    1974-01-01

    The test and checkout philosophy of the test program for the Skylab ATM module and the overall test flow including in-process, post-manufacturing, vibration, thermal vacuum, and prelaunch checkout activities are described. Capabilities and limitations of the test complex and its use of automation are discussed. Experiences with the organizational principle of using a dedicated test team for all checkout activities are reported. Material on the development of the ATM subsystems, the experimental program and the requirements of the scientific community, and the integration and verification of the complex systems/subsystems of the ATM are presented. The performance of the ATM test program in such areas as alignment, systems and subsystems, contamination control, and experiment operation is evaluated. The conclusions and recommendations resulting from the ATM test program are enumerated.

  20. Missense Variants in ATM in 26,101 Breast Cancer Cases and 29,842 Controls

    PubMed Central

    Fletcher, Olivia; Johnson, Nichola; dos Santos Silva, Isabel; Orr, Nick; Ashworth, Alan; Nevanlinna, Heli; Heikkinen, Tuomas; Aittomäki, Kristiina; Blomqvist, Carl; Burwinkel, Barbara; Bartram, Claus R.; Meindl, Alfons; Schmutzler, Rita K.; Cox, Angela; Brock, Ian; Elliott, Graeme; Reed, Malcolm W. R.; Southey, Melissa C.; Smith, Letitia; Spurdle, Amanda B.; Hopper, John L.; Couch, Fergus J.; Olson, Janet E.; Wang, Xianshu; Fredericksen, Zachary; Schürmann, Peter; Waltes, Regina; Bremer, Michael; Dörk, Thilo; Devilee, Peter; van Asperen, Christie J.; Tollenaar, Rob A.E.M.; Seynaeve, Caroline; Hall, Per; Czene, Kamila; Humphreys, Keith; Liu, Jianjun; Ahmed, Shahana; Dunning, Alison M.; Maranian, Melanie; Pharoah, Paul D.P.; Chenevix-Trench, Georgia; Beesley, Jonathan; Investigators, kConFab; Group, AOCS; Bogdanova, Natalia V.; Antonenkova, Natalia N.; Zalutsky, Iosif V.; Anton-Culver, Hoda; Ziogas, Argyrios; Brauch, Hiltrud; Ko, Yon-Dschun; Hamann, Ute; Fasching, Peter A.; Strick, Reiner; Ekici, Arif B.; Beckmann, Matthias W.; Giles, Graham G.; Severi, Gianluca; Baglietto, Laura; English, Dallas R.; Milne, Roger L.; Benítez, Javier; Arias, José Ignacio; Pita, Guillermo; Nordestgaard, Børge G.; Bojesen, Stig E.; Flyger, Henrik; Kang, Daehee; Yoo, Keun-Young; Noh, Dong Young; Mannermaa, Arto; Kataja, Vesa; Kosma, Veli-Matti; García-Closas, Montserrat; Chanock, Stephen; Lissowska, Jolanta; Brinton, Louise A.; Chang-Claude, Jenny; Wang- Gohrke, Shan; Broeks, Annegien; Schmidt, Marjanka K; van Leeuwen, Flora E; Van ‘t Veer, Laura J; Margolin, Sara; Lindblom, Annika; Humphreys, Manjeet K.; Morrison, Jonathan; Platte, Radka; Easton, Douglas F.; Peto, Julian

    2010-01-01

    Background Truncating mutations in ATM have been shown to increase the risk of breast cancer but the effect of missense variants remains contentious. Methods We have genotyped five polymorphic (MAF 0.9% to 2.6%) missense single nucleotide polymorphisms (SNPs) in ATM (S49C, S707P, F858L, P1054R, L1420F) in 26,101 breast cancer cases and 29,842 controls from 23 studies in the Breast Cancer Association Consortium (BCAC). Results Combining data from all five SNPs, the OR was 1.05 for being a heterozygote for any of the SNPs and 1.51 for being a rare homozygote for any of the SNPs with an overall trend OR=1.06 (Ptrend=0.04). The trend OR among bilateral and familial cases was 1.12 (95% CI 1.02-1.23; Ptrend=0.02). Conclusions In this large combined analysis, these 5 missense ATM SNPs were associated with a small increased risk of breast cancer, explaining an estimated 0.03% of the excess familial risk of breast cancer. Impact Testing the combined effects of rare missense variants in known breast cancer genes in large collaborative studies should clarify their overall contribution to breast cancer susceptibility. PMID:20826828

  1. Initiation of the ATM-Chk2 DNA damage response through the base excision repair pathway.

    PubMed

    Chou, Wen-Cheng; Hu, Ling-Yueh; Hsiung, Chia-Ni; Shen, Chen-Yang

    2015-08-01

    The DNA damage response (DDR) is activated by various genotoxic stresses. Base lesions, which are structurally simple and predominantly fixed by base excision repair (BER), can trigger the ataxia telangiectasia mutated (ATM)-checkpoint kinase 2 (Chk2) pathway, a DDR component. How these lesions trigger DDR remains unclear. Here we show that, for alkylation damage, methylpurine-DNA glycosylase (MPG) and apurinic/apyrimidinic endonuclease 1, both of which function early in BER, are required for ATM-Chk2-dependent DDR. In addition, other DNA glycosylases, including uracil-DNA glycosylase and 8-oxoguanine glycosylase, which are involved in repairing deaminated bases and oxidative damage, also induced DDR. The early steps of BER therefore play a vital role in modulating the ATM-Chk2 DDR in response to base lesions, facilitating downstream BER processing for repair, in which the formation of a single-strand break was shown to play a critical role. Moreover, MPG knockdown rescued cell lethality, its overexpression led to cell death triggered by DNA damage and, more interestingly, higher MPG expression in breast and ovarian cancers corresponded with a greater probability of relapse-free survival after chemotherapy, underscoring the importance of glycosylase-dependent DDR. This study highlights the crosstalk between BER and DDR that contributes to maintaining genomic integrity and may have clinical applications in cancer therapy. © The Author 2015. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oup.com.

  2. Common variants near ATM are associated with glycemic response to metformin in type 2 diabetes.

    PubMed

    Zhou, Kaixin; Bellenguez, Celine; Spencer, Chris C A; Bennett, Amanda J; Coleman, Ruth L; Tavendale, Roger; Hawley, Simon A; Donnelly, Louise A; Schofield, Chris; Groves, Christopher J; Burch, Lindsay; Carr, Fiona; Strange, Amy; Freeman, Colin; Blackwell, Jenefer M; Bramon, Elvira; Brown, Matthew A; Casas, Juan P; Corvin, Aiden; Craddock, Nicholas; Deloukas, Panos; Dronov, Serge; Duncanson, Audrey; Edkins, Sarah; Gray, Emma; Hunt, Sarah; Jankowski, Janusz; Langford, Cordelia; Markus, Hugh S; Mathew, Christopher G; Plomin, Robert; Rautanen, Anna; Sawcer, Stephen J; Samani, Nilesh J; Trembath, Richard; Viswanathan, Ananth C; Wood, Nicholas W; Harries, Lorna W; Hattersley, Andrew T; Doney, Alex S F; Colhoun, Helen; Morris, Andrew D; Sutherland, Calum; Hardie, D Grahame; Peltonen, Leena; McCarthy, Mark I; Holman, Rury R; Palmer, Colin N A; Donnelly, Peter; Pearson, Ewan R

    2011-02-01

    Metformin is the most commonly used pharmacological therapy for type 2 diabetes. We report a genome-wide association study for glycemic response to metformin in 1,024 Scottish individuals with type 2 diabetes with replication in two cohorts including 1,783 Scottish individuals and 1,113 individuals from the UK Prospective Diabetes Study. In a combined meta-analysis, we identified a SNP, rs11212617, associated with treatment success (n = 3,920, P = 2.9 × 10(-9), odds ratio = 1.35, 95% CI 1.22-1.49) at a locus containing ATM, the ataxia telangiectasia mutated gene. In a rat hepatoma cell line, inhibition of ATM with KU-55933 attenuated the phosphorylation and activation of AMP-activated protein kinase in response to metformin. We conclude that ATM, a gene known to be involved in DNA repair and cell cycle control, plays a role in the effect of metformin upstream of AMP-activated protein kinase, and variation in this gene alters glycemic response to metformin.

  3. Mutant IDH1 downregulates ATM and alters DNA repair and sensitivity to DNA damage independent of TET2

    PubMed Central

    Inoue, Satoshi; Li, Wanda Y.; Tseng, Alan; Beerman, Isabel; Elia, Andrew J.; Bendall, Sean C.; Lemonnier, François; Kron, Ken J.; Cescon, David W.; Hao, Zhenyue; Lind, Evan F.; Takayama, Naoya; Planello, Aline C.; Shen, Shu Yi; Shih, Alan H.; Larsen, Dana M.; Li, Qinxi; Snow, Bryan E.; Wakeham, Andrew; Haight, Jillian; Gorrini, Chiara; Bassi, Christian; Thu, Kelsie L.; Murakami, Kiichi; Elford, Alisha R.; Ueda, Takeshi; Straley, Kimberly; Yen, Katharine E.; Melino, Gerry; Cimmino, Luisa; Aifantis, Iannis; Levine, Ross L.; De Carvalho, Daniel D.; Lupien, Mathieu; Rossi, Derrick J.; Nolan, Garry P.; Cairns, Rob A.; Mak, Tak W.

    2016-01-01

    SUMMARY Mutations in the isocitrate dehydrogenase-1 gene (IDH1) are common drivers of acute myeloid leukemia (AML) but their mechanism is not fully understood. It is thought that IDH1 mutants act by inhibiting TET2 to alter DNA methylation, but there are significant unexplained clinical differences between IDH1- and TET2-mutant diseases. We have discovered that mice expressing endogenous mutant IDH1 have reduced numbers of hematopoietic stem cells (HSC), in contrast to Tet2 knockout (TET2-KO) mice. Mutant IDH1 downregulates the DNA damage (DD) sensor ATM by altering histone methylation, leading to impaired DNA repair, increased sensitivity to DD, and reduced HSC self-renewal, independent of TET2. ATM expression is also decreased in human IDH1-mutated AML. These findings may have implications for treatment of IDH-mutant leukemia. PMID:27424808

  4. Mutant IDH1 Downregulates ATM and Alters DNA Repair and Sensitivity to DNA Damage Independent of TET2.

    PubMed

    Inoue, Satoshi; Li, Wanda Y; Tseng, Alan; Beerman, Isabel; Elia, Andrew J; Bendall, Sean C; Lemonnier, François; Kron, Ken J; Cescon, David W; Hao, Zhenyue; Lind, Evan F; Takayama, Naoya; Planello, Aline C; Shen, Shu Yi; Shih, Alan H; Larsen, Dana M; Li, Qinxi; Snow, Bryan E; Wakeham, Andrew; Haight, Jillian; Gorrini, Chiara; Bassi, Christian; Thu, Kelsie L; Murakami, Kiichi; Elford, Alisha R; Ueda, Takeshi; Straley, Kimberly; Yen, Katharine E; Melino, Gerry; Cimmino, Luisa; Aifantis, Iannis; Levine, Ross L; De Carvalho, Daniel D; Lupien, Mathieu; Rossi, Derrick J; Nolan, Garry P; Cairns, Rob A; Mak, Tak W

    2016-08-08

    Mutations in the isocitrate dehydrogenase-1 gene (IDH1) are common drivers of acute myeloid leukemia (AML) but their mechanism is not fully understood. It is thought that IDH1 mutants act by inhibiting TET2 to alter DNA methylation, but there are significant unexplained clinical differences between IDH1- and TET2-mutant diseases. We have discovered that mice expressing endogenous mutant IDH1 have reduced numbers of hematopoietic stem cells (HSCs), in contrast to Tet2 knockout (TET2-KO) mice. Mutant IDH1 downregulates the DNA damage (DD) sensor ATM by altering histone methylation, leading to impaired DNA repair, increased sensitivity to DD, and reduced HSC self-renewal, independent of TET2. ATM expression is also decreased in human IDH1-mutated AML. These findings may have implications for treatment of IDH-mutant leukemia. Copyright © 2016 Elsevier Inc. All rights reserved.

  5. Nbn and Atm Cooperate in a Tissue and Developmental Stage-Specific Manner to Prevent Double Strand Breaks and Apoptosis in Developing Brain and Eye

    PubMed Central

    Cavalheiro, Gabriel R.; Gomes, Anielle L.; Martins, Mauricio R.; Frappart, Lucien; Reuss, David; McKinnon, Peter J.; von Deimling, Andreas; Martins, Rodrigo A. P.; Frappart, Pierre-Olivier

    2013-01-01

    Nibrin (NBN or NBS1) and ATM are key factors for DNA Double Strand Break (DSB) signaling and repair. Mutations in NBN or ATM result in Nijmegen Breakage Syndrome and Ataxia telangiectasia. These syndromes share common features such as radiosensitivity, neurological developmental defects and cancer predisposition. However, the functional synergy of Nbn and Atm in different tissues and developmental stages is not yet understood. Here, we show in vivo consequences of conditional inactivation of both genes in neural stem/progenitor cells using Nestin-Cre mice. Genetic inactivation of Atm in the central nervous system of Nbn-deficient mice led to reduced life span and increased DSBs, resulting in increased apoptosis during neural development. Surprisingly, the increase of DSBs and apoptosis was found only in few tissues including cerebellum, ganglionic eminences and lens. In sharp contrast, we showed that apoptosis associated with Nbn deletion was prevented by simultaneous inactivation of Atm in developing retina. Therefore, we propose that Nbn and Atm collaborate to prevent DSB accumulation and apoptosis during development in a tissue- and developmental stage-specific manner. PMID:23935957

  6. Nuclear poly(A)-binding protein 1 is an ATM target and essential for DNA double-strand break repair.

    PubMed

    Gavish-Izakson, Michal; Velpula, Bhagya Bhavana; Elkon, Ran; Prados-Carvajal, Rosario; Barnabas, Georgina D; Ugalde, Alejandro Pineiro; Agami, Reuven; Geiger, Tamar; Huertas, Pablo; Ziv, Yael; Shiloh, Yosef

    2018-01-25

    The DNA damage response (DDR) is an extensive signaling network that is robustly mobilized by DNA double-strand breaks (DSBs). The primary transducer of the DSB response is the protein kinase, ataxia-telangiectasia, mutated (ATM). Here, we establish nuclear poly(A)-binding protein 1 (PABPN1) as a novel target of ATM and a crucial player in the DSB response. PABPN1 usually functions in regulation of RNA processing and stability. We establish that PABPN1 is recruited to the DDR as a critical regulator of DSB repair. A portion of PABPN1 relocalizes to DSB sites and is phosphorylated on Ser95 in an ATM-dependent manner. PABPN1 depletion sensitizes cells to DSB-inducing agents and prolongs the DSB-induced G2/M cell-cycle arrest, and DSB repair is hampered by PABPN1 depletion or elimination of its phosphorylation site. PABPN1 is required for optimal DSB repair via both nonhomologous end-joining (NHEJ) and homologous recombination repair (HRR), and specifically is essential for efficient DNA-end resection, an initial, key step in HRR. Using mass spectrometry analysis, we capture DNA damage-induced interactions of phospho-PABPN1, including well-established DDR players as well as other RNA metabolizing proteins. Our results uncover a novel ATM-dependent axis in the rapidly growing interface between RNA metabolism and the DDR. © The Author(s) 2017. Published by Oxford University Press on behalf of Nucleic Acids Research.

  7. Down-regulation of Fer induces ROS levels accompanied by ATM and p53 activation in colon carcinoma cells.

    PubMed

    Makovski, Adar; Yaffe, Etai; Shpungin, Sally; Nir, Uri

    2012-07-01

    Fer is an intracellular tyrosine kinase which resides in both the cytoplasm and nucleus of mammalian cells. This kinase was also found in all malignant cell-lines analyzed and was shown to support cell-cycle progression in cancer cells. Herein we show that knock-down of Fer, both, impairs cell-cycle progression and imposes programmed cell death in colon carcinoma (CC) cells. The cell-cycle arrest and apoptotic death invoked by the depletion of Fer were found to depend on the activity of p53. Accordingly, down regulation of Fer led to the activation of the Ataxia Telangiectasia Mutated protein (ATM) and its down-stream effector-p53. Knock-down of Fer also increased the level of Reactive-Oxygen Species (ROS) in CC cells, and subjection of Fer depleted cells to ROS neutralizing scavengers significantly decreased the induced phosphorylation and activation of ATM and p53. Notably, over-expression of Fer opposed the Doxorubicin driven activation of ATM and p53, which can be mediated by ROS. Collectively, our findings imply that Fer sustains low ROS levels in CC cells, thereby restraining the activation of ATM and p53 in these cells. Copyright © 2012 Elsevier Inc. All rights reserved.

  8. Pine needle oil induces G2/M arrest of HepG2 cells by activating the ATM pathway.

    PubMed

    Qiu, Bing; Jiang, Wei; Qiu, Wenliang; Mu, Wenling; Qin, Yujing; Zhu, Yongcui; Zhang, Jianying; Wang, Qingyi; Liu, Dongjie; Qu, Zhangyi

    2018-02-01

    Over the last two decades, inducing DNA damage of cancer cells by natural medicines has become a research hotspot in the field of cancer treatment. Although various natural medicines have anticancer effects, very few studies have been conducted to explore the anti-cancer effect of pine needle oil. In the present study, the role of pine needle oil in inducing G2/M arrest in HepG2 cells was investigated. The data revealed that pine needle oil could induce DNA damage in a dose-dependent manner. In the pine needle oil-treated HepG2 cells, the protein levels of phosphorylated (p)-ataxia-telangiectasia mutated (ATM), γ-H2A histone family, member X, p-p53, p-checkpoint kinase 2 and p-cell division cycle 25C were evidently increased, indicating that pine needle oil facilitated G2/M arrest in HepG2 cells through the ATM pathway. In response to the treatment with pine needle oil, ATM was activated in HepG2 cells, which subsequently phosphorylated downstream targets and induced G2/M arrest. In summary, the data of the present study indicated that pine needle oil induces G2/M arrest in HepG2 cells by facilitating ATM activation.

  9. Virtual C Machine and Integrated Development Environment for ATMS Controllers.

    DOT National Transportation Integrated Search

    2000-04-01

    The overall objective of this project is to develop a prototype virtual machine that fits on current Advanced Traffic Management Systems (ATMS) controllers and provides functionality for complex traffic operations.;Prepared in cooperation with Utah S...

  10. Advanced Traffic Management Systems (ATMS) research analysis database system

    DOT National Transportation Integrated Search

    2001-06-01

    The ATMS Research Analysis Database Systems (ARADS) consists of a Traffic Software Data Dictionary (TSDD) and a Traffic Software Object Model (TSOM) for application to microscopic traffic simulation and signal optimization domains. The purpose of thi...

  11. Meiotic Telomere Distribution and Sertoli Cell Nuclear Architecture Are Altered in Atm- and Atm-p53-Deficient Mice

    PubMed Central

    Scherthan, Harry; Jerratsch, Martin; Dhar, Sonu; Wang, Y. Alan; Goff, Stephen P.; Pandita, Tej K.

    2000-01-01

    The ataxia telangiectasia mutant (ATM) protein is an intrinsic part of the cell cycle machinery that surveys genomic integrity and responses to genotoxic insult. Individuals with ataxia telangiectasia as well as Atm−/− mice are predisposed to cancer and are infertile due to spermatogenesis disruption during first meiotic prophase. Atm−/− spermatocytes frequently display aberrant synapsis and clustered telomeres (bouquet topology). Here, we used telomere fluorescent in situ hybridization and immunofluorescence (IF) staining of SCP3 and testes-specific histone H1 (H1t) to spermatocytes of Atm- and Atm-p53-deficient mice and investigated whether gonadal atrophy in Atm-null mice is associated with stalling of telomere motility in meiotic prophase. SCP3-H1t IF revealed that most Atm−/− p53−/− spermatocytes degenerated during late zygotene, while a few progressed to pachytene and diplotene and some even beyond metaphase II, as indicated by the presence of a few round spermatids. In Atm−/− p53−/− meiosis, the frequency of spermatocytes I with bouquet topology was elevated 72-fold. Bouquet spermatocytes with clustered telomeres were generally void of H1t signals, while mid-late pachytene and diplotene Atm−/− p53−/− spermatocytes displayed expression of H1t and showed telomeres dispersed over the nuclear periphery. Thus, it appears that meiotic telomere movements occur independently of ATM signaling. Atm inactivation more likely leads to accumulation of spermatocytes I with bouquet topology by slowing progression through initial stages of first meiotic prophase and an ensuing arrest and demise of spermatocytes I. Sertoli cells (SECs), which contribute to faithful spermatogenesis, in the Atm mutants were found to frequently display numerous heterochromatin and telomere clusters—a nuclear topology which resembles that of immature SECs. However, Atm−/− SECs exhibited a mature vimentin and cytokeratin 8 intermediate filament expression

  12. ATM POLYMORPHISMS PREDICT SEVERE RADIATION PNEUMONITIS IN PATIENTS WITH NON-SMALL CELL LUNG CANCER TREATED WITH DEFINITIVE RADIATION THERAPY

    PubMed Central

    Xiong, Huihua; Liao, Zhongxing; Liu, Zhensheng; Xu, Ting; Wang, Qiming; Liu, Hongliang; Komaki, Ritsuko; Gomez, Daniel; Wang, Li-E; Wei, Qingyi

    2012-01-01

    Purpose The ataxia telangiectasia mutated (ATM) gene mediates detection and repair of DNA damage. We investigated associations between ATM polymorphisms and severe radiation-induced pneumonitis (RP). Methods and Materials We genotyped three potentially functional single nucleotide polymorphisms (SNPs) of ATM (rs1801516 [D1853N/5557G>A], rs189037 [−111G>A] and rs228590) in 362 patients with non-small cell lung cancer (NSCLC), who received definitive radio(chemo)therapy. The cumulative severe RP probabilities by genotypes were evaluated using the Kaplan-Meier analysis. The associations between severe RP risk and genotypes were assessed by both logistic regression analysis and Cox proportional hazard model with time to event considered. Results Of 362 patients with 82% of non-Hispanic whites, 56 (15.5%) experienced grade ≥ 3 RP. Patients carrying ATM rs189037 AG/GG or rs228590 TT/CT genotypes, or rs189037G/rs228590T/rs1801516G (G-T-G) haplotype had a lower risk of severe RP (rs189037: GG/AG vs. AA, adjusted hazard ratio [HR] = 0.49, 95% confidence interval [CI], 0.29–0.83, P = 0.009; rs228590: TT/CT vs. CC, HR=0.57, 95% CI, 0.33–0.97, P =0.036; haplotype: G-T-G vs. A-C-G, HR=0.52, 95% CI, 0.35–0.79, P =0.002). Such positive findings remained in non-Hispanic whites. CONCLUSIONS ATM polymorphisms may serve as biomarkers for susceptibility to severe RP in non-Hispanic whites. Large prospective studies are required to confirm our findings. PMID:23154078

  13. Regulation of human polλ by ATM-mediated phosphorylation during non-homologous end joining.

    PubMed

    Sastre-Moreno, Guillermo; Pryor, John M; Moreno-Oñate, Marta; Herrero-Ruiz, Andrés M; Cortés-Ledesma, Felipe; Blanco, Luis; Ramsden, Dale A; Ruiz, Jose F

    2017-03-01

    DNA double strand breaks (DSBs) trigger a variety of cellular signaling processes, collectively termed the DNA-damage response (DDR), that are primarily regulated by protein kinase ataxia-telangiectasia mutated (ATM). Among DDR activated processes, the repair of DSBs by non-homologous end joining (NHEJ) is essential. The proper coordination of NHEJ factors is mainly achieved through phosphorylation by an ATM-related kinase, the DNA-dependent protein kinase catalytic subunit (DNA-PKcs), although the molecular basis for this regulation has yet to be fully elucidated. In this study we identify the major NHEJ DNA polymerase, DNA polymerase lambda (Polλ), as a target for both ATM and DNA-PKcs in human cells. We show that Polλ is efficiently phosphorylated by DNA-PKcs in vitro and predominantly by ATM after DSB induction with ionizing radiation (IR) in vivo. We identify threonine 204 (T204) as a main target for ATM/DNA-PKcs phosphorylation on human Polλ, and establish that its phosphorylation may facilitate the repair of a subset of IR-induced DSBs and the efficient Polλ-mediated gap-filling during NHEJ. Molecular evidence suggests that Polλ phosphorylation might favor Polλ interaction with the DNA-PK complex at DSBs. Altogether, our work provides the first demonstration of how Polλ is regulated by phosphorylation to connect with the NHEJ core machinery during DSB repair in human cells. Copyright © 2017 The Authors. Published by Elsevier B.V. All rights reserved.

  14. Interplays between ATM/Tel1 and ATR/Mec1 in sensing and signaling DNA double-strand breaks.

    PubMed

    Gobbini, Elisa; Cesena, Daniele; Galbiati, Alessandro; Lockhart, Arianna; Longhese, Maria Pia

    2013-10-01

    DNA double-strand breaks (DSBs) are highly hazardous for genome integrity because they have the potential to cause mutations, chromosomal rearrangements and genomic instability. The cellular response to DSBs is orchestrated by signal transduction pathways, known as DNA damage checkpoints, which are conserved from yeasts to humans. These pathways can sense DNA damage and transduce this information to specific cellular targets, which in turn regulate cell cycle transitions and DNA repair. The mammalian protein kinases ATM and ATR, as well as their budding yeast corresponding orthologs Tel1 and Mec1, act as master regulators of the checkpoint response to DSBs. Here, we review the early steps of DSB processing and the role of DNA-end structures in activating ATM/Tel1 and ATR/Mec1 in an orderly and reciprocal manner. Copyright © 2013 Elsevier B.V. All rights reserved.

  15. High resistance to X-rays and therapeutic carbon ions in glioblastoma cells bearing dysfunctional ATM associates with intrinsic chromosomal instability.

    PubMed

    Dokic, Ivana; Mairani, Andrea; Brons, Stephan; Schoell, Brigitte; Jauch, Anna; Krunic, Damir; Debus, Jürgen; Régnier-Vigouroux, Anne; Weber, Klaus-Josef

    2015-02-01

    To investigate chromosomal instability and radiation response mechanisms in glioblastoma cells. We undertook a comparative analysis of two patient-derived glioblastoma cell lines. Their resistance to low and high linear energy transfer (LET) radiation was assessed using clonogenic survival assay and their intrinsic chromosome instability status using fluorescence in situ hybridization. DNA damage was analyzed by pulsed-field gel electrophoresis and by γ-H2AX foci quantification. Expression of DNA damage response proteins was assessed by immunoblot. Increased radioresistance to X-rays as well as carbon ions was observed in glioblastoma cells exhibiting high levels of naturally occurring chromosomal instability and impaired Ataxia-telangiectasia mutated (ATM) signaling, as reflected by lack of phosphorylation of ATM, CHK2 and p53 after double-strand breaks induction. Our results indicate the existence of highly radioresistant glioblastoma cells, characterized by dysfunctional ATM signaling and high levels of intrinsic chromosomal instability.

  16. Associations of ATM Polymorphisms With Survival in Advanced Esophageal Squamous Cell Carcinoma Patients Receiving Radiation Therapy

    SciTech Connect

    Du, Zhongli; Department of Etiology and Carcinogenesis; Zhang, Wencheng

    2015-09-01

    Purpose: To investigate whether single nucleotide polymorphisms (SNPs) in the ataxia telangiectasia mutated (ATM) gene are associated with survival in patients with esophageal squamous cell carcinoma (ESCC) receiving radiation therapy or chemoradiation therapy or surgery only. Methods and Materials: Four tagSNPs of ATM were genotyped in 412 individuals with clinical stage III or IV ESCC receiving radiation therapy or chemoradiation therapy, and in 388 individuals with stage I, II, or III ESCC treated with surgery only. Overall survival time of ESCC among different genotypes was estimated by Kaplan-Meier plot, and the significance was examined by log-rank test. The hazard ratios (HRs)more » and 95% confidence intervals (CIs) for death from ESCC among different genotypes were computed by a Cox proportional regression model. Results: We found 2 SNPs, rs664143 and rs664677, associated with survival time of ESCC patients receiving radiation therapy. Individuals with the rs664143A allele had poorer median survival time compared with the rs664143G allele (14.0 vs 20.0 months), with the HR for death being 1.45 (95% CI 1.12-1.89). Individuals with the rs664677C allele also had worse median survival time than those with the rs664677T allele (14.0 vs 23.5 months), with the HR of 1.57 (95% CI 1.18-2.08). Stratified analysis showed that these associations were present in both stage III and IV cancer and different radiation therapy techniques. Significant associations were also found between the SNPs and locosregional progression or progression-free survival. No association between these SNPs and survival time was detected in ESCC patients treated with surgery only. Conclusion: These results suggest that the ATM polymorphisms might serve as independent biomarkers for predicting prognosis in ESCC patients receiving radiation therapy.« less

  17. Assessment of asynchronous transfer mode (ATM) networks for regional teleradiology

    NASA Astrophysics Data System (ADS)

    Duerinckx, Andre J.; Hayrapetian, Alek S.; Valentino, Daniel J.; Grant, Edward G.; Rahbar, Darius; Kiszonas, Mike; Franco, Ricky; Shimabuku, Guy H.; Hagan, Girish T.; Melany, Michelle; Narin, Sherelle L.; Ragavendra, Nagesh

    1996-05-01

    The purpose of this study was to assess the effect of ATM network capabilities on the clinical practice of regional teleradiology, by providing immediate interactive radiology consultations between subspecialists and general radiologists at affiliated academic institutions. PACS installed at three affiliated hospitals (UCLA Medical Center, West LA VAMC and UCLA Olive-View Medical Centers) were connected via an ATM network. Two commercial PACS (Agfa) systems, one at the VAMC and one in an ultrasound outpatient clinic at UCLA were connected via ATM switches (Newbridge, Inc.) and a Santa Monica GTE central office switch. We evaluated this initial system configuration and measured image transfer performance, including memory-to-memory, disk-to-disk, disk-to-archive with and without DICOM protocols. Although the memory-to-memory data rate was 25 Mbps, the average remote disk-to-disk image transfer performance, using DICOM 3.0 communications protocols on SUN SPARCstation 10 servers, was 3 to 5 Mbps. Using these capabilities, timely interactive subspecialty consultations between radiologists was successfully performed while both were at different physical locations. We present the use of ATM technology in a realistic clinical environment and evaluate its impact on patient care and clinical teaching within the radiology departments of 2 institutions. Image communications over a regional PACS using an ATM network can allow interactive consultations between different subspecialist and general radiologists or other specialized radiologist spread over three different medical centers.

  18. Snowfall Rate Retrieval using NPP ATMS Passive Microwave Measurements

    NASA Technical Reports Server (NTRS)

    Meng, Huan; Ferraro, Ralph; Kongoli, Cezar; Wang, Nai-Yu; Dong, Jun; Zavodsky, Bradley; Yan, Banghua; Zhao, Limin

    2014-01-01

    Passive microwave measurements at certain high frequencies are sensitive to the scattering effect of snow particles and can be utilized to retrieve snowfall properties. Some of the microwave sensors with snowfall sensitive channels are Advanced Microwave Sounding Unit (AMSU), Microwave Humidity Sounder (MHS) and Advance Technology Microwave Sounder (ATMS). ATMS is the follow-on sensor to AMSU and MHS. Currently, an AMSU and MHS based land snowfall rate (SFR) product is running operationally at NOAA/NESDIS. Based on the AMSU/MHS SFR, an ATMS SFR algorithm has been developed recently. The algorithm performs retrieval in three steps: snowfall detection, retrieval of cloud properties, and estimation of snow particle terminal velocity and snowfall rate. The snowfall detection component utilizes principal component analysis and a logistic regression model. The model employs a combination of temperature and water vapor sounding channels to detect the scattering signal from falling snow and derive the probability of snowfall (Kongoli et al., 2014). In addition, a set of NWP model based filters is also employed to improve the accuracy of snowfall detection. Cloud properties are retrieved using an inversion method with an iteration algorithm and a two-stream radiative transfer model (Yan et al., 2008). A method developed by Heymsfield and Westbrook (2010) is adopted to calculate snow particle terminal velocity. Finally, snowfall rate is computed by numerically solving a complex integral. The ATMS SFR product is validated against radar and gauge snowfall data and shows that the ATMS algorithm outperforms the AMSU/MHS SFR.

  19. Arecoline-induced phosphorylated p53 and p21(WAF1) protein expression is dependent on ATM/ATR and phosphatidylinositol-3-kinase in clone-9 cells.

    PubMed

    Chou, Wen-Wen; Guh, Jinn-Yuh; Tsai, Jung-Fa; Hwang, Chi-Ching; Chiou, Shean-Jaw; Chuang, Lea-Yea

    2009-06-01

    Betel-quid use is associated with liver cancer whereas its constituent arecoline is cytotoxic, genotoxic, and induces p53-dependent p21(WAF1) protein expression in Clone-9 cells (rat hepatocytes). The ataxia telangiectasia mutated (ATM)/rad3-related (ATR)-p53-p21(WAF1) and the phosphatidylinositol-3-kinase (PI3K)-mammalian target of rapamycin (mTOR) pathways are involved in the DNA damage response and the pathogenesis of cancers. Thus, we studied the role of ATM/ATR and PI3K in arecoline-induced p53 and p21(WAF1) protein expression in Clone-9 cells. We found that arecoline (0.5 mM) activated the ATM/ATR kinase at 30 min. The arecoline-activated ATM/ATR substrate contained p-p53Ser15. Moreover, arecoline only increased the levels of the p-p53Ser6, p-p53Ser15, and p-p53Ser392 phosphorylated p53 isoforms among the known isoforms. ATM shRNA attenuated arecoline-induced p-p53Ser15 and p21(WAF1) at 24 h. Arecoline (0.5 mM) increased phosphorylation levels of p-AktSer473 and p-mTORSer2448 at 30-60 min. Dominant-negative PI3K plasmids attenuated arecoline-induced p21(WAF1), but not p-p53Ser15, at 24 h. Rapamycin attenuated arecoline-induced phosphrylated p-p53Ser15, but not p21(WAF1), at 24 h. ATM shRNA, but not dominant-negative PI3K plasmids, attenuated arecoline-induced p21(WAF1) gene transcription. We conclude that arecoline activates the ATM/ATR-p53-p21(WAF1) and the PI3K/Akt-mTOR-p53 pathways in Clone-9 cells. Arecoline-induced phosphorylated p-p53Ser15 expression is dependent on ATM whereas arecoline-induced p21(WAF1) protein expression is dependent on ATM and PI3K. Moreover, p21(WAF1) gene is transcriptionally induced by arecoline-activated ATM. (c) 2009 Wiley-Liss, Inc.

  20. The effect of MRN complex and ATM kinase inhibitors on Zebrafish embryonic development

    NASA Astrophysics Data System (ADS)

    Kumaran, Malina; Fazry, Shazrul

    2018-04-01

    Zebrafish is an ideal animal model to study developmental biology due to its transparent embryos and rapid development stages of embryogenesis. Here we investigate the role of DNA damage proteins, specifically Mre11/Rad50/NBN (MRN) complex and ataxia-telangiectasia mutated (ATM) kinase during embryogenesis by inhibiting its function using specific MRN complex (Mirin) and ATM Kinase inhibitors (Ku60019 and Ku55933). Zebrafish embryos at midblastula transition (MBT) stage are treated with Mirin, Ku60019 and Ku55933. The embryonic development of the embryos was monitored at 24 hours-post fertilisation (hpf), 48 hpf and 72 hpf. We observed that at the lowest concentrations (3 µM of Mirin, 1.5 nM of Ku60019 and 3 nM of Ku55933), the inhibitors treated embryos have 100% survivability. However, with increasing inhibitor concentration, the survivability drops. Control or mock treatment of all embryos shows 100 % survivability rate. This study suggests that DNA damage repair proteins may be crucial for normal zebrafish embryo development and survival.

  1. Melatonin sensitizes H1975 non-small-cell lung cancer cells harboring a T790M-targeted epidermal growth factor receptor mutation to the tyrosine kinase inhibitor gefitinib.

    PubMed

    Yun, Miyong; Kim, Eun-Ok; Lee, Duckgue; Kim, Ji-Hyun; Kim, Jaekwang; Lee, Hyemin; Lee, Jihyun; Kim, Sung-Hoon

    2014-01-01

    The use of tyrosine kinase inhibitors (TKIs) to target active epidermal growth factor receptor (EGFR)-harbouring mutations has been effective in patients with advanced non-small-cell lung cancer (NSCLC). However, the use of TKIs in NSCLS patients with somatic EGFR mutations, particularly T790M, causes drug resistance. Thus, in the present study, we investigated overcoming resistance against the TKI gefitinib by combination treatment with melatonin in H1975 NSCLC cells harbouring the T790M somatic mutation. H1975 and HCC827 cells were treated with melatonin in combination with gefitinib, and cell viability, cell cycle progression, apoptosis, and EGFR, AKT, p38, Bcl-2, Bcl-xL, caspase 3 and Bad protein levels were examined. Treatment with melatonin dose-dependently decreased the viability of H1975 cells harbouring the T790M somatic mutation compared to HCC827 cells with an EGFR active mutation. Melatonin-mediated cell death resulted in decreased phosphorylation of EGFR and Akt, leading to attenuated expression of survival proteins, such as Bcl-2, Bcl-xL and survivin, and activated caspase 3 in H1975 cells, but not in HCC827 cells. However, we did not observe a significant change in expression of cell cycle proteins, such as cyclin D, cyclin A, p21 and CDK4 in H1975 cells. Surprisingly, co-treatment of gefitinib with melatonin effectively decreased the viability of H1975 cells, but not HCC827 cells. Moreover, co-treatment of H1975 cells caused consistent down-regulation of EGFR phosphorylation and induced apoptosis compared to treatment with gefitinib or melatonin alone. Our findings demonstrate that melatonin acts as a potent chemotherapeutic agent by sensitising to gefitinib TKI-resistant H1975 cells that harbour a EGFR T790M mutation. © 2014 S. Karger AG, Basel.

  2. Differential Processing of Low and High LET Radiation Induced DNA Damage: Investigation of Switch from ATM to ATR Signaling

    NASA Technical Reports Server (NTRS)

    Saha, Janapriya; Wang, Minli; Hada, Megumi; Cucinotta, Francis A.

    2011-01-01

    The members of the phosphatidylinositol kinase-like kinase family of proteins namely ataxia-telangiectasia mutated (ATM) and ATM- and Rad3-related (ATR) are directly responsible for the maintenance of genomic integrity by mounting DDR through signaling and facilitating the recruitment of repair factors at the sites of DNA damage along with coordinating the deployment of cell cycle checkpoints to permit repair by phosphorylating Checkpoint kinase Chk1, Chk2 and p53. High LET radiation from GCR (Galactic Cosmic Rays) consisting mainly of protons and high energy and charged (HZE) particles from SPE (Solar Particle Event) pose a major health risk for astronauts on their space flight missions. The determination of these risks and the design of potential safeguards require sound knowledge of the biological consequences of lesion induction and the capability of the cells to counter them. We here strive to determine the coordination of ATM and ATR kinases at the break sites directly affecting checkpoint signaling and DNA repair and whether differential processing of breaks induced by low and high LET radiation leads to possible augmentation of swap of these damage sensors at the sites of DNA damage. Exposure of cells to IR triggers rapid autophosphorylation of serine-1981 that causes dimer dissociation and initiates monomer formation of ATM. ATM kinase activity depends on the disruption of the dimer, which allows access and phosphorylation of downstream ATM substrates like Chk2. Evidence suggests that ATM is activated by the alterations in higher-order chromatin structure although direct binding of ATM to DSB ends may be a crucial step in its activation. On the other hand, in case of ATR, RPA (replication protein A)-coated ssDNA (single-stranded DNA) generated as a result of stalled DNA replication or during processing of chromosomal lesions is crucial for the localization of ATR to sites of DNA damage in association with ATR-interacting protein (ATRIP). Although the

  3. PALB2, CHEK2 and ATM rare variants and cancer risk: data from COGS

    PubMed Central

    Southey, Melissa C; Goldgar, David E; Winqvist, Robert; Pylkäs, Katri; Couch, Fergus; Tischkowitz, Marc; Foulkes, William D; Dennis, Joe; Michailidou, Kyriaki; van Rensburg, Elizabeth J; Heikkinen, Tuomas; Nevanlinna, Heli; Hopper, John L; Dörk, Thilo; Claes, Kathleen BM; Reis-Filho, Jorge; Teo, Zhi Ling; Radice, Paolo; Catucci, Irene; Peterlongo, Paolo; Tsimiklis, Helen; Odefrey, Fabrice A; Dowty, James G; Schmidt, Marjanka K; Broeks, Annegien; Hogervorst, Frans B; Verhoef, Senno; Carpenter, Jane; Clarke, Christine; Scott, Rodney J; Fasching, Peter A; Haeberle, Lothar; Ekici, Arif B; Beckmann, Matthias W; Peto, Julian; dos-Santos-Silva, Isabel; Fletcher, Olivia; Johnson, Nichola; Bolla, Manjeet K; Sawyer, Elinor J; Tomlinson, Ian; Kerin, Michael J; Miller, Nicola; Marme, Federik; Burwinkel, Barbara; Yang, Rongxi; Guénel, Pascal; Truong, Thérèse; Menegaux, Florence; Sanchez, Marie; Bojesen, Stig; Nielsen, Sune F; Flyger, Henrik; Benitez, Javier; Zamora, M Pilar; Perez, Jose Ignacio Arias; Menéndez, Primitiva; Anton-Culver, Hoda; Neuhausen, Susan; Ziogas, Argyrios; Clarke, Christina A; Brenner, Hermann; Arndt, Volker; Stegmaier, Christa; Brauch, Hiltrud; Brüning, Thomas; Ko, Yon-Dschun; Muranen, Taru A; Aittomäki, Kristiina; Blomqvist, Carl; Bogdanova, Natalia V; Antonenkova, Natalia N; Lindblom, Annika; Margolin, Sara; Mannermaa, Arto; Kataja, Vesa; Kosma, Veli-Matti; Hartikainen, Jaana M; Spurdle, Amanda B; Investigators, kConFab; Wauters, Els; Smeets, Dominiek; Beuselinck, Benoit; Floris, Giuseppe; Chang-Claude, Jenny; Rudolph, Anja; Seibold, Petra; Flesch-Janys, Dieter; Olson, Janet E; Vachon, Celine; Pankratz, Vernon S; McLean, Catriona; Haiman, Christopher A; Henderson, Brian E; Schumacher, Fredrick; Le Marchand, Loic; Kristensen, Vessela; Alnæs, Grethe Grenaker; Zheng, Wei; Hunter, David J; Lindstrom, Sara; Hankinson, Susan E; Kraft, Peter; Andrulis, Irene; Knight, Julia A; Glendon, Gord; Mulligan, Anna Marie; Jukkola-Vuorinen, Arja; Grip, Mervi; Kauppila, Saila; Devilee, Peter; Tollenaar, Robert A E M; Seynaeve, Caroline; Hollestelle, Antoinette; Garcia-Closas, Montserrat; Figueroa, Jonine; Chanock, Stephen J; Lissowska, Jolanta; Czene, Kamila; Darabi, Hatef; Eriksson, Mikael; Eccles, Diana M; Rafiq, Sajjad; Tapper, William J; Gerty, Sue M; Hooning, Maartje J; Martens, John W M; Collée, J Margriet; Tilanus-Linthorst, Madeleine; Hall, Per; Li, Jingmei; Brand, Judith S; Humphreys, Keith; Cox, Angela; Reed, Malcolm W R; Luccarini, Craig; Baynes, Caroline; Dunning, Alison M; Hamann, Ute; Torres, Diana; Ulmer, Hans Ulrich; Rüdiger, Thomas; Jakubowska, Anna; Lubinski, Jan; Jaworska, Katarzyna; Durda, Katarzyna; Slager, Susan; Toland, Amanda E; Ambrosone, Christine B; Yannoukakos, Drakoulis; Swerdlow, Anthony; Ashworth, Alan; Orr, Nick; Jones, Michael; González-Neira, Anna; Pita, Guillermo; Alonso, M Rosario; Álvarez, Nuria; Herrero, Daniel; Tessier, Daniel C; Vincent, Daniel; Bacot, Francois; Simard, Jacques; Dumont, Martine; Soucy, Penny; Eeles, Rosalind; Muir, Kenneth; Wiklund, Fredrik; Gronberg, Henrik; Schleutker, Johanna; Nordestgaard, Børge G; Weischer, Maren; Travis, Ruth C; Neal, David; Donovan, Jenny L; Hamdy, Freddie C; Khaw, Kay-Tee; Stanford, Janet L; Blot, William J; Thibodeau, Stephen; Schaid, Daniel J; Kelley, Joseph L; Maier, Christiane; Kibel, Adam S; Cybulski, Cezary; Cannon-Albright, Lisa; Butterbach, Katja; Park, Jong; Kaneva, Radka; Batra, Jyotsna; Teixeira, Manuel R; Kote-Jarai, Zsofia; Olama, Ali Amin Al; Benlloch, Sara; Renner, Stefan P; Hartmann, Arndt; Hein, Alexander; Ruebner, Matthias; Lambrechts, Diether; Van Nieuwenhuysen, Els; Vergote, Ignace; Lambretchs, Sandrina; Doherty, Jennifer A; Rossing, Mary Anne; Nickels, Stefan; Eilber, Ursula; Wang-Gohrke, Shan; Odunsi, Kunle; Sucheston-Campbell, Lara E; Friel, Grace; Lurie, Galina; Killeen, Jeffrey L; Wilkens, Lynne R; Goodman, Marc T; Runnebaum, Ingo; Hillemanns, Peter A; Pelttari, Liisa M; Butzow, Ralf; Modugno, Francesmary; Edwards, Robert P; Ness, Roberta B; Moysich, Kirsten B; du Bois, Andreas; Heitz, Florian; Harter, Philipp; Kommoss, Stefan; Karlan, Beth Y; Walsh, Christine; Lester, Jenny; Jensen, Allan; Kjaer, Susanne Krüger; Høgdall, Estrid; Peissel, Bernard; Bonanni, Bernardo; Bernard, Loris; Goode, Ellen L; Fridley, Brooke L; Vierkant, Robert A; Cunningham, Julie M; Larson, Melissa C; Fogarty, Zachary C; Kalli, Kimberly R; Liang, Dong; Lu, Karen H; Hildebrandt, Michelle A T; Wu, Xifeng; Levine, Douglas A; Dao, Fanny; Bisogna, Maria; Berchuck, Andrew; Iversen, Edwin S; Marks, Jeffrey R; Akushevich, Lucy; Cramer, Daniel W; Schildkraut, Joellen; Terry, Kathryn L; Poole, Elizabeth M; Stampfer, Meir; Tworoger, Shelley S; Bandera, Elisa V; Orlow, Irene; Olson, Sara H; Bjorge, Line; Salvesen, Helga B; van Altena, Anne M; Aben, Katja K H; Kiemeney, Lambertus A; Massuger, Leon F A G; Pejovic, Tanja; Bean, Yukie; Brooks-Wilson, Angela; Kelemen, Linda E; Cook, Linda S; Le, Nhu D; Górski, Bohdan; Gronwald, Jacek; Menkiszak, Janusz; Høgdall, Claus K; Lundvall, Lene; Nedergaard, Lotte; Engelholm, Svend Aage; Dicks, Ed; Tyrer, Jonathan; Campbell, Ian; McNeish, Iain; Paul, James; Siddiqui, Nadeem; Glasspool, Rosalind; Whittemore, Alice S; Rothstein, Joseph H; McGuire, Valerie; Sieh, Weiva; Cai, Hui; Shu, Xiao-Ou; Teten, Rachel T; Sutphen, Rebecca; McLaughlin, John R; Narod, Steven A; Phelan, Catherine M; Monteiro, Alvaro N; Fenstermacher, David; Lin, Hui-Yi; Permuth, Jennifer B; Sellers, Thomas A; Chen, Y Ann; Tsai, Ya-Yu; Chen, Zhihua; Gentry-Maharaj, Aleksandra; Gayther, Simon A; Ramus, Susan J; Menon, Usha; Wu, Anna H; Pearce, Celeste L; Van Den Berg, David; Pike, Malcolm C; Dansonka-Mieszkowska, Agnieszka; Plisiecka-Halasa, Joanna; Moes-Sosnowska, Joanna; Kupryjanczyk, Jolanta; Pharoah, Paul DP; Song, Honglin; Winship, Ingrid; Chenevix-Trench, Georgia; Giles, Graham G; Tavtigian, Sean V; Easton, Doug F; Milne, Roger L

    2016-01-01

    Background The rarity of mutations in PALB2, CHEK2 and ATM make it difficult to estimate precisely associated cancer risks. Population-based family studies have provided evidence that at least some of these mutations are associated with breast cancer risk as high as those associated with rare BRCA2 mutations. We aimed to estimate the relative risks associated with specific rare variants in PALB2, CHEK2 and ATM via a multicentre case-control study. Methods We genotyped 10 rare mutations using the custom iCOGS array: PALB2 c.1592delT, c.2816T>G and c.3113G>A, CHEK2 c.349A>G, c.538C>T, c.715G>A, c.1036C>T, c.1312G>T, and c.1343T>G and ATM c.7271T>G. We assessed associations with breast cancer risk (42 671 cases and 42 164 controls), as well as prostate (22 301 cases and 22 320 controls) and ovarian (14 542 cases and 23 491 controls) cancer risk, for each variant. Results For European women, strong evidence of association with breast cancer risk was observed for PALB2 c.1592delT OR 3.44 (95% CI 1.39 to 8.52, p=7.1×10−5), PALB2 c.3113G>A OR 4.21 (95% CI 1.84 to 9.60, p=6.9×10−8) and ATM c.7271T>G OR 11.0 (95% CI 1.42 to 85.7, p=0.0012). We also found evidence of association with breast cancer risk for three variants in CHEK2, c.349A>G OR 2.26 (95% CI 1.29 to 3.95), c.1036C>T OR 5.06 (95% CI 1.09 to 23.5) and c.538C>T OR 1.33 (95% CI 1.05 to 1.67) (p≤0.017). Evidence for prostate cancer risk was observed for CHEK2 c.1343T>G OR 3.03 (95% CI 1.53 to 6.03, p=0.0006) for African men and CHEK2 c.1312G>T OR 2.21 (95% CI 1.06 to 4.63, p=0.030) for European men. No evidence of association with ovarian cancer was found for any of these variants. Conclusions This report adds to accumulating evidence that at least some variants in these genes are associated with an increased risk of breast cancer that is clinically important. PMID:27595995

  4. PALB2, CHEK2 and ATM rare variants and cancer risk: data from COGS.

    PubMed

    Southey, Melissa C; Goldgar, David E; Winqvist, Robert; Pylkäs, Katri; Couch, Fergus; Tischkowitz, Marc; Foulkes, William D; Dennis, Joe; Michailidou, Kyriaki; van Rensburg, Elizabeth J; Heikkinen, Tuomas; Nevanlinna, Heli; Hopper, John L; Dörk, Thilo; Claes, Kathleen Bm; Reis-Filho, Jorge; Teo, Zhi Ling; Radice, Paolo; Catucci, Irene; Peterlongo, Paolo; Tsimiklis, Helen; Odefrey, Fabrice A; Dowty, James G; Schmidt, Marjanka K; Broeks, Annegien; Hogervorst, Frans B; Verhoef, Senno; Carpenter, Jane; Clarke, Christine; Scott, Rodney J; Fasching, Peter A; Haeberle, Lothar; Ekici, Arif B; Beckmann, Matthias W; Peto, Julian; Dos-Santos-Silva, Isabel; Fletcher, Olivia; Johnson, Nichola; Bolla, Manjeet K; Sawyer, Elinor J; Tomlinson, Ian; Kerin, Michael J; Miller, Nicola; Marme, Federik; Burwinkel, Barbara; Yang, Rongxi; Guénel, Pascal; Truong, Thérèse; Menegaux, Florence; Sanchez, Marie; Bojesen, Stig; Nielsen, Sune F; Flyger, Henrik; Benitez, Javier; Zamora, M Pilar; Perez, Jose Ignacio Arias; Menéndez, Primitiva; Anton-Culver, Hoda; Neuhausen, Susan; Ziogas, Argyrios; Clarke, Christina A; Brenner, Hermann; Arndt, Volker; Stegmaier, Christa; Brauch, Hiltrud; Brüning, Thomas; Ko, Yon-Dschun; Muranen, Taru A; Aittomäki, Kristiina; Blomqvist, Carl; Bogdanova, Natalia V; Antonenkova, Natalia N; Lindblom, Annika; Margolin, Sara; Mannermaa, Arto; Kataja, Vesa; Kosma, Veli-Matti; Hartikainen, Jaana M; Spurdle, Amanda B; Investigators, kConFab; Wauters, Els; Smeets, Dominiek; Beuselinck, Benoit; Floris, Giuseppe; Chang-Claude, Jenny; Rudolph, Anja; Seibold, Petra; Flesch-Janys, Dieter; Olson, Janet E; Vachon, Celine; Pankratz, Vernon S; McLean, Catriona; Haiman, Christopher A; Henderson, Brian E; Schumacher, Fredrick; Le Marchand, Loic; Kristensen, Vessela; Alnæs, Grethe Grenaker; Zheng, Wei; Hunter, David J; Lindstrom, Sara; Hankinson, Susan E; Kraft, Peter; Andrulis, Irene; Knight, Julia A; Glendon, Gord; Mulligan, Anna Marie; Jukkola-Vuorinen, Arja; Grip, Mervi; Kauppila, Saila; Devilee, Peter; Tollenaar, Robert A E M; Seynaeve, Caroline; Hollestelle, Antoinette; Garcia-Closas, Montserrat; Figueroa, Jonine; Chanock, Stephen J; Lissowska, Jolanta; Czene, Kamila; Darabi, Hatef; Eriksson, Mikael; Eccles, Diana M; Rafiq, Sajjad; Tapper, William J; Gerty, Sue M; Hooning, Maartje J; Martens, John W M; Collée, J Margriet; Tilanus-Linthorst, Madeleine; Hall, Per; Li, Jingmei; Brand, Judith S; Humphreys, Keith; Cox, Angela; Reed, Malcolm W R; Luccarini, Craig; Baynes, Caroline; Dunning, Alison M; Hamann, Ute; Torres, Diana; Ulmer, Hans Ulrich; Rüdiger, Thomas; Jakubowska, Anna; Lubinski, Jan; Jaworska, Katarzyna; Durda, Katarzyna; Slager, Susan; Toland, Amanda E; Ambrosone, Christine B; Yannoukakos, Drakoulis; Swerdlow, Anthony; Ashworth, Alan; Orr, Nick; Jones, Michael; González-Neira, Anna; Pita, Guillermo; Alonso, M Rosario; Álvarez, Nuria; Herrero, Daniel; Tessier, Daniel C; Vincent, Daniel; Bacot, Francois; Simard, Jacques; Dumont, Martine; Soucy, Penny; Eeles, Rosalind; Muir, Kenneth; Wiklund, Fredrik; Gronberg, Henrik; Schleutker, Johanna; Nordestgaard, Børge G; Weischer, Maren; Travis, Ruth C; Neal, David; Donovan, Jenny L; Hamdy, Freddie C; Khaw, Kay-Tee; Stanford, Janet L; Blot, William J; Thibodeau, Stephen; Schaid, Daniel J; Kelley, Joseph L; Maier, Christiane; Kibel, Adam S; Cybulski, Cezary; Cannon-Albright, Lisa; Butterbach, Katja; Park, Jong; Kaneva, Radka; Batra, Jyotsna; Teixeira, Manuel R; Kote-Jarai, Zsofia; Olama, Ali Amin Al; Benlloch, Sara; Renner, Stefan P; Hartmann, Arndt; Hein, Alexander; Ruebner, Matthias; Lambrechts, Diether; Van Nieuwenhuysen, Els; Vergote, Ignace; Lambretchs, Sandrina; Doherty, Jennifer A; Rossing, Mary Anne; Nickels, Stefan; Eilber, Ursula; Wang-Gohrke, Shan; Odunsi, Kunle; Sucheston-Campbell, Lara E; Friel, Grace; Lurie, Galina; Killeen, Jeffrey L; Wilkens, Lynne R; Goodman, Marc T; Runnebaum, Ingo; Hillemanns, Peter A; Pelttari, Liisa M; Butzow, Ralf; Modugno, Francesmary; Edwards, Robert P; Ness, Roberta B; Moysich, Kirsten B; du Bois, Andreas; Heitz, Florian; Harter, Philipp; Kommoss, Stefan; Karlan, Beth Y; Walsh, Christine; Lester, Jenny; Jensen, Allan; Kjaer, Susanne Krüger; Høgdall, Estrid; Peissel, Bernard; Bonanni, Bernardo; Bernard, Loris; Goode, Ellen L; Fridley, Brooke L; Vierkant, Robert A; Cunningham, Julie M; Larson, Melissa C; Fogarty, Zachary C; Kalli, Kimberly R; Liang, Dong; Lu, Karen H; Hildebrandt, Michelle A T; Wu, Xifeng; Levine, Douglas A; Dao, Fanny; Bisogna, Maria; Berchuck, Andrew; Iversen, Edwin S; Marks, Jeffrey R; Akushevich, Lucy; Cramer, Daniel W; Schildkraut, Joellen; Terry, Kathryn L; Poole, Elizabeth M; Stampfer, Meir; Tworoger, Shelley S; Bandera, Elisa V; Orlow, Irene; Olson, Sara H; Bjorge, Line; Salvesen, Helga B; van Altena, Anne M; Aben, Katja K H; Kiemeney, Lambertus A; Massuger, Leon F A G; Pejovic, Tanja; Bean, Yukie; Brooks-Wilson, Angela; Kelemen, Linda E; Cook, Linda S; Le, Nhu D; Górski, Bohdan; Gronwald, Jacek; Menkiszak, Janusz; Høgdall, Claus K; Lundvall, Lene; Nedergaard, Lotte; Engelholm, Svend Aage; Dicks, Ed; Tyrer, Jonathan; Campbell, Ian; McNeish, Iain; Paul, James; Siddiqui, Nadeem; Glasspool, Rosalind; Whittemore, Alice S; Rothstein, Joseph H; McGuire, Valerie; Sieh, Weiva; Cai, Hui; Shu, Xiao-Ou; Teten, Rachel T; Sutphen, Rebecca; McLaughlin, John R; Narod, Steven A; Phelan, Catherine M; Monteiro, Alvaro N; Fenstermacher, David; Lin, Hui-Yi; Permuth, Jennifer B; Sellers, Thomas A; Chen, Y Ann; Tsai, Ya-Yu; Chen, Zhihua; Gentry-Maharaj, Aleksandra; Gayther, Simon A; Ramus, Susan J; Menon, Usha; Wu, Anna H; Pearce, Celeste L; Van Den Berg, David; Pike, Malcolm C; Dansonka-Mieszkowska, Agnieszka; Plisiecka-Halasa, Joanna; Moes-Sosnowska, Joanna; Kupryjanczyk, Jolanta; Pharoah, Paul Dp; Song, Honglin; Winship, Ingrid; Chenevix-Trench, Georgia; Giles, Graham G; Tavtigian, Sean V; Easton, Doug F; Milne, Roger L

    2016-12-01

    The rarity of mutations in PALB2, CHEK2 and ATM make it difficult to estimate precisely associated cancer risks. Population-based family studies have provided evidence that at least some of these mutations are associated with breast cancer risk as high as those associated with rare BRCA2 mutations. We aimed to estimate the relative risks associated with specific rare variants in PALB2, CHEK2 and ATM via a multicentre case-control study. We genotyped 10 rare mutations using the custom iCOGS array: PALB2 c.1592delT, c.2816T>G and c.3113G>A, CHEK2 c.349A>G, c.538C>T, c.715G>A, c.1036C>T, c.1312G>T, and c.1343T>G and ATM c.7271T>G. We assessed associations with breast cancer risk (42 671 cases and 42 164 controls), as well as prostate (22 301 cases and 22 320 controls) and ovarian (14 542 cases and 23 491 controls) cancer risk, for each variant. For European women, strong evidence of association with breast cancer risk was observed for PALB2 c.1592delT OR 3.44 (95% CI 1.39 to 8.52, p=7.1×10 -5 ), PALB2 c.3113G>A OR 4.21 (95% CI 1.84 to 9.60, p=6.9×10 -8 ) and ATM c.7271T>G OR 11.0 (95% CI 1.42 to 85.7, p=0.0012). We also found evidence of association with breast cancer risk for three variants in CHEK2, c.349A>G OR 2.26 (95% CI 1.29 to 3.95), c.1036C>T OR 5.06 (95% CI 1.09 to 23.5) and c.538C>T OR 1.33 (95% CI 1.05 to 1.67) (p≤0.017). Evidence for prostate cancer risk was observed for CHEK2 c.1343T>G OR 3.03 (95% CI 1.53 to 6.03, p=0.0006) for African men and CHEK2 c.1312G>T OR 2.21 (95% CI 1.06 to 4.63, p=0.030) for European men. No evidence of association with ovarian cancer was found for any of these variants. This report adds to accumulating evidence that at least some variants in these genes are associated with an increased risk of breast cancer that is clinically important. Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://www.bmj.com/company/products-services/rights-and-licensing/.

  5. Skylab ATM/S-056 X-ray event analyzer observations versus solar flare activity: An event compilation. [tables (data)

    NASA Technical Reports Server (NTRS)

    Wilson, R. M.

    1977-01-01

    An event compilation is presented which correlates ATM/S-056 X-ray event analyzer solar observations with solar flare activity. Approximately 1,070 h of pulse height analyzed X-ray proportional counter data were obtained with the X-ray event analyzer during Skylab. During its operation, 449 flares (including 343 flare peaks) were observed. Seventy events of peak X-ray emission or = Cl were simultaneously observed by ground based telescopes, SOLRAD 9 and/or Vela, and the X-ray event analyzer. These events were observed from preflare through flare rise to peak and through flare decline.

  6. High-performance testbed network with ATM technology for neuroimaging

    NASA Astrophysics Data System (ADS)

    Huang, H. K.; Arenson, Ronald L.; Dillon, William P.; Lou, Shyhliang A.; Bazzill, Todd M.; Wong, Albert W. K.; Gould, Robert G.

    1995-05-01

    Today's teleradiology transmits images with telephone lines (from 14400 to 1.5 Mbits/sec). However, the large amount of data commonly produced during an MR or CT procedure can limit some applications of teleradiology. This paper is a progress report of a high speed (155 Mbits/sec) testbed teleradiology network using asynchronous transfer mode (ATM OC 3) technology for neuroradiology. The network connects radiology departments of four affiliated hospitals and one MR imaging center within the San Francisco Bay Area with ATM switches through the Pacific Bell ATM main switch at Oakland, California; they are: University of California at San Francisco Hospital and Medical School (UCSF), Mt. Zion Hospital (MZH), San Francisco VA Medical Center (SFVAMC), San Francisco General Hospital (SFGH), and San Francisco Magnetic Resonance Imaging Center (SFMRC). UCSF serves as the expert center and the ATM switch is connected to its PACS infrastructure, the others are considered as satellite sites. Images and related patient data are transmitted from the four satellite sites to the expert canter for interpretation and consultation.

  7. Using ATM over hybrid fiber-coax networks

    NASA Astrophysics Data System (ADS)

    Laubach, Mark

    1995-11-01

    Cable TV companies and regional Bell operating companies, e.g. PacBell, are preparing for the future by installing or rebuilding existing all-coaxial cable plants into hybrid-fiber coaxial plants and by offering a wide range of interactive services which they feel will be most attractive to their subscriber base. These new-to-cable services span a wide range of performance attributes, each placing its own demands on the capabilities of the broadband bearer service system. These services include, but are not limited to: video-on-demand, digital video, video telephony, voice telephony, and a suite of interactive digital data services ranging from traditional Internet and information service access (e.g., Compuserve and Prodigy) to multi-player gaming. The future broadband infrastructure challenge can be met by developing a novel family of integrated bearer service products which communicate using asynchronous transfer mode protocols over the cable TV network. This paper summarizes the ATM over HFC definition work taking place in the ATM Forum's Residential Broadband Working Group and the standards progress in the IEEE P802.14 Cable TV Media Access Control and Physical Protocol Working Group. Finally, an example of bridging Ethernet packets over ATM over HFC is discussed. This paper focuses on the aspects of ATM and the MAC layer and does not detail the rf or physical environment.

  8. Environmental considerations of the NGATS ATM-airportal concept

    DOT National Transportation Integrated Search

    2008-01-31

    This report discusses some of the environmental considerations of the Airportal Concept. This information in this report is based on the NGATS ATM-Airportal Concept by J. Lee, et al., version 1.0 dated September 28, 2007. This report is intended to p...

  9. Coinheritance of a novel mutation on the HBA1 gene: c.187delG (p.W62fsX66) [codon 62 (-G) (α1)] with the α212 patchwork allele and Hb S [β6(A3)Glu→Val, GAG>GTG; HBB: c.20A>T].

    PubMed

    Scheps, Karen G; De Paula, Silvia M; Bitsman, Alicia R; Freigeiro, Daniel H; Basack, F Nora; Pennesi, Sandra P; Varela, Viviana

    2013-01-01

    We describe a novel frameshift mutation on the HBA1 gene (c.187delG), causative of α-thalassemia (α-thal) in a Black Cuban family with multiple sequence variants in the HBA genes and the Hb S [β6(A3)Glu→Val, GAG>GTG; HBB: c.20A>T] mutation. The deletion of the first base of codon 62 resulted in a frameshift at amino acid 62 with a putative premature termination codon (PTC) at amino acid 66 on the same exon (p.W62fsX66), which most likely triggers nonsense mediated decay of the resulting mRNA. This study also presents the first report of the α212 patchwork allele in Latin America and the description of two new sequence variants in the HBA2 region (c.-614G>A in the promoter region and c.95+39 C>T on the first intron).

  10. Interaction of the MexA and MexB components of the MexAB-OprM multidrug efflux system of Pseudomonas aeruginosa: identification of MexA extragenic suppressors of a T578I mutation in MexB.

    PubMed

    Nehme, Dominic; Poole, Keith

    2005-10-01

    A T578I mutation in MexB compromised the protein's contribution to antimicrobial resistance and negatively impacted its interaction with MexA. Mutations causing single amino acid changes in the C-terminal domain of MexA (R221H, L245F, E254K, and V259I) suppressed the antimicrobial susceptibility of a MexB(T578I)-expressing Pseudomonas aeruginosa strain and restored a MexA interaction with MexB(T578I). These data confirm the importance of the MexA C-terminal region in MexB binding and the likely significance of the region surrounding T587I of MexB in MexA interaction.

  11. Requirement of protein phosphatase 5 in DNA-damage-induced ATM activation

    PubMed Central

    Ali, Ambereen; Zhang, Ji; Bao, Shideng; Liu, Irene; Otterness, Diane; Dean, Nicholas M.; Abraham, Robert T.; Wang, Xiao-Fan

    2004-01-01

    The checkpoint kinase ATM is centrally involved in the cellular response to DNA double-strand breaks. However, the mechanism of ATM activation during genotoxicstress is only partially understood. Here we report a direct regulatory linkage between the protein serine-threonine phosphatase 5 (PP5) and ATM. PP5 interacts with ATM in a DNA-damage-inducible manner. Reduced expression of PP5 attenuated DNA-damage-induced activation of ATM. Expression of a catalytically inactive PP5 mutant inhibited the phosphorylation of ATM substrates and the autophosphorylation of ATM on Ser 1981, and caused an S-phase checkpoint defect in DNA-damaged cells. Together our findings indicate that PP5 plays an essential role in the activation and checkpoint signaling functions of ATM in cells that have suffered DNA double-strand breaks. PMID:14871926

  12. The RETAIN project: DICOM teleradiology over an ATM-based network. Radiological Examinations Transfer on an ATM Integrated Network.

    PubMed

    Heautot, J F; Eichelberg, M; Gibaud, B; Tréguier, C; Lemoine, D; Scarabin, J M; Piqueras, J; Carsin, M; Gandon, Y

    2000-01-01

    The RETAIN project (Radiological Examinations Transfer on an ATM Integrated Network) has aimed at testing videoconferencing and DICOM image transfers to get advice about difficult radiological cases over an asynchronous transfer mode (ATM)-based network, which affords a more comfortable interface than narrow-band networks and allows exchange of complete image series using the DICOM format of studies. For this purpose, an experimental ATM network was applied between six university hospitals in four different countries. An assessment of the functionalities of the system was performed by means of log-file analysis, video recording of the sessions and forms filled out by the participants at the end of each session. Questionnaires were answered by the users at the end of the project to bring out perspectives of utilisation and added value. We discussed 43 cases during 20 sessions. For technical or organisational problems, only 20 of the 36 planned sessions took place. The throughput over ATM (10.5 Mbit/s, 20 times faster than six ISDN B-channels) was adequate. Despite the experimental configuration of the network, the system was considered as satisfactory by all the physicians. In 72 % of the sessions, the expected result (answer to the question) was gained. By common consent, videoconferencing was unanimously regarded as a prominent tool in improving the interaction quality. Asynchronous transfer mode is an efficient method for fast transferring of radiologic examinations in DICOM format and for discussing them through high-quality videoconferencing.

  13. Tyrosinase overexpression promotes ATM-dependent p53 phosphorylation by quercetin and sensitizes melanoma cells to dacarbazine.

    PubMed

    Thangasamy, Thilakavathy; Sittadjody, Sivanandane; Limesand, Kirsten H; Burd, Randy

    2008-01-01

    Dacarbazine (DTIC) has been used for the treatment of melanoma for decades. However, monotherapy with this chemotherapeutic agent results only in moderate response rates. To improve tumor response to DTIC current clinical trials in melanoma focus on combining a novel targeted agent with chemotherapy. Here, we demonstrate that tyrosinase which is commonly overexpressed in melanoma activates the bioflavonoid quercetin (Qct) and promotes an ataxia telangiectasia mutated (ATM)-dependent DNA damage response. This response sensitizes melanoma cells that overexpress tyrosinase to DTIC. In DB-1 melanoma cells that overexpress tyrosinase (Tyr(+) cells), the threshold for phosphorylation of ATM and p53 at serine 15 was observed at a low dose of Qct (25 microM) when compared to the mock transfected pcDNA3 cells, which required a higher dose (75 microM). Both pcDNA3 and Tyr(+) DB-1 cells demonstrated similar increases in phosphorylation of p53 at other serine sites, but in the Tyr(+) cells, DNApk expression was found to be reduced compared to control cells, indicating a shift towards an ATM-mediated response. The DB-1 control cells were resistant to DTIC, but were sensitized to apoptosis with high dose Qct, while Tyr(+) cells were sensitized to DTIC with low or high dose Qct. Qct also sensitized SK Mel 5 (p53 wildtype) and 28 (p53 mutant) cells to DTIC. However, when SK Mel 5 cells were transiently transfected with tyrosinase and treated with Qct plus DTIC, SK Mel 5 cells demonstrated a more than additive induction of apoptosis. Therefore, this study demonstrates that tyrosinase overexpression promotes an ATM-dependent p53 phosphorylation by Qct treatment and sensitizes melanoma cells to dacarbazine. In conclusion, these results suggest that Qct or Qct analogues may significantly improve DTIC response rates in tumors that express tyrosinase.

  14. Tyrosinase Overexpression Promotes ATM-Dependent p53 Phosphorylation by Quercetin and Sensitizes Melanoma Cells to Dacarbazine

    PubMed Central

    Thangasamy, Thilakavathy; Sittadjody, Sivanandane; H. Limesand, Kirsten; Burd, Randy

    2008-01-01

    Dacarbazine (DTIC) has been used for the treatment of melanoma for decades. However, monotherapy with this chemotherapeutic agent results only in moderate response rates. To improve tumor response to DTIC current clinical trials in melanoma focus on combining a novel targeted agent with chemotherapy. Here, we demonstrate that tyrosinase which is commonly overexpressed in melanoma activates the bioflavonoid quercetin (Qct) and promotes an ataxia telangiectasia mutated (ATM)-dependent DNA damage response. This response sensitizes melanoma cells that overexpress tyrosinase to DTIC. In DB-1 melanoma cells that overexpress tyrosinase (Tyr cells), the threshold for phosphorylation of ATM and p53 at serine 15 was observed at a low dose of Qct (25 μM) when compared to the mock transfected pcDNA3 cells, which required a higher dose (75 μM). Both pcDNA3 and Tyr DB-1 cells demonstrated similar increases in phosphorylation of p53 at other serine sites, but in the Tyr cells, DNApk expression was found to be reduced compared to control cells, indicating a shift towards an ATM-mediated response. The DB-1 control cells were resistant to DTIC, but were sensitized to apoptosis with high dose Qct, while Tyr cells were sensitized to DTIC with low or high dose Qct. Qct also sensitized SK Mel 5 (p53 wildtype) and 28 (p53 mutant) cells to DTIC. However, when SK Mel 5 cells were transiently transfected with tyrosinase and treated with Qct plus DTIC, SK Mel 5 cells demonstrated a more than additive induction of apoptosis. Therefore, this study demonstrates that tyrosinase overexpression promotes an ATM-dependent p53 phosphorylation by Qct treatment and sensitizes melanoma cells to dacarbazine. In conclusion, these results suggest that Qct or Qct analogues may significantly improve DTIC response rates in tumors that express tyrosinase. PMID:18791269

  15. ATM influences the efficiency of TCRβ rearrangement, subsequent TCRβ-dependent T cell development, and generation of the pre-selection TCRβ CDR3 repertoire.

    PubMed

    Hathcock, Karen S; Bowen, Steven; Livak, Ferenc; Hodes, Richard J

    2013-01-01

    Generation and resolution of DNA double-strand breaks is required to assemble antigen-specific receptors from the genes encoding V, D, and J gene segments during recombination. The present report investigates the requirement for ataxia telangiectasia-mutated (ATM) kinase, a component of DNA double-strand break repair, during TCRβ recombination and in subsequent TCRβ-dependent repertoire generation and thymocyte development. CD4(-)CD8(-) double negative stage 2/3 thymocytes from ATM-deficient mice have both an increased frequency of cells with DNA break foci at TCRβ loci and reduced Vβ-DJβ rearrangement. Sequencing of TCRβ complementarity-determining region 3 demonstrates that ATM-deficient CD4(+)CD8(+) double positive thymocytes and peripheral T cells have altered processing of coding ends for both in-frame and out-of-frame TCRβ rearrangements, providing the unique demonstration that ATM deficiency alters the expressed TCRβ repertoire by a selection-independent mechanism. ATMKO thymi exhibit a partial developmental block in DN cells as they negotiate the β-selection checkpoint to become double negative stage 4 and CD4(+)CD8(+) thymocytes, resulting in reduced numbers of CD4(+)CD8(+) cells. Importantly, expression of a rearranged TCRβ transgene substantially reverses this defect in CD4(+)CD8(+) cells, directly linking a requirement for ATM during endogenous TCRβ rearrangement to subsequent TCRβ-dependent stages of development. These results demonstrate that ATM plays an important role in TCRβ rearrangement, generation of the TCRβ CDR3 repertoire, and efficient TCRβ-dependent T cell development.

  16. Application of Computer Simulation to Teach ATM Access to Individuals with Intellectual Disabilities

    ERIC Educational Resources Information Center

    Davies, Daniel K.; Stock, Steven E.; Wehmeyer, Michael L.

    2003-01-01

    This study investigates use of computer simulation for teaching ATM use to adults with intellectual disabilities. ATM-SIM is a computer-based trainer used for teaching individuals with intellectual disabilities how to use an automated teller machine (ATM) to access their personal bank accounts. In the pilot evaluation, a prototype system was…

  17. Molecular Characterization and Subcellular Localization of Arabidopsis Class VIII Myosin, ATM1*

    PubMed Central

    Haraguchi, Takeshi; Tominaga, Motoki; Matsumoto, Rie; Sato, Kei; Nakano, Akihiko; Yamamoto, Keiichi; Ito, Kohji

    2014-01-01

    Land plants possess myosin classes VIII and XI. Although some information is available on the molecular properties of class XI myosins, class VIII myosins are not characterized. Here, we report the first analysis of the enzymatic properties of class VIII myosin. The motor domain of Arabidopsis class VIII myosin, ATM1 (ATM1-MD), and the motor domain plus one IQ motif (ATM1-1IQ) were expressed in a baculovirus system and characterized. ATM1-MD and ATM1-1IQ had low actin-activated Mg2+-ATPase activity (Vmax = 4 s−1), although their affinities for actin were high (Kactin = 4 μm). The actin-sliding velocities of ATM1-MD and ATM1-1IQ were 0.02 and 0.089 μm/s, respectively, from which the value for full-length ATM1 is calculated to be ∼0.2 μm/s. The results of actin co-sedimentation assay showed that the duty ratio of ATM1 was ∼90%. ADP dissociation from the actin·ATM1 complex (acto-ATM1) was extremely slow, which accounts for the low actin-sliding velocity, low actin-activated ATPase activity, and high duty ratio. The rate of ADP dissociation from acto-ATM1 was markedly biphasic with fast and slow phase rates (5.1 and 0.41 s−1, respectively). Physiological concentrations of free Mg2+ modulated actin-sliding velocity and actin-activated ATPase activity by changing the rate of ADP dissociation from acto-ATM1. GFP-fused full-length ATM1 expressed in Arabidopsis was localized to plasmodesmata, plastids, newly formed cell walls, and actin filaments at the cell cortex. Our results suggest that ATM1 functions as a tension sensor/generator at the cell cortex and other structures in Arabidopsis. PMID:24637024

  18. Toward multidomain integrated network management for ATM and SDH networks

    NASA Astrophysics Data System (ADS)

    Galis, Alex; Gantenbein, Dieter; Covaci, Stefan; Bianza, Carlo; Karayannis, Fotis; Mykoniatis, George

    1996-12-01

    ACTS Project AC080 MISA has embarked upon the task of realizing and validating via European field trials integrated end-to-end management of hybrid SDH and ATM networks in the framework of open network provision. This paper reflects the initial work of the project and gives an overview of the proposed MISA system architecture and initial design. We describe our understanding of the underlying enterprise model in the network management context, including the concept of the MISA Global Broadband Connectivity Management service. It supports Integrated Broadband Communication by defining an end-to-end broadband connection service in a multi-domain business environment. Its implementation by the MISA consortium within trials across Europe aims for an efficient management of network resources of the SDH and ATM infrastructure, considering optimum end-to-end quality of service and the needs of a number of telecommunication actors: customers, value-added service providers, and network providers.

  19. Scalable end-to-end ATM encryption test results

    SciTech Connect

    Pierson, L.G.

    1995-10-01

    Customers of Asynchronous Transfer Mode (ATM) services may need a variety of data authenticity and privacy assurances. Cryptographic methods can be used to assure authenticity and privacy, but are hard to scale for implementation at high speed. The incorporation of these methods into computer networks can severely impact functionality, reliability, and performance. To study these trade-offs, a prototype encryptor/decryptor was developed. This effort demonstrated the viability of implementing certain encryption techniques in high speed networks. The research prototype processes ATM cells in a SONET OC-3 payload. This paper describes the functionality, reliability, security, and performance design trade-offs investigated with themore » prototype.« less

  20. Estimating TC Intensity Using the SSMIS and ATMS Sounders

    DTIC Science & Technology

    2012-04-01

    P1.21 Estimating TC Intensity Using the SSMIS and ATMS Sounders Derrick C. Herndon* and Christopher Velden University of Wisconsin... SSMIS ) flown aboard the DMSP series of satellites. The SSMIS temperature sounder has a resolution of 37.5 km for channels 1-7. Channels 3...while SSMIS uses a conical scanning strategy. This is a key difference between the instruments that has a direct impact on TC intensity

  1. ATM Coastal Topography-Texas, 2001: UTM Zone 14

    USGS Publications Warehouse

    Klipp, Emily S.; Nayegandhi, Amar; Brock, John C.; Sallenger, A.H.; Bonisteel, Jamie M.; Yates, Xan; Wright, C. Wayne

    2009-01-01

    These remotely sensed, geographically referenced elevation measurements of lidar-derived first-surface (FS) topography were produced collaboratively by the U.S. Geological Survey (USGS), Florida Integrated Science Center (FISC), St. Petersburg, FL, and the National Aeronautics and Space Administration (NASA), Wallops Flight Facility, VA. This project provides highly detailed and accurate datasets of a portion of the Texas coastline within UTM zone 14, acquired October 12-13, 2001. The datasets are made available for use as a management tool to research scientists and natural-resource managers. An innovative scanning lidar instrument originally developed by NASA, and known as the Airborne Topographic Mapper (ATM), was used during data acquisition. The ATM system is a scanning lidar system that measures high-resolution topography of the land surface and incorporates a green-wavelength laser operating at pulse rates of 2 to 10 kilohertz. Measurements from the laser-ranging device are coupled with data acquired from inertial navigation system (INS) attitude sensors and differentially corrected global positioning system (GPS) receivers to measure topography of the surface at accuracies of +/-15 centimeters. The nominal ATM platform is a Twin Otter or P-3 Orion aircraft, but the instrument may be deployed on a range of light aircraft. Elevation measurements were collected over the survey area using the ATM system, and the resulting data were then processed using the Airborne Lidar Processing System (ALPS), a custom-built processing system developed in a NASA-USGS collaboration. ALPS supports the exploration and processing of lidar data in an interactive or batch mode. Modules for presurvey flight-line definition, flight-path plotting, lidar raster and waveform investigation, and digital camera image playback have been developed. Processing algorithms have been developed to extract the range to the first and last significant return within each waveform. ALPS is used

  2. ATM Coastal Topography-Texas, 2001: UTM Zone 15

    USGS Publications Warehouse

    Klipp, Emily S.; Nayegandhi, Amar; Brock, John C.; Sallenger, A.H.; Bonisteel, Jamie M.; Yates, Xan; Wright, C. Wayne

    2009-01-01

    These remotely sensed, geographically referenced elevation measurements of lidar-derived first-surface (FS) topography were produced collaboratively by the U.S. Geological Survey (USGS), Florida Integrated Science Center (FISC), St. Petersburg, FL, and the National Aeronautics and Space Administration (NASA), Wallops Flight Facility, VA. This project provides highly detailed and accurate datasets of a portion of the Texas coastline within UTM zone 15, from Matagorda Peninsula to Galveston Island, acquired October 12-13, 2001. The datasets are made available for use as a management tool to research scientists and natural-resource managers. An innovative scanning lidar instrument originally developed by NASA, and known as the Airborne Topographic Mapper (ATM), was used during data acquisition. The ATM system is a scanning lidar system that measures high-resolution topography of the land surface and incorporates a green-wavelength laser operating at pulse rates of 2 to 10 kilohertz. Measurements from the laser-ranging device are coupled with data acquired from inertial navigation system (INS) attitude sensors and differentially corrected global positioning system (GPS) receivers to measure topography of the surface at accuracies of +/-15 centimeters. The nominal ATM platform is a Twin Otter or P-3 Orion aircraft, but the instrument may be deployed on a range of light aircraft. Elevation measurements were collected over the survey area using the ATM system, and the resulting data were then processed using the Airborne Lidar Processing System (ALPS), a custom-built processing system developed in a NASA-USGS collaboration. ALPS supports the exploration and processing of lidar data in an interactive or batch mode. Modules for presurvey flight-line definition, flight-path plotting, lidar raster and waveform investigation, and digital camera image playback have been developed. Processing algorithms have been developed to extract the range to the first and last significant

  3. ATM Coastal Topography-Florida 2001: Eastern Panhandle

    USGS Publications Warehouse

    Yates, Xan; Nayegandhi, Amar; Brock, John C.; Sallenger, A.H.; Bonisteel, Jamie M.; Klipp, Emily S.; Wright, C. Wayne

    2009-01-01

    These remotely sensed, geographically referenced elevation measurements of Lidar-derived first surface (FS) topography were produced collaboratively by the U.S. Geological Survey (USGS), Florida Integrated Science Center (FISC), St. Petersburg, FL, and the National Aeronautics and Space Administration (NASA), Wallops Flight Facility, VA. This project provides highly detailed and accurate datasets of the eastern Florida panhandle coastline, acquired October 2, 2001. The datasets are made available for use as a management tool to research scientists and natural resource managers. An innovative scanning Lidar instrument originally developed by NASA, and known as the Airborne Topographic Mapper (ATM), was used during data acquisition. The ATM system is a scanning Lidar system that measures high-resolution topography of the land surface and incorporates a green-wavelength laser operating at pulse rates of 2 to 10 kilohertz. Measurements from the laser-ranging device are coupled with data acquired from inertial navigation system (INS) attitude sensors and differentially corrected global positioning system (GPS) receivers to measure topography of the surface at accuracies of +/-15 centimeters. The nominal ATM platform is a Twin Otter or P-3 Orion aircraft, but the instrument may be deployed on a range of light aircraft. Elevation measurements were collected over the survey area using the ATM system, and the resulting data were then processed using the Airborne Lidar Processing System (ALPS), a custom-built processing system developed in a NASA-USGS collaboration. ALPS supports the exploration and processing of Lidar data in an interactive or batch mode. Modules for presurvey flight line definition, flight path plotting, Lidar raster and waveform investigation, and digital camera image playback have been developed. Processing algorithms have been developed to extract the range to the first and last significant return within each waveform. ALPS is routinely used to create

  4. ATM Coastal Topography-Florida 2001: Western Panhandle

    USGS Publications Warehouse

    Yates, Xan; Nayegandhi, Amar; Brock, John C.; Sallenger, A.H.; Bonisteel, Jamie M.; Klipp, Emily S.; Wright, C. Wayne

    2009-01-01

    These remotely sensed, geographically referenced elevation measurements of Lidar-derived first surface (FS) topography were produced collaboratively by the U.S. Geological Survey (USGS), Florida Integrated Science Center (FISC), St. Petersburg, FL, and the National Aeronautics and Space Administration (NASA), Wallops Flight Facility, VA. This project provides highly detailed and accurate datasets of the western Florida panhandle coastline, acquired October 2-4 and 7-10, 2001. The datasets are made available for use as a management tool to research scientists and natural resource managers. An innovative scanning Lidar instrument originally developed by NASA, and known as the Airborne Topographic Mapper (ATM), was used during data acquisition. The ATM system is a scanning Lidar system that measures high-resolution topography of the land surface and incorporates a green-wavelength laser operating at pulse rates of 2 to 10 kilohertz. Measurements from the laser-ranging device are coupled with data acquired from inertial navigation system (INS) attitude sensors and differentially corrected global positioning system (GPS) receivers to measure topography of the surface at accuracies of +/-15 centimeters. The nominal ATM platform is a Twin Otter or P-3 Orion aircraft, but the instrument may be deployed on a range of light aircraft. Elevation measurements were collected over the survey area using the ATM system, and the resulting data were then processed using the Airborne Lidar Processing System (ALPS), a custom-built processing system developed in a NASA-USGS collaboration. ALPS supports the exploration and processing of Lidar data in an interactive or batch mode. Modules for presurvey flight line definition, flight path plotting, Lidar raster and waveform investigation, and digital camera image playback have been developed. Processing algorithms have been developed to extract the range to the first and last significant return within each waveform. ALPS is routinely used

  5. The effect of algorithm-agile encryption on ATM quality of service

    SciTech Connect

    Sholander, P.; Tarman, T.; Pierson, L.

    1997-04-01

    Asynchronous Transfer Mode (ATM) users often open multiple ATM Virtual Circuits (VCs) to multiple ATM users on multiple ATM networks. Each network and user may implement a different encryption policy. Hence ATM users may need shared, flexible hardware-based 3encryption that supports multiple encryption algorithms for multiple concurrent ATM users and VCs. An algorithm-agile encryption architecture, that uses multiple, parallel encryption-pipelines, is proposed. That algorithm-agile encryptor`s effect on the ATM Quality of Service (QoS) metrics, such as Cell Transfer Delay (CTD) and Cell Delay Variation (CDV), is analyzed. Bounds on the maximum CDV and the CDV`s probability density are derived.

  6. RUG3 and ATM synergistically regulate the alternative splicing of mitochondrial nad2 and the DNA damage response in Arabidopsis thaliana.

    PubMed

    Su, Chao; Zhao, Hongtao; Zhao, Yankun; Ji, Hongtao; Wang, Youning; Zhi, Liya; Li, Xia

    2017-03-06

    The root apical meristem (RAM) determines both RAM activity and the growth of roots. Plant roots are constantly exposed to adverse environmental stresses that can cause DNA damage or cell cycle arrest in the RAM; however, the mechanism linking root meristematic activity and RAM size to the DNA damage response (DDR) is unclear. Here, we demonstrate that a loss of function in RCC1/UVR8/GEF-Like 3 (RUG3) substantially augmented the DDR and produced a cell cycle arrest in the RAM in rug3 mutant, leading to root growth retardation. Furthermore, the mutation of RUG3 caused increased intracellular reactive oxygen species (ROS) levels, and ROS scavengers improved the observed cell cycle arrest and reduced RAM activity level in rug3 plants. Most importantly, we detected a physical interaction between RUG3 and ataxia telangiectasia mutated (ATM), a key regulator of the DDR, suggesting that they synergistically modulated the alternative splicing of nad2. Our findings reveal a novel synergistic effect of RUG3 and ATM on the regulation of mitochondrial function, redox homeostasis, and the DDR in the RAM, and outline a protective mechanism for DNA damage repair and the restoration of mitochondrial function that involves RUG3-mediated mitochondrial retrograde signaling and the activation of an ATM-mediated DDR pathway.

  7. RUG3 and ATM synergistically regulate the alternative splicing of mitochondrial nad2 and the DNA damage response in Arabidopsis thaliana

    PubMed Central

    Su, Chao; Zhao, Hongtao; Zhao, Yankun; Ji, Hongtao; Wang, Youning; Zhi, Liya; Li, Xia

    2017-01-01

    The root apical meristem (RAM) determines both RAM activity and the growth of roots. Plant roots are constantly exposed to adverse environmental stresses that can cause DNA damage or cell cycle arrest in the RAM; however, the mechanism linking root meristematic activity and RAM size to the DNA damage response (DDR) is unclear. Here, we demonstrate that a loss of function in RCC1/UVR8/GEF-Like 3 (RUG3) substantially augmented the DDR and produced a cell cycle arrest in the RAM in rug3 mutant, leading to root growth retardation. Furthermore, the mutation of RUG3 caused increased intracellular reactive oxygen species (ROS) levels, and ROS scavengers improved the observed cell cycle arrest and reduced RAM activity level in rug3 plants. Most importantly, we detected a physical interaction between RUG3 and ataxia telangiectasia mutated (ATM), a key regulator of the DDR, suggesting that they synergistically modulated the alternative splicing of nad2. Our findings reveal a novel synergistic effect of RUG3 and ATM on the regulation of mitochondrial function, redox homeostasis, and the DDR in the RAM, and outline a protective mechanism for DNA damage repair and the restoration of mitochondrial function that involves RUG3-mediated mitochondrial retrograde signaling and the activation of an ATM-mediated DDR pathway. PMID:28262819

  8. HealthATM: personal health cyberinfrastructure for underserved populations.

    PubMed

    Botts, Nathan E; Horan, Thomas A; Thoms, Brian P

    2011-05-01

    There is an opportunity for personal health record (PHR) systems to play a vital role in fostering health self-management within underserved populations. If properly designed and promoted, it is possible that patients will use PHRs to become more empowered in taking an active role toward managing their health needs. This research examines the potential of a cyberinfrastructure-based PHR to encourage patient activation in health care, while also having population health implications. A multi-phased, iterative research approach was used to design and evaluate a PHR system called HealthATM, which utilizes services from a cloud computing environment. These services were integrated into an ATM-style interface aimed at providing a broad range of health consumers with the ability to manage health conditions and encourage accomplishment of health goals. Evaluation of the PHR included 115 patients who were clients of several free clinics in Los Angeles County. The majority of patients perceived ease of use (74%) and confidence (73%) in using the HealthATM system, and thought they would like to use it frequently (73%). Patients also indicated a belief in being responsible for their own health. However, fewer felt as though they were able to maintain necessary life changes to improve their health. Findings from the field tests suggest that PHRs can be a beneficial health management tool for underserved populations. In order for these types of tools to be effective within safety-net communities, they must be technically accessible and provide meaningful opportunities to increase patient engagement in their health care. Copyright © 2011. Published by Elsevier Inc.

  9. Reaction test revealed impaired performance at 6.0 atm abs but not at 1.9 atm abs in professional divers.

    PubMed

    Tikkinen, Janne; Parkkola, Kai; Siimes, Martti A

    2013-01-01

    In order to evaluate the effects of ambient pressure on reaction and movement times we investigated 60 professional divers by a computerized test (Reaction Test). The experiments were carried out four times in a hyperbaric chamber: prior to pressure, at 6.0 and 1.9 atm abs and after decompression. Reaction time varied from 202 to 443 milliseconds (275 +/- 42 ms), but the individual levels remained similar. The reaction time increased between precompression and 6.0 atm abs (p < 0.05), decreased between 6.0 and 1.9 atm abs (p < 0.05) and remained at the original level at 1.9 and 1.0 atm abs after decompression. Ten divers had an increase of more than 1SD in the reaction time at 6.0 atm abs. The number of mistakes was small and not influenced by elevation of pressure. Further, the movement time remained unchanged throughout the experiment. We conclude that the response time increases due to ambient pressure and the increase in simple reaction time is detectable in professional divers at 6.0 atm not at 1.9 atm abs. At the same time accuracy stays constant. We speculate that our findings are caused by nitrogen narcosis in some divers.

  10. Design Issues for Traffic Management for the ATM UBR + Service for TCP Over Satellite Networks

    NASA Technical Reports Server (NTRS)

    Jain, Raj

    1999-01-01

    This project was a comprehensive research program for developing techniques for improving the performance of Internet protocols over Asynchronous Transfer Mode (ATM) based satellite networks. Among the service categories provided by ATM networks, the most commonly used category for data traffic is the unspecified bit rate (UBR) service. UBR allows sources to send data into the network without any feedback control. The project resulted in the numerous ATM Forum contributions and papers.

  11. Achieving High Throughput for Data Transfer over ATM Networks

    NASA Technical Reports Server (NTRS)

    Johnson, Marjory J.; Townsend, Jeffrey N.

    1996-01-01

    File-transfer rates for ftp are often reported to be relatively slow, compared to the raw bandwidth available in emerging gigabit networks. While a major bottleneck is disk I/O, protocol issues impact performance as well. Ftp was developed and optimized for use over the TCP/IP protocol stack of the Internet. However, TCP has been shown to run inefficiently over ATM. In an effort to maximize network throughput, data-transfer protocols can be developed to run over UDP or directly over IP, rather than over TCP. If error-free transmission is required, techniques for achieving reliable transmission can be included as part of the transfer protocol. However, selected image-processing applications can tolerate a low level of errors in images that are transmitted over a network. In this paper we report on experimental work to develop a high-throughput protocol for unreliable data transfer over ATM networks. We attempt to maximize throughput by keeping the communications pipe full, but still keep packet loss under five percent. We use the Bay Area Gigabit Network Testbed as our experimental platform.

  12. Future ATM Concepts Evaluation Tool (FACET) Interface Control Document

    NASA Technical Reports Server (NTRS)

    Grabbe, Shon R.

    2017-01-01

    This Interface Control Document (ICD) documents the airspace adaptation and air traffic inputs of NASA's Future ATM Concepts and Evaluation Tool (FACET). Its intended audience is the project manager, project team, development team, and stakeholders interested in interfacing with the system. FACET equips Air Traffic Management (ATM) researchers and service providers with a way to explore, develop and evaluate advanced air transportation concepts before they are field-tested and eventually deployed. FACET is a flexible software tool that is capable of quickly generating and analyzing thousands of aircraft trajectories. It provides researchers with a simulation environment for preliminary testing of advanced ATM concepts. Using aircraft performance profiles, airspace models, weather data, and flight schedules, the tool models trajectories for the climb, cruise, and descent phases of flight for each type of aircraft. An advanced graphical interface displays traffic patterns in two and three dimensions, under various current and projected conditions for specific airspace regions or over the entire continental United States. The system is able to simulate a full day's dynamic national airspace system (NAS) operations, model system uncertainty, measure the impact of different decision-makers in the NAS, and provide analysis of the results in graphical form, including sector, airport, fix, and airway usage statistics. NASA researchers test and analyze the system-wide impact of new traffic flow management algorithms under anticipated air traffic growth projections on the nation's air traffic system. In addition to modeling the airspace system for NASA research, FACET has also successfully transitioned into a valuable tool for operational use. Federal Aviation Administration (FAA) traffic flow managers and commercial airline dispatchers have used FACET technology for real-time operations planning. FACET integrates live air traffic data from FAA radar systems and weather data

  13. ATM Quality of Service Parameters at 45 Mbps Using a Satellite Emulator: Laboratory Measurements

    NASA Technical Reports Server (NTRS)

    Ivancic, William D.; Bobinsky, Eric A.

    1997-01-01

    Results of 45-Mbps DS3 intermediate-frequency loopback measurements of asynchronous transfer mode (ATM) quality of service parameters (cell error ratio and cell loss ratio) are presented. These tests, which were conducted at the NASA Lewis Research Center in support of satellite-ATM interoperability research, represent initial efforts to quantify the minimum parameters for stringent ATM applications, such as MPEG-1 and MPEG-2 video transmission. Portions of these results were originally presented to the International Telecommunications Union's ITU-R Working Party 4B in February 1996 in support of their Draft Preliminary Recommendation on the Transmission of ATM Traffic via Satellite.

  14. A Novel ATM/TP53/p21-Mediated Checkpoint Only Activated by Chronic γ-Irradiation

    PubMed Central

    Sasatani, Megumi; Iizuka, Daisuke; Masuda, Yuji; Inaba, Toshiya; Suzuki, Keiji; Ootsuyama, Akira; Umata, Toshiyuki; Kamiya, Kenji; Suzuki, Fumio

    2014-01-01

    Different levels or types of DNA damage activate distinct signaling pathways that elicit various cellular responses, including cell-cycle arrest, DNA repair, senescence, and apoptosis. Whereas a range of DNA-damage responses have been characterized, mechanisms underlying subsequent cell-fate decision remain elusive. Here we exposed cultured cells and mice to different doses and dose rates of γ-irradiation, which revealed cell-type-specific sensitivities to chronic, but not acute, γ-irradiation. Among tested cell types, human fibroblasts were associated with the highest levels of growth inhibition in response to chronic γ-irradiation. In this context, fibroblasts exhibited a reversible G1 cell-cycle arrest or an irreversible senescence-like growth arrest, depending on the irradiation dose rate or the rate of DNA damage. Remarkably, when the same dose of γ-irradiation was delivered chronically or acutely, chronic delivery induced considerably more cellular senescence. A similar effect was observed with primary cells isolated from irradiated mice. We demonstrate a critical role for the ataxia telangiectasia mutated (ATM)/tumor protein p53 (TP53)/p21 pathway in regulating DNA-damage-associated cell fate. Indeed, blocking the ATM/TP53/p21 pathway deregulated DNA damage responses, leading to micronucleus formation in chronically irradiated cells. Together these results provide insights into the mechanisms governing cell-fate determination in response to different rates of DNA damage. PMID:25093836

  15. Huntingtin is a scaffolding protein in the ATM oxidative DNA damage response complex.

    PubMed

    Maiuri, Tamara; Mocle, Andrew J; Hung, Claudia L; Xia, Jianrun; van Roon-Mom, Willeke M C; Truant, Ray

    2017-01-15

    Huntington's disease (HD) is an age-dependent neurodegenerative disease. DNA repair pathways have recently been implicated as the most predominant modifiers of age of onset in HD patients. We report that endogenous huntingtin protein directly participates in oxidative DNA damage repair. Using novel chromobodies to detect endogenous human huntingtin in live cells, we show that localization of huntingtin to DNA damage sites is dependent on the kinase activity of ataxia telangiectasia mutated (ATM) protein. Super-resolution microscopy and biochemical assays revealed that huntingtin co-localizes with and scaffolds proteins of the DNA damage response pathway in response to oxidative stress. In HD patient fibroblasts bearing typical clinical HD allele lengths, we demonstrate that there is deficient oxidative DNA damage repair. We propose that DNA damage in HD is caused by dysfunction of the mutant huntingtin protein in DNA repair, and accumulation of DNA oxidative lesions due to elevated reactive oxygen species may contribute to the onset of HD. © The Author 2016. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oup.com.

  16. A mathematical model for the detection mechanism of DNA double-strand breaks depending on autophosphorylation of ATM.

    PubMed

    Mouri, Kazunari; Nacher, Jose C; Akutsu, Tatsuya

    2009-01-01

    After IR stress, DNA double-strand breaks (DSBs) occur and repair proteins (RPs) bind to them, generating DSB-RP complexes (DSBCs), which results in repaired DSBs (RDSBs). In recent experimental studies, it is suggested that the ATM proteins detect these DNA lesions depending on the autophosphorylation of ATM which exists as a dimer before phosphorylation. Interestingly, the ATM proteins can work as a sensor for a small number of DSBs (approximately 18 DSBs in a cell after exposure to IR). Thus the ATM proteins amplify the small input signals based on the phosphorylation of the ATM dimer proteins. The true DSB-detection mechanism depending on ATM autophosphorylation has yet to be clarified. We propose a mathematical model for the detection mechanism of DSBs by ATM. Our model includes both a DSB-repair mechanism and an ATM-phosphorylation mechanism. We model the former mechanism as a stochastic process, and obtain theoretical mean values of DSBs and DSBCs. In the latter mechanism, it is known that ATM autophosphorylates itself, and we find that the autophosphorylation induces bifurcation of the phosphorylated ATM (ATM*). The bifurcation diagram depends on the total concentration of ATM, which makes three types of steady state diagrams of ATM*: monostable, reversible bistable, and irreversible bistable. Bistability exists depending on the Hill coefficient in the equation of ATM autophosphorylation, and it emerges as the total concentration of ATM increases. Combining these two mechanisms, we find that ATM* exhibits switch-like behaviour in the presence of bistability, and the detection time after DNA damage decreases when the total concentration of ATM increases. This work provides a mathematical model that explains the DSB-detection mechanism depending on ATM autophosphorylation. These results indicate that positive auto-regulation works both as a sensor and amplifier of small input signals.

  17. Apigenin induces DNA damage through the PKCδ-dependent activation of ATM and H2AX causing down-regulation of genes involved in cell cycle control and DNA repair

    PubMed Central

    Arango, Daniel; Parihar, Arti; Villamena, Frederick A.; Wang, Liwen; Freitas, Michael A.; Grotewold, Erich; Doseff, Andrea I.

    2014-01-01

    Apigenin, an abundant plant flavonoid, exhibits anti-proliferative and anti-carcinogenic activities through mechanisms yet not fully defined. In the present study, we show that the treatment of leukemia cells with apigenin resulted in the induction of DNA damage preceding the activation of the apoptotic program. Apigenin-induced DNA damage was mediated by p38 and protein kinase C-delta (PKCδ), yet was independent of reactive oxygen species or caspase activity. Treatment of monocytic leukemia cells with apigenin induced the phosphorylation of the ataxia-telangiectasia mutated (ATM) kinase and histone H2AX, two key regulators of the DNA damage response, without affecting the ataxia-telangiectasia mutated and Rad-3-related (ATR) kinase. Silencing and pharmacological inhibition of PKCδ abrogated ATM and H2AX phosphorylation, whereas inhibition of p38 reduced H2AX phosphorylation independently of ATM. We established that apigenin delayed cell cycle progression at G1/S and increased the number of apoptotic cells. In addition, genome-wide mRNA analyses showed that apigenin-induced DNA damage led to down-regulation of genes involved in cell-cycle control and DNA repair. Taken together, the present results show that the PKCδ-dependent activation of ATM and H2AX define the signaling networks responsible for the regulation of DNA damage promoting genome-wide mRNA alterations that result in cell cycle arrest, hence contributing to the anti-carcinogenic activities of this flavonoid. PMID:22985621

  18. Fragments of ATM which have dominant-negative or complementing activity.

    PubMed Central

    Morgan, S E; Lovly, C; Pandita, T K; Shiloh, Y; Kastan, M B

    1997-01-01

    The ATM protein has been implicated in pathways controlling cell cycle checkpoints, radiosensitivity, genetic instability, and aging. Expression of ATM fragments containing a leucine zipper motif in a human tumor cell line abrogated the S-phase checkpoint after ionizing irradiation and enhanced radiosensitivity and chromosomal breakage. These fragments did not abrogate irradiation-induced G1 or G2 checkpoints, suggesting that cell cycle checkpoint defects alone cannot account for chromosomal instability in ataxia telangiectasia (AT) cells. Expression of the carboxy-terminal portion of ATM, which contains the PI-3 kinase domain, complemented radiosensitivity and the S-phase checkpoint and reduced chromosomal breakage after irradiation in AT cells. These observations suggest that ATM function is dependent on interactions with itself or other proteins through the leucine zipper region and that the PI-3 kinase domain contains much of the significant activity of ATM. PMID:9121450

  19. The Relationships Between Selected Organizational Variables and ATM Technology Adoption in Campus Networking

    NASA Astrophysics Data System (ADS)

    Yao, Engui

    1998-06-01

    ATM (Asynchronous Transfer Mode) is an emerging technology in computer networking, which, in turn, is the physical media of information systems and networking/telecommunication systems. The technology provides potentiality for universities to build their networks based on the future vision of uniting voice, data, and video communications on ATM-technology-based equipment. A review of the literature revealed that minimal evidence exists to indicate whether the size, type, financial factors, and information processing maturity of a university affect a university's high-tech innovation adoptions. No research of this nature has been undertaken in the study of ATM adoption in any institutions of higher learning, nor has any research of this nature been found in other organizations, either. Such evidence is needed by university administrators, information systems managers, and LAN managers to understand their universities better, whether they have or have not adopted ATM, and to evaluate their current administrative, academic, and financial situations and current campus networking situations. The purpose of this study was to determine the relationships between ATM adoption and four organizational variables: university size, type, finances, and information processing maturity. Another purpose of the study was to identify the current status of ATM adoption in campus networking in the United States. Logistic regression was used as the statistical data analysis method. The results of the study provided evidence to show that ATM adoption in campus networking is significantly related to university size, university type, university finances, and university information processing maturity.

  20. Anomalous preservation of pure methane hydrate at 1 atm

    USGS Publications Warehouse

    Stern, L.A.; Circone, S.; Kirby, S.H.; Durham, W.B.

    2001-01-01

    Direct measurement of decomposition rates of pure, polycrystalline methane hydrate reveals a thermal regime where methane hydrate metastably `preserves' in bulk by as much as 75 K above its nominal equilibrium temperature (193 K at 1 atm). Rapid release of the sample pore pressure at isothermal conditions between 242 and 271 K preserves up to 93% of the hydrate for at least 24 h, reflecting the greatly suppressed rates of dissociation that characterize this regime. Subsequent warming through the H2O ice point then induces rapid and complete dissociation, allowing controlled recovery of the total expected gas yield. This behavior is in marked contrast to that exhibited by methane hydrate at both colder (193-240 K) and warmer (272-290 K) test conditions, where dissociation rates increase monotonically with increasing temperature. Anomalous preservation has potential application for successful retrieval of natural gas hydrate or hydrate-bearing sediments from remote settings, as well as for temporary low-pressure transport and storage of natural gas.

  1. Video transmission on ATM networks. Ph.D. Thesis

    NASA Technical Reports Server (NTRS)

    Chen, Yun-Chung

    1993-01-01

    The broadband integrated services digital network (B-ISDN) is expected to provide high-speed and flexible multimedia applications. Multimedia includes data, graphics, image, voice, and video. Asynchronous transfer mode (ATM) is the adopted transport techniques for B-ISDN and has the potential for providing a more efficient and integrated environment for multimedia. It is believed that most broadband applications will make heavy use of visual information. The prospect of wide spread use of image and video communication has led to interest in coding algorithms for reducing bandwidth requirements and improving image quality. The major results of a study on the bridging of network transmission performance and video coding are: Using two representative video sequences, several video source models are developed. The fitness of these models are validated through the use of statistical tests and network queuing performance. A dual leaky bucket algorithm is proposed as an effective network policing function. The concept of the dual leaky bucket algorithm can be applied to a prioritized coding approach to achieve transmission efficiency. A mapping of the performance/control parameters at the network level into equivalent parameters at the video coding level is developed. Based on that, a complete set of principles for the design of video codecs for network transmission is proposed.

  2. NASA's ATM Technology Demonstration-1: Integrated Concept of Arrival Operations

    NASA Technical Reports Server (NTRS)

    Baxley, Brian T.; Swenson, Harry N.; Prevot, Thomas; Callantine, Todd J.

    2012-01-01

    This paper describes operations and procedures envisioned for NASA s Air Traffic Management (ATM) Technology Demonstration #1 (ATD-1). The ATD-1 Concept of Operations (ConOps) demonstration will integrate three NASA technologies to achieve high throughput, fuel-efficient arrival operations into busy terminal airspace. They are Traffic Management Advisor with Terminal Metering (TMA-TM) for precise time-based schedules to the runway and points within the terminal area, Controller-Managed Spacing (CMS) decision support tools for terminal controllers to better manage aircraft delay using speed control, and Flight deck Interval Management (FIM) avionics and flight crew procedures to conduct airborne spacing operations. The ATD-1 concept provides de-conflicted and efficient operations of multiple arrival streams of aircraft, passing through multiple merge points, from top-of-descent (TOD) to touchdown. It also enables aircraft to conduct Optimized Profile Descents (OPDs) from en route altitude to the runway, using primarily speed control to maintain separation and schedule. The ATD-1 project is currently addressing the challenges of integrating the three technologies, and implantation into an operational environment. Goals of the ATD-1 demonstration include increasing the throughput of high-density airports, reducing controller workload, increasing efficiency of arrival operations and the frequency of trajectory-based operations, and promoting aircraft ADS-B equipage.

  3. Reliable medical imaging transmission for PACS over ATM networks

    NASA Astrophysics Data System (ADS)

    Wei, Wang; Subramanian, K. R.; Zhang, Liren

    2000-05-01

    In an ATM (Asynchronous Transfer Mode)-based PAC system, cell losses during the transmission might cause degradation on the quality of medical images. This in turn will affect the accuracy of the diagnosis. A three-step scheme to minimize the effect of cell losses on the quality of medical images is proposed in this paper. The first step is related to the medical imaging coding before it enters the network, in which, ROIs (Regions of Interest) of the medical imaging which are crucial to diagnosis are kept non-compressed and packetized with pixel-level inter-leaving. Non-compression can make the data of ROIs to be more robust to cell losses than any compression algorithms, while pixel-level inter-leaving is strong for bursty cell losses recovery combined with FEC (Forward Error Correction) at the receiver. The background part of the medical imaging will be compressed using fractal algorithm, which can get very high compression ratio to balance the large amount data of the ROIs. In the second step, the ROIs will be allocated the highest priority during transmission. While in the third step, FEC will be used to minimize the existed cell losses at the receiver. The balance and optimal of these three stages are discussed from the system-level point of view.

  4. Exonuclease mutations in DNA polymerase epsilon reveal replication strand specific mutation patterns and human origins of replication

    PubMed Central

    Shinbrot, Eve; Henninger, Erin E.; Weinhold, Nils; Covington, Kyle R.; Göksenin, A. Yasemin; Schultz, Nikolaus; Chao, Hsu; Doddapaneni, HarshaVardhan; Muzny, Donna M.; Gibbs, Richard A.; Sander, Chris; Pursell, Zachary F.

    2014-01-01

    Tumors with somatic mutations in the proofreading exonuclease domain of DNA polymerase epsilon (POLE-exo*) exhibit a novel mutator phenotype, with markedly elevated TCT→TAT and TCG→TTG mutations and overall mutation frequencies often exceeding 100 mutations/Mb. Here, we identify POLE-exo* tumors in numerous cancers and classify them into two groups, A and B, according to their mutational properties. Group A mutants are found only in POLE, whereas Group B mutants are found in POLE and POLD1 and appear to be nonfunctional. In Group A, cell-free polymerase assays confirm that mutations in the exonuclease domain result in high mutation frequencies with a preference for C→A mutation. We describe the patterns of amino acid substitutions caused by POLE-exo* and compare them to other tumor types. The nucleotide preference of POLE-exo* leads to increased frequencies of recurrent nonsense mutations in key tumor suppressors such as TP53, ATM, and PIK3R1. We further demonstrate that strand-specific mutation patterns arise from some of these POLE-exo* mutants during genome duplication. This is the first direct proof of leading strand-specific replication by human POLE, which has only been demonstrated in yeast so far. Taken together, the extremely high mutation frequency and strand specificity of mutations provide a unique identifier of eukaryotic origins of replication. PMID:25228659

  5. ATM QoS Experiments Using TCP Applications: Performance of TCP/IP Over ATM in a Variety of Errored Links

    NASA Technical Reports Server (NTRS)

    Frantz, Brian D.; Ivancic, William D.

    2001-01-01

    Asynchronous Transfer Mode (ATM) Quality of Service (QoS) experiments using the Transmission Control Protocol/Internet Protocol (TCP/IP) were performed for various link delays. The link delay was set to emulate a Wide Area Network (WAN) and a Satellite Link. The purpose of these experiments was to evaluate the ATM QoS requirements for applications that utilize advance TCP/IP protocols implemented with large windows and Selective ACKnowledgements (SACK). The effects of cell error, cell loss, and random bit errors on throughput were reported. The detailed test plan and test results are presented herein.

  6. Dimer monomer transition and dimer re-formation play important role for ATM cellular function during DNA repair

    PubMed Central

    Du, Fengxia; Zhang, Minjie; Li, Xiaohua; Yang, Caiyun; Meng, Hao; Wang, Dong; Chang, Shuang; Xu, Ye; Price, Brendan; Sun, Yingli

    2015-01-01

    The ATM protein kinase, is a serine/threonine protein kinase that is recruited and activated by DNA double-strand breaks, mediates responses to ionizing radiation in mammalian cells. Here we show that ATM is held inactive in unirradiated cells as a dimer and phosphorylates the opposite strand of the dimer in response to DNA damage. Cellular irradiation induces rapid intermolecular autophosphorylation of serine 1981 that causes dimer dissociation and initiates cellular ATM kinase activity. ATM cannot phosphorylate the substrates when it could not undergo dimer monomer transition. After DNA repair, the active monomer will undergo dephosphorylation to form dimer again and dephosphorylation is critical for dimer reformation. Our work reveals novel function of ATM dimer monomer transition and explains why ATM dimer monomer transition plays such important role for ATM cellular activity during DNA repair. PMID:25240135

  7. Early Deployment Of Atms/Atis For Metropolitan Detroit, Final Report

    DOT National Transportation Integrated Search

    1994-09-26

    TECHNOLOGY, ARCHITECTURE, CONTRACTING, AND DEPLOYMENT RECOMMENDATIONS RESULTING FROM THE STUDY ENABLE MDOT TO BEGIN SYSTEM DESIGN AND CONSTRUCTION. HOWEVER, IN ORDER TO DEMONSTRATE THE IMPLEMENTATION METHODS OF NEW ATMS/ATIS COMPONENTS AND SYSTEM ARC...

  8. Michigan Department of Transportation statewide advanced traffic management system (ATMS) procurement evaluation - phase I : software procurement.

    DOT National Transportation Integrated Search

    2009-04-01

    This project evaluates the process that was followed by MDOT and other stakeholders for the acquisition : of new Advanced Traffic Management System (ATMS) software aiming to integrate and facilitate the : management of various Intelligent Transportat...

  9. Gender, academic achievement, and ownership of ATM as predictors of accounting students’ financial literacy

    NASA Astrophysics Data System (ADS)

    Susanti; Hardini, H. T.

    2018-01-01

    This study examined the relationships between GPA, gender, and ownership of ATM on accounting students’ financial literacy (n = 184). Financial literacy was assessed using a paper-and-pencil objective (multiple choice) test measuring general knowledge of finance, income, money management savings, loans, and investment. Gender and GPA data were obtained from the university records. Regression analysis found that GPA and ownership of ATM were associated with financial literacy, but gender was not. Female students with an ownership of ATM and those with a high GPA were found to be superior to males. The implication of this research is that students are expected to increase their GPA and utilize financial facilities in the form of ownership ATM and other financial instruments so as to increase financial literacy. In addition, the need for financial literacy training from related parties to improve financial literacy for students who have low financial literacy.

  10. The Advanced Technology Microwave Sounder (ATMS): A New Operational Sensor Series

    NASA Technical Reports Server (NTRS)

    Kim, Edward; Lyu, Cheng-H Joseph; Leslie, R. Vince; Baker, Neal; Mo, Tsan; Sun, Ninghai; Bi, Li; Anderson, Mike; Landrum, Mike; DeAmici, Giovanni; hide

    2012-01-01

    ATMS is a new satellite microwave sounding sensor designed to provide operational weather agencies with atmospheric temperature and moisture profile information for global weather forecasting and climate applications. ATMS will continue the microwave sounding capabilities first provided by its predecessors, the Microwave Sounding Unit (MSU) and Advanced Microwave Sounding Unit (AMSU). The first ATMS was launched October 28, 2011 on board the Suomi National Polar-orbiting Partnership (S-NPP) satellite. Microwave soundings by themselves are the highest-impact input data used by Numerical Weather Prediction (NWP) models; and ATMS, when combined with the Cross-track Infrared Sounder (CrIS), forms the Cross-track Infrared and Microwave Sounding Suite (CrIMSS). The microwave soundings help meet NWP sounding requirements under cloudy sky conditions and provide key profile information near the surface

  11. Anacardic acid inhibits pancreatic cancer cell growth, and potentiates chemotherapeutic effect by Chmp1A - ATM - p53 signaling pathway.

    PubMed

    Park, Maiyon; Upton, Danielle; Blackmon, Melodie; Dixon, Valerie; Craver, Scott; Neal, Dawn; Perkins, Derek

    2018-02-20

    Pancreatic cancer is one of the leading causes of cancer related death and its incidence has risen steadily. Although anticancer drugs have been developed based on the new molecular findings, the drugs have produced unsatisfactory results due to toxicity and resistance. Thus, a complementary therapeutic intervention is urgently needed for pancreatic cancer patients. The aim of this study was to assess the potential therapeutic effect of Anacardic acid on pancreatic cancer in vitro and elucidate its underlying mechanisms. Human pancreatic cancer cells were treated with Anacardic acid and assessed for the cytotoxic effect using MTT and spheroid formation assays. Using the same methods, the synergy between Anacardic acid and 5-Fluorouracil or Gemcitabine was determined. To elucidate the underlying molecular mechanisms, Western blot analysis and immunocytochemistry were performed on cancer cells treated with Anacardic acid alone or in combination with 5-Fluorouracil or Gemcitabine. Chromatin Modifying Protein 1A (Chmp1A), Ataxia Telangiectasia Mutated (ATM), and p53 were the primary signaling molecules examined. In addition, Chmp1A was silenced with shRNA to examine the necessity of Chmp1A for the anticancer effect of Anacardic acid, 5-Fluorouracil, or Gemcitabine. Anacardic acid induced an anticancer effect in pancreatic cancer cell lines in a dose dependent manner, and increased the cytotoxicity of 5-Fluorouracil or Gemcitabine in MTT cell viability assays. In spheroid formation assays, spheroids formed were smaller in size and in number upon Anacardic acid treatment compared to control. Mechanistically, Anacardic acid exerted its anticancer activity via the activation of Chmp1A, ATM, and p53. Interestingly, 5-Fluorouracil and Gemcitabine also induced an increase in Chmp1A protein level, suggesting that Chmp1A might mediate the cytotoxic action of chemotherapeutics. Silencing experiments indicate that Chmp1A is required for the action of Anacardic acid, but not for 5

  12. Metformin inhibits growth and enhances radiation response of non-small cell lung cancer (NSCLC) through ATM and AMPK

    PubMed Central

    Storozhuk, Y; Hopmans, S N; Sanli, T; Barron, C; Tsiani, E; Cutz, J-C; Pond, G; Wright, J; Singh, G; Tsakiridis, T

    2013-01-01

    Background: We examined the potential of metformin (MET) to enhance non-small cell lung cancer (NSCLC) responses to ionising radiation (IR). Methods: Human NSCLC cells, mouse embryonic fibroblasts from wild-type and AMP-activated kinase (AMPK) α1/2-subunit−/− embryos (AMPKα1/2−/−-MEFs) and NSCLC tumours grafted into Balb/c-nude mice were treated with IR and MET and subjected to proliferation, clonogenic, immunoblotting, cell cycle and apoptosis assays and immunohistochemistry (IHC). Results: Metformin (2.5 μℳ–5 mℳ) inhibited proliferation and radio-sensitised NSCLC cells. Metformin (i) activated the ataxia telengiectasia-mutated (ATM)–AMPK–p53/p21cip1 and inhibited the Akt–mammalian target of rapamycin (mTOR)–eIF4E-binding protein 1 (4EBP1) pathways, (ii) induced G1 cycle arrest and (iii) enhanced apoptosis. ATM inhibition blocked MET and IR activation of AMPK. Non-small cell lung cancer cells with inhibited AMPK and AMPKα1/2−/−-MEFs were resistant to the antiproliferative effects of MET and IR. Metformin or IR inhibited xenograft growth and combined treatment enhanced it further than each treatment alone. Ionising radiation and MET induced (i) sustained activation of ATM–AMPK–p53/p21cip1 and inhibition of Akt–mTOR–4EBP1 pathways in tumours, (ii) reduced expression of angiogenesis and (iii) enhanced expression of apoptosis markers. Conclusion: Clinically achievable MET doses inhibit NSCLC cell and tumour growth and sensitise them to IR. Metformin and IR mediate their action through an ATM–AMPK-dependent pathway. Our results suggest that MET can be a clinically useful adjunct to radiotherapy in NSCLC. PMID:23632475

  13. The ATM kinase restrains joining of both VDJ signal and coding ends1

    PubMed Central

    Meek, Katheryn; Xu, Yao; Bailie, Caleb; Yu, Kefei; Neal, Jessica A.

    2016-01-01

    The evidence that ATM affects resolution of RAG induced DNA double strand breaks (DSBs) is profuse and unequivocal; moreover, it is clear that the RAG complex itself cooperates (in an undetermined way) with ATM to facilitate repair of these DSBs by the classical non-homologous end joining pathway (c-NHEJ). The mechanistic basis for the cooperation between ATM and the RAG complex has not been defined, although proposed models invoke ATM and RAG2’s C-terminus in maintaining the RAG post-cleavage complex (PCC). Here we show that ATM reduces the rate of both coding and signal joining in a robust episomal assay; we suggest that this is the result of increased stability of the PCC. ATM’s ability to inhibit VDJ joining requires its enzymatic activity. The “non-core” C-termini of both RAG1 and RAG2 are also required for ATM’s capacity to limit signal (but not coding) joining. Moreover, potential phosphorylation targets within the C-terminus of RAG2 are also required for ATM’s capacity to limit signal joining. These data suggest a model whereby the RAG signal end complex is stabilized by phosphorylation of RAG2 by ATM. PMID:27574300

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

    NASA Technical Reports Server (NTRS)

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

    2001-01-01

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

  15. Dimer monomer transition and dimer re-formation play important role for ATM cellular function during DNA repair

    SciTech Connect

    Du, Fengxia; Zhang, Minjie; University of Chinese Academy of Sciences, Beijing 100049

    2014-10-03

    Highlights: • ATM phosphorylates the opposite strand of the dimer in response to DNA damage. • The PETPVFRLT box of ATM plays a key role in its dimer dissociation in DNA repair. • The dephosphorylation of ATM is critical for dimer re-formation after DNA repair. - Abstract: The ATM protein kinase, is a serine/threonine protein kinase that is recruited and activated by DNA double-strand breaks, mediates responses to ionizing radiation in mammalian cells. Here we show that ATM is held inactive in unirradiated cells as a dimer and phosphorylates the opposite strand of the dimer in response to DNA damage.more » Cellular irradiation induces rapid intermolecular autophosphorylation of serine 1981 that causes dimer dissociation and initiates cellular ATM kinase activity. ATM cannot phosphorylate the substrates when it could not undergo dimer monomer transition. After DNA repair, the active monomer will undergo dephosphorylation to form dimer again and dephosphorylation is critical for dimer re-formation. Our work reveals novel function of ATM dimer monomer transition and explains why ATM dimer monomer transition plays such important role for ATM cellular activity during DNA repair.« less

  16. Clinic and Functional Analysis of p73R1 Mutations in Prostate Cancer

    DTIC Science & Technology

    2006-02-01

    sequence variants in Marfan syndrome and related connective tissue disorders. Genet Test 1:237-42. Matsuoka S, Huang M, Elledge SJ. 1998. Linkage of ATM... Syndrome (LFS; MIM# 151623), a highly penetrant familial cancer phenotype, usually associated with inherited mutations in TP53 (Bell, et al., 1999...TP53 (Table 1). Mutually exclusive mutations of CHEK2 and TP53 have been reported in patients with Li-Fraumeni syndrome (LFS) and also in patients

  17. Analysis of CrIS-ATMS Data Using an AIRS Science Team Version 6 - Like Retrieval Algorithm

    NASA Technical Reports Server (NTRS)

    Susskind, Joel; Kouvaris, Louis C.

    2013-01-01

    CrIS/ATMS is flying on NPP and is scheduled to fly on JPSS-1. CrIS/ATMS has roughly equivalent capabilities to AIRS/AMSU. The AIRS Science Team Version 6 retrieval algorithm is currently producing very high quality level-3 Climate Data Records (CDR's) that will be critical for understanding climate processes AIRS CDRs should eventually cover the period September 2002 through at least 2020. CrIS/ATMS is the only scheduled follow on to AIRS AMSU. I have been asked by Ramesh Kakar if CrIS/ATMS can be counted on to adequately continue the AIRS/AMSU CDRs beyond 2020, or is something better needed? This research is being done to answer that question. A minimum requirement to obtain a yes answer is that CrIS/ATMS be analyzed using an AIRS Version 6 - like algorithm. NOAA is currently generating CrIS/ATMS products using 2 algorithms: IDPS and NUCAPS

  18. BMI1 attenuates etoposide-induced G2/M checkpoints via reducing ATM activation.

    PubMed

    Wei, F; Ojo, D; Lin, X; Wong, N; He, L; Yan, J; Xu, S; Major, P; Tang, D

    2015-06-04

    The BMI1 protein contributes to stem cell pluripotency and oncogenesis via multiple functions, including its newly identified role in DNA damage response (DDR). Although evidence clearly demonstrates that BMI1 facilitates the repair of double-stranded breaks via homologous recombination (HR), it remains unclear how BMI1 regulates checkpoint activation during DDR. We report here that BMI1 has a role in G2/M checkpoint activation in response to etoposide (ETOP) treatment. Ectopic expression of BMI1 in MCF7 breast cancer and DU145 prostate cancer cells significantly reduced ETOP-induced G2/M arrest. Conversely, knockdown of BMI1 in both lines enhanced the arrest. Consistent with ETOP-induced activation of the G2/M checkpoints via the ATM pathway, overexpression and knockdown of BMI1, respectively, reduced and enhanced ETOP-induced phosphorylation of ATM at serine 1981 (ATM pS1981). Furthermore, the phosphorylation of ATM targets, including γH2AX, threonine 68 (T68) on CHK2 (CHK2 pT68) and serine 15 (S15) on p53 were decreased in overexpression and increased in knockdown BMI1 cells in response to ETOP. In line with the requirement of NBS1 in ATM activation, we were able to show that BMI1 associates with NBS1 and that this interaction altered the binding of NBS1 with ATM. BMI1 consists of a ring finger (RF), helix-turn-helix-turn-helix-turn (HT), proline/serine (PS) domain and two nuclear localization signals (NLS). Although deletion of either RF or HT did not affect the association of BMI1 with NBS1, the individual deletions of PS and one NLS (KRMK) robustly reduced the interaction. Stable expression of these BMI1 mutants decreased ETOP-induced ATM pS1981 and CHK2 pT68, but not ETOP-elicited γH2AX in MCF7 cells. Furthermore, ectopic expression of BMI1 in non-transformed breast epithelial MCF10A cells also compromised ETOP-initiated ATM pS1981 and γH2AX. Taken together, we provide compelling evidence that BMI1 decreases ETOP-induced G2/M checkpoint activation via

  19. Existing and Required Modeling Capabilities for Evaluating ATM Systems and Concepts

    NASA Technical Reports Server (NTRS)

    Odoni, Amedeo R.; Bowman, Jeremy; Delahaye, Daniel; Deyst, John J.; Feron, Eric; Hansman, R. John; Khan, Kashif; Kuchar, James K.; Pujet, Nicolas; Simpson, Robert W.

    1997-01-01

    ATM systems throughout the world are entering a period of major transition and change. The combination of important technological developments and of the globalization of the air transportation industry has necessitated a reexamination of some of the fundamental premises of existing Air Traffic Management (ATM) concepts. New ATM concepts have to be examined, concepts that may place more emphasis on: strategic traffic management; planning and control; partial decentralization of decision-making; and added reliance on the aircraft to carry out strategic ATM plans, with ground controllers confined primarily to a monitoring and supervisory role. 'Free Flight' is a case in point. In order to study, evaluate and validate such new concepts, the ATM community will have to rely heavily on models and computer-based tools/utilities, covering a wide range of issues and metrics related to safety, capacity and efficiency. The state of the art in such modeling support is adequate in some respects, but clearly deficient in others. It is the objective of this study to assist in: (1) assessing the strengths and weaknesses of existing fast-time models and tools for the study of ATM systems and concepts and (2) identifying and prioritizing the requirements for the development of additional modeling capabilities in the near future. A three-stage process has been followed to this purpose: 1. Through the analysis of two case studies involving future ATM system scenarios, as well as through expert assessment, modeling capabilities and supporting tools needed for testing and validating future ATM systems and concepts were identified and described. 2. Existing fast-time ATM models and support tools were reviewed and assessed with regard to the degree to which they offer the capabilities identified under Step 1. 3 . The findings of 1 and 2 were combined to draw conclusions about (1) the best capabilities currently existing, (2) the types of concept testing and validation that can be carried

  20. The association of single nucleotide polymorphism rs189037C>T in ATM gene with coronary artery disease in Chinese Han populations: A case control study.

    PubMed

    Ding, Xiang; He, Yong; Hao, Qiukui; Chen, Shanping; Yang, Ming; Leng, Sean X; Yue, Jirong; Dong, Birong

    2018-01-01

    Accumulated evidence has indicated that ataxia telangiectasia mutated (ATM) is closely related to atherosclerosis and cardiovascular diseases. So we aimed to examine potential association between a gene variant [single nucleotide polymorphisms (SNPs), i.e., rs189037C>T] in the promoter of ATM gene and coronary artery disease (CAD) in Chinese Han populations.In this hospital-based case-control study, a total of 1308 participants were divided into CAD group (652 patients) and control group (656 subjects) after performing coronary angiography. The SNP rs189037 was genotyped by using polymerase chain reaction-restriction fragment length polymorphism.The distribution of rs189037 genotypes and alleles showed a significant difference between CAD and control subjects (genotypes: P = .032; alleles: P = .028). The percentage of the TT genotype is much higher in control group than that in CAD group (22.0% vs 16.3%, P = .009). After adjustment of the major confounding factors, such difference remained significant (OR = 0.62, 95% CI = 0.43-0.89, P = .010). After analyzing data from different groups divided by genders and smoking status respectively, we found that the protective effect of TT genotype on CAD was significant in males (P = .007) and smokers (P = .031). The difference remained statistically significant after multivariate adjustment (adjusted in males: OR = 0.60, 95% CI = 0.38-0.93, P = .022; adjusted in smokers: OR = 0.47, 95% CI = 0.27-0.81, P = .006).Our study suggests that ATM rs189037 polymorphism is associated with CAD in Chinese Han populations. The TT genotype of rs189037 seems to be associated with a lower risk of CAD and a protective genetic marker of CAD, especially in males and smokers.

  1. Pentose phosphate pathway activation via HSP27 phosphorylation by ATM kinase: A putative endogenous antioxidant defense mechanism during cerebral ischemia-reperfusion.

    PubMed

    Yamamoto, Yusuke; Hosoda, Kohkichi; Imahori, Taichiro; Tanaka, Jun; Matsuo, Kazuya; Nakai, Tomoaki; Irino, Yasuhiro; Shinohara, Masakazu; Sato, Naoko; Sasayama, Takashi; Tanaka, Kazuhiro; Nagashima, Hiroaki; Kohta, Masaaki; Kohmura, Eiji

    2018-05-15

    Molecular mechanism underlying ischemic stroke remains poorly understood. We previously reported glucose 6-phosphate dehydrogenase (G6PD) activity in pentose phosphate pathway (PPP) is activated via heat shock protein 27 (HSP27) phosphorylation at serine 85 (S85) by ataxia telangiectasia mutated (ATM) kinase during cerebral ischemia. This mechanism seems to be endogenous antioxidative system. To determine whether this system also works during reperfusion, we performed comparative metabolic analysis of reperfusion effect on metabolism in rat cortex using middle cerebral artery occlusion (MCAO). Metabolic profiling using gas-chromatography/mass-spectrometry analysis showed changes in metabolic state that depended on reperfusion time. Enrichment analysis showed PPP was significantly upregulated during ischemia-reperfusion. Significant increases in fructose 6-phosphate and ribulose 5-phosphate after reperfusion also suggested enhancement of PPP. In relation to PPP, ischemia-reperfusion induced an increase of up to 69-fold in HSP27 transcripts after 24-h reperfusion. Immunoblotting showed gradual increase in HSP27 protein and marked increase in HSP27 phosphorylation (S85) that were time-dependent (4.5-fold after 24-h reperfusion). G6PD activity was significantly elevated after 1-h MCAO (20%), reduced after 1-h reperfusion, increased gradually thereafter and significantly elevated after 24-h reperfusion. The NADPH/NAD + ratio displayed similar increasing pattern. Intracerebroventricular injection of ATM kinase inhibitor (KU-55933) significantly reduced HSP27 phosphorylation and G6PD activity, significantly increased protein carbonyl, and resulted in increase in infarct size (100%) 24-h after reperfusion following 90-min MCAO. Consequently, G6PD activation via HSP27 phosphorylation by ATM kinase may be part of endogenous antioxidant defense neuroprotection mechanism that is activated during ischemia-reperfusion. These findings have important implications for treatment of

  2. The association of single nucleotide polymorphism rs189037C>T in ATM gene with coronary artery disease in Chinese Han populations

    PubMed Central

    Ding, Xiang; He, Yong; Hao, Qiukui; Chen, Shanping; Yang, Ming; Leng, Sean X.; Yue, Jirong; Dong, Birong

    2018-01-01

    Abstract Accumulated evidence has indicated that ataxia telangiectasia mutated (ATM) is closely related to atherosclerosis and cardiovascular diseases. So we aimed to examine potential association between a gene variant [single nucleotide polymorphisms (SNPs), i.e., rs189037C>T] in the promoter of ATM gene and coronary artery disease (CAD) in Chinese Han populations. In this hospital-based case–control study, a total of 1308 participants were divided into CAD group (652 patients) and control group (656 subjects) after performing coronary angiography. The SNP rs189037 was genotyped by using polymerase chain reaction-restriction fragment length polymorphism. The distribution of rs189037 genotypes and alleles showed a significant difference between CAD and control subjects (genotypes: P = .032; alleles: P = .028). The percentage of the TT genotype is much higher in control group than that in CAD group (22.0% vs 16.3%, P = .009). After adjustment of the major confounding factors, such difference remained significant (OR = 0.62, 95% CI = 0.43–0.89, P = .010). After analyzing data from different groups divided by genders and smoking status respectively, we found that the protective effect of TT genotype on CAD was significant in males (P = .007) and smokers (P = .031). The difference remained statistically significant after multivariate adjustment (adjusted in males: OR = 0.60, 95% CI = 0.38–0.93, P = .022; adjusted in smokers: OR = 0.47, 95% CI = 0.27–0.81, P = .006). Our study suggests that ATM rs189037 polymorphism is associated with CAD in Chinese Han populations. The TT genotype of rs189037 seems to be associated with a lower risk of CAD and a protective genetic marker of CAD, especially in males and smokers. PMID:29369221

  3. Striping noise mitigation in ATMS brightness temperatures and its impact on cloud LWP retrievals

    NASA Astrophysics Data System (ADS)

    Ma, Yuan; Zou, Xiaolei

    2015-07-01

    Advanced Technology Microwave Sounder (ATMS) on board Suomi National Polar-orbiting Partnership (NPP) satellite provides global distributions of microwave brightness temperature measurements at 22 temperature and humidity sounding channels twice daily. However, the differences between observations and brightness temperature simulations exhibit a systematic along-track striping noise for all channels. In this study, a set of 22 "optimal" filters is designed to remove the striping noise in different channels. It is shown that the original method for ATMS striping noise mitigation developed by Qin et al. can be simplified and made suitable for use in an operational context. Impacts of striping noise mitigation on small-scale weather features are investigated by comparing ATMS cloud liquid water path (LWP) retrieved before and after striping noise mitigation. It is shown that the optimal filters do not affect small-scale cloud features while smoothing out striping noise in brightness temperatures. It is also shown that the striping noise is present in the LWP retrievals if the striping noise in brightness temperatures of ATMS channels 1 and 2 is not removed. The amplitude of the striping noise in LWP is linearly related to the magnitude of striping noise in ATMS brightness temperature observations.

  4. ARF and ATM/ATR cooperate in p53-mediated apoptosis upon oncogenic stress

    SciTech Connect

    Pauklin, Siim; Kristjuhan, Arnold; Maimets, Toivo

    2005-08-26

    Induction of apoptosis is pivotal for eliminating cells with damaged DNA or deregulated proliferation. We show that tumor suppressor ARF and ATM/ATR kinase pathways cooperate in the induction of apoptosis in response to elevated expression of c-myc, {beta}-catenin or human papilloma virus E7 oncogenes. Overexpression of oncogenes leads to the formation of phosphorylated H2AX foci, induction of Rad51 protein levels and ATM/ATR-dependent phosphorylation of p53. Inhibition of ATM/ATR kinases abolishes both induction of Rad51 and phosphorylation of p53, and remarkably reduces the level of apoptosis induced by co-expression of oncogenes and ARF. However, the induction of apoptosis is downregulated inmore » p53-/- cells and does not depend on activities of ATM/ATR kinases, indicating that efficient induction of apoptosis by oncogene activation depends on coordinated action of ARF and ATM/ATR pathways in the regulation of p53.« less

  5. Defining ATM-independent Functions of the Mre11 Complex with a Novel Mouse Model

    PubMed Central

    Balestrini, Alessia; Nicolas, Laura; Yang-lott, Katherine; Guryanova, Olga A.; Levine, Ross L.; Bassing, Craig H.; Chaudhuri, Jayanta; Petrini, John H.J.

    2015-01-01

    The Mre11 complex (Mre11, Rad50 and Nbs1) occupies a central node of the DNA damage response (DDR) network, and is required for ATM activation in response to DNA damage. Hypomorphic alleles of MRE11 and NBS1 confer embryonic lethality in ATM deficient mice, indicating that the complex exerts ATM independent functions that are essential when ATM is absent. To delineate those functions, a conditional ATM allele (ATMflox) was crossed to hypomorphic NBS1 mutants (Nbs1ΔB/ΔB mice). Nbs1ΔB/ΔB Atm−/− hematopoietic cells derived by crossing to vavcre were viable in vivo. Nbs1ΔB/ΔB Atm−/− VAV mice exhibited a pronounced defect in double strand break (DSB) repair, and completely penetrant early onset lymphomagenesis. In addition to repair defects observed, fragile site instability was noted, indicating that the Mre11 complex promotes genome stability upon replication stress in vivo. The data suggest combined influences of the Mre11 complex on DNA repair, as well as the responses to DNA damage and DNA replication stress. PMID:26538284

  6. Activation of the ATM-Snail pathway promotes breast cancer metastasis

    PubMed Central

    Sun, Mianen; Guo, Xiaojing; Qian, Xiaolong; Wang, Haibo; Yang, Chunying; Brinkman, Kathryn L.; Serrano-Gonzalez, Monica; Jope, Richard S.; Zhou, Binhua; Engler, David A.; Zhan, Ming; Wong, Stephen T.C.; Fu, Li; Xu, Bo

    2012-01-01

    The DNA damage response (DDR) is critical for the maintenance of genetic stability and serves as an anti-cancer barrier during early tumorigenesis. However, the role of the DDR in tumor progression and metastasis is less known. Here, we demonstrate that the ATM kinase, one of the critical DDR elements, is hyperactive in late stage breast tumor tissues with lymph-node metastasis and this hyperactivity correlates with elevated expression of the epithelial–mesenchymal transition marker, Snail. At the molecular level, we demonstrate that ATM regulates Snail stabilization by phosphorylation on Serine-100. Using mass spectrometry, we identified HSP90 as a critical binding protein of Snail in response to DNA damage. HSP90 binds to and stabilizes phosphorylated Snail. We further provide in vitro and in vivo evidence that activation of ATM-mediated Snail phosphorylation promotes tumor invasion and metastasis. Finally, we demonstrate that Snail Serine-100 phosphorylation is elevated in breast cancer tissues with lymph-node metastasis, indicating clinical significance of the ATM-Snail pathway. Together, our findings provide strong evidence that the ATM-Snail pathway promotes tumor metastasis, highlighting a previously undescribed role of the DDR in tumor invasion and metastasis. PMID:22923499

  7. European project RETAIN: new approach for IBC in teleradiology and PACS based on full ATM network

    NASA Astrophysics Data System (ADS)

    Cordonnier, Emmanuel; Jensch, Peter F.; Piqueras, Joachim; Gandon, Yves

    1995-05-01

    This paper describes the RETAIN project (radiological examination transfer on ATM Integrated Network), which is supported by the European Community, in the frame of the TEN-IBC program (trans-European networks integrated broad band communication). It links together three European sites in France (Rennes), Spain (Barcelona), and Germany (Oldenburg) and involves a partnership between the public national operators France Telecom, Telefonica, and Telekom. One important reason to explicitly consider asynchronous transfer mode (ATM) for medical imaging is that multimedia applications on such networks allow integration of digital data and person-to-person communication. The RETAIN project includes trials of teleworking sessions between radiologists of Rennes and Barcelona within a clinical and/or scientific context based on ATM equipments performing DICOM transfer on examination, digital remote manipulation within a comprehensive dialogue, and high quality visiophony on ATM adaptation layer (AAL) type 1. The project includes also visiophony trials with Oldenburg and preparation of harmonized regional experimentation within an emergency context. The network used is a full 10 Mbits/s ATM network directly connected to local PACSs.

  8. Irradiated HMEC from A-T Heterozygous Breast Tissue

    NASA Technical Reports Server (NTRS)

    Richmond, Robert; Bors, Karen; Cruz, Angela; Pettengil, Olive; Curreri, Peter A. (Technical Monitor)

    2002-01-01

    Women who are heterozygous for ataxia-telangiectasia (A-T) carry a single defective ATM gene in chromosome 11 q22-23, and have been statistically determined with high significance within a defined database to be approximately 5-fold more susceptible for developing breast cancer than their noma1 counterpart. Breast cancer susceptibility of these A-T heterozygotes has been hypothesized to include consequence of response to damage caused by low levels of ionizing radiation. Prophylactic mastectomy specimens were donated by a 41 year-old obligate A-T heterozygote who was located prior to her elective surgery through an existing pedigree. Harvest of that breast tissue provided an isolate of long-term growth human mammary epithelial cells (HMEC), designated WH612/3. An isolate of presumed normal long-term growth HMEC, designated 48R, was obtained from Dr. Martha Stampfer (Lawrence Berkeley Laboratory, University of California), and the A-T heterozygous HMEC were transformed with E6 and E7 oncogenes of human papilloma virus Type-16 in the laboratory of Dr. Ray White (Hunt- Cancer Institute, University of Utah) for use in this study. The objective of this study is to study the expression of end points that may bear on cancer outcome following irradiation of HMEC. Specific end points are cell survival, cell cycle, p53 expression, and apoptosis. Survival curves, immunostaining, and flow cytometery are used to examine these end points. Radiation-induced cell killing shows less shoulder development in the survival curve for WH61U3 compared to 48R HMEC, suggesting less repair of damage in the former HMEC. Additional information is included in the original extended abstract.

  9. Role of ataxia telangiectasia mutated in insulin signaling of muscle-derived cell lines and mouse soleus

    PubMed Central

    Jeong, ImJu; Patel, Akshar Y.; Zhang, Zhihong; Patil, Pankaj B.; Nadella, Shravan T.; Nair, Supriya; Ralston, Lyle; Hoormann, Janie K.; Fisher, Jonathan S.

    2010-01-01

    Aim Ataxia telangiectasia mutated (ATM) reportedly plays a role in insulin-stimulated activation of Akt in some cell types but not others. The role of ATM in insulin signaling has not been firmly resolved for skeletal muscle cells, for which Akt phosphorylation is a pivotal step in stimulation of glucose transport. Accordingly, our aim was to determine the role of ATM in insulin effects for cell lines derived from skeletal muscle and for skeletal muscle. Methods: We examined insulin effects in L6 myotubes, mouse soleus, C2C12 myotubes, and differentiated rhabdomyosarcoma (RD) cells in the presence and absence of a low concentration (1 μM) of the ATM inhibitor KU55933. We also compared insulin signaling in C2C12 cells expressing shRNA against ATM and control cell lines (empty vector; cells expressing non-targeting shRNA). Results In L6 myotubes and mouse soleus muscle, KU55933 inhibited insulin-stimulated phosphorylation of the 160 kDa substrate of Akt (AS160) despite no effect on Akt. In contrast, KU55933 prevented insulin-stimulated Akt phosphorylation in C2C12 myotubes. Futhermore, C2C12 myotubes expressing shRNA against ATM displayed reduced insulin-stimulated Akt phosphorylation compared to controls. KU55933 also decreased insulin-stimulated Akt phosphorylation in differentiated RD cells. Conclusion These model-dependent differences in the role of ATM in insulin action demonstrate a role of ATM in insulin-stimulated phosphorylation of Akt (in C2C12 and RD cells) but also allow the elucidation of a novel, Akt-independent role of ATM (in L6 myotubes and mouse soleus, at the level of AS160) in insulin signaling. PMID:20003097

  10. [The role of cell cycle arrest in radiosensitization of nasopharyngeal carcinoma cell line CNE1 by inhibiting ATM expression].

    PubMed

    Wang, Hong-Mei; Chen, Long-Hua; Zheng, Xiao-Kang; Wu, Xin-Yao; Xia, Yun-Fei

    2008-05-01

    Cell cycle regulation is one of the most important determinants to ionizing radiosensitivity of cells. ATM gene is closely related with DNA damage repair and cell cycle checkpoints control. We previously reported that suppressing ATM expression with antisense ATM RNA could enhance radiosensitivity of nasopharyngeal carcinoma (NPC) cell line CNE1. This study was to explore the involved changes of cell cycle and the mechanisms of cell cycle arrest. ATM gene was constructed into retrovirus vector pDOR to form recombinant pDOR-atm. CNE1 cells were transfected with pDOR-atm (CNE1/pDOR-atm cells) or pDOR (CNE1/pDOR cells) and irradiated with X-ray. Cell cycle and cell apoptosis were detected by flow cytometry at different time points after irradiation. S phase arrest was detected at 1, 4, and 8 h after irradiation in both groups, and G2 arrest at 24, and 48 h, while no comparable G1 arrest and apoptosis were revealed. The mean percentage of S phase cells was lower, and G2 phase cells was higher in CNE1/pDOR-atm group than in CNE1/pDOR group (P<0.05). The mechanisms of cell cycle regulation in radiosensitized CNE1 cells by inhibiting ATM expression might be related with the decreased accumulation of S phase cells and increased accumulation of G2/M phase cells, while have no relationship with G1 arrest and apoptosis.

  11. KRAS Mutation

    PubMed Central

    Franklin, Wilbur A.; Haney, Jerry; Sugita, Michio; Bemis, Lynne; Jimeno, Antonio; Messersmith, Wells A.

    2010-01-01

    Treatment of colon carcinoma with the anti-epidermal growth factor receptor antibody Cetuximab is reported to be ineffective in KRAS-mutant tumors. Mutation testing techniques have therefore become an urgent concern. We have compared three methods for detecting KRAS mutations in 59 cases of colon carcinoma: 1) high resolution melting, 2) the amplification refractory mutation system using a bifunctional self-probing primer (ARMS/Scorpion, ARMS/S), and 3) direct sequencing. We also evaluated the effects of the methods of sectioning and coring of paraffin blocks to obtain tumor DNA on assay sensitivity and specificity. The most sensitive and specific combination of block sampling and mutational analysis was ARMS/S performed on DNA derived from 1-mm paraffin cores. This combination of tissue sampling and testing method detected KRAS mutations in 46% of colon tumors. Four samples were positive by ARMS/S, but initially negative by direct sequencing. Cloned DNA samples were retested by direct sequencing, and in all four cases KRAS mutations were identified in the DNA. In six cases, high resolution melting abnormalities could not be confirmed as specific mutations either by ARMS/S or direct sequencing. We conclude that coring of the paraffin blocks and testing by ARMS/S is a sensitive, specific, and efficient method for KRAS testing. PMID:20007845

  12. Analysis of CrIs/ATMS Using AIRS Version-7 Retrieval and QC Methodology

    NASA Technical Reports Server (NTRS)

    Susskind, Joel; Kouvaris, Louis; Blaisdell, John M.; Iredell, Lena

    2017-01-01

    The objective of this research is to develop and implement an algorithm to analyze a long term data record of CrIS/ATMS observations so as to produce monthly mean gridded Level-3 products which are consistent with, and will serve as a seamless follow on to, those of AIRS Version-7. We feel the best way to achieve this result is to analyze CrIS/ATMS data using retrieval and Quality Control (QC) methodologies which are scientifically equivalent to those used in AIRS Version-7. We developed and implemented a single retrieval program that uses as input either AIRS/AMSU or CrIS/ATMS radiance observations, and has appropriate switches that take into account the spectral and radiometric differences between CrIS and AIRS. Our methodology is call CHART (Climate Heritage AIRS Retrieval Technique).

  13. Inter-calibration and validation of observations from SAPHIR and ATMS instruments

    NASA Astrophysics Data System (ADS)

    Moradi, I.; Ferraro, R. R.

    2015-12-01

    We present the results of evaluating observations from microwave instruments aboard the Suomi National Polar-orbiting Partnership (NPP, ATMS instrument) and Megha-Tropiques (SAPHIR instrument) satellites. The study includes inter-comparison and inter-calibration of observations of similar channels from the two instruments, evaluation of the satellite data using high-quality radiosonde data from Atmospheric Radiation Measurement Program and GPS Radio Occultaion Observations from COSMIC mission, as well as geolocation error correction. The results of this study are valuable for generating climate data records from these instruments as well as for extending current climate data records from similar instruments such as AMSU-B and MHS to the ATMS and SAPHIR instruments. Reference: Moradi et al., Intercalibration and Validation of Observations From ATMS and SAPHIR Microwave Sounders. IEEE Transactions on Geoscience and Remote Sensing. 01/2015; DOI: 10.1109/TGRS.2015.2427165

  14. A novel mathematical model of ATM/p53/NF- κB pathways points to the importance of the DDR switch-off mechanisms.

    PubMed

    Jonak, Katarzyna; Kurpas, Monika; Szoltysek, Katarzyna; Janus, Patryk; Abramowicz, Agata; Puszynski, Krzysztof

    2016-08-15

    Ataxia telangiectasia mutated (ATM) is a detector of double-strand breaks (DSBs) and a crucial component of the DNA damage response (DDR) along with p53 and NF- κB transcription factors and Wip1 phosphatase. Despite the recent advances in studying the DDR, the mechanisms of cell fate determination after DNA damage induction is still poorly understood. To investigate the importance of various DDR elements with particular emphasis on Wip1, we developed a novel mathematical model of ATM/p53/NF- κB pathways. Our results from in silico and in vitro experiments performed on U2-OS cells with Wip1 silenced to 25 % (Wip1-RNAi) revealed a strong dependence of cellular response to DNA damages on this phosphatase. Notably, Wip1-RNAi cells exhibited lower resistance to ionizing radiation (IR) resulting in smaller clonogenicity and higher apoptotic fraction. In this article, we demonstrated that Wip1 plays a role as a gatekeeper of apoptosis and influences the pro-survival behaviour of cells - the level of Wip1 increases to block the apoptotic decision when DNA repair is successful. Moreover, we were able to verify the dynamics of proteins and transcripts, apoptotic fractions and cells viability obtained from stochastic simulations using in vitro approaches. Taken together, we demonstrated that the model can be successfully used in prediction of cellular behaviour after exposure to IR. Thus, our studies may provide further insights into key elements involved in the underlying mechanisms of the DDR.

  15. Role of ATM in bystander signaling between human monocytes and lung adenocarcinoma cells.

    PubMed

    Ghosh, Somnath; Ghosh, Anu; Krishna, Malini

    2015-12-01

    The response of a cell or tissue to ionizing radiation is mediated by direct damage to cellular components and indirect damage mediated by radiolysis of water. Radiation affects both irradiated cells and the surrounding cells and tissues. The radiation-induced bystander effect is defined by the presence of biological effects in cells that were not themselves in the field of irradiation. To establish the contribution of the bystander effect in the survival of the neighboring cells, lung carcinoma A549 cells were exposed to gamma-irradiation, 2Gy. The medium from the irradiated cells was transferred to non-irradiated A549 cells. Irradiated A549 cells as well as non-irradiated A549 cells cultured in the presence of medium from irradiated cells showed decrease in survival and increase in γ-H2AX and p-ATM foci, indicating a bystander effect. Bystander signaling was also observed between different cell types. Phorbol-12-myristate-13-acetate (PMA)-stimulated and gamma-irradiated U937 (human monocyte) cells induced a bystander response in non-irradiated A549 (lung carcinoma) cells as shown by decreased survival and increased γ-H2AX and p-ATM foci. Non-stimulated and/or irradiated U937 cells did not induce such effects in non-irradiated A549 cells. Since ATM protein was activated in irradiated cells as well as bystander cells, it was of interest to understand its role in bystander effect. Suppression of ATM with siRNA in A549 cells completely inhibited bystander effect in bystander A549 cells. On the other hand suppression of ATM with siRNA in PMA stimulated U937 cells caused only a partial inhibition of bystander effect in bystander A549 cells. These results indicate that apart from ATM, some additional factor may be involved in bystander effect between different cell types. Copyright © 2015 Elsevier B.V. All rights reserved.

  16. Hypersensitivity of primordial germ cells to compromised replication-associated DNA repair involves ATM-p53-p21 signaling.

    PubMed

    Luo, Yunhai; Hartford, Suzanne A; Zeng, Ruizhu; Southard, Teresa L; Shima, Naoko; Schimenti, John C

    2014-07-01

    Genome maintenance in germ cells is critical for fertility and the stable propagation of species. While mechanisms of meiotic DNA repair and chromosome behavior are well-characterized, the same is not true for primordial germ cells (PGCs), which arise and propagate during very early stages of mammalian development. Fanconi anemia (FA), a genomic instability syndrome that includes hypogonadism and testicular failure phenotypes, is caused by mutations in genes encoding a complex of proteins involved in repair of DNA lesions associated with DNA replication. The signaling mechanisms underlying hypogonadism and testicular failure in FA patients or mouse models are unknown. We conducted genetic studies to show that hypogonadism of Fancm mutant mice is a result of reduced proliferation, but not apoptosis, of PGCs, resulting in reduced germ cells in neonates of both sexes. Progressive loss of germ cells in adult males also occurs, overlaid with an elevated level of meiotic DNA damage. Genetic studies indicated that ATM-p53-p21 signaling is partially responsible for the germ cell deficiency.

  17. Leo Satellite Communication through a LEO Constellation using TCP/IP Over ATM

    NASA Technical Reports Server (NTRS)

    Foore, Lawrence R.; Konangi, Vijay K.; Wallett, Thomas M.

    1999-01-01

    The simulated performance characteristics for communication between a terrestrial client and a Low Earth Orbit (LEO) satellite server are presented. The client and server nodes consist of a Transmission Control Protocol /Internet Protocol (TCP/IP) over ATM configuration. The ATM cells from the client or the server are transmitted to a gateway, packaged with some header information and transferred to a commercial LEO satellite constellation. These cells are then routed through the constellation to a gateway on the globe that allows the client/server communication to take place. Unspecified Bit Rate (UBR) is specified as the quality of service (QoS). Various data rates are considered.

  18. Final Report for the Scaled Asynchronous Transfer Mode (ATM) Encryption Laboratory Directed Research and Development Project

    SciTech Connect

    Pierson, L.G.; Witzke, E.L.

    1999-01-01

    This effort studied the integration of innovative methods of key management crypto synchronization, and key agility while scaling encryption speed. Viability of these methods for encryption of ATM cell payloads at the SONET OC- 192 data rate (10 Gb/s), and for operation at OC-48 rates (2.5 Gb/s) was shown. An SNL-Developed pipelined DES design was adapted for the encryption of ATM cells. A proof-of-principle prototype circuit board containing 11 Electronically Programmable Logic Devices (each holding the equivalent of 100,000 gates) was designed, built, and used to prototype a high speed encryptor.

  19. Experiments at SRT Using the NOAA CrIS/ATMS Proxy Data Set

    NASA Technical Reports Server (NTRS)

    Susskind, Joel; Kouvaris, Louis; Iredell, Lena

    2011-01-01

    The objectives of the talk are: (1) Assess the performance of NGAS Version-1.5.03.00 CrIS/ATMS retrieval algorithm as delivered by LaRC, modified to include the MW and IR tuning coefficients and new CrIS noise model (a) Percent acceptance (b) RMS and mean differences of T(p) vs. ECMWF truth as a function of % yield (2) Compare performance of NGAS retrieval algorithm with an AIRS Science Team Version-6 like retrieval algorithm modified at Sounder Research Team (SRT) for CrIS/ATMS

  20. Thermal control evaluation of a Shuttle Orbiter solar observatory using Skylab ATM backup hardware

    NASA Technical Reports Server (NTRS)

    Class, C. R.; Presta, G.; Trucks, H.

    1975-01-01

    A study under the sponsorship of Marshall Space Flight Center (MSFC) established the feasibility to utilize the Skylab Apollo Telescope Mount (ATM) backup hardware for early low cost Shuttle Orbiter solar observation missions. A solar inertial attitude and a seven-day, full sun exposure were baselined. As a portion of the study, a series of thermal control evaluations were performed to resolve the problems caused by the relocation of the ATM to the Shuttle Orbiter bay and resulting configuration changes. Thermal control requirements, problems, the use of solar shields, Spacelab supplied fluid cooling and component placement are discussed.

  1. Mdm2 inhibitor Nutlin-3a induces p53-mediated apoptosis by transcription-dependent and transcription-independent mechanisms and may overcome Atm-mediated resistance to fludarabine in chronic lymphocytic leukemia.

    PubMed

    Kojima, Kensuke; Konopleva, Marina; McQueen, Teresa; O'Brien, Susan; Plunkett, William; Andreeff, Michael

    2006-08-01

    Although TP53 mutations are rare in B-cell chronic lymphocytic leukemia (CLL), Mdm2 overexpression has been reported as an alternative cause of p53 dysfunction. We investigated the potential therapeutic use of nongenotoxic p53 activation by a small-molecule antagonist of Mdm2, Nutlin-3a, in CLL. Nutlin-3a induced significant apoptosis in 30 (91%) of 33 samples from previously untreated patients with CLL; all resistant samples had TP53 mutations. Low levels of Atm (ataxia telangiectasia mutated) or high levels of Mdm2 (murine double minute 2) did not prevent Nutlin-3a from inducing apoptosis. Nutlin-3a used transcription-dependent and transcription-independent pathways to induce p53-mediated apoptosis. Predominant activation of the transcription-independent pathway induced more pronounced apoptosis than that of the transcription-dependent pathway, suggesting that activation of the transcription-independent pathway is sufficient to initiate p53-mediated apoptosis in CLL. Combination treatment of Nutlin-3a and fludarabine synergistically increased p53 levels, and induced conformational change of Bax and apoptosis in wild-type p53 cells but not in cells with mutant p53. The synergistic apoptotic effect was maintained in samples with low Atm that were fludarabine resistant. Results suggest that the nongenotoxic activation of p53 by targeting the Mdm2-p53 interaction provides a novel therapeutic strategy for CLL.

  2. An evaluation of the ATM man/machine interface. Phase 3: Analysis of SL-3 and SL-4 data

    NASA Technical Reports Server (NTRS)

    Bathurst, J. R., Jr.; Pain, R. F.; Ludewig, D. B.

    1974-01-01

    The functional adequacy of human factored crew operated systems under operational zero-gravity conditions is considered. Skylab ATM experiment operations generated sufficient telemetry and voice transcript data to support such an assessment effort. Discussions are presented pertaining to the methodology and procedures used to evaluate the hardware, training and directive aspects of Skylab 3 and Skylab 4 manned ATM experiment operations.

  3. Development of a queue warning system utilizing ATM infrastructure system development and field-testing : final report.

    DOT National Transportation Integrated Search

    2017-06-13

    MnDOT has already deployed an extensive infrastructure for Active Traffic Management (ATM) on I-35W and I-94 with plans to expand on other segments of the Twin Cities freeway network. The ATM system includes intelligent lane control signals (ILCS) sp...

  4. Designing a Strategic Plan through an Emerging Knowledge Generation Process: The ATM Experience

    ERIC Educational Resources Information Center

    Zanotti, Francesco

    2012-01-01

    Purpose: The aim of this contribution is to describe a new methodology for designing strategic plans and how it was implemented by ATM, a public transportation agency based in Milan, Italy. Design/methodology/approach: This methodology is founded on a new system theory, called "quantum systemics". It is based on models and metaphors both…

  5. Earth-viewing methods for on orbit assessment of ATMS observation system spatial response function

    NASA Astrophysics Data System (ADS)

    sun, H.; Wolf, W.; Thomas, K. S.; Maddy, E. S.; Sampson, S.; Keehn, P.

    2013-12-01

    As a key instrument on board the S-NPP satellite and future JPSS satellites, the Advanced Technology Microwave Sounder (ATMS), a cross-track scanner with 22 channels, provides sounding observations needed to retrieve profiles of atmospheric temperature and moisture for civilian operational weather forecasting, as well as continuity of these measurements for climate monitoring purposes. The ATMS observation system spatial response function is a fundamental important parameter since it enables an objective assessment of spatial resolution and provides basic characteristic data for instrument calibration and satellite data algorithm development. The ATMS observation system spatial response function is a combined result of the antenna pattern as well as the motion introduced by both cross track scanning and along track satellite movement during the sensor integration time. There is no on-board calibration device fully appropriate for the assessment of the observation effective system spatial response function. In this paper, an observation system spatial response retrieval algorithm based upon the earth-viewing is described. The algorithm uses a knife-edge scanning method to retrieve the line spread function (LSF) of the ATMS observation and a Filtered Back Projection algorithm based upon the Fourier slice theorem is applied to rebuild the instrument spatial response function. Preliminary retrieval results are presented.

  6. ATAXIA - TELANGIECTASIA – A HISTORICAL REVIEW AND A PROPOSAL FOR A NEW NAME: ATM SYNDROME

    PubMed Central

    Teive, Hélio A. G.; Moro, Adriana; Moscovich, Mariana; Munhoz, Renato P.; Ashizawa, Tetsuo

    2016-01-01

    The authors review ataxia telangiectasia, emphasizing historical aspects, genetic discoveries and the clinical presentations of the classical and atypical forms. Our conclusion is that the term ataxia telangiectasia is a misnomer because it represents a multisystem entity with pleomorphic neurological and systemic manifestations. ATM syndrome is proposed as a more adequate designation for this entity. PMID:26050521

  7. The Advanced Technology Microwave Sounder (ATMS): The First 10 Months On-Orbit

    NASA Technical Reports Server (NTRS)

    Kim, Edward; Lyu, C-H Joseph; Blackwell, Willaim; Leslie, R. Vince; Baker, Neal; Mo, Tsan; Sun, Ninghai; Bi, Li; Anderson, Kent; Landrum, Mike; hide

    2012-01-01

    The Advanced Technology Microwave Sounder (ATMS) is a new satellite microwave sounding sensor designed to provide operational weather agencies with atmospheric temperature and moisture profile information for global weather forecasting and climate applications. A TMS will continue the microwave sounding capabilities first provided by its predecessors, the Microwave Sounding Unit (MSU) and Advanced Microwave Sounding Unit (AMSU). The first ATMS was launched October 28, 2011 on board the NPOESS Preparatory Project (NPP) satellite. Microwave soundings by themselves are the highest-impact input data used by Numerical Weather Prediction (NWP) models, especially under cloudy sky conditions. ATMS has 22 channels spanning 23-183 GHz, closely following the channel set of the MSU, AMSU-A1/2, AMSU-B, Microwave Humidity Sounder (MHS), and Humidity Sounder for Brazil (HSB). All this is accomplished with approximately 1/4 the volume, 1/2 the mass, and 1/2 the power of the three AMSUs. A description of ATMS cal/val activities will be presented followed by examples of its performance after its first 10 months on orbit.

  8. The Advanced Technology Microwave Sounder (ATMS): First Year On-Orbit

    NASA Astrophysics Data System (ADS)

    Kim, E. J.; Lyu, C.; Blackwell, W. J.; Leslie, V.; Baker, N.; Mo, T.; Sun, N.; Bi, L.; Anderson, K.; Landrum, M.; De Amici, G.; Gu, D.; Foo, A.; Ibrahim, W.; Robinson, K.

    2012-12-01

    The Advanced Technology Microwave Sounder (ATMS) is a new satellite microwave sounding sensor designed to provide operational weather agencies with atmospheric temperature and moisture profile information for global weather forecasting and climate applications. ATMS will continue the microwave sounding capabilities first provided by its predecessors, the Microwave Sounding Unit (MSU) and Advanced Microwave Sounding Unit (AMSU). The first ATMS was launched October 28, 2011 on board the Suomi-NPOESS Preparatory Project (S-NPP) satellite and has just finished its first year on orbit. Microwave soundings by themselves are the highest-impact input data used by Numerical Weather Prediction (NWP) models; and ATMS, when combined with the Cross-track Infrared Sounder (CrIS), forms the Cross-track Infrared and Microwave Sounding Suite (CrIMSS). The microwave soundings help meet NWP sounding requirements under cloudy sky conditions and provide key profile information near the surface. Designed & built by Aerojet Corporation in Azusa, California, (now Northrop Grumman Electronic Systems), ATMS has 22 channels spanning 23—183 GHz, closely following the channel set of the MSU, AMSU-A1 and A2, AMSU-B, Microwave Humidity Sounder (MHS), and Humidity Sounder for Brazil (HSB). It continues their cross-track scanning geometry, but for the first time, provides Nyquist sample spacing. All this is accomplished with approximately one quarter the volume, one half the mass, and one half the power of the three AMSUs. A summary description of the ATMS design will be presented. Post-launch calibration/validation activities include geolocation determination, radiometric calibration using the on-board warm targets and cold space views, simultaneous observations by microwave sounders on other satellites, comparison vs. pre-launch thermovacuum test performance; observations vs. atmospheric model predicted radiances, and comparisons of soundings vs. radiosondes. Brief descriptions of these

  9. The nucleo-shuttling of the ATM protein as a basis for a novel theory of radiation response: resolution of the linear-quadratic model.

    PubMed

    Bodgi, Larry; Foray, Nicolas

    2016-01-01

    For 50 years, cellular radiosensitivity has been defined in vitro as the lack of clonogenic capacity of irradiated cells and its mathematical link with dose has been described by the target theory. Among the numerous formulas provided from the target theory, the linear-quadratic (LQ) model empirically describes cell survival as a negative exponential of a second degree polynomial dose-function in which αD is the linear component and βD(2) is the quadratic one. The LQ model is extensively used in radiobiology (to describe survival curves) and in radiotherapy (the α/β ratio indicates whether tissue reactions can occur early or late after the treatment). However, no biological interpretation of the LQ parameters was proposed to explain together the radiation response in a wide dose range, the radiosensitivity of some genetic syndromes caused by the mutation of cytoplasmic proteins and the hyper-radiosensitivity phenomenon specific to low-dose. From a solid amount of experimental data, we hypothesized that the major forms of ataxia telangiectasia mutated (ATM) are cytoplasmic dimers and that ionizing radiation induce ATM monomerization. The resulting ATM monomers diffuse into nucleus to facilitate double-strand-breaks (DSB) recognition and repair. Such hypotheses lead to a coherent molecular interpretation of the LQ model by considering the yield of recognized but unrepaired (α-type) DSB and the non-recognized (β-type) DSB. The notion of cell tolerance to unrepaired DSB was introduced by considering that not all DSB are lethal. Cell survival and DSB repair and signaling immunofluorescence data from 42 normal skin fibroblast and 18 tumor human cell lines were used to verify the validity of this biomathematical model proposed. Our model is validated at different levels by one of the widest spectrum of radiosensitivity. That mathematical developments of the present model imply that β is a Lorentzian function of α was confirmed experimentally. Our model is also

  10. Association of ATM and BMI-1 genetic variation with breast cancer risk in Han Chinese.

    PubMed

    Yue, Li-Ling; Wang, Fu-Chao; Zhang, Ming-Long; Liu, Dan; Chen, Ping; Mei, Qing-Bu; Li, Peng-Hui; Pan, Hong-Ming; Zheng, Li-Hong

    2018-04-24

    We tested the hypothesis that genetic variation in ATM and BMI-1 genes can alter the risk of breast cancer through genotyping 6 variants among 524 breast cancer cases and 518 cancer-free controls of Han nationality. This was an observational, hospital-based, case-control association study. Analyses of single variant, linkage, haplotype, interaction and nomogram were performed. Risk was expressed as odds ratio (OR) and 95% confidence interval (CI). All studied variants were in the Hardy-Weinberg equilibrium and were not linked. The mutant allele frequencies of rs1890637, rs3092856 and rs1801516 in ATM gene were significantly higher in cases than in controls (P = .005, <.001 and .001, respectively). Two variants, rs1042059 and rs201024480, in BMI-1 gene were low penetrant, with no detectable significance. After adjustment, rs189037 and rs1801516 were significantly associated with breast cancer under the additive model (OR: 1.37 and 1.52, 95% CI: 1.10-1.71 and 1.14-2.04, P: .005 and .005, respectively). In haplotype analysis, haplotypes A-C-G-G (in order of rs189037, rs3092856, rs1801516 and rs373759) and A-C-A-A in ATM gene were significantly associated with 1.98-fold and 6.04-fold increased risk of breast cancer (95% CI: 1.36-2.90 and 1.65-22.08, respectively). Nomogram analysis estimated that the cumulative proportion of 3 significant variants in ATM gene was about 12.5%. Our findings collectively indicated that ATM gene was a candidate gene in susceptibility to breast cancer in Han Chinese. © 2018 The Authors. Journal of Cellular and Molecular Medicine published by John Wiley & Sons Ltd and Foundation for Cellular and Molecular Medicine.

  11. S-NPP ATMS Instrument Prelaunch and On-Orbit Performance Evaluation

    NASA Technical Reports Server (NTRS)

    Kim, Edward; Lyu, Cheng-Hsuan; Anderson, Kent; Leslie, Vincent R.; Blackwell, William J.

    2014-01-01

    The first of a new generation of microwave sounders was launched aboard the Suomi-National Polar-Orbiting Partnership satellite in October 2011. The Advanced Technology Microwave Sounder (ATMS) combines the capabilities and channel sets of three predecessor sounders into a single package to provide information on the atmospheric vertical temperature and moisture profiles that are the most critical observations needed for numerical weather forecast models. Enhancements include size/mass/power approximately one third of the previous total, three new sounding channels, the first space-based, Nyquist-sampled cross-track microwave temperature soundings for improved fusion with infrared soundings, plus improved temperature control and reliability. This paper describes the ATMS characteristics versus its predecessor, the advanced microwave sounding unit (AMSU), and presents the first comprehensive evaluation of key prelaunch and on-orbit performance parameters. Two-year on-orbit performance shows that the ATMS has maintained very stable radiometric sensitivity, in agreement with prelaunch data, meeting requirements for all channels (with margins of 40% for channels 1-15), and improvements over AMSU-A when processed for equivalent spatial resolution. The radiometric accuracy, determined by analysis from ground test measurements, and using on-orbit instrument temperatures, also shows large margins relative to requirements (specified as <1.0K for channels 1, 2, and 16-22 and <0.75 K for channels 3-15). A thorough evaluation of the performance of ATMS is especially important for this first proto-flight model unit of what will eventually be a series of ATMS sensors providing operational sounding capability for the U.S. and its international partners well into the next decade.

  12. A Methodology to Adjust ATMS Observations for Limb Effect and Its Applications

    NASA Astrophysics Data System (ADS)

    Zhang, Kexin; Zhou, Lihang; Goldberg, Mitch; Liu, Xingpin; Wolf, Walter; Tan, Changyi; Liu, Quanhua

    2017-11-01

    The Advanced Technology Microwave Sounders (ATMS), carried on the Suomi National Polar-orbiting Partnership (SNPP) satellite, was launched on 28 October 2011. The ATMS is a follow-on instrument to advanced microwave sounding unit (AMSU), currently flying on National Oceanic and Atmospheric Administration (NOAA) satellites. The primary new ATMS features are a reduced hardware package and improved gap coverage. One thing in common about cross-track sounders is a scan perpendicular to the motion of the satellite, allowing a broad swath of measurements to be taken. But an undesirable feature is that the measurements vary with scan angle because of changes in the optical pathlength through the Earth's atmosphere between the Earth and the satellite. One approach to this problem is to limb adjust the measurements to a fixed view angle. The limb correction algorithm applied to ATMS is based on the heritage methodology originally applied to MSU and later to AMSU. The limb correction method is applied to each of the 96 ATMS field of view (FOV) per scan line, adjusting the off-nadir FOV to the nadir view with fitting error generally within the instrumental noise. The limb-adjusted brightness temperature were used in the original, legacy TIROS Operational Vertical Sounder, and Advanced TIROS Operational Vertical Sounder NOAA sounding product algorithms and more recently to derive the total precipitation water (TPW) retrieval over ocean, with a bias of 0.046 mm and a standard deviation of 3.43 mm, when compared with European Centre for Medium-Range Weather Forecasts TPW data. The limb-corrected brightness temperature can be used to detect the atmospheric weather features, such as the warm cores for tropical cyclones, and the imagery presents snapshots for quick weather signal diagnosis.

  13. A T67A mutation in the proximal pocket of the high-spin heme of MauG stabilizes formation of a mixed-valent FeII/FeIII state and enhances charge resonance stabilization of the bis-FeIV state.

    PubMed

    Shin, Sooim; Feng, Manliang; Li, Chao; Williamson, Heather R; Choi, Moonsung; Wilmot, Carrie M; Davidson, Victor L

    2015-08-01

    The diheme enzyme MauG catalyzes a six-electron oxidation required for posttranslational modification of a precursor of methylamine dehydrogenase (preMADH) to complete the biosynthesis of its protein-derived tryptophan tryptophylquinone (TTQ) cofactor. One heme is low-spin with ligands provided by His205 and Tyr294, and the other is high-spin with a ligand provided by His35. The side chain methyl groups of Thr67 and Leu70 are positioned at a distance of 3.4Å on either side of His35, maintaining a hydrophobic environment in the proximal pocket of the high-spin heme and restricting the movement of this ligand. Mutation of Thr67 to Ala in the proximal pocket of the high-spin heme prevented reduction of the low-spin heme by dithionite, yielding a mixed-valent state. The mutation also enhanced the stabilization of the charge-resonance-transition of the high-valent bis-FeIV state that is generated by addition of H2O2. The rates of electron transfer from TTQ biosynthetic intermediates to the high-valent form of T67A MauG were similar to that of wild-type MauG. These results are compared to those previously reported for mutation of residues in the distal pocket of the high-spin heme that also affected the redox properties and charge resonance transition stabilization of the high-valent state of the hemes. However, given the position of residue 67, the structure of the variant protein and the physical nature of the T67A mutation, the basis for the effects of the T67A mutation must be different from those of the mutations of the residues in the distal heme pocket. Copyright © 2015 Elsevier B.V. All rights reserved.

  14. Somatic Hypermutation at A/T-Rich Oligonucleotide Substrates Shows Different Strand Polarities in Ung-Deficient or -Proficient Backgrounds

    PubMed Central

    Zivojnovic, Marija; Delbos, Frédéric; Girelli Zubani, Giulia; Julé, Amélie; Alcais, Alexandre; Storck, Sébastien

    2014-01-01

    A/T mutations at immunoglobulin loci are introduced by DNA polymerase η (Polη) during an Msh2/6-dependent repair process which results in A's being mutated 2-fold more often than T's. This patch synthesis is initiated by a DNA incision event whose origin is still obscure. We report here the analysis of A/T oligonucleotide mutation substrates inserted at the heavy chain locus, including or not including internal C's or G's. Surprisingly, the template composed of only A's and T's was highly mutated over its entire 90-bp length, with a 2-fold decrease in mutation from the 5′ to the 3′ end and a constant A/T ratio of 4. These results imply that Polη synthesis was initiated from a break in the 5′-flanking region of the substrate and proceeded over its entire length. The A/T bias was strikingly altered in an Ung−/− background, which provides the first experimental evidence supporting a concerted action of Ung and Msh2/6 pathways to generate mutations at A/T bases. New analysis of Pms2−/− animals provided a complementary picture, revealing an A/T mutation ratio of 4. We therefore propose that Ung and Pms2 may exert a mutual backup function for the DNA incision that promotes synthesis by Polη, each with a distinct strand bias. PMID:24710273

  15. MPEG-2 Over Asynchronous Transfer Mode (ATM) Over Satellite Quality of Service (QoS) Experiments: Laboratory Tests

    NASA Technical Reports Server (NTRS)

    Ivancic, William D.; Frantz, Brian D.; Spells, Marcus J.

    1998-01-01

    Asynchronous transfer mode (ATM) quality of service (QoS) experiments were performed using MPEG-2 (ATM application layer 5, AAL5) over ATM over an emulated satellite link. The purpose of these experiments was to determine the free-space link quality necessary to transmit high-quality multimedia information by using the ATM protocol. The detailed test plan and test configuration are described herein as are the test results. MPEG-2 transport streams were baselined in an errored environment, followed by a series of tests using, MPEG-2 over ATM. Errors were created both digitally as well as in an IF link by using a satellite modem and commercial gaussian noise test set for two different MPEG-2 decoder implementations. The results show that ITU-T Recommendation 1.356 Class 1, stringent ATM applications will require better link quality than currently specified; in particular, cell loss ratios of better than 1.0 x 10(exp -8) and cell error ratios of better than 1.0 x 10(exp -7) are needed. These tests were conducted at the NASA Lewis Research Center in support of satellite-ATM interoperability research.

  16. Skylab ATM/S-056 X-ray event analyzer: Instrument description, parameter determination, and analysis example (15 June 1973 1B/M3 flare)

    NASA Technical Reports Server (NTRS)

    Wilson, R. M.

    1976-01-01

    The Skylab ATM/S-056 X-Ray Event Analyzer, part of an X-ray telescope experiment, is described. The techniques employed in the analysis of its data to determine electron temperatures and emission measures are reviewed. The analysis of a sample event - the 15 June 1973 1B/M3 flare - is performed. Comparison of the X-Ray Event Analyzer data with that of the SolRad 9 observations indicates that the X-Ray Event Analyzer accurately monitored the sun's 2.5 to 7.25 A X-ray emission and to a lesser extent the 6.1 to 20 A emission. A mean average peak temperature of 15 million K at 1,412 UT and a mean average peak electron density (assuming a flare volume of 10 to the 13 power cu km) of 27 million/cu mm at 1,416 to 1,417 UT are deduced for the event. The X-Ray Event Analyzer data, having a 2.5 s time resolution, should be invaluable in comparisons with other high-time resolution data (e.g., radio bursts).

  17. Results from CrIS-ATMS Obtained Using the AIRS Science Team Retrieval Methodology

    NASA Technical Reports Server (NTRS)

    Susskind, Joel; Kouvaris, Louis C.; Iredell, Lena

    2013-01-01

    AIRS was launched on EOS Aqua in May 2002, together with AMSU-A and HSB (which subsequently failed early in the mission), to form a next generation polar orbiting infrared and microwave atmospheric sounding system. AIRS/AMSU had two primary objectives. The first objective was to provide real-time data products available for use by the operational Numerical Weather Prediction Centers in a data assimilation mode to improve the skill of their subsequent forecasts. The second objective was to provide accurate unbiased sounding products with good spatial coverage that are used to generate stable multi-year climate data sets to study the earth's interannual variability, climate processes, and possibly long-term trends. AIRS/AMSU data for all time periods are now being processed using the state of the art AIRS Science Team Version-6 retrieval methodology. The Suomi-NPP mission was launched in October 2011 as part of a sequence of Low Earth Orbiting satellite missions under the "Joint Polar Satellite System" (JPSS). NPP carries CrIS and ATMS, which are advanced infra-red and microwave atmospheric sounders that were designed as follow-ons to the AIRS and AMSU instruments. The main objective of this work is to assess whether CrIS/ATMS will be an adequate replacement for AIRS/AMSU from the perspective of the generation of accurate and consistent long term climate data records, or if improved instruments should be developed for future flight. It is critical for CrIS/ATMS to be processed using an algorithm similar to, or at least comparable to, AIRS Version-6 before such an assessment can be made. We have been conducting research to optimize products derived from CrIS/ATMS observations using a scientific approach analogous to the AIRS Version-6 retrieval algorithm. Our latest research uses Version-5.70 of the CrIS/ATMS retrieval algorithm, which is otherwise analogous to AIRS Version-6, but does not yet contain the benefit of use of a Neural-Net first guess start-up system

  18. Experimental investigation and model development of the Skylab ATM secondary nickel-cadmium batteries

    NASA Technical Reports Server (NTRS)

    Kirsch, W. W.

    1974-01-01

    The performance of a Ni-Cd battery was evaluated and the cyclic battery controls to be used on the ATM batteries were determined. Cell and battery performance models were developed which to predict the performance of the secondary Ni-Cd batteries on the ATM. Capacity degradation and charge acceptance characteristics were considered. Mathematical models for each of these operating areas were developed based on data from two separate test programs. The capacity degradation model describes the expected usable battery capacity as a function of time, temperature, and depth-of-discharge. The charge acceptance model describes the cell charge acceptance as a function of charge rate, temperature, and state of charge. The models were designed for computer use and to facilitate possible battery modification. They can be used to predict expected performance or to compare real time performance during flight.

  19. D-ATM, a working example of health care interoperability: From dirt path to gravel road.

    PubMed

    DeClaris, John-William

    2009-01-01

    For many years, there have been calls for interoperability within health care systems. The technology currently exists and is being used in business areas like banking and commerce, to name a few. Yet the question remains, why has interoperability not been achieved in health care? This paper examines issues encountered and success achieved with interoperability during the development of the Digital Access To Medication (D-ATM) project, sponsored by the Substance Abuse and Mental Health Services Administration (SAMHSA). D-ATM is the first government funded interoperable patient management system. The goal of this paper is to provide lessons learned and propose one possible road map for health care interoperability within private industry and how government can help.

  20. CIPP: a versatile analytical model for VBR traffic in ATM networks

    NASA Astrophysics Data System (ADS)

    Manivasakan, R.; Desai, U. B.; Karandikar, Abhay

    1999-08-01

    Correlated Interarrival time Process (CIPP) has been proposed, for modeling both the composite arrival process of packets in broadband networks and the individual source modeling. The CIPP--a generalization of the Poisson process- - is a stationary counting process and is parameterized by a correlation parameter `p' which represents the degree of correlation in adjacent interarrivals in addition to `(lambda) ' the intensity of the process. In this paper, we present the performance modeling of VBR video traffic in ATM networks, using CIPP/M/1 queue. We first give the expressions for stationary distributions for CIPP/M/1 queue. The, we derive the queuing measures of interest. We simulate a queue with smoothed VBR video trace data as input (with exponential services) to compare with the theoretical measures derived above. Experimental results show that the CIPP/M/1 queue, models well with ATM multiplexer performance with the real world VBR video traffic input.

  1. Issues in ATM Support of High-Performance, Geographically Distributed Computing

    NASA Technical Reports Server (NTRS)

    Claus, Russell W.; Dowd, Patrick W.; Srinidhi, Saragur M.; Blade, Eric D.G

    1995-01-01

    This report experimentally assesses the effect of the underlying network in a cluster-based computing environment. The assessment is quantified by application-level benchmarking, process-level communication, and network file input/output. Two testbeds were considered, one small cluster of Sun workstations and another large cluster composed of 32 high-end IBM RS/6000 platforms. The clusters had Ethernet, fiber distributed data interface (FDDI), Fibre Channel, and asynchronous transfer mode (ATM) network interface cards installed, providing the same processors and operating system for the entire suite of experiments. The primary goal of this report is to assess the suitability of an ATM-based, local-area network to support interprocess communication and remote file input/output systems for distributed computing.

  2. Analysis of CrIS ATMS and AIRS AMSU Data Using Scientifically Equivalent Retrieval Algorithms

    NASA Technical Reports Server (NTRS)

    Susskind, Joel; Kouvaris, Louis; Iredell, Lena; Blaisdell, John

    2016-01-01

    Monthly mean August 2014 Version-6.28 AIRS and CrIS products agree well with OMPS and CERES, and reasonably well with each other. Version-6.28 CrIS total precipitable water is biased dry compared to AIRS. AIRS and CrIS Version-6.36 water vapor products are both improved compared to Version-6.28. Version-6.36 AIRS and CrIS total precipitable water also shows improved agreement with each other. AIRS Version-6.36 total ozone agrees even better with OMPS than does AIRS Version-6.28, and gives reasonable results during polar winter where OMPS does not generate products. CrIS and ATMS are high spectral resolution IR and Microwave atmospheric sounders currently flying on the SNPP satellite, and are also scheduled for flight on future NPOESS satellites. CrIS/ATMS have similar sounding capabilities to those of the AIRS/AMSU sounder suite flying on EOS Aqua. The objective of this research is to develop and implement scientifically equivalent AIRS/AMSU and CrIS/ATMS retrieval algorithms with the goal of generating a continuous data record of AIRS/AMSU and CrIS/ATMS level-3 data products with a seamless transition between them in time. To achieve this, monthly mean AIRS/AMSU and CrIS/ATMS retrieved products, and more importantly their interannual differences, should show excellent agreement with each other. The currently operational AIRS Science Team Version-6 retrieval algorithm has generated 14 years of level-3 data products. A scientifically improved AIRS Version-7 retrieval algorithm is expected to become operational in 2017. We see significant improvements in water vapor and ozone in Version-7 retrieval methodology compared to Version-6.We are working toward finalization and implementation of scientifically equivalent AIRS/AMSU and CrIS/ATMS Version-7 retrieval algorithms to be used for the eventual processing of all AIRS/AMSU and CrIS/ATMS data. The latest version of our retrieval algorithm is Verison-6.36, which includes almost all the improvements we want in Version-7

  3. Results from CrIS/ATMS Obtained Using an "AIRS Version-6 Like" Retrieval Algorithm

    NASA Technical Reports Server (NTRS)

    Susskind, Joel; Kouvaris, Louis; Iredell, Lena; Blaisdell, John

    2015-01-01

    AIRS and CrIS Version-6.22 O3(p) and q(p) products are both superior to those of AIRS Version-6.Monthly mean August 2014 Version-6.22 AIRS and CrIS products agree reasonably well with OMPS, CERES, and witheach other. JPL plans to process AIRS and CrIS for many months and compare interannual differences. Updates to thecalibration of both CrIS and ATMS are still being finalized. We are also working with JPL to develop a joint AIRS/CrISlevel-1 to level-3 processing system using a still to be finalized Version-7 retrieval algorithm. The NASA Goddard DISCwill eventually use this system to reprocess all AIRS and recalibrated CrIS/ATMS. .

  4. Fielded ATM network for the Air National Guard Global Yankee Fort Drum exercise

    NASA Astrophysics Data System (ADS)

    Kaminski, Robert L.; Hague, Daniel; Maciag, Chester

    1996-06-01

    This paper will review the deployment, demonstration, and test of an Asynchronous Transfer Mode (ATM) network to support the Air National Guard `Global Yankee' field exercise held at Fort Drum, New York. The network provided forty five (45) megabit per second (mbps) ATM connections between the Air Operations Center (AOC) and Forward Operating Location (FOL) located at Fort Drum, the State University of New York (SUNY) Health Science Center located in Syracuse, New York and Rome Laboratory located in Rome, New York. Connections were made with both fiber and free space equipment. The fiber connections used were part of the existing ATM New York Network (NYNet) between Rome Lab, SUNY Health Science Center and NYNEX Corporation. This network was extended to Watertown, New York by NYNEX to provide connectivity to Fort Drum. The free space links were provided by commercial DS-3 (45 mbps) radios, and 2 to 6 mbps Troposcatter Satellite Support Radios (TSSRs). This paper will also discuss significant digital Command, Control, Communications and Intelligence enhancements to the battlefield provided by the deployed ATM network. For example, videoconferencing and shared workspace capability was demonstrated over the AOC-to-FOL TSSR link, enabling remote intelligence briefings, pilot Battle Damage Assessment, and Search and Rescue coordination. Remote Medical Diagnostics videoconferencing with MRI high resolution digital imagery was demonstrated between the FOL, AOC, and SUNY Health Science Center. Finally, the network provided connectivity between the AOC and the Joint Surveillance System (JSS) radar's located at Griffiss Air Force BAse. The JSS data combined with the Rome Lab developed Radar Analysis Program provided AOC personnel with air picture areas of interest.

  5. Bundling Internet Traffic over VBR ATM Networks, Canada - Germany Research Activity

    DTIC Science & Technology

    1998-12-01

    national ATM Test Network facilities, was supported by the CANARIE Test Network Operations Committee (TNOC) in Canada and by Deutsche Telekom and...Deutsche Telekom and DeTeBerkom in providing the use of CANT AT -3 and the access infrastructure. The following individuals provided valuable...submarine fibre cable. The CANARIE Test Network Operations Committee (TNOC) in Canada and Deutsche Telekom and DeTe- Berkom in Germany supported

  6. ATM Coastal Topography-Louisiana, 2001: UTM Zone 15 (Part 1 of 2)

    USGS Publications Warehouse

    Yates, Xan; Nayegandhi, Amar; Brock, John C.; Sallenger, A.H.; Klipp, Emily S.; Wright, C. Wayne

    2010-01-01

    These remotely sensed, geographically referenced elevation measurements of lidar-derived first-surface (FS) topography were produced collaboratively by the U.S. Geological Survey (USGS), Florida Integrated Science Center (FISC), St. Petersburg, FL, and the National Aeronautics and Space Administration (NASA), Wallops Flight Facility, VA. This project provides highly detailed and accurate datasets of a portion of the Louisiana coastline beach face within UTM Zone 15, from Isles Dernieres to Grand Isle, acquired September 7 and 10, 2001. The datasets are made available for use as a management tool to research scientists and natural-resource managers. An innovative scanning lidar instrument originally developed by NASA, and known as the Airborne Topographic Mapper (ATM), was used during data acquisition. The ATM system is a scanning lidar system that measures high-resolution topography of the land surface and incorporates a green-wavelength laser operating at pulse rates of 2 to 10 kilohertz. Measurements from the laser-ranging device are coupled with data acquired from inertial navigation system (INS) attitude sensors and differentially corrected global positioning system (GPS) receivers to measure topography of the surface at accuracies of +/-15 centimeters. The nominal ATM platform is a Twin Otter or P-3 Orion aircraft, but the instrument may be deployed on a range of light aircraft. Elevation measurements were collected over the survey area using the ATM system, and the resulting data were then processed using the Airborne Lidar Processing System (ALPS), a custom-built processing system developed in a NASA-USGS collaboration. ALPS supports the exploration and processing of lidar data in an interactive or batch mode. Modules for presurvey flight-line definition, flight-path plotting, lidar raster and waveform investigation, and digital camera image playback have been developed. Processing algorithms have been developed to extract the range to the first and last

  7. ATM Coastal Topography - Louisiana, 2001: UTM Zone 16 (Part 2 of 2)

    USGS Publications Warehouse

    Yates, Xan; Nayegandhi, Amar; Brock, John C.; Sallenger, Asbury H.; Klipp, Emily S.; Wright, C. Wayne

    2009-01-01

    These remotely sensed, geographically referenced elevation measurements of lidar-derived first-surface (FS) topography were produced collaboratively by the U.S. Geological Survey (USGS), Florida Integrated Science Center (FISC), St. Petersburg, FL, and the National Aeronautics and Space Administration (NASA), Wallops Flight Facility, VA. This project provides highly detailed and accurate datasets of a portion of the Louisiana coastline beach face within UTM Zone 16, from Grand Isle to the Chandeleur Islands, acquired September 7 and 9, 2001. The datasets are made available for use as a management tool to research scientists and natural-resource managers. An innovative scanning lidar instrument originally developed by NASA, and known as the Airborne Topographic Mapper (ATM), was used during data acquisition. The ATM system is a scanning lidar system that measures high-resolution topography of the land surface and incorporates a green-wavelength laser operating at pulse rates of 2 to 10 kilohertz. Measurements from the laser-ranging device are coupled with data acquired from inertial navigation system (INS) attitude sensors and differentially corrected global positioning system (GPS) receivers to measure topography of the surface at accuracies of +/-15 centimeters. The nominal ATM platform is a Twin Otter or P-3 Orion aircraft, but the instrument may be deployed on a range of light aircraft. Elevation measurements were collected over the survey area using the ATM system, and the resulting data were then processed using the Airborne Lidar Processing System (ALPS), a custom-built processing system developed in a NASA-USGS collaboration. ALPS supports the exploration and processing of lidar data in an interactive or batch mode. Modules for presurvey flight-line definition, flight-path plotting, lidar raster and waveform investigation, and digital camera image playback have been developed. Processing algorithms have been developed to extract the range to the first and

  8. Nuclear GIT2 Is an ATM Substrate and Promotes DNA Repair

    PubMed Central

    Lu, Daoyuan; Cai, Huan; Park, Sung-Soo; Siddiqui, Sana; Premont, Richard T.; Schmalzigaug, Robert; Paramasivam, Manikandan; Seidman, Michael; Bodogai, Ionoa; Biragyn, Arya; Daimon, Caitlin M.; Martin, Bronwen

    2015-01-01

    Insults to nuclear DNA induce multiple response pathways to mitigate the deleterious effects of damage and mediate effective DNA repair. G-protein-coupled receptor kinase-interacting protein 2 (GIT2) regulates receptor internalization, focal adhesion dynamics, cell migration, and responses to oxidative stress. Here we demonstrate that GIT2 coordinates the levels of proteins in the DNA damage response (DDR). Cellular sensitivity to irradiation-induced DNA damage was highly associated with GIT2 expression levels. GIT2 is phosphorylated by ATM kinase and forms complexes with multiple DDR-associated factors in response to DNA damage. The targeting of GIT2 to DNA double-strand breaks was rapid and, in part, dependent upon the presence of H2AX, ATM, and MRE11 but was independent of MDC1 and RNF8. GIT2 likely promotes DNA repair through multiple mechanisms, including stabilization of BRCA1 in repair complexes; upregulation of repair proteins, including HMGN1 and RFC1; and regulation of poly(ADP-ribose) polymerase activity. Furthermore, GIT2-knockout mice demonstrated a greater susceptibility to DNA damage than their wild-type littermates. These results suggest that GIT2 plays an important role in MRE11/ATM/H2AX-mediated DNA damage responses. PMID:25605334

  9. ATM induces MacroD2 nuclear export upon DNA damage.

    PubMed

    Golia, Barbara; Moeller, Giuliana Katharina; Jankevicius, Gytis; Schmidt, Andreas; Hegele, Anna; Preißer, Julia; Tran, Mai Ly; Imhof, Axel; Timinszky, Gyula

    2017-01-09

    ADP-ribosylation is a dynamic post-translation modification that regulates the early phase of various DNA repair pathways by recruiting repair factors to chromatin. ADP-ribosylation levels are defined by the activities of specific transferases and hydrolases. However, except for the transferase PARP1/ARDT1 little is known about regulation of these enzymes. We found that MacroD2, a mono-ADP-ribosylhydrolase, is exported from the nucleus upon DNA damage, and that this nuclear export is induced by ATM activity. We show that the export is dependent on the phosphorylation of two SQ/TQ motifs, suggesting a novel direct interaction between ATM and ADP-ribosylation. Lastly, we show that MacroD2 nuclear export temporally restricts its recruitment to DNA lesions, which may decrease the net ADP-ribosylhydrolase activity at the site of DNA damage. Together, our results identify a novel feedback regulation between two crucial DNA damage-induced signaling pathways: ADP-ribosylation and ATM activation. © The Author(s) 2016. Published by Oxford University Press on behalf of Nucleic Acids Research.

  10. Titanium dioxide nanoparticles activate the ATM-Chk2 DNA damage response in human dermal fibroblasts

    PubMed Central

    Prasad, Raju Y.; Chastain, Paul D.; Nikolaishvili-Feinberg, Nana; Smeester, Lisa M.; Kaufmann, William K.; Fry, Rebecca C.

    2013-01-01

    The use of nanoparticles in consumer products increases their prevalence in the environment and the potential risk to human health. Although recent studies have shown in vivo and in vitro toxicity of titanium dioxide nanoparticles (nano-TiO2), a more detailed view of the underlying mechanisms of this response needs to be established. Here the effects of nano-TiO2 on the DNA damage response and DNA replication dynamics were investigated in human dermal fibroblasts. Specifically, the relationship between nano-TiO2 and the DNA damage response pathways regulated by ATM/Chk2 and ATR/Chk1 were examined. The results show increased phosphorylation of H2AX, ATM, and Chk2 after exposure. In addition, nano-TiO2 inhibited the overall rate of DNA synthesis and frequency of replicon initiation events in DNA combed fibers. Taken together, these results demonstrate that exposure to nano-TiO2 activates the ATM/Chk2 DNA damage response pathway. PMID:22770119

  11. Phosphorylation of Daxx by ATM Contributes to DNA Damage-Induced p53 Activation

    PubMed Central

    Cheng, Qian; Qu, Like; Brewer, Michael D.; Chen, Jiandong; Yang, Xiaolu

    2013-01-01

    p53 plays a central role in tumor suppression. It does so by inducing anti-proliferative processes as a response to various tumor-promoting stresses. p53 is regulated by the ubiquitin ligase Mdm2. The optimal function of Mdm2 requires Daxx, which stabilizes Mdm2 through the deubiquitinase Hausp/USP7 and also directly promotes Mdm2’s ubiquitin ligase activity towards p53. The Daxx-Mdm2 interaction is disrupted upon DNA damage. However, both the mechanisms and the consequence of the Daxx-Mdm2 dissociation are not understood. Here we show that upon DNA damage Daxx is phosphorylated in a manner that is dependent on ATM, a member of the PI 3-kinase family that orchestrates the DNA damage response. The main phosphorylation site of Daxx is identified to be Ser564, which is a direct target of ATM. Phosphorylation of endogenous Daxx at Ser564 occurs rapidly during the DNA damage response and precedes p53 activation. Blockage of this phosphorylation event prevents the separation of Daxx from Mdm2, stabilizes Mdm2, and inhibits DNA damage-induced p53 activation. These results suggest that phosphorylation of Daxx by ATM upon DNA damage disrupts the Daxx-Mdm2 interaction and facilitates p53 activation. PMID:23405218

  12. ATM and MET kinases are synthetic lethal with non-genotoxic activation of p53

    PubMed Central

    Sullivan, Kelly D.; Padilla-Just, Nuria; Henry, Ryan E.; Porter, Christopher C.; Kim, Jihye; Tentler, John J.; Eckhardt, S. Gail; Tan, Aik Choon; DeGregori, James; Espinosa, Joaquín M.

    2012-01-01

    The p53 tumor suppressor orchestrates alternative stress responses including cell cycle arrest and apoptosis, but the mechanisms defining cell fate upon p53 activation are poorly understood. Several small molecule activators of p53 have been developed, including Nutlin-3, but their therapeutic potential is limited by the fact that they induce reversible cell cycle arrest in most cancer cell types. We report here the results of a ‘Synthetic Lethal with Nutlin-3’ genome-wide shRNA screen, which revealed that the ATM and MET kinases govern cell fate choice upon p53 activation. Genetic or pharmacological interference with ATM or MET activity converts the cellular response from cell cycle arrest into apoptosis in diverse cancer cell types without affecting expression of key p53 target genes. ATM and MET inhibitors enable Nutlin-3 to kill tumor spheroids. These results identify novel pathways controlling the cellular response to p53 activation and aid in the design of p53-based therapies. PMID:22660439

  13. A Benefits Assessment of the FAA's Enhanced Traffic Management System (ETMS): The Impact of Initial Products of the ATMS Program

    DOT National Transportation Integrated Search

    1992-12-01

    This study examined the benefits associated with the application of initial ATMS products, the Aircraft Situation Display and the Monitor Alert function, within the FAA's ETMS system. The benefits presented in this report represent those benefits acc...

  14. California ATMS Testbed : PHASE III: Operational Research Implementation : Final Report [Volume 1: Executive Summary ; and, Volume II: Technical Report

    DOT National Transportation Integrated Search

    2006-10-01

    This report summarizes research and development that has been conducted to position the Testbed to support prototype deployment and evaluation of Advanced Transportation Management Systems (ATMS) products and services. The various elements contained ...

  15. A case study : benefits associated with the sharing of ATMS-related video data in San Antonio, TX

    DOT National Transportation Integrated Search

    1998-08-11

    This paper summarizes various findings relating to the integration of Advanced Traffic Management System (ATMS) components of video data in San Antonio, TX. Specifically, the paper examines the perceived benefits derived from the sharing of video dat...

  16. Exploring the common molecular basis for the universal DNA mutation bias: Revival of Loewdin mutation model

    SciTech Connect

    Fu, Liang-Yu; Center for Bioinformatics, Huazhong Agricultural University, Wuhan 430070; Wang, Guang-Zhong

    2011-06-10

    Highlights: {yields} There exists a universal G:C {yields} A:T mutation bias in three domains of life. {yields} This universal mutation bias has not been sufficiently explained. {yields} A DNA mutation model proposed by Loewdin 40 years ago offers a common explanation. -- Abstract: Recently, numerous genome analyses revealed the existence of a universal G:C {yields} A:T mutation bias in bacteria, fungi, plants and animals. To explore the molecular basis for this mutation bias, we examined the three well-known DNA mutation models, i.e., oxidative damage model, UV-radiation damage model and CpG hypermutation model. It was revealed that these models cannot providemore » a sufficient explanation to the universal mutation bias. Therefore, we resorted to a DNA mutation model proposed by Loewdin 40 years ago, which was based on inter-base double proton transfers (DPT). Since DPT is a fundamental and spontaneous chemical process and occurs much more frequently within GC pairs than AT pairs, Loewdin model offers a common explanation for the observed universal mutation bias and thus has broad biological implications.« less

  17. Loss of H3K9me3 Correlates with ATM Activation and Histone H2AX Phosphorylation Deficiencies in Hutchinson-Gilford Progeria Syndrome.

    PubMed

    Zhang, Haoyue; Sun, Linlin; Wang, Kun; Wu, Di; Trappio, Mason; Witting, Celeste; Cao, Kan

    2016-01-01

    Compelling evidence suggests that defective DNA damage response (DDR) plays a key role in the premature aging phenotypes in Hutchinson-Gilford progeria syndrome (HGPS). Studies document widespread alterations in histone modifications in HGPS cells, especially, the global loss of histone H3 trimethylated on lysine 9 (H3K9me3). In this study, we explore the potential connection(s) between H3K9me3 loss and the impaired DDR in HGPS. When cells are exposed to a DNA-damaging agent Doxorubicin (Dox), double strand breaks (DSBs) are generated that result in the phosphorylation of histone H2A variant H2AX (gammaH2AX) within an hour. We find that the intensities of gammaH2AX foci appear significantly weaker in the G0/G1 phase HGPS cells compared to control cells. This reduction is associated with a delay in the recruitment of essential DDR factors. We further demonstrate that ataxia-telangiectasia mutated (ATM) is responsible for the amplification of gammaH2AX signals at DSBs during G0/G1 phase, and its activation is inhibited in the HGPS cells that display significant loss of H3K9me3. Moreover, methylene (MB) blue treatment, which is known to save heterochromatin loss in HGPS, restores H3K9me3, stimulates ATM activity, increases gammaH2AX signals and rescues deficient DDR. In summary, this study demonstrates an early DDR defect of attenuated gammaH2AX signals in G0/G1 phase HGPS cells and provides a plausible connection between H3K9me3 loss and DDR deficiency.

  18. Chemopreventive properties of pinoresinol-rich olive oil involve a selective activation of the ATM-p53 cascade in colon cancer cell lines.

    PubMed

    Fini, Lucia; Hotchkiss, Erin; Fogliano, Vincenzo; Graziani, Giulia; Romano, Marco; De Vol, Edward B; Qin, Huanying; Selgrad, Michael; Boland, C Richard; Ricciardiello, Luigi

    2008-01-01

    The Mediterranean diet is rich in extra virgin olive oil (EVOO) and associated with a lower incidence of colorectal cancer. EVOO contains phenolic extracts with potential anticarcinogenic activity. To assess the anticancer properties of EVOO phenolic extracts using in vitro models. Phenolic profiles of two different EVOOs (A and B) were determined. RKO and HCT116 (both p53 proficient), SW480 (p53 mutant) and HCT116(p53-/-) (p53 knocked out) cell lines were treated with EVOO extracts and assessed for cell viability. Apoptosis was determined by terminal deoxynucleotidyl transferase nick end labeling (TUNEL) assay and changes in Bax transcript levels. Cell cycle analysis was determined by flow cytometry and western blots. To confirm the data, analysis of cell viability and cell cycle was performed with purified pinoresinol. Chemical characterization showed that pinoresinol is the main phenol in EVOO-A, and oleocanthal predominates in EVOO-B. Only EVOO-A affected cell viability, which was significantly more pronounced in p53-proficient cells. At a concentration of 200 nM, p53-proficient cells showed increased apoptosis and G(2)/M arrest. In p53-proficient cells, ataxia telangiectasia mutated (ATM) and its downstream-controlled proteins were upregulated after treatment, with a parallel decrease of cyclin B/cdc2. Identical results on cell viability and cell cycle were obtained with purified pinoresinol, but this required a higher concentration than in EVOO-A. Our results demonstrate that pinoresinol-rich EVOO extracts have potent chemopreventive properties and specifically upregulate the ATM-p53 cascade. This result was achieved at substantially lower concentrations in EVOO than with purified pinoresinol, indicating a possible synergic effect between the various polyphenols in olive oil.

  19. Polychlorinated biphenyl quinone induces oxidative DNA damage and repair responses: The activations of NHEJ, BER and NER via ATM-p53 signaling axis

    SciTech Connect

    Dong, Hui; Shi, Qiong; Song, Xiufang

    2015-07-01

    Our previous studies demonstrated that polychlorinated biphenyl (PCB) quinone induced oxidative DNA damage in HepG2 cells. To promote genomic integrity, DNA damage response (DDR) coordinates cell-cycle transitions, DNA repair and apoptosis. PCB quinone-induced cell cycle arrest and apoptosis have been documented, however, whether PCB quinone insult induce DNA repair signaling is still unknown. In this study, we identified the activation of DDR and corresponding signaling events in HepG2 cells upon the exposure to a synthetic PCB quinone, PCB29-pQ. Our data illustrated that PCB29-pQ induces the phosphorylation of p53, which was mediated by ataxia telangiectasia mutated (ATM) protein kinase. The observedmore » phosphorylated histone H2AX (γ-H2AX) foci and the elevation of 8-hydroxy-2′-deoxyguanosine (8-OHdG) indicated that DDR was stimulated by PCB29-pQ treatment. Additionally, we found PCB29-pQ activates non-homologous end joining (NHEJ), base excision repair (BER) and nucleotide excision repair (NER) signalings. However, these repair pathways are not error-free processes and aberrant repair of DNA damage may cause the potential risk of carcinogenesis and mutagenesis. - Highlights: • Polychlorinated biphenyl quinone induces oxidative DNA damage in HepG2 cells. • The elevation of γ-H2AX and 8-OHdG indicates the activation of DNA damage response. • ATM-p53 signaling acts as the DNA damage sensor and effector. • Polychlorinated biphenyl quinone activates NHEJ, BER and NER signalings.« less

  20. Mice heterozygous for the ATM gene are more sensitive to heavy ions exposure than are wildtypes

    NASA Astrophysics Data System (ADS)

    Worgul, B.; Smilenov, L.; Brenner, D.; Vazquez, M.; Hall, E.

    Previous studies have shown that the eyes of atm heterozygous mice exposed to Low LET radiation (X-rays) are more susceptible to the development of cataracts than are those of wildtype mice. The findings, as well as others, run counter to the assumption underpinning current radiation safety guidelines, that individuals are all equally sensitive to the biological effects of radiation. A question, highly relevant to human space activities is whether or not, in similar fashion there may exist a genetic predisposition to High LET radiation damage. Again the lens and, its primary radiopathy, cataract, were used to assay for the effects of ATM deficiency in a late-responding tissue. Together with those of wildtypes, the eyes of AT heterozygous knockout mice were exposed to 325 mGy of 1 GEV/amu 56Fe ions at the AGS facility of Brookhaven National Laboratory. The fluence was equivalent to 1 ion per nuclear area. As was the case in the earlier X-ray studies all irradiations were done on the 28th day after birth. Controls consisted of wildtype irradiated as well as unirradiated wildtype and heterozygotes. Ten mice from each group were examined weekly by conventional slitlamp biomicroscopy for a total of 35 weeks. The time required for prevalence to reach 50% (T50) as an endpoint for each stage indicated that not only cataract onset but also progression were accelerated in the mice haplo-deficient for the atm gene. For example the T50 for definitive cataract onset (stage 1) in the atm heterozygotes was 10 weeks whereas 17 weeks were required for the wildtypes. Similarly at the conclusion of the experiment (35 weeks), 40% of the lenses of allele-deficient mice had progressed to stage 3 (near fully opaque and obviously visually debilitating), while only one lens (5%) from the wildtype irradiated eyes achieved that stage. The data show that heterozygosity for the atm gene predisposes the eye to the cataractogenic influence of heavy ions and suggest that AT heterozygotes in the

  1. Results from CrIS/ATMS Obtained Using an "AIRS Version-6 Like Retrieval Algorithm

    NASA Astrophysics Data System (ADS)

    Susskind, J.

    2015-12-01

    A main objective of AIRS/AMSU on EOS is to provide accurate sounding products that are used to generate climate data sets. Suomi NPP carries CrIS/ATMS that were designed as follow-ons to AIRS/AMSU. Our objective is to generate a long term climate data set of products derived from CrIS/ATMS to serve as a continuation of the AIRS/AMSU products. The Goddard DISC has generated AIRS/AMSU retrieval products, extending from September 2002 through real time, using the AIRS Science Team Version-6 retrieval algorithm. Level-3 gridded monthly mean values of these products, generated using AIRS Version-6, form a state of the art multi-year set of Climate Data Records (CDRs), which is expected to continue through 2022 and possibly beyond, as the AIRS instrument is extremely stable. The goal of this research is to develop and implement a CrIS/ATMS retrieval system to generate CDRs that are compatible with, and are of comparable quality to, those generated operationally using AIRS/AMSU data. The AIRS Science Team has made considerable improvements in AIRS Science Team retrieval methodology and is working on the development of an improved AIRS Science Team Version-7 retrieval methodology to be used to reprocess all AIRS data in the relatively near future. Research is underway by Dr. Susskind and co-workers at the NASA GSFC Sounder Research Team (SRT) towards the finalization of the AIRS Version-7 retrieval algorithm, the current version of which is called SRT AIRS Version-6.22. Dr. Susskind and co-workers have developed analogous retrieval methodology for analysis of CrIS/ATMS data, called SRT CrIS Version-6.22. Results will be presented that show that AIRS and CrIS products derived using a common further improved retrieval algorithm agree closely with each other and are both superior to AIRS Version 6. The goal of the AIRS Science Team is to continue to improve both AIRS and CrIS retrieval products and then use the improved retrieval methodology for the processing of past and

  2. Induction of ATM/ATR pathway combined with Vγ2Vδ2 T cells enhance cytotoxicity of ovarian cancer cells

    PubMed Central

    Lu, Jingwei; Das, Manjusri; Kanji, Suman; Aggarwal, Reeva; Joseph, Matthew; Ray, Alo; Shapiro, Charles L.; Pompili, Vincent J.; Das, Hiranmoy

    2014-01-01

    Summary Many ovarian cancer cells express stress-related molecule MICA/B on their surface that is recognized by Vγ2Vδ2 T cells through their NKG2D receptor, which is transmitted to downstream stress-signaling pathway. However, it is yet to be established how Vγ2Vδ2 T cells-mediated recognition of MICA/B signal is transmitted to downstream stress-related molecules. Identifying targeted molecules would be critical to develop a better therapy for ovarian cancer cells. It is well established that ATM/ATR signal transduction pathways, which is modulated by DNA damage, replication stress, and oxidative stress play central role in stress signaling pathway regulating cell cycle checkpoint and apoptosis. We investigated whether ATM/ATR and its down stream molecules affect Vγ2Vδ2 T cells-mediated cytotoxicity. Herein, we show that ATM/ATR pathway is modulated in ovarian cancer cells in presence of Vγ2Vδ2 T cells. Furthermore, downregulation of ATM pathway resulted downregulation of MICA, and reduced Vγ2Vδ2 T cells-mediated cytotoxicity. Alternately, stimulating ATM pathway enhanced expression of MICA, and sensitized ovarian cancer cells for cytotoxic lysis by Vγ2Vδ2 T cells. We further show that combining currently approved chemotherapeutic drugs, which induced ATM signal transduction, along with Vγ2Vδ2 T cells enhanced cytotoxicity of resistant ovarian cancer cells. These findings indicate that ATM/ATR pathway plays an important role in tumor recognition, and drugs promoting ATM signaling pathway might be considered as a combination therapy together with Vγ2Vδ2 T cells for effectively treating resistant ovarian cancer cells. PMID:24726882

  3. ATM inhibition induces synthetic lethality and enhances sensitivity of PTEN-deficient breast cancer cells to cisplatin.

    PubMed

    Li, Ke; Yan, Huaying; Guo, Wenhao; Tang, Mei; Zhao, Xinyu; Tong, Aiping; Peng, Yong; Li, Qintong; Yuan, Zhu

    2018-05-01

    PTEN deficiency often causes defects in DNA damage repair. Currently, effective therapies for breast cancer are lacking. ATM is an attractive target for cancer treatment. Previous studies suggested a synthetic lethality between PTEN and PARP. However, the synthetically lethal interaction between PTEN and ATM in breast cancer has not been reported. Moreover, the mechanism remains elusive. Here, using KU-60019, an ATM kinase inhibitor, we investigated ATM inhibition as a synthetically lethal strategy to target breast cancer cells with PTEN defects. We found that KU-60019 preferentially sensitizes PTEN-deficient MDA-MB-468 breast cancer cells to cisplatin, though it also slightly enhances sensitivity of PTEN wild-type breast cancer cells. The increased cytotoxic sensitivity is associated with apoptosis, as evidenced by flow cytometry and PARP cleavage. Additionally, the increase of DNA damage accumulation due to the decreased capability of DNA repair, as indicated by γ-H2AX and Rad51 foci, also contributed to this selective cytotoxicity. Mechanistically, compared with PTEN wild-type MDA-MB-231 cells, PTEN-deficient MDA-MB-468 cells have lower level of Rad51, higher ATM kinase activity, and display the elevated level of DNA damage. Moreover, these differences could be further enlarged by cisplatin. Our findings suggest that ATM is a promising target for PTEN-defective breast cancer. Copyright © 2018 Elsevier Inc. All rights reserved.

  4. Loss of the DNA Damage Repair Kinase ATM Impairs Inflammasome-Dependent Anti-Bacterial Innate Immunity.

    PubMed

    Erttmann, Saskia F; Härtlova, Anetta; Sloniecka, Marta; Raffi, Faizal A M; Hosseinzadeh, Ava; Edgren, Tomas; Rofougaran, Reza; Resch, Ulrike; Fällman, Maria; Ek, Torben; Gekara, Nelson O

    2016-07-19

    The ATM kinase is a central component of the DNA damage repair machinery and redox balance. ATM dysfunction results in the multisystem disease ataxia-telangiectasia (AT). A major cause of mortality in AT is respiratory bacterial infections. Whether ATM deficiency causes innate immune defects that might contribute to bacterial infections is not known. Here we have shown that loss of ATM impairs inflammasome-dependent anti-bacterial innate immunity. Cells from AT patients or Atm(-/-) mice exhibited diminished interleukin-1β (IL-1β) production in response to bacteria. In vivo, Atm(-/-) mice were more susceptible to pulmonary S. pneumoniae infection in a manner consistent with inflammasome defects. Our data indicate that such defects were due to oxidative inhibition of inflammasome complex assembly. This study reveals an unanticipated function of reactive oxygen species (ROS) in negative regulation of inflammasomes and proposes a theory for the notable susceptibility of AT patients to pulmonary bacterial infection. Copyright © 2016 Elsevier Inc. All rights reserved.

  5. The "S.W.A.T." Concept.

    ERIC Educational Resources Information Center

    Williamson, Bob; And Others

    1985-01-01

    Describes Statistical Work Analysis Teams (S.W.A.T.), which marry the two factors necessary for successful statistical analysis with the personal nature of attribute data into a single effort. Discusses S.W.A.T. project guidelines, implementation of the first S.W.A.T. projects, team training, and project completion. (CT)

  6. Retrieving Atmospheric Temperature and Moisture Profiles from NPP CRIS/ATMS Sensors Using Crimss EDR Algorithm

    NASA Technical Reports Server (NTRS)

    Liu, X.; Kizer, S.; Barnet, C.; Dvakarla, M.; Zhou, D. K.; Larar, A. M.

    2012-01-01

    The Joint Polar Satellite System (JPSS) is a U.S. National Oceanic and Atmospheric Administration (NOAA) mission in collaboration with the U.S. National Aeronautical Space Administration (NASA) and international partners. The NPP Cross-track Infrared Microwave Sounding Suite (CrIMSS) consists of the infrared (IR) Crosstrack Infrared Sounder (CrIS) and the microwave (MW) Advanced Technology Microwave Sounder (ATMS). The CrIS instrument is hyperspectral interferometer, which measures high spectral and spatial resolution upwelling infrared radiances. The ATMS is a 22-channel radiometer similar to Advanced Microwave Sounding Units (AMSU) A and B. It measures top of atmosphere MW upwelling radiation and provides capability of sounding below clouds. The CrIMSS Environmental Data Record (EDR) algorithm provides three EDRs, namely the atmospheric vertical temperature, moisture and pressure profiles (AVTP, AVMP and AVPP, respectively), with the lower tropospheric AVTP and the AVMP being JPSS Key Performance Parameters (KPPs). The operational CrIMSS EDR an algorithm was originally designed to run on large IBM computers with dedicated data management subsystem (DMS). We have ported the operational code to simple Linux systems by replacing DMS with appropriate interfaces. We also changed the interface of the operational code so that we can read data from both the CrIMSS science code and the operational code and be able to compare lookup tables, parameter files, and output results. The detail of the CrIMSS EDR algorithm is described in reference [1]. We will present results of testing the CrIMSS EDR operational algorithm using proxy data generated from the Infrared Atmospheric Sounding Interferometer (IASI) satellite data and from the NPP CrIS/ATMS data.

  7. Convective transport in ATM simulations and its relation to the atmospheric stability conditions

    NASA Astrophysics Data System (ADS)

    Kusmierczyk-Michulec, Jolanta

    2017-04-01

    The International Monitoring System (IMS) developed by the Comprehensive Nuclear-Test-Ban Treaty Organization (CTBTO) is a global system of monitoring stations, using four complementary technologies: seismic, hydroacoustic, infrasound and radionuclide. Data from all stations, belonging to IMS, are collected and transmitted to the International Data Centre (IDC) in Vienna, Austria. The radionuclide network comprises 80 stations, of which more than 60 are certified. The aim of radionuclide stations is a global monitoring of radioactive aerosols and radioactive noble gases, in particular xenon isotopes, supported by the atmospheric transport modeling (ATM). One of the important noble gases, monitored on a daily basis, is radioxenon. It can be produced either during a nuclear explosion with a high fission yield, and thus be considered as an important tracer to prove the nuclear character of an explosion, or be emitted from nuclear power plants (NPPs) or from isotope production facilities (IPFs). To investigate the transport of xenon emissions, the Provisional Technical Secretariat (PTS) operates an Atmospheric Transport Modelling (ATM) system based on the Lagrangian Particle Dispersion Model FLEXPART. To address the question whether including the convective transport in ATM simulations will change the results significantly, the differences between the outputs with the convective transport turned off and turned on, were computed and further investigated taking into account the atmospheric stability conditions. For that purpose series of 14 days forward simulations, with convective transport and without it, released daily in the period January 2011 to February 2012, were analysed. The release point was at the ANSTO facility in Australia. The unique opportunity of having access to both daily emission values for ANSTO as well as measured Xe-133 activity concentration (AC) values at the IMS stations, gave a chance to validate the simulations.

  8. Possession of ATM Sequence Variants as Predictor for Late Normal Tissue Responses in Breast Cancer Patients Treated With Radiotherapy

    SciTech Connect

    Ho, Alice Y.; Fan, Grace; Atencio, David P.

    2007-11-01

    Purpose: The ATM gene product is a central component of cell cycle regulation and genomic surveillance. We hypothesized that DNA sequence alterations in ATM predict for adverse effects after external beam radiotherapy for early breast cancer. Methods and Materials: A total of 131 patients with a minimum of 2 years follow-up who had undergone breast-conserving surgery and adjuvant radiotherapy were screened for sequence alterations in ATM using DNA from blood lymphocytes. Genetic variants were identified using denaturing high performance liquid chromatography. The Radiation Therapy Oncology Group late morbidity scoring schemes for skin and subcutaneous tissues were applied to quantify themore » radiation-induced effects. Results: Of the 131 patients, 51 possessed ATM sequence alterations located within exons or in short intron regions flanking each exon that encompass putative splice site regions. Of these 51 patients, 21 (41%) exhibited a minimum of a Grade 2 late radiation response. In contrast, of the 80 patients without an ATM sequence variation, only 18 (23%) had radiation-induced adverse responses, for an odds ratio of 2.4 (95% confidence interval, 1.1-5.2). Fifteen patients were heterozygous for the G{yields}A polymorphism at nucleotide 5557, which causes substitution of asparagine for aspartic acid at position 1853 of the ATM protein. Of these 15 patients, 8 (53%) exhibited a Grade 2-4 late response compared with 31 (27%) of the 116 patients without this alteration, for an odds ratio of 3.1 (95% confidence interval, 1.1-9.4). Conclusion: Sequence variants located in the ATM gene, in particular the 5557 G{yields}A polymorphism, may predict for late adverse radiation responses in breast cancer patients.« less

  9. ATM C and D panel/EREP cooling system contamination problem. [on Skylab

    NASA Technical Reports Server (NTRS)

    Williamson, J. G.

    1973-01-01

    This report presents the history of a preflight contamination problem that occurred in the ATM C and D panel/EREP cooling system on the Skylab, the studies that were made to determine the cause of the problem, and corrective actions that were made prior to lift-off. The results of all the observations, analyses and laboratory testing indicated that the contamination came from one or more of the EREP tape recorder coldplates and was caused by some abnormal electrolytic action, either during bench testing or in the spacecraft. Studies indicate that no such electrolytic action is likely to occur under normal operating conditions.

  10. Beta-binomial video traffic modeling for the knockout ATM multicasting switch

    NASA Astrophysics Data System (ADS)

    Rodriguez-Dagnino, Ramon M.; Bustos-Gardea, Raime A.

    1998-10-01

    Performance studies of ATM switches typically consider the binomial distribution to model the traffic behavior at the input of the switch. For instance, the basic knockout principle for the packet loss performance measure, has been solved by considering the binomial assumption in most of the cases. In this paper, we have found that the binomial distribution remains essentially valid for modeling MPEG video traces at the input of the switch, however, in video- on-demand applications with multicasting, the binomial assumption is no longer valid. In this case we have found that the beta-binomial model for the knockout switch gives a better cell loss performance prediction.

  11. Novel quinazoline HMJ-30 induces U-2 OS human osteogenic sarcoma cell apoptosis through induction of oxidative stress and up-regulation of ATM/p53 signaling pathway.

    PubMed

    Chiu, Yu-Jen; Hour, Mann-Jen; Lu, Chi-Cheng; Chung, Jing-Gung; Kuo, Sheng-Chu; Huang, Wen-Wen; Chen, Hui-Jye; Jin, Yi-An; Yang, Jai-Sing

    2011-09-01

    Human osteogenic sarcoma is the most common primary bone tumor. Despite of the success of frontline therapy, about 40% of patients have disease progression and further therapy is palliative and toxic. In this study, we developed a novel quinazoline HMJ-30 to investigate the cell growth inhibition and apoptotic responses in U-2 OS human osteogenic sarcoma cells. Our results demonstrated that HMJ-30 significantly reduced cell viabilities of U-2 OS, HOS, and 143B cells in a dose-dependent manner, but it exhibited low cytotoxicity in normal hFOB cells. HMJ-30 induced DNA damage and apoptosis in U-2 OS cells as revealed by morphologic changes, comet assay and DAPI staining. Immuno-staining, colorimetric assays, and Western blotting analyses indicated that activities of caspase-8, caspase-9, and caspase-3 and the levels of Bcl-2 family-related proteins (Bcl-2, Mcl-1, Bax, BAD, and t-Bid) were altered in HMJ-30-treated U-2 OS cells. Pretreatment of cells with caspase-8, -9, and -3 specific inhibitors significantly reduced the cell growth inhibition. HMJ-30-induced apoptosis was mediated through both death-receptor and mitochondria-dependent apoptotic pathways in U-2 OS cells. HMJ-30 induced early phosphorylation of p53(Ser18) was through the activation of ataxia telangiectasia mutated (ATM) in U-2 OS cells. The cell growth inhibition by HMJ-30 was substantially attenuated either by the pre-incubation of U-2 OS cells with N-acetylcysteine (NAC, an antioxidant) and caffeine (an ATM kinase inhibitor) or by p53 knockdown via RNAi. In conclusion, ROS dependent-ATM/p53 signaling pathway is involved in HMJ-30-induced apoptosis in U-2 OS cells. Copyright © 2011 Orthopaedic Research Society.

  12. Autophagy inhibition enhances apoptosis triggered by BO-1051, an N-mustard derivative, and involves the ATM signaling pathway.

    PubMed

    Chen, Li-Hsin; Loong, Che-Chuan; Su, Tsann-Long; Lee, Yi-Jang; Chu, Pei-Ming; Tsai, Ming-Long; Tsai, Ping-Hsin; Tu, Pang-Hsien; Chi, Chin-Wen; Lee, Hsin-Chen; Chiou, Shih-Hwa

    2011-03-01

    In a previous study, BO-1051, an N-mustard linked with a DNA-affinic molecule, was shown to target various types of cancer cell lines. In the present study, we aimed to investigate the cytotoxicity, as well as the underlying mechanism, of BO-1051. We found that BO-1051 simultaneously induced apoptosis and autophagy in hepatocellular carcinoma cell lines. DNA double strand breaks induced by BO-1051 activated the ATM signaling pathway and subsequently resulted in caspase-dependent apoptosis. When autophagy was inhibited in its early or late stages, apoptosis was significantly enhanced. This result indicated autophagy as a cytoprotective effect against BO-1051-induced cell death. We further inhibited ATM activation using an ATM kinase inhibitor or ATM-specific siRNA and found that while apoptosis was blocked, autophagy also diminished in response to BO-1051. We not only determined a signaling pathway induced by BO-1051 but also clarified the linkage between DNA damage-induced apoptosis and autophagy. We also showed that BO-1051-induced autophagy acts as a cytoprotective reaction and downstream target of the ATM-signaling pathway. This research revealed autophagy as a universal cytoprotective response against DNA damage-inducing chemotherapeutic agents, including BO-1051, cisplatin, and doxorubicin, in hepatocellular carcinoma cell lines. Autophagy contributes to the remarkable drug resistance ability of liver cancer. Copyright © 2011 Elsevier Inc. All rights reserved.

  13. Development of a model and test equipment for cold flow tests at 500 atm of small nuclear light bulb configurations

    NASA Technical Reports Server (NTRS)

    Jaminet, J. F.

    1972-01-01

    A model and test equipment were developed and cold-flow-tested at greater than 500 atm in preparation for future high-pressure rf plasma experiments and in-reactor tests with small nuclear light bulb configurations. With minor exceptions, the model chamber is similar in design and dimensions to a proposed in-reactor geometry for tests with fissioning uranium plasmas in the nuclear furnace. The model and the equipment were designed for use with the UARL 1.2-MW rf induction heater in tests with rf plasmas at pressures up to 500 atm. A series of cold-flow tests of the model was then conducted at pressures up to about 510 atm. At 504 atm, the flow rates of argon and cooling water were 3.35 liter/sec (STP) and 26 gal/min, respectively. It was demonstrated that the model is capable of being operated for extended periods at the 500-atm pressure level and is, therefore, ready for use in initial high-pressure rf plasma experiments.

  14. AES Cardless Automatic Teller Machine (ATM) Biometric Security System Design Using FPGA Implementation

    NASA Astrophysics Data System (ADS)

    Ahmad, Nabihah; Rifen, A. Aminurdin M.; Helmy Abd Wahab, Mohd

    2016-11-01

    Automated Teller Machine (ATM) is an electronic banking outlet that allows bank customers to complete a banking transactions without the aid of any bank official or teller. Several problems are associated with the use of ATM card such card cloning, card damaging, card expiring, cast skimming, cost of issuance and maintenance and accessing customer account by third parties. The aim of this project is to give a freedom to the user by changing the card to biometric security system to access the bank account using Advanced Encryption Standard (AES) algorithm. The project is implemented using Field Programmable Gate Array (FPGA) DE2-115 board with Cyclone IV device, fingerprint scanner, and Multi-Touch Liquid Crystal Display (LCD) Second Edition (MTL2) using Very High Speed Integrated Circuit Hardware (VHSIC) Description Language (VHDL). This project used 128-bits AES for recommend the device with the throughput around 19.016Gbps and utilized around 520 slices. This design offers a secure banking transaction with a low rea and high performance and very suited for restricted space environments for small amounts of RAM or ROM where either encryption or decryption is performed.

  15. Semantic Service Matchmaking in the ATM Domain Considering Infrastructure Capability Constraints

    NASA Astrophysics Data System (ADS)

    Moser, Thomas; Mordinyi, Richard; Sunindyo, Wikan Danar; Biffl, Stefan

    In a service-oriented environment business processes flexibly build on software services provided by systems in a network. A key design challenge is the semantic matchmaking of business processes and software services in two steps: 1. Find for one business process the software services that meet or exceed the BP requirements; 2. Find for all business processes the software services that can be implemented within the capability constraints of the underlying network, which poses a major problem since even for small scenarios the solution space is typically very large. In this chapter we analyze requirements from mission-critical business processes in the Air Traffic Management (ATM) domain and introduce an approach for semi-automatic semantic matchmaking for software services, the “System-Wide Information Sharing” (SWIS) business process integration framework. A tool-supported semantic matchmaking process like SWIS can provide system designers and integrators with a set of promising software service candidates and therefore strongly reduces the human matching effort by focusing on a much smaller space of matchmaking candidates. We evaluate the feasibility of the SWIS approach in an industry use case from the ATM domain.

  16. ATM-dependent chromatin remodeler Rsf-1 facilitates DNA damage checkpoints and homologous recombination repair.

    PubMed

    Min, Sunwoo; Jo, Sujin; Lee, Ho-Soo; Chae, Sunyoung; Lee, Jong-Soo; Ji, Jae-Hoon; Cho, Hyeseong

    2014-01-01

    As a member of imitation switch (ISWI) family in ATP-dependent chromatin remodeling factors, RSF complex consists of SNF2h ATPase and Rsf-1. Although it has been reported that SNF2h ATPase is recruited to DNA damage sites (DSBs) in a poly(ADP-ribosyl) polymerase 1 (PARP1)-dependent manner in DNA damage response (DDR), the function of Rsf-1 is still elusive. Here we show that Rsf-1 is recruited to DSBs confirmed by various cellular analyses. Moreover, the initial recruitment of Rsf-1 and SNF2h to DSBs shows faster kinetics than that of γH2AX after micro-irradiation. Signals of Rsf-1 and SNF2h are retained over 30 min after micro-irradiation, whereas γH2AX signals are gradually reduced at 10 min. In addition, Rsf-1 is accumulated at DSBs in ATM-dependent manner, and the putative pSQ motifs of Rsf-1 by ATM are required for its accumulation at DSBs. Furtheremore, depletion of Rsf-1 attenuates the activation of DNA damage checkpoint signals and cell survival upon DNA damage. Finally, we demonstrate that Rsf-1 promotes homologous recombination repair (HRR) by recruiting resection factors RPA32 and Rad51. Thus, these findings reveal a new function of chromatin remodeler Rsf-1 as a guard in DNA damage checkpoints and homologous recombination repair.

  17. Technologies for developing an advanced intelligent ATM with self-defence capabilities

    NASA Astrophysics Data System (ADS)

    Sako, Hiroshi

    2010-01-01

    We have developed several technologies for protecting automated teller machines. These technologies are based mainly on pattern recognition and are used to implement various self-defence functions. They include (i) banknote recognition and information retrieval for preventing machines from accepting counterfeit and damaged banknotes and for retrieving information about detected counterfeits from a relational database, (ii) form processing and character recognition for preventing machines from accepting remittance forms without due dates and/or insufficient payment, (iii) person identification to prevent machines from transacting with non-customers, and (iv) object recognition to guard machines against foreign objects such as spy cams that might be surreptitiously attached to them and to protect users against someone attempting to peek at their user information such as their personal identification number. The person identification technology has been implemented in most ATMs in Japan, and field tests have demonstrated that the banknote recognition technology can recognise more then 200 types of banknote from 30 different countries. We are developing an "advanced intelligent ATM" that incorporates all of these technologies.

  18. Homeostatic nuclear RAGE-ATM interaction is essential for efficient DNA repair.

    PubMed

    Kumar, Varun; Fleming, Thomas; Terjung, Stefan; Gorzelanny, Christian; Gebhardt, Christoffer; Agrawal, Raman; Mall, Marcus A; Ranzinger, Julia; Zeier, Martin; Madhusudhan, Thati; Ranjan, Satish; Isermann, Berend; Liesz, Arthur; Deshpande, Divija; Häring, Hans-Ulrich; Biswas, Subrata K; Reynolds, Paul R; Hammes, Hans-Peter; Peperkok, Rainer; Angel, Peter; Herzig, Stephan; Nawroth, Peter P

    2017-10-13

    The integrity of genome is a prerequisite for healthy life. Indeed, defects in DNA repair have been associated with several human diseases, including tissue-fibrosis, neurodegeneration and cancer. Despite decades of extensive research, the spatio-mechanical processes of double-strand break (DSB)-repair, especially the auxiliary factor(s) that can stimulate accurate and timely repair, have remained elusive. Here, we report an ATM-kinase dependent, unforeseen function of the nuclear isoform of the Receptor for Advanced Glycation End-products (nRAGE) in DSB-repair. RAGE is phosphorylated at Serine376 and Serine389 by the ATM kinase and is recruited to the site of DNA-DSBs via an early DNA damage response. nRAGE preferentially co-localized with the MRE11 nuclease subunit of the MRN complex and orchestrates its nucleolytic activity to the ATR kinase signaling. This promotes efficient RPA2S4-S8 and CHK1S345 phosphorylation and thereby prevents cellular senescence, IPF and carcinoma formation. Accordingly, loss of RAGE causatively linked to perpetual DSBs signaling, cellular senescence and fibrosis. Importantly, in a mouse model of idiopathic pulmonary fibrosis (RAGE-/-), reconstitution of RAGE efficiently restored DSB-repair and reversed pathological anomalies. Collectively, this study identifies nRAGE as a master regulator of DSB-repair, the absence of which orchestrates persistent DSB signaling to senescence, tissue-fibrosis and oncogenesis. © The Author(s) 2017. Published by Oxford University Press on behalf of Nucleic Acids Research.

  19. Mutation of Ataxia–Telangiectasia Mutated is Associated with Dysfunctional Glutathione Homeostasis in Cerebellar Astroglia

    PubMed Central

    Campbell, Andrew; Bushman, Jared; Munger, Joshua; Noble, Mark; Pröoschel, Christoph; Mayer-Pröoschel, Margot

    2017-01-01

    Astroglial dysfunction plays an important role in neurodegenerative diseases otherwise attributed to neuronal loss of function. Here we focus on the role of astroglia in ataxia–telangiectasia (A–T), a disease caused by mutations in the ataxia–telangiectasia mutated (ATM) gene. A hallmark of A–T pathology is progressive loss of cerebellar neurons, but the mechanisms that impact neuronal survival are unclear. We now provide a possible mechanism by which A–T astroglia affect the survival of cerebellar neurons. As astroglial functions are difficult to study in an in vivo setting, particularly in the cerebellum where these cells are intertwined with the far more numerous neurons, we conducted in vitro coculture experiments that allow for the generation and pharmacological manipulation of purified cell populations. Our analyses revealed that cerebellar astroglia isolated from Atm mutant mice show decreased expression of the cystine/glutamate exchanger subunit xCT, glutathione (GSH) reductase, and glutathione-S-transferase. We also found decreased levels of intercellular and secreted GSH in A–T astroglia. Metabolic labeling of L-cystine, the major precursor for GSH, revealed that a key component of the defect in A–T astroglia is an impaired ability to import this rate-limiting precursor for the production of GSH. This impairment resulted in suboptimal extracellular GSH supply, which in turn impaired survival of cerebellar neurons. We show that by circumventing the xCT-dependent import of L-cystine through addition of N-acetyl-L-cysteine (NAC) as an alternative cysteine source, we were able to restore GSH levels in A–T mutant astroglia providing a possible future avenue for targeted therapeutic intervention. PMID:26469940

  20. Defective ATM-Kap-1-mediated chromatin remodeling impairs DNA repair and accelerates senescence in progeria mouse model.

    PubMed

    Liu, Baohua; Wang, Zimei; Ghosh, Shrestha; Zhou, Zhongjun

    2013-04-01

    ATM-mediated phosphorylation of KAP-1 triggers chromatin remodeling and facilitates the loading and retention of repair proteins at DNA lesions. Mouse embryonic fibroblasts (MEFs) derived from Zmpste24(-/-) mice undergo early senescence, attributable to delayed recruitment of DNA repair proteins. Here, we show that ATM-Kap-1 signaling is compromised in Zmpste24(-/-) MEFs, leading to defective DNA damage-induced chromatin remodeling. Knocking down Kap-1 rescues impaired chromatin remodeling, defective DNA repair and early senescence in Zmpste24(-/-) MEFs. Thus, ATM-Kap-1-mediated chromatin remodeling plays a critical role in premature aging, carrying significant implications for progeria therapy. © 2012 The Authors Aging Cell © 2012 Blackwell Publishing Ltd/Anatomical Society of Great Britain and Ireland.

  1. DNA damage induces a kinetochore-based ATM/ATR-independent SAC arrest unique to the first meiotic division in mouse oocytes

    PubMed Central

    Morgan, Stephanie L.; Wu, Tianyu; Collins, Josie K.; Merriman, Julie A.; ElInati, Elias; Turner, James M.

    2017-01-01

    Mouse oocytes carrying DNA damage arrest in meiosis I, thereby preventing creation of embryos with deleterious mutations. The arrest is dependent on activation of the spindle assembly checkpoint, which results in anaphase-promoting complex (APC) inhibition. However, little is understood about how this checkpoint is engaged following DNA damage. Here, we find that within minutes of DNA damage checkpoint proteins are assembled at the kinetochore, not at damage sites along chromosome arms, such that the APC is fully inhibited within 30 min. Despite this robust response, there is no measurable loss in k-fibres, or tension across the bivalent. Through pharmacological inhibition we observed that the response is dependent on Mps1 kinase, aurora kinase and Haspin. Using oocyte-specific knockouts we find the response does not require the DNA damage response kinases ATM or ATR. Furthermore, checkpoint activation does not occur in response to DNA damage in fully mature eggs during meiosis II, despite the divisions being separated by just a few hours. Therefore, mouse oocytes have a unique ability to sense DNA damage rapidly by activating the checkpoint at their kinetochores. PMID:28851706

  2. Comparative Results of AIRS/AMSU and CrIS/ATMS Retrievals Using a Scientifically Equivalent Retrieval Algorithm

    NASA Technical Reports Server (NTRS)

    Susskind, Joel; Kouvaris, Louis; Iredell, Lena

    2016-01-01

    The AIRS Science Team Version-6 retrieval algorithm is currently producing high quality level-3 Climate Data Records (CDRs) from AIRS/AMSU which are critical for understanding climate processes. The AIRS Science Team is finalizing an improved Version-7 retrieval algorithm to reprocess all old and future AIRS data. AIRS CDRs should eventually cover the period September 2002 through at least 2020. CrIS/ATMS is the only scheduled follow on to AIRS/AMSU. The objective of this research is to prepare for generation of long term CrIS/ATMS CDRs using a retrieval algorithm that is scientifically equivalent to AIRS/AMSU Version-7.

  3. Project W.A.T.E.R.

    ERIC Educational Resources Information Center

    EnviroTeach, 1992

    1992-01-01

    Introduces networking projects for studying rivers and water quality. Describes two projects in South Africa (Project W.A.T.E.R and SWAP) associated with the international network, Global Rivers Environmental Education Network. Discusses water test kits and educational material developed through Project W.A.T.E.R. (Water Awareness through…

  4. The Advanced Technology Microwave Sounder (ATMS): First Year On-Orbit

    NASA Technical Reports Server (NTRS)

    Kim, Edward J.

    2012-01-01

    The Advanced Technology Microwave Sounder (ATMS) is a new satellite microwave sounding sensor designed to provide operational weather agencies with atmospheric temperature and moisture profile information for global weather forecasting and climate applications. A TMS will continue the microwave sounding capabilities first provided by its predecessors, the Microwave Sounding Unit (MSU) and Advanced Microwave Sounding Unit (AMSU). The first flight unit was launched a year ago in October, 2011 aboard the Suomi-National Polar-Orbiting Partnership (S-NPP) satellite, part of the new Joint Polar-Orbiting Satellite System (JPSS). Microwave soundings by themselves are the highest-impact input data used by Numerical Weather Prediction models; and A TMS, when combined with the Cross-track Infrared Sounder (CrIS), forms the Cross-track Infrared and Microwave Sounding Suite (CrIMSS). The microwave soundings help meet sounding requirements under cloudy sky conditions and provide key profile information near the surface. ATMS was designed & built by Aerojet Corporation in Azusa, California, (now Northrop Grumman Electronic Systems). It has 22 channels spanning 23-183 GHz, closely following the channel set of the MSU, AMSU-AI/2, AMSU-B, Microwave Humidity Sounder (MHS), and Humidity Sounder for Brazil (HSB). It continues their cross-track scanning geometry, but for the first time, provides Nyquist sample spacing. All this is accomplished with approximately V. the volume, Y, the mass, and Y, the power of the three AMSUs. A description will be given of its performance from its first year of operation as determined by post-launch calibration activities. These activities include radiometric calibration using the on-board warm targets and cold space views, and geolocation determination. Example imagery and zooms of specific weather events will be shown. The second ATMS flight model is currently under construction and planned for launch on the "Jl" satellite of the JPSS program in

  5. Antennas Designed for Advanced Communications for Air Traffic Management (AC/ATM) Project

    NASA Technical Reports Server (NTRS)

    Zakrajsek, Robert J.

    2000-01-01

    The goal of the Advanced Communications for Air Traffic Management (AC/ATM) Project at the NASA Glenn Research Center at Lewis Field is to enable a communications infrastructure that provides the capacity, efficiency, and flexibility necessary to realize a mature free-flight environment. The technical thrust of the AC/ATM Project is targeted at the design, development, integration, test, and demonstration of enabling technologies for global broadband aeronautical communications. Since Ku-band facilities and equipment are readily available, one of the near-term demonstrations involves a link through a Kuband communications satellite. Two conformally mounted antennas will support the initial AC/ATM communications links. Both of these are steered electronically through monolithic microwave integrated circuit (MMIC) amplifiers and phase shifters. This link will be asymmetrical with the downlink to the aircraft (mobile vehicle) at a throughput rate of greater than 1.5 megabits per second (Mbps), whereas the throughput rate of the uplink from the aircraft will be greater than 100 kilobits per second (kbps). The data on the downlink can be narrow-band, wide-band, or a combination of both, depending on the requirements of the experiment. The AC/ATM project is purchasing a phased-array Ku-band transmitting antenna for the uplink from the test vehicle. Many Ku-band receiving antennas have been built, and one will be borrowed for a short time to perform the initial experiments at the NASA Glenn Research Center at Lewis Field. The Ku-band transmitting antenna is a 254-element MMIC phased-array antenna being built by Boeing Phantom Works. Each element can radiate 100 mW. The antenna is approximately 43-cm high by 24-cm wide by 3.3-cm thick. It can be steered beyond 60 from broadside. The beamwidth varies from 6 at broadside to 12 degrees at 60 degrees, which is typical of phased-array antennas. When the antenna is steered to 60 degrees, the beamwidth will illuminate

  6. The study of an ATM switch system used for on-board processing

    NASA Astrophysics Data System (ADS)

    Li, Yong; Xiong, Huibo

    2007-11-01

    On-board processing (OBP) is one of significant satellite communication technologies, and the Asynchronous Transfer Mode (ATM) is widely used in the OBP which can guarantee the QoS. This article presents the CAC (Call Admission Control) algorithm and Congestion Control algorithm. We combine with B-CAC algorithm, Bahadur-Rao's theory, Weiss theory, to improve the old method, and the simulation results show that when the PDR/LR is small the burst is high, the chain utilization and statistic multiplexing gain get a big advantage. Besides, concerning TCP congestion control, the article compared five strategies: Tahoe, Reno, Newreno, Sack and Vegas. The simulation results show that the Vegas can be used to predict congestion conditions correctly; its congestion window (cwnd) control is smoother and is superior to other algorithms in average RTT.

  7. ATM-like kinases and regulation of telomerase: lessons from yeast and mammals

    PubMed Central

    Sabourin, Michelle; Zakian, Virginia A.

    2008-01-01

    Telomeres, the essential structures at the ends of eukaryotic chromosomes, are composed of G-rich DNA and asociated proteins. These structures are crucial for the integrity of the genome, because they protect chromosome ends from degradation and distinguish natural ends from chromosomal breaks. The complete replication of telomeres requires a telomere-dedicated reverse transcriptase called telomerase. Paradoxically, proteins that promote the very activities against which telomeres protect, namely DNA repair, recombination and checkpoint activation, are integral to both telomeric chromatin and telomere elongation. This review focuses on recent findings that shed light on the roles of ATM-like kinases and other checkpoint and repair proteins in telomere maintenance, replication and checkpoint signaling. PMID:18502129

  8. Fenómenos solares que afectan la atmósfera terrestre

    NASA Astrophysics Data System (ADS)

    Rovira, M.

    Se describen los principales fenómenos solares como fulguraciones, prominencias eruptivas, viento solar y eyecciones de masa coronal (CME) que tienen consecuencias en la atmósfera terrestre. En algunos casos el material es eyectado a velocidades superiores a los 900 km/seg y tarda menos de 48 horas en llegar a la Tierra. En general, estos CME no son peligrosos ya que el campo magnético terrestre actúa como protector siendo un aislante efectivo. Si el viento solar es muy intenso puede comprimir la magnetósfera y producir una tormenta geomagnética. En casos extremos, puede interferir la transmisión de potencia eléctrica, perturbar los satélites y producir auroras polares.

  9. NRL-ATM extreme ultraviolet solar image TV monitor flown on Skylab

    NASA Technical Reports Server (NTRS)

    Crockett, W. R.; Purcell, J. D.; Schumacher, R. J.; Tousey, R.; Patterson, N. P.

    1977-01-01

    An instrument for recording extreme ultraviolet television images of the sun was flown in the Apollo Telescope Mount on Skylab. Solar radiation in the 171-630 A wavelength range, defined by the transmission band of three thin-film aluminum filters, was focused onto a p-quaterphenyl photon conversion layer by a platinum-coated mirror at normal incidence. The conversion layer was attached to the faceplate of a low light level SEC vidicon. An onboard video monitor enabled the Skylab crews to observe the images in real-time and to identify and follow the development of solar features. Images were also transmitted to the mission control center, where they were used in planning the ATM observing schedule.

  10. End-to-End QoS for Differentiated Services and ATM Internetworking

    NASA Technical Reports Server (NTRS)

    Su, Hongjun; Atiquzzaman, Mohammed

    2001-01-01

    The Internet was initially design for non real-time data communications and hence does not provide any Quality of Service (QoS). The next generation Internet will be characterized by high speed and QoS guarantee. The aim of this paper is to develop a prioritized early packet discard (PEPD) scheme for ATM switches to provide service differentiation and QoS guarantee to end applications running over next generation Internet. The proposed PEPD scheme differs from previous schemes by taking into account the priority of packets generated from different application. We develop a Markov chain model for the proposed scheme and verify the model with simulation. Numerical results show that the results from the model and computer simulation are in close agreement. Our PEPD scheme provides service differentiation to the end-to-end applications.

  11. Peptide Immunoaffinity Enrichment with Targeted Mass Spectrometry: Application to Quantification of ATM Kinase Phospho-signaling

    PubMed Central

    Whiteaker, Jeffrey R.; Zhao, Lei; Schoenherr, Regine M.; Kennedy, Jacob J.; Ivey, Richard G.; Paulovich, Amanda G.

    2017-01-01

    Summary Peptide immunoaffinity enrichment coupled with targeted mass spectrometry is a quantitative approach for the robust and reproducible quantification of peptide analytes. The approach is capable of multiplexed quantification of peptides, including post-translational modifications such as phosphorylation. Anti-peptide antibodies are used to enrich analytes and heavy stable isotope-labeled standards. The enriched peptides are directly measured by multiple reaction monitoring (MRM), a well characterized quantitative mass spectrometry-based method. Quantification is performed by measuring the analyte (light) peptide response relative to the heavy standard, which is spiked at a known concentration. Here, we describe the methodology for multiplexed measurement of phosphorylated peptides on the ATM kinase and their non-modified peptide analogs in cellular lysates. The method provides quantitative measurements of phospho-signaling and can be extended to a number of other phosphopeptides and sample types. PMID:28477121

  12. Walking ATMs and the immigration spillover effect: The link between Latino immigration and robbery victimization.

    PubMed

    Barranco, Raymond E; Shihadeh, Edward S

    2015-07-01

    Media reports and prior research suggest that undocumented Latino migrants are disproportionately robbed because they rely on a cash-only economy and they are reluctant to report crimes to law-enforcement (the Walking ATM phenomenon). From this we generate two specific research questions. First, we probe for an immigration spillover effect - defined as increased native and documented Latino robbery victimization due to offenders' inability to distinguish between the statuses of potential victims. Second, we examine the oft-repeated claim that Blacks robbers disproportionately target Latino victims. Using National Incident-Based Reporting System (NIBRS) data from 282 counties, results show (1) support for an immigration spillover effect but, (2) no support for the claim that Latinos are disproportionately singled out by Black robbers. We discuss the implications of our findings. Copyright © 2015 Elsevier Inc. All rights reserved.

  13. Cris-atms Retrievals Using an AIRS Science Team Version 6-like Retrieval Algorithm

    NASA Technical Reports Server (NTRS)

    Susskind, Joel; Kouvaris, Louis C.; Iredell, Lena

    2014-01-01

    CrIS is the infrared high spectral resolution atmospheric sounder launched on Suomi-NPP in 2011. CrISATMS comprise the IRMW Sounding Suite on Suomi-NPP. CrIS is functionally equivalent to AIRS, the high spectral resolution IR sounder launched on EOS Aqua in 2002 and ATMS is functionally equivalent to AMSU on EOS Aqua. CrIS is an interferometer and AIRS is a grating spectrometer. Spectral coverage, spectral resolution, and channel noise of CrIS is similar to AIRS. CrIS spectral sampling is roughly twice as coarse as AIRSAIRS has 2378 channels between 650 cm-1 and 2665 cm-1. CrIS has 1305 channels between 650 cm-1 and 2550 cm-1. Spatial resolution of CrIS is comparable to AIRS.

  14. Modular and Stochastic Approaches to Molecular Pathway Models of ATM, TGF beta, and WNT Signaling

    NASA Technical Reports Server (NTRS)

    Cucinotta, Francis A.; O'Neill, Peter; Ponomarev, Artem; Carra, Claudio; Whalen, Mary; Pluth, Janice M.

    2009-01-01

    Deterministic pathway models that describe the biochemical interactions of a group of related proteins, their complexes, activation through kinase, etc. are often the basis for many systems biology models. Low dose radiation effects present a unique set of challenges to these models including the importance of stochastic effects due to the nature of radiation tracks and small number of molecules activated, and the search for infrequent events that contribute to cancer risks. We have been studying models of the ATM, TGF -Smad and WNT signaling pathways with the goal of applying pathway models to the investigation of low dose radiation cancer risks. Modeling challenges include introduction of stochastic models of radiation tracks, their relationships to more than one substrate species that perturb pathways, and the identification of a representative set of enzymes that act on the dominant substrates. Because several pathways are activated concurrently by radiation the development of modular pathway approach is of interest.

  15. Laser deuterium streamer chamber at 5 atm in self-shunt regime

    NASA Astrophysics Data System (ADS)

    Exnerova, Ya.; Falomkin, I. V.; Ivanov, I. Ts.; Khristov, V.; Lyashenko, V. I.; Panyushkin, V. A.; Pontecorvo, G. B.; Shcherbakov, Yu. A.; Trifonov, A.; Troshev, T.; Yani, Ya.

    1983-12-01

    Electron track holograms along the electric field in the deuterium high pressure streamer chamber were registered at 5 atm. The holograms were made with Rodhamin 6G dye laser pumped by a nitrogen pulse laser in the Gabor holographic scheme. The chamber worked in a so-called "self-shunt" regime. The value of the streamer density is 9±2 str/cm and is independent on the laser pulse time-delay. The registered streamer centers r.m.s. from the electron track is ˜80 μm. The real streamer diameter is ˜120 μm and was estimated from comparison with the diffraction pictures of the electrode wires.

  16. Metformin and the ATM DNA damage response (DDR): accelerating the onset of stress-induced senescence to boost protection against cancer.

    PubMed

    Menendez, Javier A; Cufí, Sílvia; Oliveras-Ferraros, Cristina; Martin-Castillo, Begoña; Joven, Jorge; Vellon, Luciano; Vazquez-Martin, Alejandro

    2011-11-01

    By activating the ataxia telangiectasia mutated (ATM)-mediated DNA Damage Response (DDR), the AMPK agonist metformin might sensitize cells against further damage, thus mimicking the precancerous stimulus that induces an intrinsic barrier against carcinogenesis. Herein, we present the new hypothesis that metformin might function as a tissue sweeper of pre-malignant cells before they gain stem cell/tumor initiating properties. Because enhanced glycolysis (the Warburg effect) plays a causal role in the gain of stem-like properties of tumor-initiating cells by protecting them from the pro-senescent effects of mitochondrial respiration-induced oxidative stress, metformin's ability to disrupt the glycolytic metabotype may generate a cellular phenotype that is metabolically protected against immortalization. The bioenergetic crisis imposed by metformin, which may involve enhanced mitochondrial biogenesis and oxidative stress, can lower the threshold for cellular senescence by pre-activating an ATM-dependent pseudo-DDR. This allows an accelerated onset of cellular senescence in response to additional oncogenic stresses. By pushing cancer cells to use oxidative phosphorylation instead of glycolysis, metformin can rescue cell surface major histocompatibility complex class I (MHC-I) expression that is downregulated by oncogenic transformation, a crucial adaptation of tumor cells to avoid the adaptive immune response by cytotoxic T-lymphocytes (CTLs). Aside from restoration of tumor immunosurveillance at the cell-autonomous level, metformin can activate a senescence-associated secretory phenotype (SASP) to reinforce senescence growth arrest, which might trigger an immune-mediated clearance of the senescent cells in a non-cell-autonomous manner. By diminishing the probability of escape from the senescence anti-tumor barrier, the net effect of metformin should be a significant decrease in the accumulation of dysfunctional, pre-malignant cells in tissues, including those with the

  17. Development of Attitudes towards Mathematics Scale (ATMS) Using Nigerian Data - Factor Analysis as a Determinant of Attitude Subcategories

    ERIC Educational Resources Information Center

    Zakariya, Yusuf F.

    2017-01-01

    This study was aimed at the development of an instrument for measuring students' attitudes towards mathematics. A survey research design was adopted involving 510 students randomly selected. Exploratory factor analysis (EFA) was carried out to determine the number of factors to be retained in the ATMS. The adequacy of the sample was confirmed by…

  18. Hazards of high altitude decompression sickness during falls in barometric pressure from 1 atm to a fraction thereof

    NASA Technical Reports Server (NTRS)

    Genin, A. M.

    1980-01-01

    Various tests related to studies concerning the effects of decompression sicknesses at varying pressure levels and physical activity are described. The tests indicate that there are no guarantees of freedom from decompression sicknesses when man transitions from a normally oxygenated normobaric nitrogen-oxygen atmosphere into an environment having a 0.4 atm or lower pressure and he is performing physical work.

  19. Fy00 Treasure Valley ITS Deployment Project : advanced traffic management system (ATMS) software procurement and implementation process

    DOT National Transportation Integrated Search

    2006-08-02

    In 2000, the Treasure Valley area of the State of Idaho received a federal earmark of $390,000 to develop an Advanced Transportation Management System (ATMS) for the Treasure Valley region of Idaho. The Ada County Highway District (ACHD), located in ...

  20. Development of an FAA-EUROCONTROL technique for the analysis of human error in ATM : final report.

    DOT National Transportation Integrated Search

    2002-07-01

    Human error has been identified as a dominant risk factor in safety-oriented industries such as air traffic control (ATC). However, little is known about the factors leading to human errors in current air traffic management (ATM) systems. The first s...

  1. Measurement of Atmospheric Black Carbon Concentrations, [BC]atm, in the Arctic Region from ~1700 to 2013

    NASA Astrophysics Data System (ADS)

    Husain, L.; Sarkar, S.; Jyethi, D. S.; Ruppel, M.; Dutkiewicz, V. A.

    2015-12-01

    Atmospheric black carbon (BC) aerosols play a key role in Earth's climate through direct and indirect effects. Due to a lack of long-term BC data, climate models are used to estimate BC based on fuel inventories, which have large uncertainties. Hence, long term BC data is needed to verify global models. We report here the first measurements of atmospheric BC concentrations, [BC]atm, from ~1700 to 2013 using sediments from Finnish lakes, Saanajarvi (SJ)(690 44' N, 200 52' E), and Vuoskojarvi (VJ)(69044'N, 26057'E). The cores were collected from the deepest parts of the lakes using a HTH gravity corer, sliced in 0.25 cm sections; freeze dried, and ages determined using 210Pb dating method. The BC was chemically separated, and [BC] determined by the thermal optical method. The [BC] varied from 50 to 1140µg/gdry weight in SJ; and 20 to 130µg/gdry weight in VJ. Husain et al.,(JGR, vol 113, D13102,doi:10.1029/2007JD009398, 2008) showed that the atmospheric deposition of BC into lake sediments depends on the characteristic of individual lakes, BC washout ratios, precipitation intensity, and sedimentation rates. The deposition rate, K, for a lake is defined by, [BC]sed = K[BC]atm where [BC]sed, is the concentration of BC in the sediment. We have measured [BC]atm from 1970 to 2010 in Kevo, Finland, where VJ and SJ are located. The [BC]atm from Kevo, and [BC]sed from VJ, and SJ were used to determine K for each of the lake. Owing to the availability of the long term atmospheric BC data from 1970 to 2010 multiple measurements of K were made, and provided a high measure of precision. The mean values of K for VJ, and SJ were 226 ± 60, and 830 ± 290 (m3air/ gdry weight). The K values were used to determine [BC]atm for the years before 1970. The [BC]atm from 2013 to 2006 was 82ng/m3. It increased slowly reaching a peak value of about 947 ± 322 ng/m3.The concentrations decreased subsequently to 244 ± 83ng/m3 in 1920, and changed little ~ 1774.The lowest concentration, 77

  2. [MiR-18a Can Regulate Chemotherapy Sensitivity of Leukemia Cell HL-60 to VP-16 and VCR by Targeting ATM].

    PubMed

    Xiao, Yue; Hu, Rong

    2015-08-01

    To investigate the regulatory effects of miR-18a on chemotherapeutic sensitivity of leukemia cell HL-60 to VP-16 and VCR, and explore its molecular mechamism. The HL-60 PC DNA3.1-miR-18A cell line with stably overexpressing miR-18a was constructed and their sensitivity to VP-16 and VCR was detected. The luciferase reporter vector of ATM 3'UTR region was constructed and the targeting effect of miR-18a on ATM was identified. The expression level of ATM in HL-60 cells overexpressing miR-18a was detected by Western blot. The seusitivity of HL-60 cells with knockdown of ATM to VP-16 and VCR was detected by CCK-8 method. The ATM expression level in HL-60 cells with stably overexpression miR-18a after transfection of miR-18a inhibitor was detected by using Western blot and the sensitivity changes of these HL-60 cells to VP-16 and BCR were detected. After overexpression of miR-18a, the viability of HL-60 cells treated with VP-16 and VCR of same concentration decreased; the detectiion of luciferase activity showed that the miR-18a could inhitit activity of luciferase reporter vector of ATM; the expression level of ATM in HL-60 cells was down-regulated after transfection with miR-18a; the cell viability decreased when HL-60 cells were treated with VP-16 and VCR after knockdown of ATM; the expression level of ATM was up-regulated and the cell viability decreased when HL-60 cells were treated with VP-16 and VCR after transfection with miR-18a inhibitor. The miR-18a can regulated the sensitivity of leukemia HL-60 cells to VP-16 and VCR by targeting ATM.

  3. Prevalence and Spectrum of Germline Cancer Susceptibility Gene Mutations Among Patients With Early-Onset Colorectal Cancer

    PubMed Central

    Pearlman, Rachel; Frankel, Wendy L.; Swanson, Benjamin; Zhao, Weiqiang; Yilmaz, Ahmet; Miller, Kristin; Bacher, Jason; Bigley, Christopher; Nelsen, Lori; Goodfellow, Paul J.; Goldberg, Richard M.; Paskett, Electra; Shields, Peter G.; Freudenheim, Jo L.; Stanich, Peter P; Lattimer, Ilene; Arnold, Mark; Liyanarachchi, Sandya; Kalady, Matthew; Heald, Brandie; Greenwood, Carla; Paquette, Ian; Prues, Marla; Draper, David J.; Lindeman, Carolyn; Kuebler, J. Philip; Reynolds, Kelly; Brell, Joanna M.; Shaper, Amy A.; Mahesh, Sameer; Buie, Nicole; Weeman, Kisa; Shine, Kristin; Haut, Mitchell; Edwards, Joan; Bastola, Shyamal; Wickham, Karen; Khanduja, Karamjit S.; Zacks, Rosemary; Pritchard, Colin C.; Shirts, Brian H.; Jacobson, Angela; Allen, Brian; de la Chapelle, Albert; Hampel, Heather

    2017-01-01

    IMPORTANCE Hereditary cancer syndromes infer high cancer risks and require intensive cancer surveillance, yet the prevalence and spectrum of these conditions among unselected patients with early-onset colorectal cancer (CRC) is largely undetermined. OBJECTIVE To determine the frequency and spectrum of cancer susceptibility gene mutations among patients with early-onset CRC. DESIGN, SETTING, AND PARTICIPANTS Overall, 450 patients diagnosed with colorectal cancer younger than 50 years were prospectively accrued from 51 hospitals into the Ohio Colorectal Cancer Prevention Initiative from January 1, 2013, to June 20, 2016. Mismatch repair (MMR) deficiency was determined by microsatellite instability and/or immunohistochemistry. Germline DNA was tested for mutations in 25 cancer susceptibility genes using next-generation sequencing. MAIN OUTCOMES AND MEASURES Mutation prevalence and spectrum in patients with early-onset CRC was determined. Clinical characteristics were assessed by mutation status. RESULTS In total 450 patients younger than 50 years were included in the study, and 75 gene mutations were found in 72 patients (16%). Forty-eight patients (10.7%) had MMR-deficient tumors, and 40 patients (83.3%) had at least 1 gene mutation: 37 had Lynch syndrome (13, MLH1 [including one with constitutional MLH1 methylation]; 16, MSH2; 1, MSH2/monoallelic MUTYH; 2, MSH6; 5, PMS2); 1 patient had the APC c.3920T>A, p.I1307K mutation and a PMS2 variant; 9 patients (18.8%) had double somatic MMR mutations (including 2 with germline biallelic MUTYH mutations); and 1 patient had somatic MLH1 methylation. Four hundred two patients (89.3%) had MMR-proficient tumors, and 32 patients (8%) had at least 1 gene mutation: 9 had mutations in high-penetrance CRC genes (5, APC; 1, APC/PMS2; 2, biallelic MUTYH; 1, SMAD4); 13 patients had mutations in high- or moderate-penetrance genes not traditionally associated with CRC (3, ATM; 1, ATM/CHEK2; 2, BRCA1; 4, BRCA2; 1, CDKN2A; 2, PALB2); 10

  4. Moisture Flux Application and Other Uses of the ATMS-MIRS Retrievals for Tropical Cyclone Intensity Forecasting

    NASA Astrophysics Data System (ADS)

    Chirokova, G.; Demaria, M.; DeMaria, R.; Dostalek, J.; Knaff, J. A.; Beven, J. L.

    2016-12-01

    The ATMS-MIRS (Advanced Technology Microwave Sounder - Microwave Integrated Retrieval System) and NUCAPS (NOAA Unique Combined Atmosphere Processing System) temperature and moisture retrievals from the ATMS and CrIS (Cross-Track Infrared Sounder) on-board of the JPSS Suomi National Polar-Orbiting Partnership satellite (S-NPP) provide unique information about tropical cyclone (TC) structure and environmental conditions that could be critical for the forecasting of TC intensity. Such information is generally underutilized and this presentation will discuss a moisture flux application that uses ATMS-MIRS and NUCAPS data to diagnose dry air intrusions into the near TC environment. Dry air intrusions are important to TC intensity changes as the entrainment of the dry air impacts deep convection and is one of the environmental parameters routinely evaluated by forecasters. Statistics showing that MIRS and NUCAPS moisture profiles provide better information about the TC environment as compared to the GFS (Global Forecast System) model, and that the ATMS-MIRS provides additional and unique information about the TC warm core structure will be presented together with the examples of the standalone moisture flux application and its uses. For instance, the integrated moisture flux can be converted to a predictor for the Rapid Intensification Index (RII), the statistical-dynamical tool used operationally at the National Hurricane Center (NHC) and the Joint Typhoon Warning Center (JTWC) to forecast TC Rapid Intensification (RI) events - a challenging and very important intensity forecast problem. In addition, the possibility of using the ATMS-MIRS retrievals to detect warm core changes during RI evens and to provide a quantitative estimate of those changes will be discussed. Disclaimer: The views, opinions, and findings contained in this article are those of the authors and should not be construed as an official National Oceanic and Atmospheric Administration (NOAA) or U

  5. First six months of clinical usage of an ATM network link between two Veterans Affairs Medical Centers

    NASA Astrophysics Data System (ADS)

    Duerinckx, Andre J.; Gentili, Amilcare; El-Saden, Suzie; Harmon, Craig; Kenagy, John J.; Grant, Edward G.

    1998-07-01

    Purpose/Background: Asynchronous transfer mode (ATM) network technology has recently been used for high speed transmission of radiological images between hospitals and inside hospitals. However, the number of clinical sites which routinely use this technology is limited. The purpose of this study was to analyze the very early impact of an ATM link between a large tertiary referral center and small peripheral clinic on cost and clinical practice. Methodology: An ATM link using 155 bps (OC3) technology was installed between the West Los Angeles VA Medical Center and the Sepulveda VA, a large outpatient facility which provides full service radiological services. The West Los Angeles VA Medical Center is a large tertiary referral center with sub-specialist radiologist. The clinical impact of this ATM link between a large full-scale DICOM-3 compliant PACS system at the West LA VA on a smaller PACS system at the Sepulveda VA was evaluated. Results: The ability to freely exchange complicated MRI and CT studies between a tertiary referral center and a clinic could have a direct impact on patient care. Over the last six months, all and CT studies from Sepulveda VA were readily available via the ATM connection to all radiologists at the West LA VA. On average the workload at the Sepulveda VA in CT and MRI was about one tenth of the same workload at West LA VA, thus creating interesting possibilities for sharing or radiologist resources. Conclusions: Although our preliminary data and work loads have been too limited to draw any final conclusions yet, we feel that future results will show that the ability to provide immediate and fast interactive consultation between general radiologists in a large outpatient facility and sub- specialists at a tertiary referral center can have an impact upon the quality of patient care.

  6. [Topoisomerase inhibitor upregulates MICA/B expression in breast cancer cells through ATM/ATR and NF-κB pathway].

    PubMed

    Zhu, Y; Shi, Y J; Zhao, Y L; Zhu, P

    2018-04-18

    To investigate the effects of chemotherapeutic agents widely used in clinical practice on major histocompatibility complex class I-related chain A and B (MICA/B) expression in breast cancer cells, and to explore the molecular mechanisms involved. We examined MICA/B mRNA and surface protein expressions in breast cancer cells treated with chemotherapeutic agents by real-time RT-PCR and flow cytometry respectively. The blocking effects of ataxia telangiectasia mutated and Rad3-related kinase (ATM/ATR) inhibitor caffeine and nuclear factor κB (NF-κB) inhibitor pynolidine dithiocarbamate (PDTC) on etoposide-upregulated MICA/B mRNA and surface protein expressions were investigated. Electrophoretic mobility shift assay (EMSA) was taken to investigate whether etoposide enhanced the binding of NF-κB to MICA/B gene promoter. Three topoisomerase inhibitors etoposide, camptothecin and doxorubicine upregulated MICA and MICB mRNA expressions in breast cancer cell MCF-7. Comparing to no-drug-treated cells, MICA mRNA levels increased to (1.68±0.17), (2.54±0.25) and (3.42±0.15) fold, and levels of MICB mRNA increased to (1.82±0.24), (1.56±0.05) and (5.84±0.57) fold respectively in cancer cells treated by etoposide at the concentrations of 5, 20 and 100 μmol/L (P<0.05). MICA and MICB mRNA levels also increased significantly when MCF-7 cells were incubated with camptothecin or doxorubicine at the specific concentrations (P<0.05). MICB mRNA expression also increased slightly in another breast cancer cell SK-BR-3 treated by topoisomerase II inhibitors etoposide and camptothecin (P<0.05). Furthermore, etoposide and camptothecin upregulated MICA/B surface protein expression in MCF-7 cells (P<0.05), and the upregulation was found in both living and apoptotic cells. Our study showed that etoposide induced-MICA/B expression in MCF-7 was inhibited by caffeine at different concentrations. When cancer cells were treated by caffeine with 1, 5 and 10 mmol/L, MICA mRNA levels decreased

  7. Mechanisms of viral mutation.

    PubMed

    Sanjuán, Rafael; Domingo-Calap, Pilar

    2016-12-01

    The remarkable capacity of some viruses to adapt to new hosts and environments is highly dependent on their ability to generate de novo diversity in a short period of time. Rates of spontaneous mutation vary amply among viruses. RNA viruses mutate faster than DNA viruses, single-stranded viruses mutate faster than double-strand virus, and genome size appears to correlate negatively with mutation rate. Viral mutation rates are modulated at different levels, including polymerase fidelity, sequence context, template secondary structure, cellular microenvironment, replication mechanisms, proofreading, and access to post-replicative repair. Additionally, massive numbers of mutations can be introduced by some virus-encoded diversity-generating elements, as well as by host-encoded cytidine/adenine deaminases. Our current knowledge of viral mutation rates indicates that viral genetic diversity is determined by multiple virus- and host-dependent processes, and that viral mutation rates can evolve in response to specific selective pressures.

  8. Revisiting breast cancer patients who previously tested negative for BRCA mutations using a 12-gene panel.

    PubMed

    Moran, Olivia; Nikitina, Dina; Royer, Robert; Poll, Aletta; Metcalfe, Kelly; Narod, Steven A; Akbari, Mohammad R; Kotsopoulos, Joanne

    2017-01-01

    BRCA mutations contribute to about 20% of all hereditary breast cancers. With full-genome sequencing as the emerging standard for genetic testing, other breast cancer susceptibility genes have been identified and may collectively contribute to up to 30% of all hereditary breast cancers. We re-assessed women who had previously tested negative for a BRCA mutation when outdated techniques were used, and discuss the implications of identifying a mutation several years after initial genetic testing. We evaluated the prevalence of mutations in 12 breast cancer susceptibility genes (including BRCA1 and BRCA2) in 190 breast cancer patients with a strong family history of breast cancer. These women had previously tested negative for mutations in the large coding exons of BRCA1 and BRCA2 using the protein truncation test (PTT) between the years of 1996 and 2013. We identified pathogenic mutations in 17 of 190 (9%) women. Six mutations were detected in BRCA1 (n = 2) and BRCA2 (n = 4). Eleven mutations were found in other breast cancer susceptibility genes including CHEK2 (n = 5), PALB2 (n = 2), BLM (n = 2), ATM (n = 1) and TP53 (n = 1). Among 190 breast cancer patients with a family history of the disease, and who previously received a negative result for BRCA mutations using the PTT, 17 (9%) women were found to carry a high-risk pathogenic mutation in a breast cancer susceptibility gene. Six of these women were BRCA mutation carriers who were missed previously. These findings support the rationale for updated genetic testing in patients who tested BRCA mutation negative using outdated techniques.

  9. Exploring the common molecular basis for the universal DNA mutation bias: revival of Löwdin mutation model.

    PubMed

    Fu, Liang-Yu; Wang, Guang-Zhong; Ma, Bin-Guang; Zhang, Hong-Yu

    2011-06-10

    Recently, numerous genome analyses revealed the existence of a universal G:C→A:T mutation bias in bacteria, fungi, plants and animals. To explore the molecular basis for this mutation bias, we examined the three well-known DNA mutation models, i.e., oxidative damage model, UV-radiation damage model and CpG hypermutation model. It was revealed that these models cannot provide a sufficient explanation to the universal mutation bias. Therefore, we resorted to a DNA mutation model proposed by Löwdin 40 years ago, which was based on inter-base double proton transfers (DPT). Since DPT is a fundamental and spontaneous chemical process and occurs much more frequently within GC pairs than AT pairs, Löwdin model offers a common explanation for the observed universal mutation bias and thus has broad biological implications. Copyright © 2011 Elsevier Inc. All rights reserved.

  10. Creating a AIRS/AMSU and CrIS/ATMS continuity sounding product

    NASA Astrophysics Data System (ADS)

    Barnet, C. D.; Gambacorta, A.; Smith, N.; Wheeler, A. A.

    2017-12-01

    The AIRS/AMSU (Atmospheric Infrared Sounder; Advanced Microwave Sounding Unit) onboard the EOS/Aqua was launched in 2002. CrIS/ATMS (CrossTrack Infrared Sounder; Advanced Technology Microwave Sounder) onboard Suomi NPP was launched in 2011 and will also be launched on the Joint Polar Sounding System (JPSS) series of satellites beginning in 2017. Suomi NPP and EOS/Aqua now have more than five years of overlap. Demonstrating data continuity between these two platforms has become a priority especially since EOS/Aqua is well past its design lifetime. Additionally, with JPSS, this record of soundings will be extended into future decades and will enable critically important scientific research on large scale (long term) atmospheric processes. The AIRS/AMSU and CrIS/ATMS have many differences in instrument design, spatial sampling, spectral coverage and resolution. Instruments also degrade with time. It is only with careful, deliberate and transparent error characterization and propagation that systematic effects can be accounted for, and preferably minimized, in retrieved sounding products. We have developed the Community Long-term Infrared Microwave Coupled Product System (CLIMCAPS) to achieve a seamless record of satellite soundings. A CLIMCAPS sounding is comprised of a set of parameters that characterizes the full atmospheric state and includes profiles of temperature, moisture, cloud and surface products, and trace gas species (O3, CH4, CO, SO2, HNO3, N2O and CO2). The trace gases are by-products necessary to remove biases in temperature and moisture retrievals; however, they can also be readily ingested into science applications. The information content of an IR sounder such as AIRS and CrIS is a function of lapse rate, the quantity of absorbers such as clouds, moisture and trace gases, as well as the instrument's sensitivity. Information content can vary vertically, spatially, and temporally. CLIMCAPS uses the NASA Modern-Era Retrospective Analysis for Research

  11. Spatio-temporal mutation profiles of case-matched colorectal carcinomas and their metastases reveal unique de novo mutations in metachronous lung metastases by targeted next generation sequencing.

    PubMed

    Kovaleva, Valentina; Geissler, Anna-Lena; Lutz, Lisa; Fritsch, Ralph; Makowiec, Frank; Wiesemann, Sebastian; Hopt, Ulrich T; Passlick, Bernward; Werner, Martin; Lassmann, Silke

    2016-10-18

    Targeted next generation sequencing (tNGS) has become part of molecular pathology diagnostics for determining RAS mutation status in colorectal cancer (CRC) patients as predictive tool for decision on EGFR-targeted therapy. Here, we investigated mutation profiles of case-matched tissue specimens throughout the disease course of CRC, to further specify RAS-status dynamics and to identify de novo mutations associated with distant metastases. Case-matched formalin-fixed and paraffin-embedded (FFPE) resection specimens (n = 70; primary tumours, synchronous and/or metachronous liver and/or lung metastases) of 14 CRC cases were subjected to microdissection of normal colonic epithelial, primary and metastatic tumour cells, their DNA extraction and an adapted library protocol for limited DNA using the 48 gene TruSeq Amplicon Cancer Panel TM , MiSeq sequencing and data analyses (Illumina). By tNGS primary tumours were RAS wildtype in 5/14 and mutated in 9/14 (8/9 KRAS exon 2; 1/9 NRAS Exon 3) of cases. RAS mutation status was maintained in case-matched metastases throughout the disease course, albeit with altered allele frequencies. Case-matched analyses further identified a maximum of three sequence variants (mainly in APC, KRAS, NRAS, TP53) shared by all tumour specimens throughout the disease course per individual case. In addition, further case-matched de novo mutations were detected in synchronous and/or metachronous liver and/or lung metastases (e.g. in APC, ATM, FBXW7, FGFR3, GNAQ, KIT, PIK3CA, PTEN, SMAD4, SMO, STK11, TP53, VHL). Moreover, several de novo mutations were more frequent in synchronous (e.g. ATM, KIT, PIK3CA, SMAD4) or metachronous (e.g. FBXW7, SMO, STK11) lung metastases. Finally, some de novo mutations occurred only in metachronous lung metastases (CDKN2A, FGFR2, GNAS, JAK3, SRC). Together, this study employs an adapted FFPE-based tNGS approach to confirm conservation of RAS mutation status in primary and metastatic tissue specimens of CRC

  12. UV Signature Mutations

    PubMed Central

    2014-01-01

    Sequencing complete tumor genomes and exomes has sparked the cancer field's interest in mutation signatures for identifying the tumor's carcinogen. This review and meta-analysis discusses signatures and their proper use. We first distinguish between a mutagen's canonical mutations – deviations from a random distribution of base changes to create a pattern typical of that mutagen – and the subset of signature mutations, which are unique to that mutagen and permit inference backward from mutations to mutagen. To verify UV signature mutations, we assembled literature datasets on cells exposed to UVC, UVB, UVA, or solar simulator light (SSL) and tested canonical UV mutation features as criteria for clustering datasets. A confirmed UV signature was: ≥60% of mutations are C→T at a dipyrimidine site, with ≥5% CC→TT. Other canonical features such as a bias for mutations on the non-transcribed strand or at the 3' pyrimidine had limited application. The most robust classifier combined these features with criteria for the rarity of non-UV canonical mutations. In addition, several signatures proposed for specific UV wavelengths were limited to specific genes or species; non-signature mutations induced by UV may cause melanoma BRAF mutations; and the mutagen for sunlight-related skin neoplasms may vary between continents. PMID:25354245

  13. BRAT1 Mutations Present with a Spectrum of Clinical Severity

    PubMed Central

    Srivastava, Siddharth; Olson, Heather E.; Cohen, Julie S.; Gubbels, Cynthia S.; Lincoln, Sharyn; Davis, Brigette Tippin; Shahmirzadi, Layla; Gupta, Siddharth; Picker, Jonathan; Yu, Timothy W.; Miller, David T.; Soul, Janet S.; Poretti, Andrea; Naidu, SakkuBai

    2017-01-01

    Mutations in BRAT1, encoding BRCA1-associated ATM activator 1, are associated with a severe phenotype known as rigidity and multifocal seizure syndrome, lethal neonatal (RMFSL; OMIM # 614498), characterized by intractable seizures, hypertonia, autonomic instability, and early death. We expand the phenotypic spectrum of BRAT1 related disorders by reporting on four individuals with various BRAT1 mutations resulting in clinical severity that is either mild or moderate compared to the severe phenotype seen in RMFSL. Representing mild severity are three individuals (Patients 1–3), who are girls (including two sisters, Patients 1–2) between 4–10 years old, with subtle dysmorphisms, intellectual disability, ataxia or dyspraxia, and cerebellar atrophy on brain MRI; additionally, Patient 3 has well-controlled epilepsy and microcephaly. Representing moderate severity is a 15 month old boy (Patient 4) with severe global developmental delay, refractory epilepsy, microcephaly, spasticity, hyperkinetic movements, dysautonomia, and chronic lung disease. In contrast to RMFSL, his seizure onset occurred later at 4 months of age, and he is still alive. All four of the individuals have compound heterozygous BRAT1 mutations discovered via whole exome sequencing: c.638dupA (p.Val214Glyfs*189); c.803+1G>C (splice site mutation) in Patients 1–2; c.638dupA (p.Val214Glyfs*189); c.419T>C (p.Leu140Pro) in Patient 3; and c.171delG (p.Glu57Aspfs*7); c.419T>C (p.Leu140Pro) in Patient 4. Only the c.638dupA (p.Val214Glyfs*189) mutation has been previously reported in association with RMFSL. These patients illustrate that, compared with RMFSL, BRAT1 mutations can result in both moderately severe presentations evident by later-onset epilepsy and survival past infancy, as well as milder presentations that include intellectual disability, ataxia/dyspraxia, and cerebellar atrophy. PMID:27282546

  14. Reduced cost alternatives to premise wiring using ATM and microcellular technologies

    NASA Technical Reports Server (NTRS)

    Gejji, Raghvendra R.

    1993-01-01

    The cost of premises wiring keeps increasing due to personnel moves, new equipment, capacity upgrades etc. It would be desirable to have a wireless interface from the workstations to the fixed network, so as to minimize the wiring changes needed. New technologies such as microcellular personal communication systems are promising to bring down the cost of wireless communication. Another promising technology is Code Division Multiple Access (CDMA), which could dramatically increase the bandwidth available for wireless connections. In addition, Asynchronous Transfer Mode (ATM) technology is emerging as a technique for integrated management of voice, data, and video traffic on a single network. The focus of this investigation will be to assess the future utility of these new technologies for reducing the premise wiring cost at KSC. One of the issues to be studied is the cost comparison of 'old' versus 'new,' especially as time and technology progress. An additional issue for closer study is a feasible time-line for progress in technological capability.

  15. Distributed medical services within the ATM-based Berlin regional test bed

    NASA Astrophysics Data System (ADS)

    Thiel, Andreas; Bernarding, Johannes; Krauss, Manfred; Schulz, Sandra; Tolxdorff, Thomas

    1996-05-01

    The ATM-based Metropolitan Area Network (MAN) of Berlin connects two university hospitals (Benjamin Franklin University Hospital and Charite) with the computer resources of the Technical University of Berlin (TUB). Distributed new medical services have been implemented and will be evaluated within the highspeed MAN of Berlin. The network with its data transmission rates of up to 155 Mbit/s renders these medical services externally available to practicing physicians. Resource and application sharing is demonstrated by the use of two software systems. The first software system is an interactive 3D reconstruction tool (3D- Medbild), based on a client-server mechanism. This structure allows the use of high- performance computers at the TUB from the low-level workstations in the hospitals. A second software system, RAMSES, utilizes a tissue database of Magnetic Resonance Images. For the remote control of the software, the developed applications use standards such as DICOM 3.0 and features of the World Wide Web. Data security concepts are being tested and integrated for the needs of the sensitive medical data. The highspeed network is the necessary prerequisite for the clinical evaluation of data in a joint teleconference. The transmission of digitized real-time sequences such as video and ultrasound and the interactive manipulation of data are made possible by Multi Media tools.

  16. Congestion control for ATM multiplexers using neural networks: multiple sources/single buffer scenario.

    PubMed

    Du, Shu-xin; Yuan, Shi-yong

    2004-09-01

    A new neural network based method for solving the problem of congestion control arising at the user network interface (UNI) of ATM networks is proposed in this paper. Unlike the previous methods where the coding rate for all traffic sources as controller output signals is tuned in a body, the proposed method adjusts the coding rate for only a part of the traffic sources while the remainder sources send the cells in the previous coding rate in case of occurrence of congestion. The controller output signals include the source coding rate and the percentage of the sources that send cells at the corresponding coding rate. The control methods not only minimize the cell loss rate but also guarantee the quality of information (such as voice sources) fed into the multiplexer buffer. Simulations with 150 ADPCM voice sources fed into the multiplexer buffer showed that the proposed methods have advantage over the previous methods in the aspect of the performance indices such as cell loss rate (CLR) and voice quality.

  17. Mutation accumulation and fitness in mutator subpopulations of Escherichia coli

    PubMed Central

    Maharjan, Ram P.; Liu, Bin; Li, Yang; Reeves, Peter R.; Wang, Lei; Ferenci, Thomas

    2013-01-01

    Bacterial populations in clinical and laboratory settings contain a significant proportion of mutants with elevated mutation rates (mutators). Mutators have a particular advantage when multiple beneficial mutations are needed for fitness, as in antibiotic resistance. Nevertheless, high mutation rates potentially lead to increasing numbers of deleterious mutations and subsequently to the decreased fitness of mutators. To test how fitness changed with mutation accumulation, genome sequencing and fitness assays of nine Escherichia coli mutY mutators were undertaken in an evolving chemostat population at three time points. Unexpectedly, the fitness in members of the mutator subpopulation became constant despite a growing number of mutations over time. To test if the accumulated mutations affected fitness, we replaced each of the known beneficial mutations with wild-type alleles in a mutator isolate. We found that the other 25 accumulated mutations were not deleterious. Our results suggest that isolates with deleterious mutations are eliminated by competition in a continuous culture, leaving mutators with mostly neutral mutations. Interestingly, the mutator–non-mutator balance in the population reversed after the fitness plateau of mutators was reached, suggesting that the mutator–non-mutator ratio in populations has more to do with competition between members of the population than the accumulation of deleterious mutations. PMID:23221876

  18. Germline and somatic mutations in homologous recombination genes predict platinum response and survival in ovarian, fallopian tube, and peritoneal carcinomas.

    PubMed

    Pennington, Kathryn P; Walsh, Tom; Harrell, Maria I; Lee, Ming K; Pennil, Christopher C; Rendi, Mara H; Thornton, Anne; Norquist, Barbara M; Casadei, Silvia; Nord, Alexander S; Agnew, Kathy J; Pritchard, Colin C; Scroggins, Sheena; Garcia, Rochelle L; King, Mary-Claire; Swisher, Elizabeth M

    2014-02-01

    Hallmarks of germline BRCA1/2-associated ovarian carcinomas include chemosensitivity and improved survival. The therapeutic impact of somatic BRCA1/2 mutations and mutations in other homologous recombination DNA repair genes is uncertain. Using targeted capture and massively parallel genomic sequencing, we assessed 390 ovarian carcinomas for germline and somatic loss-of-function mutations in 30 genes, including BRCA1, BRCA2, and 11 other genes in the homologous recombination pathway. Thirty-one percent of ovarian carcinomas had a deleterious germline (24%) and/or somatic (9%) mutation in one or more of the 13 homologous recombination genes: BRCA1, BRCA2, ATM, BARD1, BRIP1, CHEK1, CHEK2, FAM175A, MRE11A, NBN, PALB2, RAD51C, and RAD51D. Nonserous ovarian carcinomas had similar rates of homologous recombination mutations to serous carcinomas (28% vs. 31%, P = 0.6), including clear cell, endometrioid, and carcinosarcoma. The presence of germline and somatic homologous recombination mutations was highly predictive of primary platinum sensitivity (P = 0.0002) and improved overall survival (P = 0.0006), with a median overall survival of 66 months in germline homologous recombination mutation carriers, 59 months in cases with a somatic homologous recombination mutation, and 41 months for cases without a homologous recombination mutation. Germline or somatic mutations in homologous recombination genes are present in almost one third of ovarian carcinomas, including both serous and nonserous histologies. Somatic BRCA1/2 mutations and mutations in other homologous recombination genes have a similar positive impact on overall survival and platinum responsiveness as germline BRCA1/2 mutations. The similar rate of homologous recombination mutations in nonserous carcinomas supports their inclusion in PARP inhibitor clinical trials. ©2013 AACR.

  19. ATR signaling cooperates with ATM in the mechanism of low dose hypersensitivity induced by carbon ion beam.

    PubMed

    Xue, Lian; Furusawa, Yoshiya; Yu, Dong

    2015-10-01

    Little work has been done on the mechanism of low dose hyper-radiosensitivity (HRS) and later appeared radioresistance (termed induced radioresistance (IRR)) after irradiation with medium and high linear energy transfer (LET) particles. The aim of this study was to find out whether ATR pathway is involved in the mechanism of HRS induced by high LET radiation. GM0639 cells and two ATM deficient/mutant cells, AT5BIVA and AT2KY were irradiated by carbon ion beam. Thymidine block technique was developed to enrich the G2-phase population. Radiation induced early G2/M checkpoint was quantitatively assess with dual-parameter flow cytometry by detecting the cells positive for phospho-histone H3. The involvement of ATR pathway in HRS/IRR response was detected with pretreatment of specific inhibitors prior to carbon ion beam. The link between the early G2/M checkpoint and HRS/IRR under carbon ion beam was first confirmed in GM0639 cells, through the enrichment of cell population in G2-phase or with Aurora kinase inhibitor that attenuates the transition from G2 to M phase. Interestingly, the early G2/M arrest could still be observed in ATM deficient/mutant cells with an effect of ATR signaling, which was discovered to function in an LET-dependent manner, even as low as 0.2Gy for carbon ion radiation. The involvement of ATR pathway in heavy particles induced HRS/IRR was determined with the specific ATR inhibitor in GM0639 cells, which affected the HRS/IRR occurrence similarly as ATM inhibitor. These data demonstrate that ATR pathway may cooperate with ATM in the mechanism of low dose hypersensitivity induced by carbon ion beam. Copyright © 2015 Elsevier B.V. All rights reserved.

  20. Regulation of ATM-Dependent DNA Damage Responses in Breast Cancer by the RhoGEF Net1

    DTIC Science & Technology

    2015-05-01

    Award Number: W81XWH-12-1-0014 TITLE: Regulation of ATM-Dependent DNA Damage Responses in Breast Cancer by the RhoGEF Net1 PRINCIPAL INVESTIGATOR...Introduction In the United States, breast cancer is the second most frequently diagnosed cancer in women (1). Ionizing radiation (IR) is commonly...used to treat breast cancer patients after surgery, as well as for care of inoperable metastatic tumors (2). However, despite advances in the use of

  1. Quercetin reduces obesity-associated ATM infiltration and inflammation in mice: a mechanism including AMPKα1/SIRT1[S

    PubMed Central

    Dong, Jing; Zhang, Xian; Zhang, Lei; Bian, Hui-Xi; Xu, Na; Bao, Bin; Liu, Jian

    2014-01-01

    Adipose tissue macrophage (ATM) plays a central role in obesity-associated inflammation and insulin resistance. Quercetin, a dietary flavonoid, possesses anti-inflammation and anti-insulin resistance properties. However, it is unclear whether quercetin can alleviate high-fat diet (HFD)-induced ATM infiltration and inflammation in mice. In this study, 5-week-old C57BL/6 mice were fed low-fat diet, HFD, or HFD with 0.l% quercetin for 12 weeks, respectively. Dietary quercetin reduced HFD-induced body weight gain and improved insulin sensitivity and glucose intolerance in mice. Meanwhile, dietary quercetin enhanced glucose transporter 4 translocation and protein kinase B signal in epididymis adipose tissues (EATs), suggesting that it heightened glucose uptake in adipose tissues. Histological and real-time PCR analysis revealed that quercetin attenuated mast cell and macrophage infiltration into EATs in HFD-fed mice. Dietary quercetin also modified the phenotype ratio of M1/M2 macrophages, lowered the levels of proinflammatory cytokines, and enhanced adenosine monophosphate-activated protein kinase (AMPK) α1 phosphorylation and silent information regulator 1 (SIRT1) expression in EATs. Further, using AMPK activator 5-aminoimidazole-4-carboxamide-1-β4-ribofuranoside and inhibitor Compound C, we found that quercetin inhibited polarization and inflammation of mouse bone marrow-derived macrophages through an AMPKα1/SIRT1-mediated mechanism. In conclusion, dietary quercetin might suppress ATM infiltration and inflammation through the AMPKα1/SIRT1 pathway in HFD-fed mice PMID:24465016

  2. RiceATM: a platform for identifying the association between rice agronomic traits and miRNA expression

    PubMed Central

    Liu, Wei-Ting; Yang, Chia-Chun; Chen, Rong-Kuen; Jwo, Woei-Shyuan; Wu, Chih-Wen; Ting, Wen-Yen; Shung, Dah-Pyng; Liu, Chun-Chi; Chen, Jeremy J.W.

    2016-01-01

    MicroRNAs (miRNAs) are known to play critical roles in plant development and stress-response regulation, and they frequently display multi-targeting characteristics. The control of defined rice phenotypes occurs through multiple genes; however, evidence demonstrating the relationship between agronomic traits and miRNA expression profiles is lacking. In this study, we investigated eight yield-related traits in 187 local rice cultivars and profiled the expression levels of 193 miRNAs in these cultivars using microarray analyses. By integrating the miRBase database, the rice annotation project database, and the miRanda and psRNATarget web servers, we constructed a database (RiceATM) that can be employed to investigate the association between rice agronomic traits and miRNA expression. The functions of this platform include phenotype selection, sample grouping, microarray data pretreatment, statistical analysis and target gene predictions. To demonstrate the utility of RiceATM, we used the database to identify four miRNAs associated with the heading date and validated their expression trends in the cultivars with early or late heading date by real-time PCR. RiceATM is a useful tool for researchers seeking to characterize the role of certain miRNAs for a specific phenotype and discover potential biomarkers for breeding or functional studies. Database URL: http://syslab3.nchu.edu.tw/rice/ PMID:28025342

  3. Requirement of ATM-Dependent Monoubiquitylation of Histone H2B for Timely Repair of DNA Double-Strand Breaks

    PubMed Central

    Moyal, Lilach; Lerenthal, Yaniv; Gana-Weisz, Mali; Mass, Gilad; So, Sairei; Wang, Shih-Ya; Eppink, Berina; Chung, Young Min; Shalev, Gil; Shema, Efrat; Shkedy, Dganit; Smorodinsky, Nechama I.; van Vliet, Nicole; Kuster, Bernhard; Mann, Matthias; Ciechanover, Aaron; Dahm-Daphi, Jochen; Kanaar, Roland; Hu, Mickey C.-T.; Chen, David J.; Oren, Moshe; Shiloh, Yosef

    2012-01-01

    SUMMARY The cellular response to DNA double-strand breaks (DSBs) is mobilized by the protein kinase ATM, which phosphorylates key players in the DNA damage response (DDR) network. A major question is how ATM controls DSB repair. Optimal repair requires chromatin relaxation at damaged sites. Chromatin reorganization is coupled to dynamic alterations in histone posttranslational modifications. Here, we show that in human cells, DSBs induce monoubiquitylation of histone H2B, a modification that is associated in undamaged cells with transcription elongation. We find that this process relies on recruitment to DSB sites and ATM-dependent phosphorylation of the responsible E3 ubiquitin ligase: the RNF20-RNF40 heterodimer. H2B monoubiquitylation is required for timely recruitment of players in the two major DSB repair pathways—nonhomologous end-joining and homologous recombination repair—and optimal repair via both pathways. Our data and previous data suggest a two-stage model for chromatin decondensation that facilitates DSB repair. PMID:21362549

  4. Investigation of the impact of the I-94 ATM system on the safety of the I-94 commons high crash area : final report.

    DOT National Transportation Integrated Search

    2014-05-01

    Active Traffic Management (ATM) strategies are being deployed in major cities worldwide to deal with pervasive system : congestion and safety concerns. While such strategies include a diverse array of components, in the Twin Cities metropolitan : are...

  5. Randomized, Double-Blind Phase II Trial With Prospective Classification by ATM Protein Level to Evaluate the Efficacy and Tolerability of Olaparib Plus Paclitaxel in Patients With Recurrent or Metastatic Gastric Cancer.

    PubMed

    Bang, Yung-Jue; Im, Seock-Ah; Lee, Keun-Wook; Cho, Jae Yong; Song, Eun-Kee; Lee, Kyung Hee; Kim, Yeul Hong; Park, Joon Oh; Chun, Hoo Geun; Zang, Dae Young; Fielding, Anitra; Rowbottom, Jacqui; Hodgson, Darren; O'Connor, Mark J; Yin, Xiaolu; Kim, Woo Ho

    2015-11-20

    Gastric cancer cell lines, particularly those with low levels of ataxia telangiectasia mutated (ATM), a key activator of DNA damage response, are sensitive to the poly (ADP-ribose) polymerase inhibitor olaparib. We compared the efficacy of olaparib plus paclitaxel (olaparib/paclitaxel) with paclitaxel alone in patients with recurrent or metastatic gastric cancer and assessed whether low ATM expression is predictive of improved clinical outcome for olaparib/paclitaxel. In this phase II, double-blind study (Study 39; NCT01063517), patients were randomly assigned to oral olaparib 100 mg twice per day (tablets) plus paclitaxel (80 mg/m(2) per day intravenously on days 1, 8, and 15 of every 28-day cycle) or placebo plus paclitaxel (placebo/paclitaxel), followed by maintenance monotherapy with olaparib (200 mg twice per day) or placebo. The study population was enriched to 50% for patients with low or undetectable ATM levels (ATMlow). Primary end point was progression-free survival (PFS). One hundred twenty-three of 124 randomly assigned patients received treatment (olaparib/paclitaxel, n = 61; placebo/paclitaxel, n = 62). The screening prevalence of ATMlow patients was 14%. Olaparib/paclitaxel did not lead to a significant improvement in PFS versus placebo/paclitaxel (overall population: hazard ratio [HR], 0.80; median PFS, 3.91 v 3.55 months, respectively; ATMlow population: HR, 0.74; median PFS, 5.29 v 3.68 months, respectively). However, olaparib/paclitaxel significantly improved overall survival (OS) versus placebo/paclitaxel in both the overall population (HR, 0.56; 80% CI, 0.41 to 0.75; P = .005; median OS, 13.1 v 8.3 months, respectively) and the ATMlow population (HR, 0.35; 80% CI, 0.22 to 0.56; P = .002; median OS, not reached v 8.2 months, respectively). Olaparib/paclitaxel was generally well tolerated, with no unexpected safety findings. Olaparib/paclitaxel is active in the treatment of patients with metastatic gastric cancer, with a greater OS benefit in

  6. Mutational Spectrum Analysis of Neurodegenerative Diseases and Its Pathogenic Implication.

    PubMed

    Shen, Liang; Ji, Hong-Fang

    2015-10-14

    One of the most conspicuous features of neurodegenerative diseases (NDs) is the occurrence of dramatic conformation change of individual proteins. We performed a mutational spectrum analysis of disease-causing missense mutations in seven types of NDs at nucleotide and amino acid levels, and compared the results with those of non-NDs. The main findings included: (i) The higher mutation ratio of G:C→T:A transversion to G:C→A:T transition was observed in NDs than in non-NDs, interpreting the excessive guanine-specific oxidative DNA damage in NDs; (ii) glycine and proline had highest mutability in NDs than in non-NDs, which favor the protein conformation change in NDs; (iii) surprisingly low mutation frequency of arginine was observed in NDs. These findings help to understand how mutations may cause NDs.

  7. Mutational Spectrum Analysis of Neurodegenerative Diseases and Its Pathogenic Implication

    PubMed Central

    Shen, Liang; Ji, Hong-Fang

    2015-01-01

    One of the most conspicuous features of neurodegenerative diseases (NDs) is the occurrence of dramatic conformation change of individual proteins. We performed a mutational spectrum analysis of disease-causing missense mutations in seven types of NDs at nucleotide and amino acid levels, and compared the results with those of non-NDs. The main findings included: (i) The higher mutation ratio of G:C→T:A transversion to G:C→A:T transition was observed in NDs than in non-NDs, interpreting the excessive guanine-specific oxidative DNA damage in NDs; (ii) glycine and proline had highest mutability in NDs than in non-NDs, which favor the protein conformation change in NDs; (iii) surprisingly low mutation frequency of arginine was observed in NDs. These findings help to understand how mutations may cause NDs. PMID:26473852

  8. Reduced Crossover Interference and Increased ZMM-Independent Recombination in the Absence of Tel1/ATM

    PubMed Central

    Anderson, Carol M.; Oke, Ashwini; Yam, Phoebe; Zhuge, Tangna; Fung, Jennifer C.

    2015-01-01

    Meiotic recombination involves the repair of double-strand break (DSB) precursors as crossovers (COs) or noncrossovers (NCOs). The proper number and distribution of COs is critical for successful chromosome segregation and formation of viable gametes. In budding yeast the majority of COs occurs through a pathway dependent on the ZMM proteins (Zip2-Zip3-Zip4-Spo16, Msh4-Msh5, Mer3), which form foci at CO-committed sites. Here we show that the DNA-damage-response kinase Tel1/ATM limits ZMM-independent recombination. By whole-genome mapping of recombination products, we find that lack of Tel1 results in higher recombination and reduced CO interference. Yet the number of Zip3 foci in tel1Δ cells is similar to wild type, and these foci show normal interference. Analysis of recombination in a tel1Δ zip3Δ double mutant indicates that COs are less dependent on Zip3 in the absence of Tel1. Together these results reveal that in the absence of Tel1, a significant proportion of COs occurs through a non-ZMM-dependent pathway, contributing to a CO landscape with poor interference. We also see a significant change in the distribution of all detectable recombination products in the absence of Tel1, Sgs1, Zip3, or Msh4, providing evidence for altered DSB distribution. These results support the previous finding that DSB interference depends on Tel1, and further suggest an additional level of DSB interference created through local repression of DSBs around CO-designated sites. PMID:26305689

  9. High LET Radiation Can Enhance TGF(Beta) Induced EMT and Cross-Talk with ATM Pathways

    NASA Technical Reports Server (NTRS)

    Wang, Minli; Hada, Megumi; Huff, Janice; Pluth, Janice M.; Anderson, Janniffer; ONeill, Peter; Cucinotta, Francis A.

    2010-01-01

    The TGF(Beta) pathway has been shown to regulate or directly interact with the ATM pathway in the response to radiation in mammary epithelial cells. We investigated possible interactions between the TGF(Beta) and ATM pathways following simulated space radiation using hTERT immortalized human esophageal epithelial cells (EPC-hTERT), mink lung epithelial cells (Mv1lu), and several human fibroblast cell lines. TGF(Beta) is a key modulator of the Epithelial-Mesenchymal Transition (EMT), important in cancer progression and metastasis. The implication of EMT by radiation also has several lines of developing evidence, however is poorly understood. The identification of TGF(Beta) induced EMT can be shown in changes to morphology, related gene over expression or down regulation, which can be detected by RT-PCR, and immunostaining and western blotting. In this study, we have observed morphologic and molecular alternations consistent with EMT after Mv1lu cells were treated with TGF(Beta) High LET radiation enhanced TGF(Beta) mediated EMT with a dose as low as 0.1Gy. In order to consider the TGF(Beta) interaction with ATM we used a potent ATM inhibitor Ku55933 and investigated gene expression changes and Smad signaling kinetics. Ku559933 was observed to reverse TGF(Beta) induced EMT, while this was not observed in dual treated cells (radiation+TGF(Beta)). In EPC-hTERT cells, TGF(Beta) alone was not able to induce EMT after 3 days of application. A combined treatment with high LET, however, significantly caused the alteration of EMT markers. To study the function of p53 in the process of EMT, we knocked down P53 through RNA interference. Morphology changes associated with EMT were observed in epithelial cells with silenced p53. Our study indicates: high LET radiation can enhance TGF(Beta) induced EMT; while ATM is triggering the process of TGF(Beta)-induced EMT, p53 might be an essential repressor for EMT phenotypes.

  10. Relatively high rates of G:C → A:T transitions at CpG sites were observed in certain epithelial tissues including pancreas and submaxillary gland of adult big blue® mice.

    PubMed

    Prtenjaca, Anita; Tarnowski, Heather E; Marr, Alison M; Heney, Melanie A; Creamer, Laura; Sathiamoorthy, Sarmitha; Hill, Kathleen A

    2014-01-01

    With few exceptions, spontaneous mutation frequency and pattern are similar across tissue types and relatively constant in young to middle adulthood in wild type mice. Underrepresented in surveys of spontaneous mutations across murine tissues is the diversity of epithelial tissues. For the first time, spontaneous mutations were detected in pancreas and submaxillary gland and compared with kidney, lung, and male germ cells from five adult male Big Blue® mice. Mutation load was assessed quantitatively through measurement of mutant and mutation frequency and qualitatively through identification of mutations and characterization of recurrent mutations, multiple mutations, mutation pattern, and mutation spectrum. A total of 9.6 million plaque forming units were screened, 226 mutants were collected, and 196 independent mutations were identified. Four novel mutations were discovered. Spontaneous mutation frequency was low in pancreas and high in the submaxillary gland. The submaxillary gland had multiple recurrent mutations in each of the mice and one mutant had two independent mutations. Mutation patterns for epithelial tissues differed from that observed in male germ cells with a striking bias for G:C to A:T transitions at CpG sites. A comprehensive review of lacI spontaneous mutation patterns in young adult mice and rats identified additional examples of this mutational bias. An overarching observation about spontaneous mutation frequency in adult tissues of the mouse remains one of stability. A repeated observation in certain epithelial tissues is a higher rate of G:C to A:T transitions at CpG sites and the underlying mechanisms for this bias are not known. Copyright © 2013 Wiley Periodicals, Inc.

  11. Activation of H2AX and ATM in varicella-zoster virus (VZV)-infected cells is associated with expression of specific VZV genes.

    PubMed

    Yamamoto, Takenobu; Ali, Mir A; Liu, XueQiao; Cohen, Jeffrey I

    2014-03-01

    Mammalian cells activate DNA damage response pathways in response to virus infections. Activation of these pathways can enhance replication of many viruses, including herpesviruses. Activation of cellular ATM results in phosphorylation of H2AX and recruits proteins to sites of DNA damage. We found that varicella-zoster (VZV) infected cells had elevated levels of phosphorylated H2AX and phosphorylated ATM and that these levels increased in cells infected with VZV deleted for ORF61 or ORF63, but not deleted for ORF67. Expression of VZV ORF61, ORF62, or ORF63 alone did not result in phosphorylation of H2AX. While BGLF4, the Epstein-Barr virus homolog of VZV ORF47 protein kinase, phosphorylates H2AX and ATM, neither VZV ORF47 nor ORF66 protein kinase phosphorylated H2AX or ATM. Cells lacking ATM had no reduction in VZV replication. Thus, VZV induces phosphorylation of H2AX and ATM and this effect is associated with the presence of specific VZV genes in virus-infected cells. Published by Elsevier Inc.

  12. Enzymological Characterization of Atm, the First Laccase from Agrobacterium sp. S5-1, with the Ability to Enhance In Vitro digestibility of Maize Straw

    PubMed Central

    Si, Wei; Wu, ZhaoWei; Wang, LiangLiang; Yang, MingMing; Zhao, Xin

    2015-01-01

    Laccase is an enzyme that catalyzes oxidation of phenolic compounds, diamines and aromatic amines. In this study, a novel laccase-like gene (atm) in a ligninolyitic isolate Agrobacterium sp. S5-1 from soil humus was identified and heterologously expressed in Escherichia coli. Atm exhibited its maximal activity at pH 4.5 and at 50°C. This enzyme was tolerant to high temperature, a broad range of pH, heavy metal ions (Co3+, Mn2+, Cu2+ and Ni2+, 20 mM) and all tested organic solvents. Furthermore, Atm significantly (p<0.05) increased dry matter digestibility of maize straw from 23.44% to 27.96% and from 29.53% to 37.10% after 8 or 24 h of digestion and improved acid detergent fiber digestibility from 5.81% to 10.33% and from 12.80% to 19.07% after 8 or 24 h of digestion, respectively. The combination of Atm and fibrolytic enzymes significantly (p<0.05) enhanced neutral detergent fiber digestibility from 19.02% to 24.55% after 24 h of digestion respectively. Results showed treatment with Atm effectively improved in vitro digestibility of maize straw, thus suggesting that Atm has an application potential for bioconversion of lignin rich agricultural byproducts into animal feed and cellulosic ethanol. PMID:26010258

  13. Isoliquiritigenin as a cause of DNA damage and inhibitor of ataxia-telangiectasia mutated expression leading to G2/M phase arrest and apoptosis in oral squamous cell carcinoma.

    PubMed

    Hsia, Shih-Min; Yu, Cheng-Chia; Shih, Yin-Hua; Yuanchien Chen, Michael; Wang, Tong-Hong; Huang, Yu-Ting; Shieh, Tzong-Ming

    2016-04-01

    Isoliquiritigenin (ISL), a natural compound extracted from licorice, has chemopreventive and antitumor activities. The purpose of this study was to investigate the anticancer effect of ISL on human oral squamous cell carcinoma (OSCC). The anti-OSCC effects of ISL were evaluated using the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide test, flow cytometry, reverse transcription-polymerase chain reaction, Western blotting, promoter activity, terminal deoxynucleotidyl transferase dUTP nick-end labeling assay, malignant phenotype analysis, microRNA, and xenografting. ISL induced OSCC cell cycle G2/M phase arrest, apoptosis, and DNA damage. However, the DNA repair-associated ataxia telangiectasia mutated (ATM) and phospho-ATM were downregulated, ATM mRNA remained unchanged, and the downstream signals were inhibited. ATM recovered when the caspase activity was blocked by Z-DVED-FMK. A low dose of ISL inhibited OSCC malignancy in vitro and reduced the tumor size in vivo. ATM was cleaved by ISL-activated caspase, thus inhibiting DNA repair in OSCC cells. Therefore, ISL is a promising chemopreventive agent against oral cancer. © 2015 Wiley Periodicals, Inc. Head Neck 38: E360-E371, 2016. © 2015 Wiley Periodicals, Inc.

  14. Mutation of the BTK gene and clinical feature of X-linked agammaglobulinemia in mainland China.

    PubMed

    Wang, Ying; Kanegane, Hirokazu; Wang, Xiaochuan; Han, Xiaohua; Zhang, Qian; Zhao, Shunying; Yu, Yeheng; Wang, Jingyi; Miyawaki, Toshio

    2009-05-01

    X-Linked agammaglobulinemia is a prototypical humoral immunodeficiency with the mutation of the Bruton's tyrosine kinase gene. We investigated the gene mutation and clinical features of 30 Chinese X-linked agammaglobulinemia (XLA) patients from 27 families. There were 26 mutations, including 11 novel and 15 recurrent mutations, distributing over the entire gene. The nucleotide and amino acid aberration, 1129C>T(H333Y) and 1196T>A(I355N), in SH2 have not been reported before. Five (I355N, W124R, R520X, I590F, G594E) of the 24 mutations not detected in the mothers receiving gene analysis were determined to be de novo. Two mutations occurred within intronic splice-site sequences (intron5(-2)A>G, intron17(-2)A>T). There are eight mutations in the PH domain, two mutations in the SH3 domain, three mutations in the SH2 domain, one mutation in the TH domain, and other 16 mutations in the TK domain. The mutations of protein domain is most common in TK (53%) domain and then in PH(8%) domain. Missense and nonsense mutations were found equal in 46% of the detected mutations. All of the patients are alive, but one died of liver cancer. Clinical features and serum Igs levels range variedly and were not correlated with genotypes. Our results demonstrated molecular genetic characteristics of XLA in mainland China.

  15. Role of the ATM Gene in Bilateral Breast Cancer Following Radiotherapy.

    DTIC Science & Technology

    1999-08-01

    PREPARED FOR: Commander U.S. Army Medical Research and Materiel Command Fort Detrick, Maryland 21702-5012 DISTRIBUTION STATEMENT: Approved for...ADORESS(ES) U.S. Army Medical Research And Materiel Command ATTN: MCMR-RMI-S 504 Scott Street Fort Detrick, Maryland 21702-5012 10. SPONSORING...using a /Von-radio/’ sotopic flNase Cleavage- based Assay (NIRCA). No mutations were discovered in these exons from any of the bilateral breast cancer

  16. Mutation and premating isolation

    NASA Technical Reports Server (NTRS)

    Woodruff, R. C.; Thompson, J. N. Jr

    2002-01-01

    While premating isolation might be traceable to different genetic mechanisms in different species, evidence supports the idea that as few as one or two genes may often be sufficient to initiate isolation. Thus, new mutation can theoretically play a key role in the process. But it has long been thought that a new isolation mutation would fail, because there would be no other individuals for the isolation-mutation-carrier to mate with. We now realize that premeiotic mutations are very common and will yield a cluster of progeny carrying the same new mutant allele. In this paper, we discuss the evidence for genetically simple premating isolation barriers and the role that clusters of an isolation mutation may play in initiating allopatric, and even sympatric, species divisions.

  17. Multi-objective optimisation of aircraft flight trajectories in the ATM and avionics context

    NASA Astrophysics Data System (ADS)

    Gardi, Alessandro; Sabatini, Roberto; Ramasamy, Subramanian

    2016-05-01

    The continuous increase of air transport demand worldwide and the push for a more economically viable and environmentally sustainable aviation are driving significant evolutions of aircraft, airspace and airport systems design and operations. Although extensive research has been performed on the optimisation of aircraft trajectories and very efficient algorithms were widely adopted for the optimisation of vertical flight profiles, it is only in the last few years that higher levels of automation were proposed for integrated flight planning and re-routing functionalities of innovative Communication Navigation and Surveillance/Air Traffic Management (CNS/ATM) and Avionics (CNS+A) systems. In this context, the implementation of additional environmental targets and of multiple operational constraints introduces the need to efficiently deal with multiple objectives as part of the trajectory optimisation algorithm. This article provides a comprehensive review of Multi-Objective Trajectory Optimisation (MOTO) techniques for transport aircraft flight operations, with a special focus on the recent advances introduced in the CNS+A research context. In the first section, a brief introduction is given, together with an overview of the main international research initiatives where this topic has been studied, and the problem statement is provided. The second section introduces the mathematical formulation and the third section reviews the numerical solution techniques, including discretisation and optimisation methods for the specific problem formulated. The fourth section summarises the strategies to articulate the preferences and to select optimal trajectories when multiple conflicting objectives are introduced. The fifth section introduces a number of models defining the optimality criteria and constraints typically adopted in MOTO studies, including fuel consumption, air pollutant and noise emissions, operational costs, condensation trails, airspace and airport operations

  18. Prediction of plagioclase-melt equilibria in anhydrous silicate melts at 1-atm

    NASA Astrophysics Data System (ADS)

    Namur, Olivier; Charlier, Bernard; Toplis, Michael J.; Vander Auwera, Jacqueline

    2012-01-01

    Many models for plagioclase-melt equilibria have been proposed over the past 30 years, but the focus is increasingly on the effects of water content and pressure. However, many geological and petrological applications concern low pressure and low water systems, such as the differentiation of large terrestrial basaltic magma chambers, and lunar and asteroidal magmatism. There is, therefore, a justified need to quantify the influence of anhydrous liquid composition on the composition of equilibrium plagioclase at 1-atm. With this in mind, a database of over 500 experimentally determined plagioclase-liquid pairs has been created. The selected low pressure, anhydrous, experiments include both natural and synthetic liquids, whose compositions range from basalt to rhyolite. Four equations are proposed, derived from this data. The first is based on a thermodynamically inspired formalism, explicitly integrating the effect of temperature. This equation uses free energies and activities of crystalline anorthite available from the literature. For the activity of anorthite in the liquid phase, it is found that current models of the activity of individual oxides are insufficient to account for the experimental results. We have therefore derived an empirical expression for the variation of anorthite activity in the liquid as a function of melt composition, based upon inversion of the experimental data. Using this expression allows the calculation of plagioclase composition with a relative error less than 10%. However, in light of the fact that temperature is not necessarily known for many petrological applications, an alternative set of T-independent equations is also proposed. For this entirely empirical approach, the database has been divided into three compositional groups, treated independently for regression purposes: mafic-ultramafic, alkali-rich mafic-ultramafic, and intermediate-felsic. This separation into distinct subgroups was found to be necessary to maintain errors

  19. Development and Evaluation of a Gridded CrIS/ATMS Visualization for Operational Forecasting

    NASA Astrophysics Data System (ADS)

    Zavodsky, B.; Smith, N.; Dostalek, J.; Stevens, E.; Nelson, K.; Weisz, E.; Berndt, E.; Line, W.; Barnet, C.; Gambacorta, A.; Reale, A.; Hoese, D.

    2016-12-01

    Upper-air observations from radiosondes are limited in spatial coverage and are primarily launched only at synoptic times, potentially missing evolving air masses. For forecast challenges which require diagnosis of the three-dimensional extent of the atmosphere, these observations may not be enough for forecasters. Currently, forecasters rely on model output alongside the sparse network of radiosondes for characterizing the three-dimensional atmosphere. However, satellite information can help fill in the spatial and temporal gaps in radiosonde observations. In particular, temperature and moisture retrievals from the NOAA-Unique Combined Atmospheric Processing System (NUCAPS), which combines infrared soundings from the Cross-track Infrared Sounder (CrIS) with the Advanced Technology Microwave Sounder (ATMS) to retrieve profiles of temperature and moisture. NUCAPS retrievals are available in a wide swath of observations with approximately 45-km spatial resolution at nadir and a local Equator crossing time of 1:30 A.M./P.M. enabling three-dimensional observations at asynoptic times. For forecasters to make the best use of these observations, these satellite-based soundings must be displayed in the National Weather Service's decision support system, the Advanced Weather Interactive Processing System (AWIPS). NUCAPS profiles are currently available in AWIPS as point observations that can be displayed on Skew-T diagrams. This presentation discusses the development of a new visualization capability for NUCAPS within AWIPS that will allow the data to be viewed in gridded horizontal maps or as vertical cross sections, giving forecasters additional tools for diagnosing atmospheric features. Forecaster feedback and examples of operational applications from two testbed activities will be highlighted. First is a product evaluation at the Hazardous Weather Testbed for severe weather—such as high winds, large hail, tornadoes—where the vertical distribution of temperature and

  20. Real-time telemedicine using shared three-dimensional workspaces over ATM

    NASA Astrophysics Data System (ADS)

    Cahoon, Peter; Forsey, David R.; Hutchison, Susan

    1999-03-01

    During the past five years a high speed ATM network has been developed at UBC that provides a campus testbed, a local testbed to the hospitals, and a National testbed between here and the BADLAB in Ottawa. This testbed has been developed to combine a commercial shared audio/video/whiteboard environment coupled with a shared interactive 3-dimensional solid model. This solid model ranges from a skull reconstructed from a CT scan with muscles and an overlying skin, to a model of the ventricle system of the human brain. Typical interactions among surgeon, radiologist and modeler consist of having image slices of the original scan shared by all and the ability to adjust the surface of the model to conform to each individuals perception of what the final object should look like. The purpose of this interaction can range from forensic reconstruction from partial remains to pre-maxillofacial surgery. A joint project with the forensic unit of the R.C.M.P. in Ottawa using the BADLAB is now in the stages of testing this methodology on a real case beginning with a CT scan of partial remains. A second study underway with the department of Maxiofacial reconstruction at Dalhousie University in Halifax Nova Scotia and concerns a subject who is about to undergo orthognathic surgery, in particular a mandibular advancement. This subject has been MRI scanned, a solid model constructed of the mandible and the virtual surgery constructed on the model. This model and the procedure have been discussed and modified by the modeler and the maxillofacial specialist using these shared workspaces. The procedure will be repeated after the actual surgery to verify the modeled procedure. The advantage of this technique is that none of the specialists need be in the same room, or city. Given the scarcity of time and specialists this methodology shows great promise. In November of this last year a shared live demonstration of this facial modeler was done between Vancouver and Dalhousie University in

  1. Results from Evaluations of Gridded CrIS/ATMS Visualization for Operational Forecasting

    NASA Astrophysics Data System (ADS)

    Stevens, E.; Zavodsky, B.; Dostalek, J.; Berndt, E.; Hoese, D.; White, K.; Bowlan, M.; Gambacorta, A.; Wheeler, A.; Haisley, C.; Smith, N.

    2017-12-01

    For forecast challenges which require diagnosis of the three-dimensional atmosphere, current observations, such as radiosondes, may not offer enough information. Satellite data can help fill the spatial and temporal gaps between soundings. In particular, temperature and moisture retrievals from the NOAA-Unique Combined Atmospheric Processing System (NUCAPS), which combines infrared soundings from the Cross-track Infrared Sounder (CrIS) with the Advanced Technology Microwave Sounder (ATMS) to retrieve profiles of temperature and moisture. NUCAPS retrievals are available in a wide swath with approximately 45-km spatial resolution at nadir and a local Equator crossing time of 1:30 A.M./P.M. enabling three-dimensional observations at asynoptic times. This abstract focuses on evaluation of a new visualization for NUCAPS within the operational National Weather Service Advanced Weather Interactive Processing System (AWIPS) decision support system that allows these data to be viewed in gridded horizontal maps or vertical cross sections. Two testbed evaluations have occurred in 2017: a Cold Air Aloft (CAA) evaluation at the Alaska Center Weather Service Unit and a Convective Potential evaluation at the NOAA Hazardous Weather Testbed. For CAA, at high latitudes during the winter months, the air at altitudes used by passenger and cargo aircraft can reach temperatures cold enough (-65°C) to begin to freeze jet fuel, and Gridded NUCAPS visualization was shown to help fill in the spatial and temporal gaps in data-sparse areas across the Alaskan airspace by identifying the 3D spatial extent of cold air features. For convective potential, understanding the vertical distribution of temperature and moisture is also very important for forecasting the potential for convection related to severe weather such as lightning, large hail, and tornadoes. The Gridded NUCAPS visualization was shown to aid forecasters in understanding temperature and moisture characteristics at critical levels

  2. High-resolution melting curve analysis for rapid detection of mutations in a Medaka TILLING library.

    PubMed

    Ishikawa, Tomoko; Kamei, Yasuhiro; Otozai, Shinji; Kim, Jinhyong; Sato, Ayuko; Kuwahara, Yoshikazu; Tanaka, Minoru; Deguchi, Tomonori; Inohara, Hidenori; Tsujimura, Tohru; Todo, Takeshi

    2010-09-15

    During the last two decades, DNA sequencing has led to the identification of numerous genes in key species; however, in most cases, their functions are still unknown. In this situation, reverse genetics is the most suitable method to assign function to a gene. TILLING (Targeting Induced Local Lesions IN Genomes) is a reverse-genetic strategy that combines random chemical mutagenesis with high-throughput discovery of the induced mutations in target genes. The method has been applied to a variety of plant and animal species. Screening of the induced mutations is the most important step in TILLING. Currently, direct sequencing or nuclease-mediated screening of heteroduplexes is widely used for detection of mutations in TILLING. Both methods are useful, but the costs are substantial and turnaround times are relatively long. Thus, there is a need for an alternative method that is of higher throughput and more cost effective. In this study, we developed a high resolution melting (HRM) assay and evaluated its effectiveness for screening ENU-induced mutations in a medaka TILLING library. We had previously screened mutations in the p53 gene by direct sequencing. Therefore, we first tested the efficiency of the HRM assay by screening mutations in p53, which indicated that the HRM assay is as useful as direct sequencing. Next, we screened mutations in the atr and atm genes with the HRM assay. Nonsense mutations were identified in each gene, and the phenotypes of these nonsense mutants confirmed their loss-of-function nature. These results demonstrate that the HRM assay is useful for screening mutations in TILLING. Furthermore, the phenotype of the obtained mutants indicates that medaka is an excellent animal model for investigating genome stability and gene function, especially when combined with TILLING.

  3. Use of JPSS ATMS, CrIS, and VIIRS data to Improve Tropical Cyclone Track and Intensity Forecasting

    NASA Astrophysics Data System (ADS)

    Chirokova, G.; Demaria, M.; DeMaria, R.; Knaff, J. A.; Dostalek, J.; Musgrave, K. D.; Beven, J. L.

    2015-12-01

    JPSS data provide unique information that could be critical for the forecasting of tropical cyclone (TC) track and intensity and is currently underutilized. Preliminary results from several TC applications using data from the Advanced Technology Microwave Sounder (ATMS), the Cross-Track Infrared Sounder (CrIS), and the Visible Infrared Imaging Radiometer Suite (VIIRS), carried by the Suomi National Polar-Orbiting Partnership satellite (SNPP), will be discussed. The first group of applications, which includes applications for moisture flux and for eye-detection, aims to improve rapid intensification (RI) forecasts, which is one of the highest priorities within NOAA. The applications could be used by forecasters directly and will also provide additional input to the Rapid Intensification Index (RII), the statistical-dynamical tool for forecasting RI events that is operational at the National Hurricane Center. The moisture flux application uses bias-corrected ATMS-MIRS (Microwave Integrated Retrieval System) and NUCAPS (NOAA Unique CrIS ATMS Processing System), retrievals that provide very accurate temperature and humidity soundings in the TC environment to detect dry air intrusions. The objective automated eye-detection application uses geostationary and VIIRS data in combination with machine learning and computer vision techniques for determining the onset of eye formation which is very important for TC intensity forecast but is usually determined by subjective methods. First version of the algorithm showed very promising results with a 75% success rate. The second group of applications develops tools to better utilize VIIRS data, including day-night band (DNB) imagery, for tropical cyclone forecasting. Disclaimer: The views, opinions, and findings contained in this article are those of the authors and should not be construed as an official National Oceanic and Atmospheric Administration (NOAA) or U.S. Government position, policy, or decision.

  4. Low-Dose Radiation Promotes Dendritic Cell Migration and IL-12 Production via the ATM/NF-KappaB Pathway.

    PubMed

    Yu, Nan; Wang, Sinian; Song, Xiujun; Gao, Ling; Li, Wei; Yu, Huijie; Zhou, Chuanchuan; Wang, Zhenxia; Li, Fengsheng; Jiang, Qisheng

    2018-04-01

    For dendritic cells (DCs) to initiate an immune response, their ability to migrate and to produce interleukin-12 (IL-12) is crucial. It has been previously shown that low-dose radiation (LDR) promoted IL-12 production by DCs, resulting in increased DC activity that contributed to LDR hormesis in the immune system. However, the molecular mechanism of LDR-induced IL-12 production, as well as the effect of LDR on DC migration capacity require further elucidation. Using the JAWSII immortalized mouse dendritic cell line, we showed that in vitro X-ray irradiation (0.2 Gy) of DCs significantly increased DC migration and IL-12 production, and upregulated CCR7. The neutralizing antibody against CCR7 has been shown to abolish LDR-enhanced DC migration, demonstrating that CCR7 mediates LDR-promoting DC migration. We identified nuclear factor kappaB (NF-κB) as the central signaling pathway that mediated LDR-enhanced expression of IL-12 and CCR7 based on findings that 0.2 Gy X-ray irradiation activated NF-κB, showing increased nuclear p65 translocation and NF-κB DNA-binding activity, while an NF-κB inhibitor blocked LDR-enhanced expression of IL-12 and CCR7, as well as DC migration. Finally, we demonstrated that 0.2 Gy X-ray irradiation promoted ATM phosphorylation and reactive oxygen species generation; however, only the ATM inhibitor abolished the LDR-induced NF-κB-mediated expression of IL-12 and CCR7. Altogether, our data show that exposure to LDR resulted in a hormetic effect on DCs regarding CCR7-mediated migration and IL-12 production by activating the ATM/NF-κB pathway.

  5. Kaempferol induces ATM/p53-mediated death receptor and mitochondrial apoptosis in human umbilical vein endothelial cells.

    PubMed

    Lee, Chiu-Fang; Yang, Jai-Sing; Tsai, Fuu-Jen; Chiang, Ni-Na; Lu, Chi-Cheng; Huang, Yu-Syuan; Chen, Chun; Chen, Fu-An

    2016-05-01

    Kaempferol is a member of the flavonoid compounds found in vegetables and fruits. It is shown to exhibit biological impact and anticancer activity, but no report exists on the angiogenic effect of kaempferol and induction of cell apoptosis in vitro. In this study, we investigated the role of kaempferol on anti-angiogenic property and the apoptotic mechanism of human umbilical vein endothelial cells (HUVECs). Our results demonstrated that kaempferol decreased HUVEC viability in a time- and concentration-dependent manner. Kaempferol also induced morphological changes and sub-G1 phase cell population (apoptotic cells). Kaempferol triggered apoptosis of HUVECs as detecting by DNA fragmentation, comet assay and immunofluorescent staining for activated caspase-3. The caspase signals, including caspase-8, -9 and -3, were time-dependently activated in HUVECs after kaempferol exposure. Furthermore, pre-treatment with a specific inhibitor of caspase-8 (Z-IETD-FMK) significantly reduced the activity of caspase-8, -9 and -3, indicating that extrinsic pathway is a major signaling pathway in kaempferol-treated HUVECs. Importantly, kaempferol promoted reactive oxygen species (ROS) evaluated using flow cytometric assay in HUVECs. We further investigated the upstream extrinsic pathway and showed that kaempferol stimulated death receptor signals [Fas/CD95, death receptor 4 (DR4) and DR5] through increasing the levels of phosphorylated p53 and phosphorylated ATM pathways in HUVECs, which can be individually confirmed by N-acetylcysteine (NAC), ATM specific inhibitor (caffeine) and p53 siRNA. Based on these results, kaempferol-induced HUVEC apoptosis was involved in an ROS-mediated p53/ATM/death receptor signaling. Kaempferol might possess therapeutic effects on cancer treatment in anti-vascular targeting.

  6. An assessment of the impact of ATMS and CrIS data assimilation on precipitation prediction over the Tibetan Plateau

    NASA Astrophysics Data System (ADS)

    Xue, Tong; Xu, Jianjun; Guan, Zhaoyong; Chen, Han-Ching; Chiu, Long S.; Shao, Min

    2017-07-01

    Using the National Oceanic and Atmospheric Administration's Gridpoint Statistical Interpolation data assimilation system and the National Center for Atmospheric Research's Advanced Research Weather Research and Forecasting (WRF-ARW) regional model, the impact of assimilating Advanced Technology Microwave Sounder (ATMS) and Cross-track Infrared Sounder (CrIS) satellite data on precipitation prediction over the Tibetan Plateau in July 2015 was evaluated. Four experiments were designed: a control experiment and three data assimilation experiments with different data sets injected: conventional data only, a combination of conventional and ATMS satellite data, and a combination of conventional and CrIS satellite data. The results showed that the monthly mean of precipitation is shifted northward in the simulations and showed an orographic bias described as an overestimation upwind of the mountains and an underestimation in the south of the rain belt. The rain shadow mainly influenced prediction of the quantity of precipitation, although the main rainfall pattern was well simulated. For the first 24 h and last 24 h of accumulated daily precipitation, the model generally overestimated the amount of precipitation, but it was underestimated in the heavy-rainfall periods of 3-5, 13-16, and 22-25 July. The observed water vapor conveyance from the southeastern Tibetan Plateau was larger than in the model simulations, which induced inaccuracies in the forecast of heavy rain on 3-5 July. The data assimilation experiments, particularly the ATMS assimilation, were closer to the observations for the heavy-rainfall process than the control. Overall, based on the experiments in July 2015, the satellite data assimilation improved to some extent the prediction of the precipitation pattern over the Tibetan Plateau, although the simulation of the rain belt without data assimilation shows the regional shifting.

  7. Using ATM laser altimetry to constrain surface mass balance estimates and supraglacial hydrology of the Greenland Ice Sheet

    NASA Astrophysics Data System (ADS)

    Studinger, M.; Medley, B.; Manizade, S.; Linkswiler, M. A.

    2016-12-01

    Repeat airborne laser altimetry measurements can provide large-scale field observations to better quantify spatial and temporal variability of surface processes contributing to seasonal elevation change and therefore surface mass balance. As part of NASA's Operation IceBridge the Airborne Topographic Mapper (ATM) laser altimeter measured the surface elevation of the Greenland Ice Sheet during spring (March - May) and fall (September - October) of 2015. Comparison of the two surveys reveals a general trend of thinning for outlet glaciers and for the ice sheet in a manner related to elevation and latitude. In contrast, some thickening is observed on the west (but not on the east) side of the ice divide above 2200 m elevation in the southern half, below latitude 69°N.The observed magnitude and spatial patterns of the summer melt signal can be utilized as input into ice sheet models and for validating reanalysis of regional climate models such as RACMO and MAR. We use seasonal anomalies in MERRA-2 climate fields (temperature, precipitation) to understand the observed spatial signal in seasonal change. Aside from surface elevation change, runoff from meltwater pooling in supraglacial lakes and meltwater channels accounts for at least half of the total mass loss. The ability of the ATM laser altimeters to image glacial hydrological features in 3-D and determine the depth of supraglacial lakes could be used for process studies and for quantifying melt processes over large scales. The 1-meter footprint diameter of ATM laser on the surface, together with a high shot density, allows for the production of large-scale, high-resolution, geodetic quality DEMs (50 x 50 cm) suitable for fine-scale glacial hydrology research and as input to hydrological models quantifying runoff.

  8. Changes in the response of MCF-7 cells to ionizing radiation after the combination of ATM and DNA-PK inhibition.

    PubMed

    Ćmielová, Jana; Havelek, Radim; Vávrová, Jiřina; Řezáčová, Martina

    2015-05-01

    The aim of the present study is to evaluate the role of ATM (KU55933) and DNA-PK (NU7441) inhibitors in the repair of double-strand breaks and downstream signaling of DNA damage introduced by ionizing radiation. The irradiation of MCF-7 cells alone increased the proportion of cells in the G1 phase in comparison with mock-treated cells. After ATM inhibitor pretreatment, the cells were more accumulated in the G2 phase, whereas DNA-PK inhibitor application increased the percentage of cells in the G1 phase. ATM and DNA-PK inhibitor application alone increased the sensitivity of MCF-7 cells to ionizing radiation; however, combining both inhibitors together resulted in a further enhancement of cell death. Unexpectedly, combining both inhibitors decreased the percentage of senescent cells and increased G2 cell cycle arrest 3 days after treatment. After irradiation, the p21 protein was increased and Chk1 and Chk2 were activated. These proteins were not increased in cells pretreated with the ATM inhibitor prior to ionizing radiation exposure, albeit DNA-PK inhibitor application did not affect the amount of proteins detected. Formation of γH2AX was found to be ATM and DNA-PK dependent, application of the ATM inhibitor suppressed incidence of γH2AX, whereas DNA-PK caused persistence of γH2AX. Our results suggest that the further investigation of the ATM inhibitor in combination with the DNA-PK inhibitor as sensitizers preventing cell senescence and promoting cell death in breast carcinoma MCF-7 cells is warranted.

  9. Low doses of X-rays induce prolonged and ATM-independent persistence of γH2AX foci in human gingival mesenchymal stem cells.

    PubMed

    Osipov, Andreyan N; Pustovalova, Margarita; Grekhova, Anna; Eremin, Petr; Vorobyova, Natalia; Pulin, Andrey; Zhavoronkov, Alex; Roumiantsev, Sergey; Klokov, Dmitry Y; Eremin, Ilya

    2015-09-29

    Diagnostic imaging delivering low doses of radiation often accompany human mesenchymal stem cells (MSCs)-based therapies. However, effects of low dose radiation on MSCs are poorly characterized. Here we examine patterns of phosphorylated histone H2AX (γH2AX) and phospho-S1981 ATM (pATM) foci formation in human gingiva-derived MSCs exposed to X-rays in time-course and dose-response experiments. Both γH2AX and pATM foci accumulated linearly with dose early after irradiation (5-60 min), with a maximum induction observed at 30-60 min (37 ± 3 and 32 ± 3 foci/cell/Gy for γH2AX and pATM, respectively). The number of γH2AX foci produced by intermediate doses (160 and 250 mGy) significantly decreased (40-60%) between 60 and 240 min post-irradiation, indicating rejoining of DNA double-strand breaks. In contrast, γH2AX foci produced by low doses (20-80 mGy) did not change after 60 min. The number of pATM foci between 60 and 240 min decreased down to control values in a dose-independent manner. Similar kinetics was observed for pATM foci co-localized with γH2AX foci. Collectively, our results suggest differential DNA double-strand break signaling and processing in response to low vs. intermediate doses of X-rays in human MSCs. Furthermore, mechanisms governing the prolonged persistence of γH2AX foci in these cells appear to be ATM-independent.

  10. IN31A-1734 Development and Evaluation of a Gridded CrIS/ATMS Visualization for Operational Forecasting

    NASA Technical Reports Server (NTRS)

    Zavodsky, Bradley; Smith, Nadia; Dostalek, Jack; Stevens, Eric; Nelson, Kristine; Weisz, Elisabeth; Berndt, Emily; Line, Bill; Barnet, Chris; Gambacorta, Antonia; hide

    2016-01-01

    A collaborative effort between SPoRT, CIMSS, CIRA, GINA, and NOAA has produced a unique gridded visualization of real-time CrIS/ATMS sounding products. This product uses the NUCAPS retrieval algorithm and polar2grid software to generate plan-view and cross-section visualization for forecast challenges associated with cold air aloft and convective potential. Forecasters at select partner offices have been able to view the Gridded NUCAPS products in AWIPS alongside other operational data products with generally favorable feedback.

  11. Targeted-capture massively-parallel sequencing enables robust detection of clinically informative mutations from formalin-fixed tumours

    PubMed Central

    Wong, Stephen Q.; Li, Jason; Salemi, Renato; Sheppard, Karen E.; Hongdo Do; Tothill, Richard W.; McArthur, Grant A.; Dobrovic, Alexander

    2013-01-01

    Massively parallel sequencing offers the ability to interrogate a tumour biopsy for multiple mutational changes. For clinical samples, methodologies must enable maximal extraction of available sequence information from formalin-fixed and paraffin-embedded (FFPE) material. We assessed the use of targeted capture for mutation detection in FFPE DNA. The capture probes targeted the coding region of all known kinase genes and selected oncogenes and tumour suppressor genes. Seven melanoma cell lines and matching FFPE xenograft DNAs were sequenced. An informatics pipeline was developed to identify variants and contaminating mouse reads. Concordance of 100% was observed between unfixed and formalin-fixed for reported COSMIC variants including BRAF V600E. mutations in genes not conventionally screened including ERBB4, ATM, STK11 and CDKN2A were readily detected. All regions were adequately covered with independent reads regardless of GC content. This study indicates that hybridisation capture is a robust approach for massively parallel sequencing of FFPE samples. PMID:24336498

  12. Mutation of Breast Cancer Cell Genomic DNA by APOBEC3B

    DTIC Science & Technology

    2013-09-01

    mutations affecting the proofreading domains of POLE and POLD1 predispose to colorectal adenomas and carcinomas. Nat. Genet. 45, 136–144 (2013). 42... Mutational processes molding the genomes of 21 breast cancers. Cell 149, 979–993 (2012). 9. Stephens, P. J. et al. The landscape of cancer genes and...A T U R E . C O M / N A T U R E RESEARCH 5 9 Stephens, P. J. et al. The landscape of cancer genes and mutational processes in breast cancer. Nature

  13. AIP mutations and gigantism.

    PubMed

    Rostomyan, Liliya; Potorac, Iulia; Beckers, Pablo; Daly, Adrian F; Beckers, Albert

    2017-06-01

    AIP mutations are rare in sporadic acromegaly but they are seen at a higher frequency among certain specific populations of pituitary adenoma patients (pituitary gigantism cases, familial isolated pituitary adenoma (FIPA) kindreds, and patients with macroadenomas who are diagnosed ≤30 years). AIP mutations are most prevalent in patients with pituitary gigantism (29% of this group were found to have mutations in AIP gene). These data support targeted genetic screening for AIP mutations/deletions in these groups of pituitary adenoma patients. Earlier diagnosis of AIP-related acromegaly-gigantism cases enables timely clinical evaluation and treatment, thereby improving outcomes in terms of excessive linear growth and acromegaly comorbidities. Copyright © 2017 Elsevier Masson SAS. All rights reserved.

  14. Genetic Mutations in Cancer

    Cancer.gov

    Many different types of genetic mutations are found in cancer cells. This infographic outlines certain types of alterations that are present in cancer, such as missense, nonsense, frameshift, and chromosome rearrangements.

  15. CF Mutation Panel

    MedlinePlus

    ... Links Patient Resources For Health Professionals Subscribe Search Cystic Fibrosis (CF) Gene Mutations Testing Send Us Your Feedback ... ID=LTD#tabs=0. Accessed September 2012. Cystic Fibrosis Foundation. Cystic Fibrosis Newborn Screening. Available online at http://www. ...

  16. Mice heterozygous for the ATM gene are more sensitive to both X-ray and heavy ion exposure than are wildtypes

    NASA Astrophysics Data System (ADS)

    Worgul, B. V.; Smilenov, L.; Brenner, D. J.; Vazquez, M.; Hall, E. J.

    Previous studies have shown that the eyes of ATM heterozygous mice exposed to low-LET radiation (X-rays) are significantly more susceptible to the development of cataracts than are those of wildtype mice. The findings, as well as others, run counter to the assumption underpinning current radiation safety guidelines, that individuals are all equally sensitive to the biological effects of radiation. A question, highly relevant to human space activities is whether or not, in similar fashion there may exist a genetic predisposition to high-LET radiation damage. Mice haplodeficient for the ATM gene and wildtypes were exposed to 325 mGy of 1 GeV/amu 56Fe ions at the AGS facility of Brookhaven National Laboratory. The fluence was equivalent to 1 ion per lens epithelial cell nuclear area. Controls consisted of irradiated wildtype as well as unirradiated wildtype and heterozygous mice. Prevalence analyses for stage 0.5-3.0 cataracts indicated that not only cataract onset but also progression were accelerated in the mice haplo-deficient for the ATM gene. The data show that heterozygosity for the ATM gene predisposes the eye to the cataractogenic influence of heavy ions and suggest that ATM heterozygotes in the human population may also be radiosensitive. This may have to be considered in the selection of individuals who will be exposed to both HZE particles and low-LET radiation as they may be predisposed to increased late normal tissue damage.

  17. Rates of spontaneous mutation.

    PubMed Central

    Drake, J W; Charlesworth, B; Charlesworth, D; Crow, J F

    1998-01-01

    Rates of spontaneous mutation per genome as measured in the laboratory are remarkably similar within broad groups of organisms but differ strikingly among groups. Mutation rates in RNA viruses, whose genomes contain ca. 10(4) bases, are roughly 1 per genome per replication for lytic viruses and roughly 0.1 per genome per replication for retroviruses and a retrotransposon. Mutation rates in microbes with DNA-based chromosomes are close to 1/300 per genome per replication; in this group, therefore, rates per base pair vary inversely and hugely as genome sizes vary from 6 x 10(3) to 4 x 10(7) bases or base pairs. Mutation rates in higher eukaryotes are roughly 0.1-100 per genome per sexual generation but are currently indistinguishable from 1/300 per cell division per effective genome (which excludes the fraction of the genome in which most mutations are neutral). It is now possible to specify some of the evolutionary forces that shape these diverse mutation rates. PMID:9560386

  18. KRAS mutations: analytical considerations.

    PubMed

    Herreros-Villanueva, Marta; Chen, Chih-Chieh; Yuan, Shyng-Shiou F; Liu, Ta-Chih; Er, Tze-Kiong

    2014-04-20

    Colorectal cancer (CRC) is the third most common cancer and the second most common cause of cancer death globally. Significant improvements in survival have been made in patients with metastasis by new therapies. For example, Cetuximab and Panitumumab are monoclonal antibodies that inhibit the epidermal growth receptor (EGFR). KRAS mutations in codon 12 and 13 are the recognized biomarkers that are analyzed in clinics before the administration of anti-EGFR therapy. Genetic analyses have revealed that mutations in KRAS predict a lack of response to Panitumumab and Cetuximab in patients with metastatic CRC (mCRC). Notably, it is estimated that 35-45% of CRC patients harbor KRAS mutations. Therefore, KRAS mutation testing should be performed in all individuals with the advanced CRC in order to identify the patients who will not respond to the monoclonal EGFR antibody inhibitors. New techniques for KRAS testing have arisen rapidly, and each technique has advantages and disadvantages. Herein, we review the latest published literature specific to KRAS mutation testing techniques. Since reliability and feasibility are important issues in clinical analyses. Therefore, this review also summarizes the effectiveness and limitations of numerous KRAS mutation testing techniques. Copyright © 2014 Elsevier B.V. All rights reserved.

  19. Asperlin induces G₂/M arrest through ROS generation and ATM pathway in human cervical carcinoma cells.

    PubMed

    He, Long; Nan, Mei-Hua; Oh, Hyun Cheol; Kim, Young Ho; Jang, Jae Hyuk; Erikson, Raymond Leo; Ahn, Jong Seog; Kim, Bo Yeon

    2011-06-10

    We exploited the biological activity of an antibiotic agent asperlin isolated from Aspergillus nidulans against human cervical carcinoma cells. We found that asperlin dramatically increased reactive oxygen species (ROS) generation accompanied by a significant reduction in cell proliferation. Cleavage of caspase-3 and PARP and reduction of Bcl-2 could also be detected after asperlin treatment to the cells. An anti-oxidant N-acetyl-L-cysteine (NAC), however, blocked all the apoptotic effects of asperlin. The involvement of oxidative stress in asperlin induced apoptosis could be supported by the findings that ROS- and DNA damage-associated G2/M phase arrest and ATM phosphorylation were increased by asperlin. In addition, expression and phosphorylation of cell cycle proteins as well as G2/M phase arrest in response to asperlin were significantly blocked by NAC or an ATM inhibitor KU-55933 pretreatment. Collectively, our study proved for the first time that asperlin could be developed as a potential anti-cancer therapeutics through ROS generation in HeLa cells. Copyright © 2011 Elsevier Inc. All rights reserved.

  20. Galiellalactone induces cell cycle arrest and apoptosis through the ATM/ATR pathway in prostate cancer cells

    PubMed Central

    García, Víctor; Lara-Chica, Maribel; Cantarero, Irene; Sterner, Olov; Calzado, Marco A.; Muñoz, Eduardo

    2016-01-01

    Galiellalactone (GL) is a fungal metabolite that presents antitumor activities on prostate cancer in vitro and in vivo. In this study we show that GL induced cell cycle arrest in G2/M phase, caspase-dependent apoptosis and also affected the microtubule organization and migration ability in DU145 cells. GL did not induce double strand DNA break but activated the ATR and ATM-mediated DNA damage response (DDR) inducing CHK1, H2AX phosphorylation (fH2AX) and CDC25C downregulation. Inhibition of the ATM/ATR activation with caffeine reverted GL-induced G2/M cell cycle arrest, apoptosis and DNA damage measured by fH2AX. In contrast, UCN-01, a CHK1 inhibitor, prevented GL-induced cell cycle arrest but enhanced apoptosis in DU145 cells. Furthermore, we found that GL did not increase the levels of intracellular ROS, but the antioxidant N-acetylcysteine (NAC) completely prevented the effects of GL on fH2AX, G2/M cell cycle arrest and apoptosis. In contrast to NAC, other antioxidants such as ambroxol and EGCG did not interfere with the activity of GL on cell cycle. GL significantly suppressed DU145 xenograft growth in vivo and induced the expression of fH2AX in the tumors. These findings identify for the first time that GL activates DDR in prostate cancer. PMID:26683224

  1. Galiellalactone induces cell cycle arrest and apoptosis through the ATM/ATR pathway in prostate cancer cells.

    PubMed

    García, Víctor; Lara-Chica, Maribel; Cantarero, Irene; Sterner, Olov; Calzado, Marco A; Muñoz, Eduardo

    2016-01-26

    Galiellalactone (GL) is a fungal metabolite that presents antitumor activities on prostate cancer in vitro and in vivo. In this study we show that GL induced cell cycle arrest in G2/M phase, caspase-dependent apoptosis and also affected the microtubule organization and migration ability in DU145 cells. GL did not induce double strand DNA break but activated the ATR and ATM-mediated DNA damage response (DDR) inducing CHK1, H2AX phosphorylation (fH2AX) and CDC25C downregulation. Inhibition of the ATM/ATR activation with caffeine reverted GL-induced G2/M cell cycle arrest, apoptosis and DNA damage measured by fH2AX. In contrast, UCN-01, a CHK1 inhibitor, prevented GL-induced cell cycle arrest but enhanced apoptosis in DU145 cells. Furthermore, we found that GL did not increase the levels of intracellular ROS, but the antioxidant N-acetylcysteine (NAC) completely prevented the effects of GL on fH2AX, G2/M cell cycle arrest and apoptosis. In contrast to NAC, other antioxidants such as ambroxol and EGCG did not interfere with the activity of GL on cell cycle. GL significantly suppressed DU145 xenograft growth in vivo and induced the expression of fH2AX in the tumors. These findings identify for the first time that GL activates DDR in prostate cancer.

  2. Cell cycle-dependent DNA damage signaling induced by ICRF-193 involves ATM, ATR, CHK2, and BRCA1

    SciTech Connect

    Park, Iha; Avraham, Hava Karsenty

    2006-07-01

    Topoisomerase II is essential for cell proliferation and survival and has been a target of various anticancer drugs. ICRF-193 has long been used as a catalytic inhibitor to study the function of topoisomerase II. Here, we show that ICRF-193 treatment induces DNA damage signaling. Treatment with ICRF-193 induced G2 arrest and DNA damage signaling involving {gamma}-H2AX foci formation and CHK2 phosphorylation. DNA damage by ICRF-193 was further demonstrated by formation of the nuclear foci of 53BP1, NBS1, BRCA1, MDC1, and FANCD2 and increased comet tail moment. The DNA damage signaling induced by ICRF-193 was mediated by ATM and ATR andmore » was restricted to cells in specific cell cycle stages such as S, G2, and mitosis including late and early G1 phases. Downstream signaling of ATM and ATR involved the phosphorylation of CHK2 and BRCA1. Altogether, our results demonstrate that ICRF-193 induces DNA damage signaling in a cell cycle-dependent manner and suggest that topoisomerase II might be essential for the progression of the cell cycle at several stages including DNA decondensation.« less

  3. The mutation rate and cancer.

    PubMed Central

    Jackson, A L; Loeb, L A

    1998-01-01

    The stability of the human genome requires that mutations in the germ line be exceptionally rare events. While most mutations are neutral or have deleterious effects, a limited number of mutations are required for adaptation to environmental changes. Drake has provided evidence that DNA-based microbes have evolved a mechanism to yield a common spontaneous mutation rate of approximately 0.003 mutations per genome per replication (Drake 1991). In contrast, mutation rates of RNA viruses are much larger (Holland et al. 1982) and can approach the maximum tolerable deleterious mutation rate of one per genome (Eigen and Schuster 1977; Eigen 1993). Drake calculates that lytic RNA viruses display spontaneous mutation rates of approximately one per genome while most have mutation rates that are approximately 0.1 per genome (Drake 1993). This constancy of germline mutation rates among microbial species need not necessarily mean constancy of the somatic mutation rates. Furthermore, there need not be a constant rate for somatic mutations during development. In this review, we consider mutations in cancer, a pathology in which there appears to be an increase in the rate of somatic mutations throughout the genome. Moreover, within the eukaryotic genome, as in microbes, there are "hot-spots" that exhibit unusually high mutation frequencies. It seems conceivable to us that many tumors contain thousands of changes in DNA sequence. The major question is: how do these mutations arise, and how many are rate-limiting for tumor progression? PMID:9560368

  4. The Passive Microwave Neural Network Precipitation Retrieval (PNPR) for AMSU/MHS and ATMS cross-track scanning radiometers

    NASA Astrophysics Data System (ADS)

    Sano', Paolo; Casella, Daniele; Panegrossi, Giulia; Cinzia Marra, Anna; Dietrich, Stefano

    2016-04-01

    Spaceborne microwave cross-track scanning radiometers, originally developed for temperature and humidity sounding, have shown great capabilities to provide a significant contribution in precipitation monitoring both in terms of measurement quality and spatial/temporal coverage. The Passive microwave Neural network Precipitation Retrieval (PNPR) algorithm for cross-track scanning radiometers, originally developed for the Advanced Microwave Sounding Unit/Microwave Humidity Sounder (AMSU-A/MHS) radiometers (on board the European MetOp and U.S. NOAA satellites), was recently newly designed to exploit the Advanced Technology Microwave Sounder (ATMS) on board the Suomi-NPP satellite and the future JPSS satellites. The PNPR algorithm is based on the Artificial Neural Network (ANN) approach. The main PNPR-ATMS algorithm changes with respect to PNPR-AMSU/MHS are the design and implementation of a new ANN able to manage the information derived from the additional ATMS channels (respect to the AMSU-A/MHS radiometer) and a new screening procedure for not-precipitating pixels. In order to achieve maximum consistency of the retrieved surface precipitation, both PNPR algorithms are based on the same physical foundation. The PNPR is optimized for the European and the African area. The neural network was trained using a cloud-radiation database built upon 94 cloud-resolving simulations over Europe and the Mediterranean and over the African area and radiative transfer model simulations of TB vectors consistent with the AMSU-A/MHS and ATMS channel frequencies, viewing angles, and view-angle dependent IFOV sizes along the scan projections. As opposed to other ANN precipitation retrieval algorithms, PNPR uses a unique ANN that retrieves the surface precipitation rate for all types of surface backgrounds represented in the training database, i.e., land (vegetated or arid), ocean, snow/ice or coast. This approach prevents different precipitation estimates from being inconsistent with one

  5. Design and development of cell queuing, processing, and scheduling modules for the iPOINT input-buffered ATM testbed

    NASA Astrophysics Data System (ADS)

    Duan, Haoran

    1997-12-01

    This dissertation presents the concepts, principles, performance, and implementation of input queuing and cell-scheduling modules for the Illinois Pulsar-based Optical INTerconnect (iPOINT) input-buffered Asynchronous Transfer Mode (ATM) testbed. Input queuing (IQ) ATM switches are well suited to meet the requirements of current and future ultra-broadband ATM networks. The IQ structure imposes minimum memory bandwidth requirements for cell buffering, tolerates bursty traffic, and utilizes memory efficiently for multicast traffic. The lack of efficient cell queuing and scheduling solutions has been a major barrier to build high-performance, scalable IQ-based ATM switches. This dissertation proposes a new Three-Dimensional Queue (3DQ) and a novel Matrix Unit Cell Scheduler (MUCS) to remove this barrier. 3DQ uses a linked-list architecture based on Synchronous Random Access Memory (SRAM) to combine the individual advantages of per-virtual-circuit (per-VC) queuing, priority queuing, and N-destination queuing. It avoids Head of Line (HOL) blocking and provides per-VC Quality of Service (QoS) enforcement mechanisms. Computer simulation results verify the QoS capabilities of 3DQ. For multicast traffic, 3DQ provides efficient usage of cell buffering memory by storing multicast cells only once. Further, the multicast mechanism of 3DQ prevents a congested destination port from blocking other less- loaded ports. The 3DQ principle has been prototyped in the Illinois Input Queue (iiQueue) module. Using Field Programmable Gate Array (FPGA) devices, SRAM modules, and integrated on a Printed Circuit Board (PCB), iiQueue can process incoming traffic at 800 Mb/s. Using faster circuit technology, the same design is expected to operate at the OC-48 rate (2.5 Gb/s). MUCS resolves the output contention by evaluating the weight index of each candidate and selecting the heaviest. It achieves near-optimal scheduling and has a very short response time. The algorithm originates from a

  6. DNA polymerase eta is the sole contributor of A/T modifications during immunoglobulin gene hypermutation in the mouse.

    PubMed

    Delbos, Frédéric; Aoufouchi, Said; Faili, Ahmad; Weill, Jean-Claude; Reynaud, Claude-Agnès

    2007-01-22

    Mutations at A/T bases within immunoglobulin genes have been shown to be generated by a repair pathway involving the DNA-binding moiety of the mismatch repair complex constituted by the MSH2-MSH6 proteins, together with DNA polymerase eta (pol eta). However, residual A/T mutagenesis is still observed upon inactivation in the mouse of each of these factors, suggesting that the panel of activities involved might be more complex. We reported previously (Delbos, F., A. De Smet, A. Faili, S. Aoufouchi, J.-C. Weill, and C.-A. Reynaud. 2005. J. Exp. Med. 201:1191-1196) that residual A/T mutagenesis in pol eta-deficient mice was likely contributed by another enzyme not normally involved in hypermutation, DNA polymerase kappa, which is mobilized in the absence of the normal polymerase partner. We report the complete absence of A/T mutations in MSH2-pol eta double-deficient mice, thus indicating that the residual A/T mutagenesis in MSH2-deficient mice is contributed by pol eta, now recruited by uracil N-glycosylase, the second DNA repair pathway involved in hypermutation. We propose that this particular recruitment of pol eta corresponds to a profound modification of the function of uracil glycosylase in the absence of the mismatch repair complex, suggesting that MSH2-MSH6 actively prevent uracil glycosylase from error-free repair during hypermutation. pol eta thus appears to be the sole contributor of A/T mutations in the normal physiological context.

  7. Mutational spectrum drives the rise of mutator bacteria.

    PubMed

    Couce, Alejandro; Guelfo, Javier R; Blázquez, Jesús

    2013-01-01

    Understanding how mutator strains emerge in bacterial populations is relevant both to evolutionary theory and to reduce the threat they pose in clinical settings. The rise of mutator alleles is understood as a result of their hitchhiking with linked beneficial mutations, although the factors that govern this process remain unclear. A prominent but underappreciated fact is that each mutator allele increases only a specific spectrum of mutational changes. This spectrum has been speculated to alter the distribution of fitness effects of beneficial mutations, potentially affecting hitchhiking. To study this possibility, we analyzed the fitness distribution of beneficial mutations generated from different mutator and wild-type Escherichia coli strains. Using antibiotic resistance as a model system, we show that mutational spectra can alter these distributions substantially, ultimately determining the competitive ability of each strain across environments. Computer simulation showed that the effect of mutational spectrum on hitchhiking dynamics follows a non-linear function, implying that even slight spectrum-dependent fitness differences are sufficient to alter mutator success frequency by several orders of magnitude. These results indicate an unanticipated central role for the mutational spectrum in the evolution of bacterial mutation rates. At a practical level, this study indicates that knowledge of the molecular details of resistance determinants is crucial for minimizing mutator evolution during antibiotic therapy.

  8. Caffeine Suppresses Apoptosis of Bladder Cancer RT4 Cells in Response to Ionizing Radiation by Inhibiting Ataxia Telangiectasia Mutated-Chk2-p53 Axis

    PubMed Central

    Zhang, Zhe-Wei; Xiao, Jing; Luo, Wei; Wang, Bo-Han; Chen, Ji-Min

    2015-01-01

    Background: Caffeine suppresses ataxia telangiectasia and Rad3 related and ataxia telangiectasia mutated (ATM) activities; ATM is the major kinase for DNA damage detection. This study aimed to investigate the effects of caffeine on DNA damage responses in cells from the bladder cancer cell line RT4 those were exposed to ionizing radiation (IR). Methods: Immunofluorescent staining was performed to investigate changes in the proteins involved in DNA damage responses with or without caffeine. A mouse xenograft model was used to study the effects of caffeine on the DNA damage responses. Western blotting was used to investigate the effects of caffeine pretreatment on the ATM-Chk2-p53-Puma axis, while real-time polymerase chain reaction (RT-PCR) assessed changes in messenger RNA levels of p53 and downstream targets responding to IR. Finally, terminal deoxynucleotidyl transferase-dUTP nick end labeling assay. Western blotting and colony formation assay were used to measure the effects of caffeine on radiation-related apoptosis. All of the data were analyzed with a two-tailed Student's t-test. Results: Immunofluorescent staining showed that caffeine pretreatment profoundly suppressed the formation of γH2AXand p53-binding protein 1 foci in RT4 cells in response to irradiation. Cellular and animal experiments suggested that this suppression was mediated by suppression of the ATM-Chk2-p53-Puma DNA damage-signaling axis. RT-PCR indicated caffeine also attenuated transactivation of p53 and p53-inducible genes. The colony formation assay revealed that caffeine displayed radioprotective effects on RT4 cells in response to low-dose radiation compared to the radiosensitization effects on T24 cells. Conclusion: Caffeine may inhibit IR-related apoptosis of bladder cancer RT4 cells by suppressing activation of the ATM-Chk2-p53-Puma axis. PMID:26521794

  9. Is psoriasis a T-cell disease?

    PubMed

    Nickoloff, B J; Schröder, J M; von den Driesch, P; Raychaudhuri, S P; Farber, E M; Boehncke, W H; Morhenn, V B; Rosenberg, E W; Schön, M P; Holick, M F

    2000-10-01

    The etiology and pathogenesis of psoriasis--one of the most common chronic, inflammatory, hyperproliferative skin disorders of man--have long fascinated dermatologists, pathologists and biologists alike. Here, we have a model disease that offers to study neuroectodermal-mesenchymal interactions in the widest sense possible. Epithelial, endothelial, and hematopoietic cells as well as neurons projecting into the skin apparently all interact with each other to generate the characteristic psoriatic lesion. For decades, the ongoing controversy on the molecular nature, choreography and hierarchy of these complex interactions e.g. between epidermal keratinocytes, T cells, neurotrophils, endothelial cells and sensory nerves has served as a driving force propelling investigative dermatology to ever new horizons. This debate has not only been at the heart of our quest to develop more effective forms of therapy for this socially crippling disease, but it also has profoundly influenced how we view the skin as a whole: the numerous competing theories on the pathogenesis of psoriasis published so far also are reflections on the evolution of mainstream thought in skin biology over the last decades. These days, conventional wisdom infatuated with a T-cell-centered approach to inflammatory skin diseases-- portrays psoriasis as an autoimmune disease, where misguided T lymphocyte activities cause secondary epithelial abnormalities. And yet, as this CONTROVERSIES feature reminds us, some authoritative "pockets of academic resistance" are still quite alive, and interpret psoriasis e.g. as a genetically determined, abnormal epithelial response pattern to infectious and/or physicochemical skin insults. Weighing the corresponding lines of argumentation is not only an intriguing, clinically relevant intellectual exercise, but also serves as a wonderful instrument for questioning our own views of the skin universe and its patterns of deviation from a state of homeostasis.

  10. Starvation-induced activation of ATM/Chk2/p53 signaling sensitizes cancer cells to cisplatin

    PubMed Central

    2012-01-01

    Background Optimizing the safety and efficacy of standard chemotherapeutic agents such as cisplatin (CDDP) is of clinical relevance. Serum starvation in vitro and short-term food starvation in vivo both stress cells by the sudden depletion of paracrine growth stimulation. Methods The effects of serum starvation on CDDP toxicity were investigated in normal and cancer cells by assessing proliferation, cell cycle distribution and activation of DNA-damage response and of AMPK, and were compared to effects observed in cells grown in serum-containing medium. The effects of short-term food starvation on CDDP chemotherapy were assessed in xenografts-bearing mice and were compared to effects on tumor growth and/or regression determined in mice with no diet alteration. Results We observed that serum starvation in vitro sensitizes cancer cells to CDDP while protecting normal cells. In detail, in normal cells, serum starvation resulted in a complete arrest of cellular proliferation, i.e. depletion of BrdU-incorporation during S-phase and accumulation of the cells in the G0/G1-phase of the cell cycle. Further analysis revealed that proliferation arrest in normal cells is due to p53/p21 activation, which is AMPK-dependent and ATM-independent. In cancer cells, serum starvation also decreased the fraction of S-phase cells but to a minor extent. In contrast to normal cells, serum starvation-induced p53 activation in cancer cells is both AMPK- and ATM-dependent. Combination of CDDP with serum starvation in vitro increased the activation of ATM/Chk2/p53 signaling pathway compared to either treatment alone resulting in an enhanced sensitization of cancer cells to CDDP. Finally, short-term food starvation dramatically increased the sensitivity of human tumor xenografts to cisplatin as indicated not only by a significant growth delay, but also by the induction of complete remission in 60% of the animals bearing mesothelioma xenografts, and in 40% of the animals with lung carcinoma

  11. Starvation-induced activation of ATM/Chk2/p53 signaling sensitizes cancer cells to cisplatin.

    PubMed

    Shi, Yandong; Felley-Bosco, Emanuela; Marti, Thomas M; Orlowski, Katrin; Pruschy, Martin; Stahel, Rolf A

    2012-12-04

    Optimizing the safety and efficacy of standard chemotherapeutic agents such as cisplatin (CDDP) is of clinical relevance. Serum starvation in vitro and short-term food starvation in vivo both stress cells by the sudden depletion of paracrine growth stimulation. The effects of serum starvation on CDDP toxicity were investigated in normal and cancer cells by assessing proliferation, cell cycle distribution and activation of DNA-damage response and of AMPK, and were compared to effects observed in cells grown in serum-containing medium. The effects of short-term food starvation on CDDP chemotherapy were assessed in xenografts-bearing mice and were compared to effects on tumor growth and/or regression determined in mice with no diet alteration. We observed that serum starvation in vitro sensitizes cancer cells to CDDP while protecting normal cells. In detail, in normal cells, serum starvation resulted in a complete arrest of cellular proliferation, i.e. depletion of BrdU-incorporation during S-phase and accumulation of the cells in the G0/G1-phase of the cell cycle. Further analysis revealed that proliferation arrest in normal cells is due to p53/p21 activation, which is AMPK-dependent and ATM-independent. In cancer cells, serum starvation also decreased the fraction of S-phase cells but to a minor extent. In contrast to normal cells, serum starvation-induced p53 activation in cancer cells is both AMPK- and ATM-dependent. Combination of CDDP with serum starvation in vitro increased the activation of ATM/Chk2/p53 signaling pathway compared to either treatment alone resulting in an enhanced sensitization of cancer cells to CDDP. Finally, short-term food starvation dramatically increased the sensitivity of human tumor xenografts to cisplatin as indicated not only by a significant growth delay, but also by the induction of complete remission in 60% of the animals bearing mesothelioma xenografts, and in 40% of the animals with lung carcinoma xenografts. In normal cells

  12. ALS2 mutations

    PubMed Central

    Schneider, Susanne A.; Carr, Lucinda; Deuschl, Guenther; Hopfner, Franziska; Stamelou, Maria; Wood, Nicholas W.; Bhatia, Kailash P.

    2014-01-01

    Objective: To determine the genetic etiology in 2 consanguineous families who presented a novel phenotype of autosomal recessive juvenile amyotrophic lateral sclerosis associated with generalized dystonia. Methods: A combination of homozygosity mapping and whole-exome sequencing in the first family and Sanger sequencing of candidate genes in the second family were used. Results: Both families were found to have homozygous loss-of-function mutations in the amyotrophic lateral sclerosis 2 (juvenile) (ALS2) gene. Conclusions: We report generalized dystonia and cerebellar signs in association with ALS2-related disease. We suggest that the ALS2 gene should be screened for mutations in patients who present with a similar phenotype. PMID:24562058

  13. Single-sperm sequencing reveals the accelerated mitochondrial mutation rate in maleDaphnia pulex(Crustacea, Cladocera).

    PubMed

    Xu, Sen; Van Tran, Kenny; Neupane, Swatantra; Snyman, Marelize; Huynh, Trung Viet; Sung, Way

    2017-09-27

    Mutation rate in the nuclear genome differs between sexes, with males contributing more mutations than females to their offspring. The male-biased mutation rates in the nuclear genome is most likely to be driven by a higher number of cell divisions in spermatogenesis than in oogenesis, generating more opportunities for DNA replication errors. However, it remains unknown whether male-biased mutation rates are present in mitochondrial DNA (mtDNA). Although mtDNA is maternally inherited and male mtDNA mutation typically does not contribute to genetic variation in offspring, male mtDNA mutations are critical for male reproductive health. In this study, we measured male mtDNA mutation rate using publicly available whole-genome sequences of single sperm of the freshwater microcrustacean Daphnia pulex Using a stringent mutation detection pipeline, we found that the male mtDNA mutation rate is 3.32 × 10 -6 per site per generation. All the detected mutations are heteroplasmic base substitutions, with 57% of mutations converting G/C to A/T nucleotides. Consistent with the male-biased mutation in the nuclear genome, the male mtDNA mutation rate in D. pulex is approximately 20 times higher than the female rate per generation. We propose that the elevated mutation rate per generation in male mtDNA is consistent with an increased number of cell divisions during male gametogenesis. © 2017 The Author(s).

  14. Use of coincident radar and radiometer observations from GPM, ATMS, and CloudSat for global spaceborne snowfall observation assessment

    NASA Astrophysics Data System (ADS)

    Panegrossi, Giulia; Casella, Daniele; Sanò, Paolo; Cinzia Marra, Anna; Dietrich, Stefano; Johnson, Benjamin T.; Kulie, Mark S.

    2017-04-01

    Snowfall is the main component of the global precipitation amount at mid and high latitudes, and improvement of global spaceborne snowfall quantitative estimation is one of the main goals of the Global Precipitation Measurement (GPM) mission. Advancements in snowfall detection and retrieval accuracy at mid-high latitudes are expected from both instruments on board the GPM Core Observatory (GPM-CO): the GMI, the most advanced conical precipitation radiometer with respect to both channel assortment and spatial resolution; and the Dual-frequency Precipitation Radar (DPR) (Ka and Ku band). Moreover, snowfall monitoring is now possible by exploiting the high frequency channels (i.e. >100 GHz) available from most of the microwave radiometers in the GPM constellation providing good temporal coverage at mid-high latitudes (hourly or less). Among these, the Advanced Technology Microwave Sounder (ATMS) onboard Suomi-NPP is the most advanced polar-orbiting cross track radiometer with 5 channels in the 183 GHz oxygen absorption band. Finally, CloudSat carries the W-band Cloud Profiling Radar (CPR) that has collected data since its launch in 2006. While CPR was primarily designed as a cloud remote sensing mission, its high-latitude coverage (up to 82° latitude) and high radar sensitivity ( -28 dBZ) make it very suitable for snowfall-related research. In this work a number of global datasets made of coincident observations of snowfall producing clouds from the spaceborne radars DPR and CPR and from the most advanced radiometers available (GMI and ATMS) have been created and analyzed. We will show the results of a study where CPR is used to: 1) assess snowfall detection and estimate capabilities of DPR; 2) analyze snowfall signatures in the high frequency channels of the passive microwave radiometers in relation to fundamental environmental conditions. We have estimated that DPR misses a very large fraction of snowfall precipitation (more than 90% of the events and around 70% of

  15. Providing pre-Launch VIIRS, CrIS, and ATMS Proxy Datasets to facilitate NPP Validation Activities

    NASA Astrophysics Data System (ADS)

    Ullman, R.; Zajic, J.; Gonzalez, V.; Sushon, D.

    2009-12-01

    In order to facilitate preparation for the upcoming launch of the NPOESS Preparatory Project (NPP), the NPOESS Integrated Program Office has developed a set of software tools for the generation of proxy Sensor Data Records for the VIIRS, CrIS, and ATMS instruments. Proxy data files are produced in HDF5 and conform to the standards described in the NPOESS IDPS Data Format Control Book. Source code is available via SubVersion repository on the NOAA CasaNOSA website, and the IPO is routinely producing and making available a “live” data stream for each sensor on the Government Resource for Algorithm Verification, Independent Testing, and Evaluation (GRAVITE) Cal/Val support facility at the NOAA/NSOF in Suitland, MD. This presentation will describe the algorithmic basis for the proxy conversions, and discuss the range of applications to for which the data may be used effectively.

  16. Enhancement of resident education in sonography using high-speed PACS/ATM image transmission: work in progress

    NASA Astrophysics Data System (ADS)

    Duerinckx, Andre J.; Grant, Edward G.; Melany, Michelle; Narin, Sherelle L.; Hayrapetian, Alek S.; Valentino, Daniel J.

    1996-05-01

    Transmission of high quality images between hospitals would be of value by exposing residents at individual institutions to a greater mix of disease processes. This problem is particularly serious in ultrasound where individual hospitals may not perform the entire range of examinations. We undertook this study to assess the effectiveness of image transmission via a PACS/ATM global network in improving ultrasound education among residents at affiliated hospitals. Image management was performed by AGFA PACS; global network was Asynchronous Transfer Mode. Selected cases from the two hospitals (OB/GYN cases at one, vascular at the other) were transmitted. Readout/teaching sessions included cases performed at base hospital and those received via network. Evaluation forms were collected from participants at both institutions. No image degradation occurred with transmission. Residents' exposure to ultrasound cases increased at the two hospitals. The system was considered an excellent teaching tool by all faculty and residents surveyed.

  17. Mutation spectrum of PAX6 in Chinese patients with aniridia

    PubMed Central

    Zhang, Xiaohui; Wang, Panfeng; Li, Shiqiang; Xiao, Xueshan; Guo, Xiangming

    2011-01-01

    Purpose To identify mutations in the paired box 6 (PAX6) gene of 33 probands with aniridia and to reveal the mutational spectrum in the Chinese population. Methods Unrelated probands with aniridia from 27 newly selected families and six previously analyzed families participated in this study. The coding regions of PAX6 in the 27 new families were analyzed using cycle sequencing. Families that lacked detectable variations based on sequencing (14 new and six previously analyzed) were further analyzed using multiplex ligation-dependent probe amplification (MLPA). Results Fifteen mutations were identified in 16 of the 33 families: c.[65_94del30; 99_105dup7], c.101_102insA, c.177delG, c.238_239insGCGA, c.1033–42_1033–26del17insG, c.1A>G, c.120C>A, c.718C>T, c.949C>T, c.1062C>A, c.1183G>A, c.1268A>T, and three gross deletions involving exons 1–14, exons 8–14, and exons 9–14. The first five mutations were novel and the c.1268A>T mutation was present in two families. Phenotypic variations were observed between families and between different affected patients within the families. Conclusions The PAX6 mutation spectrum in Chinese aniridia patients is comparable to that reported in other ethnic groups. Further studies of the 17 families with no detected mutations may provide additional information to improve the understanding of the molecular genetics of aniridia. PMID:21850189

  18. Mutation spectrum of PAX6 in Chinese patients with aniridia.

    PubMed

    Zhang, Xiaohui; Wang, Panfeng; Li, Shiqiang; Xiao, Xueshan; Guo, Xiangming; Zhang, Qingjiong

    2011-01-01

    To identify mutations in the paired box 6 (PAX6) gene of 33 probands with aniridia and to reveal the mutational spectrum in the Chinese population. Unrelated probands with aniridia from 27 newly selected families and six previously analyzed families participated in this study. The coding regions of PAX6 in the 27 new families were analyzed using cycle sequencing. Families that lacked detectable variations based on sequencing (14 new and six previously analyzed) were further analyzed using multiplex ligation-dependent probe amplification (MLPA). Fifteen mutations were identified in 16 of the 33 families: c.[65_94del30; 99_105dup7], c.101_102insA, c.177delG, c.238_239insGCGA, c.1033-42_1033-26del17insG, c.1A>G, c.120C>A, c.718C>T, c.949C>T, c.1062C>A, c.1183G>A, c.1268A>T, and three gross deletions involving exons 1-14, exons 8-14, and exons 9-14. The first five mutations were novel and the c.1268A>T mutation was present in two families. Phenotypic variations were observed between families and between different affected patients within the families. The PAX6 mutation spectrum in Chinese aniridia patients is comparable to that reported in other ethnic groups. Further studies of the 17 families with no detected mutations may provide additional information to improve the understanding of the molecular genetics of aniridia.

  19. Resistance to DNA-damaging treatment in non-small cell lung cancer tumor-initiating cells involves reduced DNA-PK/ATM activation and diminished cell cycle arrest

    PubMed Central

    Lundholm, L; Hååg, P; Zong, D; Juntti, T; Mörk, B; Lewensohn, R; Viktorsson, K

    2013-01-01

    Increasing evidence suggests that tumor-initiating cells (TICs), also called cancer stem cells, are partly responsible for resistance to DNA-damaging treatment. Here we addressed if such a phenotype may contribute to radio- and cisplatin resistance in non-small cell lung cancer (NSCLC). We showed that four out of eight NSCLC cell lines (H125, A549, H1299 and H23) possess sphere-forming capacity when cultured in stem cell media and three of these display elevated levels of CD133. Indeed, sphere-forming NSCLC cells, hereafter called TICs, showed a reduced apoptotic response and increased survival after irradiation (IR), as compared with the corresponding bulk cell population. Decreased cytotoxicity and apoptotic signaling manifested by diminished poly (ADP-ribose) polymerase (PARP) cleavage and caspase 3 activity was also evident in TICs after cisplatin treatment. Neither radiation nor cisplatin resistance was due to quiescence as H125 TICs proliferated at a rate comparable to bulk cells. However, TICs displayed less pronounced G2 cell cycle arrest and S/G2-phase block after IR and cisplatin, respectively. Additionally, we confirmed a cisplatin-refractory phenotype of H125 TICs in vivo in a mouse xenograft model. We further examined TICs for altered expression or activation of DNA damage repair proteins as a way to explain their increased radio- and/or chemotherapy resistance. Indeed, we found that TICs exhibited increased basal γH2AX (H2A histone family, member X) expression and diminished DNA damage-induced phosphorylation of DNA-dependent protein kinase (DNA-PK), ataxia telangiectasia-mutated (ATM), Krüppel-associated protein 1 (KAP1) and monoubiquitination of Fanconi anemia, complementation group D2 (FANCD2). As a proof of principle, ATM inhibition in bulk cells increased their cisplatin resistance, as demonstrated by reduced PARP cleavage. In conclusion, we show that reduced apoptotic response, altered DNA repair signaling and cell cycle perturbations in NSCLC

  20. Enhanced radiation-induced cytotoxic effect by 2-ME in glioma cells is mediated by induction of cell cycle arrest and DNA damage via activation of ATM pathways.

    PubMed

    Zou, Huichao; Zhao, Shiguang; Zhang, Jianhua; Lv, Gongwei; Zhang, Xu; Yu, Hongwei; Wang, Huibo; Wang, Ligang

    2007-12-14

    Glioblastoma multiform is the most common malignant primary brain tumor in adults, but there remains no effective therapeutic approach. 2-methoxyestradiol (2-ME), which is a naturally occurring metabolite of 17beta-estradiol, was shown to enhance radiotherapeutic effect in certain tumors; however, whether 2-ME can also enhance the sensitivity of glioma cells to radiotherapy remains unknown. The present study, therefore, was to address this issue using two human glioma cell lines (T98G and U251MG). These cells were irradiated with and without 2-ME and then clonogenic assay, apoptosis assay, DNA damage, and cell cycle change were examined. Results showed that 2-ME significantly enhances radiation-induced cell death in both glioma cells, shown by decreasing cell viability and increasing apoptotic cell death. No such radiosensitizing effect was observed if cells pre-treated with Estrodiol, suggesting the specifically radiosensitizing effect of 2-ME rather than a general effect of estrodials. The enhanced radio-cytotoxic effect in glioma cells by 2-ME was found to be associated with its enhancement of G(2)/M arrest and DNA damage, and phosphorylated ATM protein kinases as well as cell cycle checkpoint protein Chk2. Furthermore, inhibition of ATM by ATM inhibitor abolished 2-ME-activated Chk2 and enhanced radio-cytotoxic effects. These results suggest that 2-ME enhancement of the sensitivity of glioma cell lines to radiotherapy is mediated by induction of G2/M cell cycle arrest and increased DNA damage via activation of ATM kinases.

  1. Mutation of serine 1333 in the ATR HEAT repeats creates a hyperactive kinase.

    PubMed

    Luzwick, Jessica W; Nam, Edward A; Zhao, Runxiang; Cortez, David

    2014-01-01

    Subcellular localization, protein interactions, and post-translational modifications regulate the DNA damage response kinases ATR, ATM, and DNA-PK. During an analysis of putative ATR phosphorylation sites, we found that a single mutation at S1333 creates a hyperactive kinase. In vitro and in cells, mutation of S1333 to alanine (S1333A-ATR) causes elevated levels of kinase activity with and without the addition of the protein activator TOPBP1. S1333 mutations to glycine, arginine, or lysine also create a hyperactive kinase, while mutation to aspartic acid decreases ATR activity. S1333A-ATR maintains the G2 checkpoint and promotes completion of DNA replication after transient exposure to replication stress but the less active kinase, S1333D-ATR, has modest defects in both of these functions. While we find no evidence that S1333 is phosphorylated in cultured cells, our data indicate that small changes in the HEAT repeats can have large effects on kinase activity. These mutants may serve as useful tools for future studies of the ATR pathway.

  2. Mitochondrial Mutation Rate, Spectrum and Heteroplasmy in Caenorhabditis elegans Spontaneous Mutation Accumulation Lines of Differing Population Size.

    PubMed

    Konrad, Anke; Thompson, Owen; Waterston, Robert H; Moerman, Donald G; Keightley, Peter D; Bergthorsson, Ulfar; Katju, Vaishali

    2017-06-01

    Mitochondrial genomes of metazoans, given their elevated rates of evolution, have served as pivotal markers for phylogeographic studies and recent phylogenetic events. In order to determine the dynamics of spontaneous mitochondrial mutations in small populations in the absence and presence of selection, we evolved mutation accumulation (MA) lines of Caenorhabditis elegans in parallel over 409 consecutive generations at three varying population sizes of N = 1, 10, and 100 hermaphrodites. The N =1 populations should have a minimal influence of natural selection to provide the spontaneous mutation rate and the expected rate of neutral evolution, whereas larger population sizes should experience increasing intensity of selection. New mutations were identified by Illumina paired-end sequencing of 86 mtDNA genomes across 35 experimental lines and compared with published genomes of natural isolates. The spontaneous mitochondrial mutation rate was estimated at 1.05 × 10-7/site/generation. A strong G/C→A/T mutational bias was observed in both the MA lines and the natural isolates. This suggests that the low G + C content at synonymous sites is the product of mutation bias rather than selection as previously proposed. The mitochondrial effective population size per worm generation was estimated to be 62. Although it was previously concluded that heteroplasmy was rare in C. elegans, the vast majority of mutations in this study were heteroplasmic despite an experimental regime exceeding 400 generations. The frequencies of frameshift and nonsynonymous mutations were negatively correlated with population size, which suggests their deleterious effects on fitness and a potent role for selection in their eradication. © The Author 2017. Published by Oxford University Press on behalf of the Society for Molecular Biology and Evolution. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.

  3. Novel autosomal dominant TNNT1 mutation causing nemaline myopathy.

    PubMed

    Konersman, Chamindra G; Freyermuth, Fernande; Winder, Thomas L; Lawlor, Michael W; Lagier-Tourenne, Clotilde; Patel, Shailendra B

    2017-11-01

    Nemaline myopathy (NEM) is one of the three major forms of congenital myopathy and is characterized by diffuse muscle weakness, hypotonia, respiratory insufficiency, and the presence of nemaline rod structures on muscle biopsy. Mutations in troponin T1 (TNNT1) is 1 of 10 genes known to cause NEM. To date, only homozygous nonsense mutations or compound heterozygous truncating or internal deletion mutations in TNNT1 gene have been identified in NEM. This extended family is of historical importance as some members were reported in the 1960s as initial evidence that NEM is a hereditary disorder. Proband and extended family underwent Sanger sequencing for TNNT1. We performed RT-PCR and immunoblot on muscle to assess TNNT1 RNA expression and protein levels in proband and father. We report a novel heterozygous missense mutation of TNNT1 c.311A>T (p.E104V) that segregated in an autosomal dominant fashion in a large family residing in the United States. Extensive sequencing of the other known genes for NEM failed to identify any other mutant alleles. Muscle biopsies revealed a characteristic pattern of nemaline rods and severe myofiber hypotrophy that was almost entirely restricted to the type 1 fiber population. This novel mutation alters a residue that is highly conserved among vertebrates. This report highlights not only a family with autosomal dominant inheritance of NEM, but that this novel mutation likely acts via a dominant negative mechanism. © 2017 The Authors. Molecular Genetics & Genomic Medicine published by Wiley Periodicals, Inc.

  4. Pre-Launch Characterization of the Advanced Technology Microwave Sounder (ATMS) on the Joint Polar Satellite System-1 Satellite (JPSS-1)

    NASA Astrophysics Data System (ADS)

    Kim, Edward; Leslie, Vince; Lyu, Joseph; Smith, Craig; McCormick, Lisa; Anderson, Kent

    2016-04-01

    The Advanced Technology Microwave Sounder (ATMS) is the newest generation of microwave sounder in the international fleet of polar-orbiting weather satellites, replacing the Advanced Microwave Sounding Unit (AMSU) which first entered service in 1998. The first ATMS was launched aboard the Suomi NPP (S-NPP) satellite in late 2011. The second ATMS is manifested on the Joint Polar Satellite System-1 Satellite (JPSS-1). ATMS provides 22 channels of temperature and humidity sounding observations over a frequency range from 23 to 183 GHz. These microwave soundings provide the highest impact data ingested by operational Numerical Weather Prediction (NWP) models, and are the most critical of the polar-orbiting satellite observations, particularly because microwave sensing can penetrate clouds. This paper will present performance characterizations from pre-launch calibration measurements of the JPSS-1 ATMS just completed in December, 2015. The measurements were conducted in a thermal vacuum chamber with blackbody targets simulating cold space, ambient, and a variable Earth scene. They represent the best opportunity for calibration characterization of the instrument since the environment can be carefully controlled. We will present characterizations of the sensitivity (NEDT), accuracy, nonlinearity, noise spectral characteristics, gain stability, repeatability, and inter-channel correlation. An estimate of expected "striping" will be presented, and a discussion of reflector emissivity effects will also be provided. Comparisons will be made with the S-NPP flight unit. Finally, we will describe planned on-orbit characterizations - such as pitch and roll maneuvers - that will further improve both the measurement quality and the understanding of various error contributions.

  5. Better Living with Hyper-Mutation

    PubMed Central

    Goodman, Myron F.

    2016-01-01

    The simplest forms of mutations, base substitutions, typically have negative consequences, aside from their existential role in evolution and fitness. Hypermutations, mutations on steroids, occurring at frequencies of 10−2 – 10−4 per base pair, straddle a domain between fitness and death, depending on the presence or absence of regulatory constraints. We portray two facets of hypermutation, one in Escherichia coli involving DNA polymerase V (pol V), the other in humans, involving activation-induced deoxycytidine deaminase (AID). Pol V is induced as part of the DNA-damage-induced SOS regulon, and is responsible for generating the lion’s share of mutations when catalyzing translesion DNA synthesis (TLS). Four regulatory mechanisms, temporal, internal, conformational, and spatial, activate pol V to copy damaged DNA and then deactivate it. On the flip side of the coin, SOS-induced pols V, IV and II mutate undamaged DNA, thus providing genetic diversity heightening long-term survival and evolutionary fitness. Fitness in humans is principally the domain of a remarkably versatile immune system marked by somatic hypermutations (SHM) in immunoglobulin variable (IgV) regions that ensure antibody (Ab) diversity. AID initiates SHM by deaminating C → U, favoring hot WRC (W = A/T, R = A/G) motifs. Since there are large numbers of trinucleotide motif targets throughout IgV, AID must exercise considerable catalytic restraint to avoid attacking such sites repeatedly, which would otherwise compromise diversity. Processive, random, and inefficient AID-catalyzed dC deamination simulates salient features of SHM, yet generates B-cell lymphomas when working at the wrong time in the wrong place. PMID:27273795

  6. Whole-exome sequencing in relapsing chronic lymphocytic leukemia: clinical impact of recurrent RPS15 mutations

    PubMed Central

    Ljungström, Viktor; Cortese, Diego; Young, Emma; Pandzic, Tatjana; Mansouri, Larry; Plevova, Karla; Ntoufa, Stavroula; Baliakas, Panagiotis; Clifford, Ruth; Sutton, Lesley-Ann; Blakemore, Stuart J.; Stavroyianni, Niki; Agathangelidis, Andreas; Rossi, Davide; Höglund, Martin; Kotaskova, Jana; Juliusson, Gunnar; Belessi, Chrysoula; Chiorazzi, Nicholas; Panagiotidis, Panagiotis; Langerak, Anton W.; Smedby, Karin E.; Oscier, David; Gaidano, Gianluca; Schuh, Anna; Davi, Frederic; Pott, Christiane; Strefford, Jonathan C.; Trentin, Livio; Pospisilova, Sarka; Ghia, Paolo; Stamatopoulos, Kostas; Sjöblom, Tobias

    2016-01-01

    Fludarabine, cyclophosphamide, and rituximab (FCR) is first-line treatment of medically fit chronic lymphocytic leukemia (CLL) patients; however, despite good response rates, many patients eventually relapse. Although recent high-throughput studies have identified novel recurrent genetic lesions in adverse prognostic CLL, the mechanisms leading to relapse after FCR therapy are not completely understood. To gain insight into this issue, we performed whole-exome sequencing of sequential samples from 41 CLL patients who were uniformly treated with FCR but relapsed after a median of 2 years. In addition to mutations with known adverse-prognostic impact (TP53, NOTCH1, ATM, SF3B1, NFKBIE, and BIRC3), a large proportion of cases (19.5%) harbored mutations in RPS15, a gene encoding a component of the 40S ribosomal subunit. Extended screening, totaling 1119 patients, supported a role for RPS15 mutations in aggressive CLL, with one-third of RPS15-mutant cases also carrying TP53 aberrations. In most cases, selection of dominant, relapse-specific subclones was observed over time. However, RPS15 mutations were clonal before treatment and remained stable at relapse. Notably, all RPS15 mutations represented somatic missense variants and resided within a 7 amino-acid, evolutionarily conserved region. We confirmed the recently postulated direct interaction between RPS15 and MDM2/MDMX and transient expression of mutant RPS15 revealed defective regulation of endogenous p53 compared with wild-type RPS15. In summary, we provide novel insights into the heterogeneous genetic landscape of CLL relapsing after FCR treatment and highlight a novel mechanism underlying clinical aggressiveness involving a mutated ribosomal protein, potentially representing an early genetic lesion in CLL pathobiology. PMID:26675346

  7. Molecular Characterization of β-Thalassemia Mutations in Central Vietnam.

    PubMed

    Doro, Maria G; Casu, Giuseppina; Frogheri, Laura; Persico, Ivana; Triet, Le Phan Minh; Hoa, Phan Thi Thuy; Hoang, Nguyen Huy; Pirastru, Monica; Mereu, Paolo; Cucca, Francesco; Masala, Bruno

    2017-03-01

    The molecular basis of β-thalassemia (β-thal) mutations in North and in South Vietnam have been described during the past 15 years, whereas limited data were available concerning the central area of the country. In this study, we describe the molecular characterization and frequency of β-globin gene mutations in the Thua Thien Hue Province of Central Vietnam as the result of a first survey conducted in 22 transfusion-dependent patients, and four unrelated heterozygotes. Nine different known mutations were identified (seven of the β 0 and two of the β + type) in a total of 48 chromosomes. The most common was codon 26 (G>A) or Hb E (HBB: c.79 G>A) accounting for 29.2% of the total studied chromosomes, followed by codon 17 (A>T) (HBB: c.52 A>T) (25.0%), and codons 41/42 (-TTCT) (HBB: c.126_129delCTTT) (18.8%). Other mutations with appreciable frequencies (6.3-8.3%) were IVS-I-1 (G>T) (HBB: c.92+1 G>T), codon 26 (G>T) (HBB: c.79 G>T) and codons 71/72 (+A) (HBB: c.216_217insA). Relatively rarer (2.0%) were the promoter -28 (A>G) (HBB: c.78 A>G) mutation, the codon 95 (+A) (HBB: c.287_288insA), which is reported only in the Vietnamese, and the codons 14/15 (+G) (HBB: c.45_46insG) mutation, thus far observed only in Thailand. Results are relevant for implementing appropriate measures for β-thal prevention and control in the region as well as in the whole country.

  8. HLA-B27 Selects for Rare Escape Mutations that Significantly Impair Hepatitis C Virus Replication and Require Compensatory Mutations

    PubMed Central

    Neumann-Haefelin, Christoph; Oniangue-Ndza, Cesar; Kuntzen, Thomas; Schmidt, Julia; Nitschke, Katja; Sidney, John; Caillet-Saguy, Célia; Binder, Marco; Kersting, Nadine; Kemper, Michael W.; Power, Karen A.; Ingber, Susan; Reyor, Laura L.; Hills-Evans, Kelsey; Kim, Arthur Y.; Lauer, Georg M.; Lohmann, Volker; Sette, Alessandro; Henn, Matthew R.; Bressanelli, Stéphane; Thimme, Robert; Allen, Todd M.

    2011-01-01

    HLA-B27 is associated with spontaneous viral clearance in hepatitis C virus (HCV) infection. Viral escape within the immunodominant HLA-B27 restricted HCV-specific CD8+ T cell epitope NS5B2841-2849 (ARMILMTHF) has been shown to be limited by viral fitness costs as well as broad T cell cross-recognition, suggesting a potential mechanism of protection by HLA-B27. Here, we studied the subdominant HLA-B27 restricted epitope NS5B2936-2944 (GRAAICGKY) in order to further define the mechanisms of protection by HLA-B27. We identified a unique pattern of escape mutations within this epitope in a large cohort of HCV genotype 1a infected patients. The predominant escape mutations represented conservative substitutions at the main HLA-B27 anchor residue or a T cell receptor contact site, neither of which impaired viral replication capacity as assessed in a subgenomic HCV replicon system. In contrast, however, in a subset of HLA-B27+ subjects rare escape mutations arose at the HLA-B27 anchor residue R2937, which nearly abolished viral replication. Notably, these rare mutations only occurred in conjunction with the selection of two equally rare, and structurally proximal, upstream mutations. Co-expression of these upstream mutations with the rare escape mutations dramatically restored viral replication capacity from <5% to ≥70% of wild-type levels. Conclusion The selection of rare CTL escape mutations in this HLA-B27 restricted epitope dramatically impairs viral replicative fitness unless properly compensated. These data support a role for the targeting of highly-constrained regions by HLA-B27 in its ability to assert immune control of HCV and other highly variable pathogens. PMID:22006856

  9. Systems Biology Model of Interactions Between Tissue Growth Factors and DNA Damage Pathways: Low Dose Response and Cross-Talk in TGFbeta and ATM Signaling

    SciTech Connect

    O'Neill, Peter; Anderson, Jennifer

    2014-10-02

    The etiology of radiation carcinogenesis has been described in terms of aberrant changes that span several levels of biological organization. Growth factors regulate many important cellular and tissue functions including apoptosis, differentiation and proliferation. A variety of genetic and epigenetic changes of growth factors have been shown to contribute to cancer initiation and progression. It is known that cellular and tissue damage to ionizing radiation is in part initiated by the production of reactive oxygen species, which can activate cytokine signaling, and the DNA damage response pathways, most notably the ATM signaling pathway. Recently the transforming growth factor β (TGFβ)more » pathway has been shown to regulate or directly interact with the ATM pathway in the response to radiation. The relevance of this interaction with the ATM pathway is not known although p53 becomes phosphorylated and DNA damage responses are involved. However, growth factor interactions with DNA damage responses have not been elucidated particularly at low doses and further characterization of their relationship to cancer processes is warranted. Our goal will be to use a systems biology approach to mathematically and experimentally describe the low dose responses and cross-talk between the ATM and TGFβ pathways initiated by low and high LET radiation. We will characterize ATM and TGFβ signaling in epithelial and fibroblast cells using 2D models and ultimately extending to 3D organotypic cell culture models to begin to elucidate possible differences that may occur for different cell types and/or inter-cellular communication. We will investigate the roles of the Smad and Activating transcription factor 2 (ATF2) proteins as the potential major contributors to cross- talk between the TGFβ and ATM pathways, and links to cell cycle control and/or the DNA damage response, and potential differences in their responses at low and high doses. We have developed various experimental

  10. Systems Biology Model of Interactions between Tissue Growth Factors and DNA Damage Pathways: Low Dose Response and Cross-Talk in TGFβ and ATM Signaling

    SciTech Connect

    Cucinotta, Francis A

    2016-09-01

    The etiology of radiation carcinogenesis has been described in terms of aberrant changes that span several levels of biological organization. Growth factors regulate many important cellular and tissue functions including apoptosis, differentiation and proliferation. A variety of genetic and epigenetic changes of growth factors have been shown to contribute to cancer initiation and progression. It is known that cellular and tissue damage to ionizing radiation is in part initiated by the production of reactive oxygen species, which can activate cytokine signaling, and the DNA damage response pathways, most notably the ATM signaling pathway. Recently, the transforming growth factor β (TGFβ)more » pathway has been shown to regulate or directly interact with the ATM pathway in the response to radiation. The relevance of this interaction with the ATM pathway is not known although p53 becomes phosphorylated and DNA damage responses are involved. However, growth factor interactions with DNA damage responses have not been elucidated particularly at low doses, and further characterization of their relationship to cancer processes is warranted. Our goal will be to use a systems biology approach to mathematically and experimentally describe the low-dose responses and cross-talk between the ATM and TGFβ pathways initiated by low- and high-LET radiation. We will characterize ATM and TGFβ signaling in epithelial and fibroblast cells using 2D models and ultimately extending to 3D organotypic cell culture models to begin to elucidate possible differences that may occur for different cell types and/or inter-cellular communication. We will investigate the roles of the Smad and Activating transcription factor 2 (ATF2) proteins as the potential major contributors to crosstalk between the TGFβ and ATM pathways, and links to cell cycle control and/or the DNA damage response, and potential differences in their responses at low and high doses. We have developed various experimental

  11. Gene mutations in the D-loop region of mitochondrial DNA in oral squamous cell carcinoma.

    PubMed

    Yuan, Rong-Tao; Sun, Yang; Bu, Ling-Xue; Jia, Mu-Yun

    2015-06-01

    The present study aimed to investigate gene mutations in the displacement‑loop (D‑loop) region of mitochondrial DNA (mtDNA) in patients with oral squamous cell carcinoma (OSCC) in order to examine the role of gene mutation in mtDNA in OSCC tumorigenesis. mtDNA was obtained from cancer tissues, paracancerous tissues and normal mucosal tissues of thirty patients with OSCC. The D‑loop region of the mtDNA was amplified using polymerase chain reaction, sequenced and then analyzed by Chromas software and BLAST to identify the mutation sites. Mutations in the D‑loop region were observed in the cancer tissue samples of eight out of thirty cases with OSCC, with a mutation rate of 27%. There were nine mutations in total, including one point mutation, two base deletions, three insertion mutations and three heterozygous mutations. In these mutations, base deletions were different from each other and heterozygous mutations did not have the same mutation form; however, the three insertion mutations were the same, consisting of an insertion of a C base. One case contained a T/A heterozygous mutation as well as base insertion of C. The eight cases with mutations in the D‑loop region consisted of three cases of tongue cancer, two cases of soft palate cancer, one case of floor of the mouth cancer, one case of oropharyngeal cancer and one case of lip cancer. This study demonstrated mutations in the mtDNA D‑loop region in OSCC cells; however, the association between occurrences of OSCC and mtDNA mutations requires further investigation.

  12. Mutational specificities of environmental carcinogens in the lacl gene of Escherichia coli H. V: DNA sequence analysis of mutations in bacteria recovered from the liver of Swiss mice exposed to 1,2-dimethylhydrazine, azoxymethane, and methylazoxymethanolacetate

    SciTech Connect

    Zeilmaker, M.J.; Horsfall, M.J.; van Helten, J.B.

    1991-01-01

    The host-mediated assay (HMA) was used to determine the spectra of mutations induced in the lacl gene of Escherichia coli cells recovered from the livers of Swiss mice exposed to the carcinogens 1,2-dimethylhydrazine (SDMH), azoxymethane (AOM), and methylazoxymethanolacetate (MAMA). These spectra were further compared with changes induced by dimethylnitrosamine (DMNA) in the HMA methodology. A total of 177 independent lacl mutations arising in the HMA following exposure to SDMH, AOM, and MAMA were analyzed. Single-base substitutions accounted for 97% of all mutations analyzed. The vast majority of the single-base substitutions consisted of G:C----A:T transitions (94% of all mutations). The remainingmore » mutations consisted of A:T----G:C transitions (3% of all mutations) while non-base substitutions accounted for only 3% of the total mutagenesis. The latter mutations consisted of one frameshift mutation and four lacO deletions. The distribution of G:C----A:T transitions induced by the three chemicals in the first 200 bp of the lacl gene was not random, but rather clustered at sites where a target guanine was flanked at the 5{prime} site by a purine residue.« less

  13. Characterization of mutational specificity within the lacI gene for a mutD5 mutator strain of Escherichia coli defective in 3'----5' exonuclease (proofreading) activity.

    PubMed Central

    Fowler, R G; Schaaper, R M; Glickman, B W

    1986-01-01

    The mutD (dnaQ) gene of Escherichia coli codes for the epsilon subunit of the DNA polymerase III holoenzyme which is involved in 3'----5' exonuclease proofreading activity. We determined the mutational specificity of the mutator allele, mutD5, in the lacI gene of E. coli. The mutD5 mutation preferentially produces single base substitutions as judged from the enhanced fraction of lacI nonsense mutations and the spectrum of sequenced dominant lacI (lacId) and constitutive lacO (lacOc) mutations which were predominantly (69/71) single nucleotide substitutions. The distribution of amber lacI and sequenced lacId mutations revealed that transitions occur more frequently than transversions. A . T----G . C and G . C----A . T transitions were equally frequent and, with one major exception, evenly distributed among numerous sites. Among the transversions, A . T----T . A events were the most common, A . T----C . G substitutions were rare, and G . C----C . G changes were not detected. Transversions were unequally distributed among a limited number of sites with obvious hotspots. All 11 sequenced transversions had a consensus neighboring sequence of 5'-C-C-(mutated G or A)-C-3'. Although no large deletions or complex mutational events were recovered, sequencing revealed that mutD5 induced single nucleotide deletions within consecutive G X C sequences. An extraordinary A . T----G . C transition hotspot occurred at nucleotide position +6 in the lac operator region; the mutD5 mutation frequency of this single base pair was calculated to be 1.2 X 10(-3). PMID:3522541

  14. Mutations in BRCA1, BRCA2 and other breast and ovarian cancer susceptibility genes in Central and South American populations.

    PubMed

    Jara, Lilian; Morales, Sebastian; de Mayo, Tomas; Gonzalez-Hormazabal, Patricio; Carrasco, Valentina; Godoy, Raul

    2017-10-06

    Breast cancer (BC) is the most common malignancy among women worldwide. A major advance in the understanding of the genetic etiology of BC was the discovery of BRCA1 and BRCA2 (BRCA1/2) genes, which are considered high-penetrance BC genes. In non-carriers of BRCA1/2 mutations, disease susceptibility may be explained of a small number of mutations in BRCA1/2 and a much higher proportion of mutations in ethnicity-specific moderate- and/or low-penetrance genes. In Central and South American populations, studied have focused on analyzing the distribution and prevalence of BRCA1/2 mutations and other susceptibility genes that are scarce in Latin America as compared to North America, Europe, Australia, and Israel. Thus, the aim of this review is to present the current state of knowledge regarding pathogenic BRCA variants and other BC susceptibility genes. We conducted a comprehensive review of 47 studies from 12 countries in Central and South America published between 2002 and 2017 reporting the prevalence and/or spectrum of mutations and pathogenic variants in BRCA1/2 and other BC susceptibility genes. The studies on BRCA1/2 mutations screened a total of 5956 individuals, and studies on susceptibility genes analyzed a combined sample size of 11,578 individuals. To date, a total of 190 different BRCA1/2 pathogenic mutations in Central and South American populations have been reported in the literature. Pathogenic mutations or variants that increase BC risk have been reported in the following genes or genomic regions: ATM, BARD1, CHECK2, FGFR2, GSTM1, MAP3K1, MTHFR, PALB2, RAD51, TOX3, TP53, XRCC1, and 2q35.

  15. Prediction of tropical cyclone over North Indian Ocean using WRF model: sensitivity to scatterometer winds, ATOVS and ATMS radiances

    NASA Astrophysics Data System (ADS)

    Dodla, Venkata B.; Srinivas, Desamsetti; Dasari, Hari Prasad; Gubbala, Chinna Satyanarayana

    2016-05-01

    Tropical cyclone prediction, in terms of intensification and movement, is important for disaster management and mitigation. Hitherto, research studies were focused on this issue that lead to improvement in numerical models, initial data with data assimilation, physical parameterizations and application of ensemble prediction. Weather Research and Forecasting (WRF) model is the state-of-art model for cyclone prediction. In the present study, prediction of tropical cyclone (Phailin, 2013) that formed in the North Indian Ocean (NIO) with and without data assimilation using WRF model has been made to assess impacts of data assimilation. WRF model was designed to have nested two domains of 15 and 5 km resolutions. In the present study, numerical experiments are made without and with the assimilation of scatterometer winds, and radiances from ATOVS and ATMS. The model performance was assessed in respect to the movement and intensification of cyclone. ATOVS data assimilation experiment had produced the best prediction with least errors less than 100 km up to 60 hours and producing pre-deepening and deepening periods accurately. The Control and SCAT wind assimilation experiments have shown good track but the errors were 150-200 km and gradual deepening from the beginning itself instead of sudden deepening.

  16. Amplification-refractory mutation system (ARMS) analysis of point mutations.

    PubMed

    Little, S

    2001-05-01

    The amplification-refractory mutation system (ARMS) is a simple method for detecting any mutation involving single base changes or small deletions. ARMS is based on the use of sequence-specific PCR primers that allow amplification of test DNA only when the target allele is contained within the sample. Following an ARMS reaction the presence or absence of a PCR product is diagnostic for the presence or absence of the target allele. The protocols detailed here outline methods that can be used to analyze human genomic DNA for one or more mutations. The Basic Protocol describes the development and application of an ARMS test for a single mutation; the Alternate Protocol extends this to multiplex ARMS for the analysis of two or more mutations. The Support Protocol describes a rapid DNA extraction method from blood or mouthwash samples that yields DNA compatible with the type of tests described. The amplification-refractory mutation system (ARMS) is a simple method for detecting any mutation involving single base change The amplification-refractory mutation system (ARMS) is a simple method for detecting any mutation involving single base change.

  17. Regiones de formación de la línea de He II λ 1640 en una atmósfera en expansión

    NASA Astrophysics Data System (ADS)

    Venero, R.; Cidale, L.; Ringuelet, A.

    Se calculan perfiles de la línea del He II λ1640 empleando un modelo de atmósfera en expansión con una estructura cromosférica para determinar la región de formación de la línea. El problema se trata en geometría esférica, fuera de equilibrio termodinámico. La ecuación de transporte radiativo se resuelve rigurosamente en el marco de referencia del fluído para distintas leyes de velocidad, monótonamente crecientes, y diferentes leyes de temperatura. Se buscan relaciones globales entre las características del perfil y los parámetros físicos atribuídos a la atmósfera estelar, con la finalidad de definir una herramienta de diagnóstico de las propiedades del medio.

  18. CYBB mutation analysis in X-linked chronic granulomatous disease.

    PubMed

    Jirapongsananuruk, Orathai; Niemela, Julie E; Malech, Harry L; Fleisher, Thomas A

    2002-07-01

    Chronic granulomatous disease (CGD) results from mutations of phagocyte NADPH oxidase. Seventy percent are X-linked (X-)CGD with absent or defective gp91(phox) protein encoded by the CYBB gene. A subset of X-CGD patients demonstrates partial oxidase activity and/or varied levels of the gp91(phox) protein. Definitive genotypic diagnosis in these unusual patients requires mutation analysis. Typically, CYBB mutation analysis has relied on initial screening of cDNA by single-stranded conformation polymorphism analysis, followed by selective sequencing. We report a fluorescent, automated method for CYBB mutation analysis using genomic DNA that provides more rapid and reliable results. Moreover, the use of genomic DNA in this approach allows mutation detection in the mRNA coding region, promoter/enhancer region, and intronic sequences flanking splice junctions and does not require mRNA preparation. The PCR conditions were optimized for each exon, including those with A+T-rich regions. We analyzed DNA from two unusual X-CGD patients and established the genetic basis for their phenotype. We also sequenced 100 normal X chromosomes to establish wild-type consensus sequences and identify polymorphisms.

  19. Age-related effects of increased ambient pressure on discrimination reaction time: A study in 105 professional divers at 6.0 atm abs.

    PubMed

    Tikkinen, Janne; Siimes, Martti A

    2015-01-01

    We investigated 105 professional divers using a computerized visual discrimination trial (Cognitrone) to measure the effects of ambient pressure on reaction times. The possible improvement in performance due to practice was anticipated, and the trials were carried out four times prior to pressurization in a hyperbaric chamber. The effect of increased ambient pressure was measured at 6.0 and 1.9 atm abs, and the potential for residual effects was tested after decompression. The results of our study indicate that repeated testing had a systematic influence on the measured time values. The effects of learning, which were independent of diver age, may have independently influenced response times. Exposure to 6.0 atm abs modified the systematic pattern of learning and was associated with increased reaction times. There were also age-related differences in response times associated with exposure to increased ambient pressures. Younger divers were more susceptible to elevated ambient pressure, evidenced by increased response times at 6 atm abs relative to their older colleagues. One out of every four of the younger divers could be considered susceptible to inert gas narcosis (ION) when an increase of one standard deviation/1SD (> 19%) or more in discrimination reaction time is used as an indicator. ION susceptibility appears independent of body composition and physical fitness. The slowed response speed experienced at 6.0 atm abs was of short duration and returned to baseline immediately with decompression. Our results suggest that IGN is demonstrated by an impaired learning process and decreased response speed and that some younger divers appear more susceptible.

  20. Influence of Nucleoshuttling of the ATM Protein in the Healthy Tissues Response to Radiation Therapy: Toward a Molecular Classification of Human Radiosensitivity

    SciTech Connect

    Granzotto, Adeline; Benadjaoud, Mohamed Amine; Vogin, Guillaume

    2016-03-01

    Purpose: Whereas post–radiation therapy overreactions (OR) represent a clinical and societal issue, there is still no consensual radiobiological endpoint to predict clinical radiosensitivity. Since 2003, skin biopsy specimens have been collected from patients treated by radiation therapy against different tumor localizations and showing a wide range of OR. Here, we aimed to establish quantitative links between radiobiological factors and OR severity grades that would be relevant to radioresistant and genetic hyperradiosensitive cases. Methods and Materials: Immunofluorescence experiments were performed on a collection of skin fibroblasts from 12 radioresistant, 5 hyperradiosensitive, and 100 OR patients irradiated at 2 Gy. The numbers ofmore » micronuclei, γH2AX, and pATM foci that reflect different steps of DNA double-strand breaks (DSB) recognition and repair were assessed from 10 minutes to 24 hours after irradiation and plotted against the severity grades established by the Common Terminology Criteria for Adverse Events and the Radiation Therapy Oncology Group. Results: OR patients did not necessarily show a gross DSB repair defect but a systematic delay in the nucleoshuttling of the ATM protein required for complete DSB recognition. Among the radiobiological factors, the maximal number of pATM foci provided the best discrimination among OR patients and a significant correlation with each OR severity grade, independently of tumor localization and of the early or late nature of reactions. Conclusions: Our results are consistent with a general classification of human radiosensitivity based on 3 groups: radioresistance (group I); moderate radiosensitivity caused by delay of nucleoshuttling of ATM, which includes OR patients (group II); and hyperradiosensitivity caused by a gross DSB repair defect, which includes fatal cases (group III).« less

  1. Influence of Nucleoshuttling of the ATM Protein in the Healthy Tissues Response to Radiation Therapy: Toward a Molecular Classification of Human Radiosensitivity.

    PubMed

    Granzotto, Adeline; Benadjaoud, Mohamed Amine; Vogin, Guillaume; Devic, Clément; Ferlazzo, Mélanie L; Bodgi, Larry; Pereira, Sandrine; Sonzogni, Laurène; Forcheron, Fabien; Viau, Muriel; Etaix, Aurélie; Malek, Karim; Mengue-Bindjeme, Laurence; Escoffier, Clémence; Rouvet, Isabelle; Zabot, Marie-Thérèse; Joubert, Aurélie; Vincent, Anne; Dalla Venezia, Nicole; Bourguignon, Michel; Canat, Edme-Philippe; d'Hombres, Anne; Thébaud, Estelle; Orbach, Daniel; Stoppa-Lyonnet, Dominique; Radji, Abderraouf; Doré, Eric; Pointreau, Yoann; Bourgier, Céline; Leblond, Pierre; Defachelles, Anne-Sophie; Lervat, Cyril; Guey, Stéphanie; Feuvret, Loic; Gilsoul, Françoise; Berger, Claire; Moncharmont, Coralie; de Laroche, Guy; Moreau-Claeys, Marie-Virginie; Chavaudra, Nicole; Combemale, Patrick; Biston, Marie-Claude; Malet, Claude; Martel-Lafay, Isabelle; Laude, Cécile; Hau-Desbat, Ngoc-Hanh; Ziouéche, Amira; Tanguy, Ronan; Sunyach, Marie-Pierre; Racadot, Séverine; Pommier, Pascal; Claude, Line; Baleydier, Frédéric; Fleury, Bertrand; de Crevoisier, Renaud; Simon, Jean-Marc; Verrelle, Pierre; Peiffert, Didier; Belkacemi, Yazid; Bourhis, Jean; Lartigau, Eric; Carrie, Christian; De Vathaire, Florent; Eschwege, François; Puisieux, Alain; Lagrange, Jean-Léon; Balosso, Jacques; Foray, Nicolas

    2016-03-01

    Whereas post-radiation therapy overreactions (OR) represent a clinical and societal issue, there is still no consensual radiobiological endpoint to predict clinical radiosensitivity. Since 2003, skin biopsy specimens have been collected from patients treated by radiation therapy against different tumor localizations and showing a wide range of OR. Here, we aimed to establish quantitative links between radiobiological factors and OR severity grades that would be relevant to radioresistant and genetic hyperradiosensitive cases. Immunofluorescence experiments were performed on a collection of skin fibroblasts from 12 radioresistant, 5 hyperradiosensitive, and 100 OR patients irradiated at 2 Gy. The numbers of micronuclei, γH2AX, and pATM foci that reflect different steps of DNA double-strand breaks (DSB) recognition and repair were assessed from 10 minutes to 24 hours after irradiation and plotted against the severity grades established by the Common Terminology Criteria for Adverse Events and the Radiation Therapy Oncology Group. OR patients did not necessarily show a gross DSB repair defect but a systematic delay in the nucleoshuttling of the ATM protein required for complete DSB recognition. Among the radiobiological factors, the maximal number of pATM foci provided the best discrimination among OR patients and a significant correlation with each OR severity grade, independently of tumor localization and of the early or late nature of reactions. Our results are consistent with a general classification of human radiosensitivity based on 3 groups: radioresistance (group I); moderate radiosensitivity caused by delay of nucleoshuttling of ATM, which includes OR patients (group II); and hyperradiosensitivity caused by a gross DSB repair defect, which includes fatal cases (group III). Copyright © 2016 Elsevier Inc. All rights reserved.

  2. Genetic heterogeneity in primary and relapsed mantle cell lymphomas: Impact of recurrent CARD11 mutations.

    PubMed

    Wu, Chenglin; de Miranda, Noel Fcc; Chen, Longyun; Wasik, Agata M; Mansouri, Larry; Jurczak, Wojciech; Galazka, Krystyna; Dlugosz-Danecka, Monika; Machaczka, Maciej; Zhang, Huilai; Peng, Roujun; Morin, Ryan D; Rosenquist, Richard; Sander, Birgitta; Pan-Hammarström, Qiang

    2016-06-21

    The genetic mechanisms underlying disease progression, relapse and therapy resistance in mantle cell lymphoma (MCL) remain largely unknown. Whole-exome sequencing was performed in 27 MCL samples from 13 patients, representing the largest analyzed series of consecutive biopsies obtained at diagnosis and/or relapse for this type of lymphoma. Eighteen genes were found to be recurrently mutated in these samples, including known (ATM, MEF2B and MLL2) and novel mutation targets (S1PR1 and CARD11). CARD11, a scaffold protein required for B-cell receptor (BCR)-induced NF-κB activation, was subsequently screened in an additional 173 MCL samples and mutations were observed in 5.5% of cases. Based on in vitro cell line-based experiments, overexpression of CARD11 mutants were demonstrated to confer resistance to the BCR-inhibitor ibrutinib and NF-κB-inhibitor lenalidomide. Genetic alterations acquired in the relapse samples were found to be largely non-recurrent, in line with the branched evolutionary pattern of clonal evolution observed in most cases. In summary, this study highlights the genetic heterogeneity in MCL, in particular at relapse, and provides for the first time genetic evidence of BCR/NF-κB activation in a subset of MCL.

  3. Mutations in DONSON disrupt replication fork stability and cause microcephalic dwarfism.

    PubMed

    Reynolds, John J; Bicknell, Louise S; Carroll, Paula; Higgs, Martin R; Shaheen, Ranad; Murray, Jennie E; Papadopoulos, Dimitrios K; Leitch, Andrea; Murina, Olga; Tarnauskaitė, Žygimantė; Wessel, Sarah R; Zlatanou, Anastasia; Vernet, Audrey; von Kriegsheim, Alex; Mottram, Rachel M A; Logan, Clare V; Bye, Hannah; Li, Yun; Brean, Alexander; Maddirevula, Sateesh; Challis, Rachel C; Skouloudaki, Kassiani; Almoisheer, Agaadir; Alsaif, Hessa S; Amar, Ariella; Prescott, Natalie J; Bober, Michael B; Duker, Angela; Faqeih, Eissa; Seidahmed, Mohammed Zain; Al Tala, Saeed; Alswaid, Abdulrahman; Ahmed, Saleem; Al-Aama, Jumana Yousuf; Altmüller, Janine; Al Balwi, Mohammed; Brady, Angela F; Chessa, Luciana; Cox, Helen; Fischetto, Rita; Heller, Raoul; Henderson, Bertram D; Hobson, Emma; Nürnberg, Peter; Percin, E Ferda; Peron, Angela; Spaccini, Luigina; Quigley, Alan J; Thakur, Seema; Wise, Carol A; Yoon, Grace; Alnemer, Maha; Tomancak, Pavel; Yigit, Gökhan; Taylor, A Malcolm R; Reijns, Martin A M; Simpson, Michael A; Cortez, David; Alkuraya, Fowzan S; Mathew, Christopher G; Jackson, Andrew P; Stewart, Grant S

    2017-04-01

    To ensure efficient genome duplication, cells have evolved numerous factors that promote unperturbed DNA replication and protect, repair and restart damaged forks. Here we identify downstream neighbor of SON (DONSON) as a novel fork protection factor and report biallelic DONSON mutations in 29 individuals with microcephalic dwarfism. We demonstrate that DONSON is a replisome component that stabilizes forks during genome replication. Loss of DONSON leads to severe replication-associated DNA damage arising from nucleolytic cleavage of stalled replication forks. Furthermore, ATM- and Rad3-related (ATR)-dependent signaling in response to replication stress is impaired in DONSON-deficient cells, resulting in decreased checkpoint activity and the potentiation of chromosomal instability. Hypomorphic mutations in DONSON substantially reduce DONSON protein levels and impair fork stability in cells from patients, consistent with defective DNA replication underlying the disease phenotype. In summary, we have identified mutations in DONSON as a common cause of microcephalic dwarfism and established DONSON as a critical replication fork protein required for mammalian DNA replication and genome stability.

  4. Intestinal tuft cells regulate the ATM mediated DNA Damage response via Dclk1 dependent mechanism for crypt restitution following radiation injury.

    PubMed

    Chandrakesan, Parthasarathy; May, Randal; Weygant, Nathaniel; Qu, Dongfeng; Berry, William L; Sureban, Sripathi M; Ali, Naushad; Rao, Chinthalapally; Huycke, Mark; Bronze, Michael S; Houchen, Courtney W

    2016-11-23

    Crypt epithelial survival and regeneration after injury require highly coordinated complex interplay between resident stem cells and diverse cell types. The function of Dclk1 expressing tuft cells regulating intestinal epithelial DNA damage response for cell survival/self-renewal after radiation-induced injury is unclear. Intestinal epithelial cells (IECs) were isolated and purified and utilized for experimental analysis. We found that small intestinal crypts of Villin Cre ;Dclk1 f/f mice were hypoplastic and more apoptotic 24 h post-total body irradiation, a time when stem cell survival is p53-independent. Injury-induced ATM mediated DNA damage response, pro-survival genes, stem cell markers, and self-renewal ability for survival and restitution were reduced in the isolated intestinal epithelial cells. An even greater reduction in these signaling pathways was observed 3.5 days post-TBI, when peak crypt regeneration occurs. We found that interaction with Dclk1 is critical for ATM and COX2 activation in response to injury. We determined that Dclk1 expressing tuft cells regulate the whole intestinal epithelial cells following injury through paracrine mechanism. These findings suggest that intestinal tuft cells play an important role in regulating the ATM mediated DNA damage response, for epithelial cell survival/self-renewal via a Dclk1 dependent mechanism, and these processes are indispensable for restitution and function after severe radiation-induced injury.

  5. E2F/DP Prevents Cell-Cycle Progression in Endocycling Fat Body Cells by Suppressing dATM Expression.

    PubMed

    Guarner, Ana; Morris, Robert; Korenjak, Michael; Boukhali, Myriam; Zappia, Maria Paula; Van Rechem, Capucine; Whetstine, Johnathan R; Ramaswamy, Sridhar; Zou, Lee; Frolov, Maxim V; Haas, Wilhelm; Dyson, Nicholas J

    2017-12-18

    To understand the consequences of the complete elimination of E2F regulation, we profiled the proteome of Drosophila dDP mutants that lack functional E2F/DP complexes. The results uncovered changes in the larval fat body, a differentiated tissue that grows via endocycles. We report an unexpected mechanism of E2F/DP action that promotes quiescence in this tissue. In the fat body, dE2F/dDP limits cell-cycle progression by suppressing DNA damage responses. Loss of dDP upregulates dATM, allowing cells to sense and repair DNA damage and increasing replication of loci that are normally under-replicated in wild-type tissues. Genetic experiments show that ectopic dATM is sufficient to promote DNA synthesis in wild-type fat body cells. Strikingly, reducing dATM levels in dDP-deficient fat bodies restores cell-cycle control, improves tissue morphology, and extends animal development. These results show that, in some cellular contexts, dE2F/dDP-dependent suppression of DNA damage signaling is key for cell-cycle control and needed for normal development. Copyright © 2017 Elsevier Inc. All rights reserved.

  6. Distributed Large Data-Object Environments: End-to-End Performance Analysis of High Speed Distributed Storage Systems in Wide Area ATM Networks

    NASA Technical Reports Server (NTRS)

    Johnston, William; Tierney, Brian; Lee, Jason; Hoo, Gary; Thompson, Mary

    1996-01-01

    We have developed and deployed a distributed-parallel storage system (DPSS) in several high speed asynchronous transfer mode (ATM) wide area networks (WAN) testbeds to support several different types of data-intensive applications. Architecturally, the DPSS is a network striped disk array, but is fairly unique in that its implementation allows applications complete freedom to determine optimal data layout, replication and/or coding redundancy strategy, security policy, and dynamic reconfiguration. In conjunction with the DPSS, we have developed a 'top-to-bottom, end-to-end' performance monitoring and analysis methodology that has allowed us to characterize all aspects of the DPSS operating in high speed ATM networks. In particular, we have run a variety of performance monitoring experiments involving the DPSS in the MAGIC testbed, which is a large scale, high speed, ATM network and we describe our experience using the monitoring methodology to identify and correct problems that limit the performance of high speed distributed applications. Finally, the DPSS is part of an overall architecture for using high speed, WAN's for enabling the routine, location independent use of large data-objects. Since this is part of the motivation for a distributed storage system, we describe this architecture.

  7. Adipose tissue macrophages (ATM) of obese patients are releasing increased levels of prolactin during an inflammatory challenge: a role for prolactin in diabesity?

    PubMed

    Bouckenooghe, Thomas; Sisino, Giorgia; Aurientis, Sandra; Chinetti-Gbaguidi, Giulia; Kerr-Conte, Julie; Staels, Bart; Fontaine, Pierre; Storme, Laurent; Pattou, François; Vambergue, Anne

    2014-04-01

    Obesity, characterized by low grade inflammation, induces adipose tissue macrophage (ATM) infiltration in white adipose tissue (AT) in both humans and rodents, thus contributing to insulin resistance. Previous studies have shown altered prolactin secretion in obesity, however, studies linking ATM infiltration and prolactin (PRL) secretion to the pathogenesis of the metabolic syndrome, obesity and diabetes are lacking. In vivo, qPCR and Western blot analysis demonstrated that prolactin expression was increased in AT of obese rats and also in human AT from obese, obese pre-diabetic and obese diabetic compared to lean counterparts. Immunohistochemistry of obese rat and human AT sections demonstrated a specific expression of prolactin in macrophages. In vitro, we demonstrated that hyperglycemia and inflammation stimulated macrophages (human THP-1 cell line and sorted rat ATM) to express PRL, when challenged with different glucose concentrations with or without IL1β. In in vivo and in vitro experiments, we assessed the expression of Pit-1 (PRL-specific transcription factor) and found that its expression was parallel to PRL expression. In this study, we show that rodent and human macrophages synthesize prolactin in response to inflammation and high glucose concentrations. Our data shed new light on the potential role of macrophages in the physiopathology of diabesity via the PRL expression and on its expression mechanism and regulation. Copyright © 2013 Elsevier B.V. All rights reserved.

  8. The frequency of cancer predisposition gene mutations in hereditary breast and ovarian cancer patients in Taiwan: From BRCA1/2 to multi-gene panels.

    PubMed

    Sung, Pi-Lin; Wen, Kuo-Chang; Chen, Yi-Jen; Chao, Ta-Chung; Tsai, Yi-Fang; Tseng, Ling-Ming; Qiu, Jian-Tai Timothy; Chao, Kuan-Chong; Wu, Hua-Hsi; Chuang, Chi-Mu; Wang, Peng-Hui; Huang, Chi-Ying F

    2017-01-01

    An important role of genetic factors in the development of breast cancer (BC) or ovarian cancer (OC) in Taiwanese (ethnic Chinese) patients has been suggested. However, other than germline BRCA1 or BRCA2 mutations, which are related to hereditary breast-ovarian cancer (HBOC), cancer-predisposition genes have not been well studied in this population. The aim of the present study was to more accurately summarize the prevalence of genetic mutations in HBOC patients using various gene panels ranging in size from BRCA1/2 alone to multi-gene panels. Among 272 HBOC patients analyzed, the prevalence of BRCA1, BRCA2 and non-BRCA1/2 pathogenic mutations was 7.7% (21/272), 6.8% (16/236) and 8.2% (13/159), respectively. The total mutation rate was 18.4% (50/272). Although no founder mutations were identified in this study, two recurrent mutations, BRCA1 (c.3607C>T) and BRCA2 (c.5164_5165 delAG), were found. The main pathogenic/likely pathogenic mutations in non-BRCA1/2 genes included ATM, BRIP1, FANCI, MSH2, MUYTH, RAD50, RAD51C and TP53. The prevalence rate of gene mutations in HBOC patients did not differ with respect to whether BC or OC was the first diagnosis or they presented a family history of the disease or their age at diagnosis. HBOC patients with both BC and OC exhibited a higher prevalence rate of mutations (50.0%) than patients with OC (25.0%) or BC (8.6%) alone. In conclusion, evaluation of hereditary cancer risk in Taiwan HBOC patients, particularly individuals with double cancer, is strongly encouraged. Panel testing can yield additional genomic information, and widespread and well-designed panel testing will help in assessing more accurate mutational prevalence of risk genes.

  9. Genome-wide survey of artificial mutations induced by ethyl methanesulfonate and gamma rays in tomato.

    PubMed

    Shirasawa, Kenta; Hirakawa, Hideki; Nunome, Tsukasa; Tabata, Satoshi; Isobe, Sachiko

    2016-01-01

    Genome-wide mutations induced by ethyl methanesulfonate (EMS) and gamma irradiation in the tomato Micro-Tom genome were identified by a whole-genome shotgun sequencing analysis to estimate the spectrum and distribution of whole-genome DNA mutations and the frequency of deleterious mutations. A total of ~370 Gb of paired-end reads for four EMS-induced mutants and three gamma-ray-irradiated lines as well as a wild-type line were obtained by next-generation sequencing technology. Using bioinformatics analyses, we identified 5920 induced single nucleotide variations and insertion/deletion (indel) mutations. The predominant mutations in the EMS mutants were C/G to T/A transitions, while in the gamma-ray mutants, C/G to T/A transitions, A/T to T/A transversions, A/T to G/C transitions and deletion mutations were equally common. Biases in the base composition flanking mutations differed between the mutagenesis types. Regarding the effects of the mutations on gene function, >90% of the mutations were located in intergenic regions, and only 0.2% were deleterious. In addition, we detected 1,140,687 spontaneous single nucleotide polymorphisms and indel polymorphisms in wild-type Micro-Tom lines. We also found copy number variation, deletions and insertions of chromosomal segments in both the mutant and wild-type lines. The results provide helpful information not only for mutation research, but also for mutant screening methodology with reverse-genetic approaches. © 2015 The Authors. Plant Biotechnology Journal published by Society for Experimental Biology and The Association of Applied Biologists and John Wiley & Sons Ltd.

  10. A mutational comparison of adult and adolescent and young adult (AYA) colon cancer.

    PubMed

    Tricoli, James V; Boardman, Lisa A; Patidar, Rajesh; Sindiri, Sivasish; Jang, Jin S; Walsh, William D; McGregor, Paul M; Camalier, Corinne E; Mehaffey, Michele G; Furman, Wayne L; Bahrami, Armita; Williams, P Mickey; Lih, Chih-Jian; Conley, Barbara A; Khan, Javed

    2018-03-01

    It is possible that the relative lack of progress in treatment outcomes among adolescent and young adult (AYA) patients with cancer is caused by a difference in disease biology compared with the corresponding diseases in younger and older individuals. There is evidence that colon cancer is more aggressive and has a poorer prognosis in AYA patients than in older adult patients. To further understand the molecular basis for this difference, whole-exome sequencing was conducted on a cohort of 30 adult, 30 AYA, and 2 pediatric colon cancers. A statistically significant difference in mutational frequency was observed between AYA and adult samples in 43 genes, including ROBO1, MYC binding protein 2 (MYCBP2), breast cancer 2 (early onset) (BRCA2), MAP3K3, MCPH1, RASGRP3, PTCH1, RAD9B, CTNND1, ATM, NF1; KIT, PTEN, and FBXW7. Many of these mutations were nonsynonymous, missense, stop-gain, or frameshift mutations that were damaging. Next, RNA sequencing was performed on a subset of the samples to confirm the mutations identified by exome sequencing. This confirmation study verified the presence of a significantly greater frequency of damaging mutations in AYA compared with adult colon cancers for 5 of the 43 genes (MYCBP2, BRCA2, PHLPP1, TOPORS, and ATR). The current results provide the rationale for a more comprehensive study with a larger sample set and experimental validation of the functional impact of the identified variants along with their contribution to the biologic and clinical characteristics of AYA colon cancer. Cancer 2018;124:1070-82. © 2017 American Cancer Society. © 2017 American Cancer Society.

  11. Nearest neighbor affects G:C to A:T transitions induced by alkylating agents.

    PubMed Central

    Glickman, B W; Horsfall, M J; Gordon, A J; Burns, P A

    1987-01-01

    The influence of local DNA sequence on the distribution of G:C to A:T transitions induced in the lacI gene of E. coli by a series of alkylating agents has been analyzed. In the case of nitrosoguanidine, two nitrosoureas and a nitrosamine, a strong preference for mutation at sites proceeded 5' by a purine base was noted. This preference was observed with both methyl and ethyl donors where the predicted common ultimate alkylating species is the alkyl diazonium ion. In contrast, this preference was not seen following treatment with ethylmethanesulfonate. The observed preference for 5'PuG-3' site over 5'-PyG-3' sites corresponds well with alterations observed in the Ha-ras oncogene recovered after treatment with NMU. This indicates that the mutations recovered in the oncogenes are likely the direct consequence of the alkylation treatment and that the local sequence effects seen in E. coli also appear to occur in mammalian cells. PMID:3329097

  12. Frequency of Germline Mutations in 25 Cancer Susceptibility Genes in a Sequential Series of Patients With Breast Cancer.

    PubMed

    Tung, Nadine; Lin, Nancy U; Kidd, John; Allen, Brian A; Singh, Nanda; Wenstrup, Richard J; Hartman, Anne-Renee; Winer, Eric P; Garber, Judy E

    2016-05-01

    Testing for germline mutations in BRCA1/2 is standard for select patients with breast cancer to guide clinical management. Next-generation sequencing (NGS) allows testing for mutations in additional breast cancer predisposition genes. The frequency of germline mutations detected by using NGS has been reported in patients with breast cancer who were referred for BRCA1/2 testing or with triple-negative breast cancer. We assessed the frequency and predictors of mutations in 25 cancer predisposition genes, including BRCA1/2, in a sequential series of patients with breast cancer at an academic institution to examine the utility of genetic testing in this population. Patients with stages I to III breast cancer who were seen at a single cancer center between 2010 and 2012, and who agreed to participate in research DNA banking, were included (N = 488). Personal and family cancer histories were collected and germline DNA was sequenced with NGS to identify mutations. Deleterious mutations were identified in 10.7% of women, including 6.1% in BRCA1/2 (5.1% in non-Ashkenazi Jewish patients) and 4.6% in other breast/ovarian cancer predisposition genes including CHEK2 (n = 10), ATM (n = 4), BRIP1 (n = 4), and one each in PALB2, PTEN, NBN, RAD51C, RAD51D, MSH6, and PMS2. Whereas young age (P < .01), Ashkenazi Jewish ancestry (P < .01), triple-negative breast cancer (P = .01), and family history of breast/ovarian cancer (P = .01) predicted for BRCA1/2 mutations, no factors predicted for mutations in other breast cancer predisposition genes. Among sequential patients with breast cancer, 10.7% were found to have a germline mutation in a gene that predisposes women to breast or ovarian cancer, using a panel of 25 predisposition genes. Factors that predict for BRCA1/2 mutations do not predict for mutations in other breast/ovarian cancer susceptibility genes when these genes are analyzed as a single group. Additional cohorts will be helpful to define individuals at higher risk of

  13. Frequency of Germline Mutations in 25 Cancer Susceptibility Genes in a Sequential Series of Patients With Breast Cancer

    PubMed Central

    Lin, Nancy U.; Kidd, John; Allen, Brian A.; Singh, Nanda; Wenstrup, Richard J.; Hartman, Anne-Renee; Winer, Eric P.; Garber, Judy E.

    2016-01-01

    Purpose Testing for germline mutations in BRCA1/2 is standard for select patients with breast cancer to guide clinical management. Next-generation sequencing (NGS) allows testing for mutations in additional breast cancer predisposition genes. The frequency of germline mutations detected by using NGS has been reported in patients with breast cancer who were referred for BRCA1/2 testing or with triple-negative breast cancer. We assessed the frequency and predictors of mutations in 25 cancer predisposition genes, including BRCA1/2, in a sequential series of patients with breast cancer at an academic institution to examine the utility of genetic testing in this population. Methods Patients with stages I to III breast cancer who were seen at a single cancer center between 2010 and 2012, and who agreed to participate in research DNA banking, were included (N = 488). Personal and family cancer histories were collected and germline DNA was sequenced with NGS to identify mutations. Results Deleterious mutations were identified in 10.7% of women, including 6.1% in BRCA1/2 (5.1% in non-Ashkenazi Jewish patients) and 4.6% in other breast/ovarian cancer predisposition genes including CHEK2 (n = 10), ATM (n = 4), BRIP1 (n = 4), and one each in PALB2, PTEN, NBN, RAD51C, RAD51D, MSH6, and PMS2. Whereas young age (P < .01), Ashkenazi Jewish ancestry (P < .01), triple-negative breast cancer (P = .01), and family history of breast/ovarian cancer (P = .01) predicted for BRCA1/2 mutations, no factors predicted for mutations in other breast cancer predisposition genes. Conclusion Among sequential patients with breast cancer, 10.7% were found to have a germline mutation in a gene that predisposes women to breast or ovarian cancer, using a panel of 25 predisposition genes. Factors that predict for BRCA1/2 mutations do not predict for mutations in other breast/ovarian cancer susceptibility genes when these genes are analyzed as a single group. Additional cohorts will be helpful to define

  14. IGF-1R inhibition sensitizes breast cancer cells to ATM-related kinase (ATR) inhibitor and cisplatin

    PubMed Central

    O'Flanagan, Ciara H.; O'shea, Sandra; Lyons, Amy; Fogarty, Fionola M.; McCabe, Nuala; Kennedy, Richard D.; O'Connor, Rosemary

    2016-01-01

    The complexity of the IGF-1 signalling axis is clearly a roadblock in targeting this receptor in cancer therapy. Here, we sought to identify mediators of resistance, and potential co-targets for IGF-1R inhibition. By using an siRNA functional screen with the IGF-1R tyrosine kinase inhibitor (TKI) BMS-754807 in MCF-7 cells we identified several genes encoding components of the DNA damage response (DDR) pathways as mediators of resistance to IGF-1R kinase inhibition. These included ATM and Ataxia Telangiectasia and RAD3-related kinase (ATR). We also observed a clear induction of DDR in cells that were exposed to IGF-1R TKIs (BMS-754807 and OSI-906) as indicated by accumulation of γ-H2AX, and phosphorylated Chk1. Combination of the IGF-1R/IR TKIs with an ATR kinase inhibitor VE-821 resulted in additive to synergistic cytotoxicity compared to either drug alone. In MCF-7 cells with stably acquired resistance to the IGF-1R TKI (MCF-7-R), DNA damage was also observed, and again, dual inhibition of the ATR kinase and IGF-1R/IR kinase resulted in synergistic cytotoxicity. Interestingly, dual inhibition of ATR and IGF-1R was more effective in MCF-7-R cells than parental cells. IGF-1R TKIs also potentiated the effects of cisplatin in a panel of breast cancer cell lines. Overall, our findings identify induction of DDR by IGF-1R kinase inhibition as a rationale for co-targeting the IGF-1R with ATR kinase inhibitors or cisplatin, particularly in cells with acquired resistance to TKIs. PMID:27472395

  15. Whole-Genome Sequencing and iPLEX MassARRAY Genotyping Map an EMS-Induced Mutation Affecting Cell Competition in Drosophila melanogaster.

    PubMed

    Lee, Chang-Hyun; Rimesso, Gerard; Reynolds, David M; Cai, Jinlu; Baker, Nicholas E

    2016-10-13

    Cell competition, the conditional loss of viable genotypes only when surrounded by other cells, is a phenomenon observed in certain genetic mosaic conditions. We conducted a chemical mutagenesis and screen to recover new mutations that affect cell competition between wild-type and RpS3 heterozygous cells. Mutations were identified by whole-genome sequencing, making use of software tools that greatly facilitate the distinction between newly induced mutations and other sources of apparent sequence polymorphism, thereby reducing false-positive and false-negative identification rates. In addition, we utilized iPLEX MassARRAY for genotyping recombinant chromosomes. These approaches permitted the mapping of a new mutation affecting cell competition when only a single allele existed, with a phenotype assessed only in genetic mosaics, without the benefit of complementation with existing mutations, deletions, or duplications. These techniques expand the utility of chemical mutagenesis and whole-genome sequencing for mutant identification. We discuss mutations in the Atm and Xrp1 genes identified in this screen. Copyright © 2016 Lee et al.

  16. DNA alkylation repair limits spontaneous base substitution mutations in Escherichia coli.

    PubMed Central

    Mackay, W J; Han, S; Samson, L D

    1994-01-01

    The Escherichia coli Ada and Ogt DNA methyltransferases (MTases) are known to transfer simple alkyl groups from O6-alkylguanine and O4-alkylthymine, directly restoring these alkylated DNA lesions to guanine and thymine. In addition to being exquisitely sensitive to the mutagenic effects of methylating agents, E. coli ada ogt null mutants display a higher spontaneous mutation rate than the wild type. Here, we determined which base substitution mutations are elevated in the MTase-deficient cells by monitoring the reversion of six mutated lacZ alleles that revert via each of the six possible base substitution mutations. During exponential growth, the spontaneous rate of G:C to A:T transitions and G:C to C:G transversions was elevated about fourfold in ada ogt double mutant versus wild-type E. coli. Furthermore, compared with the wild type, stationary populations of the MTase-deficient E. coli (under lactose selection) displayed increased G:C to A:T and A:T to G:C transitions (10- and 3-fold, respectively) and increased G:C to C:G, A:T to C:G, and A:T to T:A transversions (10-, 2.5-, and 1.7-fold, respectively). ada and ogt single mutants did not suffer elevated spontaneous mutation rates for any base substitution event, and the cloned ada and ogt genes each restored wild-type spontaneous mutation rates to the ada ogt MTase-deficient strains. We infer that both the Ada MTase and the Ogt MTase can repair the endogenously produced DNA lesions responsible for each of the five base substitution events that are elevated in MTase-deficient cells. Simple methylating and ethylating agents induced G:C to A:T and A:T to G:C transitions in these strains but did not significantly induce G:C to C:G, A:T to C:G, and A:T to T:A transversions. We deduce that S-adenosylmethionine (known to e a weak methylating agent) is not the only metabolite responsible for endogenous DNA alkylation and that at least some of the endogenous metabolites that cause O-alkyl DNA damage in E. coli are not

  17. Mutational landscape of MCPyV-positive and MCPyV-negative Merkel cell carcinomas with implications for immunotherapy.

    PubMed

    Goh, Gerald; Walradt, Trent; Markarov, Vladimir; Blom, Astrid; Riaz, Nadeem; Doumani, Ryan; Stafstrom, Krista; Moshiri, Ata; Yelistratova, Lola; Levinsohn, Jonathan; Chan, Timothy A; Nghiem, Paul; Lifton, Richard P; Choi, Jaehyuk

    2016-01-19

    Merkel cell carcinoma (MCC) is a rare but highly aggressive cutaneous neuroendocrine carcinoma, associated with the Merkel cell polyomavirus (MCPyV) in 80% of cases. To define the genetic basis of MCCs, we performed exome sequencing of 49 MCCs. We show that MCPyV-negative MCCs have a high mutation burden (median of 1121 somatic single nucleotide variants (SSNVs) per-exome with frequent mutations in RB1 and TP53 and additional damaging mutations in genes in the chromatin modification (ASXL1, MLL2, and MLL3), JNK (MAP3K1 and TRAF7), and DNA-damage pathways (ATM, MSH2, and BRCA1). In contrast, MCPyV-positive MCCs harbor few SSNVs (median of 12.5 SSNVs/tumor) with none in the genes listed above. In both subgroups, there are rare cancer-promoting mutations predicted to activate the PI3K pathway (HRAS, KRAS, PIK3CA, PTEN, and TSC1) and to inactivate the Notch pathway (Notch1 and Notch2). TP53 mutations appear to be clinically relevant in virus-negative MCCs as 37% of these tumors harbor potentially targetable gain-of-function mutations in TP53 at p.R248 and p.P278. Moreover, TP53 mutational status predicts death in early stage MCC (5-year survival in TP53 mutant vs wild-type stage I and II MCCs is 20% vs. 92%, respectively; P = 0.0036). Lastly, we identified the tumor neoantigens in MCPyV-negative and MCPyV-positive MCCs. We found that virus-negative MCCs harbor more tumor neoantigens than melanomas or non-small cell lung cancers (median of 173, 65, and 111 neoantigens/sample, respectively), two cancers for which immune checkpoint blockade can produce durable clinical responses. Collectively, these data support the use of immunotherapies for virus-negative MCCs.

  18. Mutations in the human phospholamban gene in patients with heart failure.

    PubMed

    Medeiros, Alessandra; Biagi, Diogo G; Sobreira, Tiago J P; de Oliveira, Paulo Sérgio L; Negrão, Carlos Eduardo; Mansur, Alfredo J; Krieger, José Eduardo; Brum, Patricia C; Pereira, Alexandre C

    2011-12-01

    Phospholamban (PLN) is a crucial Ca(2+) cycling protein and a primary mediator of the β-adrenergic effects resulting in enhanced cardiac output. Mutations in the gene encoding PLN have been associated with idiopathic dilated cardiomyopathy; however, no systematic search for PLN mutations in heart failure has been conducted. We screened a cohort of 1,014 Brazilian patients with heart failure for mutations in the PLN gene. Molecular modeling studies of the mutations found were developed. Different disease etiologies were present in our sample: idiopathic, ischemic, Chagas, valvular, hypertensive, and others. We identified 4 unrelated patients with PLN mutations (prevalence of 0.4%), 3 of them in the same amino acid residue (R9). Two patients presented a G-T missense mutation at the G26 nucleotide, which encodes an Arg-Leu substitution at codon 9 (R9L). One patient presented a G-A missense mutation at the same nucleotide, which encodes an Arg-His substitution at codon 9 (R9H). The fourth affected patient presented a T-G nonsense mutation at the nucleotide 116, substituting a termination codon for Leu-39 (L39stop). Molecular modeling studies suggested that R9L and R9H mutations might affect the region involved in protein kinase A docking and probably affect the mechanism modulating the release of phosphorylated PLN from the substrate binding site of protein kinase A. Mutations in the PLN gene are a rare cause of heart failure, present almost exclusively in patients with dilated cardiomyopathy etiology. The Arg9 and Leu39 residues are the leading location of mutations described at this locus to date. Despite the few mutated residues described to date, the clinical spectrum of presentation appears to vary considerably. Copyright © 2011 Mosby, Inc. All rights reserved.

  19. Mutation induction by heavy ions

    NASA Astrophysics Data System (ADS)

    Kiefer, J.; Stoll, U.; Schneider, E.

    1994-10-01

    Mutation induction by heavy ions is compared in yeast and mammalian cells. Since mutants can only be recovered in survivors the influence of inactivation cross sections has to be taken into account. It is shown that both the size of the sensitive cellular site as well as track structure play an important role. Another parameter which influences the probability of mutation induction is repair: Contrary to naive assumptions primary radiation damage does not directly lead to mutations but requires modification to reconstitute the genetic machinery so that mutants can survive. The molecular structure of mutations was analyzed after exposure to deuterons by amplification with the aid of polymerase chain reaction. The results-although preliminary-demonstrate that even with densely ionizing particles a large fraction does not carry big deletions which suggests that point mutations may also be induced by heavy ions.

  20. Prevalence of Catalase (-21 A/T) Gene Variant in South Indian (Tamil) Population

    PubMed Central

    Lourdhu Mary, A.; Nithya, K.; Isabel, W.

    2014-01-01

    Catalase, an endogenous antioxidant enzyme, is responsible for regulating reactive species levels. Several epidemiologic studies have suggested that single nucleotide polymorphism in catalase gene may be associated with many diseases. The genotype of CAT (-21 A/T) point mutation in promoter region of catalase gene was determined by polymerase chain based restriction fragment length polymorphism analysis in the DNA of 100 healthy volunteers. The frequency of CAT (-21 A/T) gene polymorphism AA, AT, and TT genotypes was found to be 7, 23, and 70 percent, respectively. The mutant “T” allele frequency was found to be 0.82 among the south Indian (Tamil) population. Chi square analysis showed that the study population lies within the Hardy-Weinberg equilibrium. The wild type genotype (AA) was found to be very low (7%) and the mutant genotype (AT/TT) was found to be more prevalent (93%) among the south Indian population. This suggests that the high prevalence of mutant genotype may increase the susceptibility to oxidative stress associated diseases. PMID:25057503

  1. Monoallelic mutation analysis (MAMA) for identifying germline mutations.

    PubMed

    Papadopoulos, N; Leach, F S; Kinzler, K W; Vogelstein, B

    1995-09-01

    Dissection of germline mutations in a sensitive and specific manner presents a continuing challenge. In dominantly inherited diseases, mutations occur in only one allele and are often masked by the normal allele. Here we report the development of a sensitive and specific diagnostic strategy based on somatic cell hybridization termed MAMA (monoallelic mutation analysis). We have demonstrated the utility of this strategy in two different hereditary colorectal cancer syndromes, one caused by a defective tumour suppressor gene on chromosome 5 (familial adenomatous polyposis, FAP) and the other caused by a defective mismatch repair gene on chromosome 2 (hereditary non-polyposis colorectal cancer, HNPCC).

  2. TEMPORAL DELINEATION OF SEQUENTIAL HPRT MUTATIONS ARISING IN VIVO IN A T-CELL CLONE WITH A MUTATOR PHENOTYPE. (R825810)

    EPA Science Inventory

    The perspectives, information and conclusions conveyed in research project abstracts, progress reports, final reports, journal abstracts and journal publications convey the viewpoints of the principal investigator and may not represent the views and policies of ORD and EPA. Concl...

  3. Ataxia-telangiectasia: founder effect among north African Jews.

    PubMed

    Gilad, S; Bar-Shira, A; Harnik, R; Shkedy, D; Ziv, Y; Khosravi, R; Brown, K; Vanagaite, L; Xu, G; Frydman, M; Lavin, M F; Hill, D; Tagle, D A; Shiloh, Y

    1996-12-01

    The ATM gene is responsible for the autosomal recessive disorder ataxia-telangiectasia (A-T), characterized by cerebellar degeneration, immunodeficiency and cancer predisposition. A-T carriers were reported to be moderately cancer-prone. A wide variety of A-T mutations, most of which are unique to single families, were identified in various ethnic groups, precluding carrier screening with mutation-specific assays. However, a single mutation was observed in 32/33 defective ATM alleles in Jewish A-T families of North African origin, coming from various regions of Morocco and Tunisia. This mutation, 103C-->T, results in a stop codon at position 35 of the ATM protein. In keeping with the nature of this mutation, various antibodies directed against the ATM protein failed to defect this protein in patient cells. A rapid carrier detection assay detected this mutation in three out of 488 ATM alleles of Jewish Moroccan or Tunisian origin. This founder effect provides a unique opportunity for population-based screening for A-T carriers in a large Jewish community.

  4. Mutations for Leber hereditary optic neuropathy in patients with alcohol and tobacco optic neuropathy

    PubMed Central

    Amaral-Fernandes, Marcela Scabello; Marcondes, Ana Maria; Miranda, Paulo Maurício do Amor Divino; Maciel-Guerra, Andréa Trevas

    2011-01-01

    Purpose There are many similarities in the clinical presentation of Leber hereditary optic neuropathy (LHON) and in patients who have optic neuropathy and a history of heavy tobacco and alcohol consumption. The main objective of this study is to investigate the frequency of primary and secondary mitochondrial DNA (mtDNA) mutations for LHON in patients diagnosed as having alcohol and tobacco optic neuropathy (ATON). Methods Twenty-six patients who had a history of heavy alcohol and tobacco consumption and who developed bilateral optic neuropathy were tested for primary mutations (G11778A, T14484C, and G3460A) by restriction analysis, and 14 secondary mutations in the genes mitochondrially encoded NADH dehydrogenase 1 (MT-ND1), mitochondrially encoded NADH dehydrogenase 4 (MT-ND4), mitochondrially encoded NADH dehydrogenase 4L (MT-ND4L), mitochondrially encoded NADH dehydrogenase 5 (MT-ND5), mitochondrially encoded NADH dehydrogenase 6 (MT-ND6), and mitochondrially encoded cytochrome B (MT-CYB) by direct sequencing. Results Four (15.4%) of 26 patients tested positive for LHON primary mutations, two for the G11778A mutation, and two for the T14484C mutation. No patient tested positive for any of the 14 secondary mutations. Familial recurrence was present in four patients, and only three of these patients have presented the LHON mutation. Conclusions The diagnosis of LHON should be considered in all patients diagnosed as having optic neuropathy, particularly those with familial recurrence of vision loss. PMID:22194643

  5. Characterization of Somatic Mutations in Air Pollution-Related Lung Cancer.

    PubMed

    Yu, Xian-Jun; Yang, Min-Jun; Zhou, Bo; Wang, Gui-Zhen; Huang, Yun-Chao; Wu, Li-Chuan; Cheng, Xin; Wen, Zhe-Sheng; Huang, Jin-Yan; Zhang, Yun-Dong; Gao, Xiao-Hong; Li, Gao-Feng; He, Shui-Wang; Gu, Zhao-Hui; Ma, Liang; Pan, Chun-Ming; Wang, Ping; Chen, Hao-Bin; Hong, Zhi-Peng; Wang, Xiao-Lu; Mao, Wen-Jing; Jin, Xiao-Long; Kang, Hui; Chen, Shu-Ting; Zhu, Yong-Qiang; Gu, Wen-Yi; Liu, Zi; Dong, Hui; Tian, Lin-Wei; Chen, Sai-Juan; Cao, Yi; Wang, Sheng-Yue; Zhou, Guang-Biao

    2015-06-01

    Air pollution has been classified as Group 1 carcinogenic to humans, but the underlying tumorigenesis remains unclear. In Xuanwei City of Yunnan Province, the lung cancer incidence is among the highest in China attributed to severe air pollution generated by combustion of smoky coal, providing a unique opportunity to dissect lung carcinogenesis of air pollution. Here we analyzed the somatic mutations of 164 non-small cell lung cancers (NSCLCs) from Xuanwei and control regions (CR) where smoky coal was not used. Whole genome sequencing revealed a mean of 289 somatic exonic mutations per tumor and the frequent C:G → A:T nucleotide substitutions in Xuanwei NSCLCs. Exome sequencing of 2010 genes showed that Xuanwei and CR NSCLCs had a mean of 68 and 22 mutated genes per tumor, respectively (p < 0.0001). We found 167 genes (including TP53, RYR2, KRAS, CACNA1E) which had significantly higher mutation frequencies in Xuanwei than CR patients, and mutations in most genes in Xuanwei NSCLCs differed from those in CR cases. The mutation rates of 70 genes (e.g., RYR2, MYH3, GPR144, CACNA1E) were associated with patients' lifetime benzo(a)pyrene exposure. This study uncovers the mutation spectrum of air pollution-related lung cancers, and provides evidence for pollution exposure-genomic mutation relationship at a large scale.

  6. Mutation breeding by ion implantation

    NASA Astrophysics Data System (ADS)

    Yu, Zengliang; Deng, Jianguo; He, Jianjun; Huo, Yuping; Wu, Yuejin; Wang, Xuedong; Lui, Guifu

    1991-07-01

    Ion implantation as a new mutagenic method has been used in the rice breeding program since 1986, and for mutation breeding of other crops later. It has been shown, in principle and in practice, that this method has many outstanding advantages: lower damage rate; higher mutation rate and wider mutational spectrum. Many new lines of rice with higher yield rate; broader disease resistance; shorter growing period but higher quality have been bred from ion beam induced mutants. Some of these lines have been utilized for the intersubspecies hybridization. Several new lines of cotton, wheat and other crops are now in breeding. Some biophysical effects of ion implantation for crop seeds have been studied.

  7. Reduction of Werner Syndrome Protein Enhances G:C → A:T Transition by O6-Methylguanine in Human Cells.

    PubMed

    Suzuki, Tetsuya; Kuramoto, Yoshie; Kamiya, Hiroyuki

    2018-04-12

    O 6 -Methylguanine ( O 6 -MeG) is a damaged base produced by methylating reagents. The Werner syndrome protein (WRN) is a cancer-related human DNA helicase. The effects of WRN reduction on O 6 -MeG-caused mutagenesis were assessed by an siRNA-mediated knockdown in human U2OS cells, using a shuttle plasmid with a single O 6 -MeG base in the supF gene. The plasmid DNA was replicated in the cells, isolated, and electroporated into an Escherichia coli indicator strain. The lowered amount of WRN increased the frequency of mutations induced by O 6 -MeG, mainly G:C → A:T substitution. The increased mutation rate suggested that the cancer-related WRN suppresses the G:C → A:T substitution by O 6 -MeG in human cells.

  8. Most Factor VIII B Domain Missense Mutations Are Unlikely to Be Causative Mutations for Severe Hemophilia A: Implications for Genotyping

    PubMed Central

    Ogata, Kyoichi; Selvaraj, Sundar R; Miao, Hongzhi Z; Pipe, Steven W

    2011-01-01

    Summary Background & Objective The factor VIII (FVIII) B domain shares very little amino acid homology to other known proteins and is not directly necessary for procoagulant activity. Despite this, missense mutations within the B domain have been reported in patients with hemophilia A. Given that the B domain is dispensable for secretion and function of FVIII, we hypothesized that these mutations should not be causative of hemophilia A in these patients. Methods Plasmid vectors containing B domain missense mutations that were reported to be associated with moderate/severe hemophilia A (T751S, D826E, V993L, H1047Y, T1353A, N1441K, L1462P, E1579D, A1591S, P1641L and S1669L) were analyzed for their effect on synthesis and secretion compared to FVIII wild-type (WT) following transient transfection into COS-1 and CHO cells in vitro. Further, H1047Y, N1441K and E1579D mutants were expressed in vivo in a hemophilia A mouse model by hydrodynamic tail-vein injection. Results FVIII activity and antigen levels for all mutants expressed into the conditioned media of COS-1 and CHO cells were similar to FVIII WT. Also, plasma expression of these mutants was similar to FVIII WT in hemophilia A mice. An in vivo tail clip bleeding assay also demonstrated that blood loss from hemophilia A mice expressing FVIII WT, H1047Y, N1441K and E1579D were similar. Conclusion We conclude that most missense mutations within the FVIII B domain would be unlikely to lead to severe hemophilia A and that the majority of such missense mutations represent polymorphisms or non-pathologic mutations. PMID:21645226

  9. Calcium dysregulation and Cdk5-ATM pathway involved in a mouse model of fragile X-associated tremor/ataxia syndrome.

    PubMed

    Robin, Gaëlle; López, José R; Espinal, Glenda M; Hulsizer, Susan; Hagerman, Paul J; Pessah, Isaac N

    2017-07-15

    Fragile X-associated tremor/ataxia syndrome (FXTAS) is a neurological disorder that affects premutation carriers with 55-200 CGG-expansion repeats (preCGG) in FMR1, presenting with early alterations in neuronal network formation and function that precede neurodegeneration. Whether intranuclear inclusions containing DNA damage response (DDR) proteins are causally linked to abnormal synaptic function, neuronal growth and survival are unknown. In a mouse that harbors a premutation CGG expansion (preCGG), cortical and hippocampal FMRP expression is moderately reduced from birth through adulthood, with greater FMRP reductions in the soma than in the neurite, despite several-fold elevation of Fmr1 mRNA levels. Resting cytoplasmic calcium concentration ([Ca2+]i) in cultured preCGG hippocampal neurons is chronically elevated, 3-fold compared to Wt; elevated ROS and abnormal glutamatergic responses are detected at 14 DIV. Elevated µ-calpain activity and a higher p25/p35 ratio in the cortex of preCGG young adult mice indicate abnormal Cdk5 regulation. In support, the Cdk5 substrate, ATM, is upregulated by 1.5- to 2-fold at P0 and 6 months in preCGG brain, as is p-Ser1981-ATM. Bax:Bcl-2 is 30% higher in preCGG brain, indicating a greater vulnerability to apoptotic activation. Elevated [Ca2+]i, ROS, and DDR signals are normalized with dantrolene. Chronic [Ca2+]i dysregulation amplifies Cdk5-ATM signaling, possibly linking impaired glutamatergic signaling and DDR to neurodegeneration in preCGG brain. © The Author 2017. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oup.com.

  10. Cytogenetic/mutation profile of chronic lymphocytic leukemia/malignant melanoma collision tumors of the skin.

    PubMed

    La Starza, Roberta; Pierini, Tiziana; Pastorino, Lorenza; Albi, Elisa; Matteucci, Caterina; Crescenzi, Barbara; Sportoletti, Paolo; Covarelli, Piero; Falzetti, Franca; Roti, Giovanni; Ascani, Stefano; Mecucci, Cristina

    2018-01-01

    Collision tumors are rare entities that consist of two histologically distinct tumor types arising in the same anatomic site. An association between chronic lymphocytic leukemia (CLL) and malignant melanoma (MM) has been already described. Up to now, they have been documented only at positive regional lymph nodes while we focused on collision tumor in a skin lesion. We characterized the genomic profile of a skin CLL/MM collision tumor in a patient with a 9-years story of CLL. Typical high-grade genomic biomarkers featured the CLL: the immunoglobulin heavy variable genes were unmutated; a clonal del(11q), involving ATM and BIRC3 , was present in the peripheral blood (PB) and skin lesion, while a subclonal large del(13q)/D13S319 -RB1 was detected only in the PB. Interestingly, the del(13q) clone, increased from 10% to 46% from diagnosis to relapse. NOTCH1 , SF3B1 , and TP53 were wild type. The MM lesion carried a BRAF V600E and a TERT promoter mutation.As the family story was consistent with a genetic predisposition to cancer, we performed mutational analysis of genes involved in familial melanoma and CLL, and of BRCA1 and BRCA2 . No germinal mutation known to predispose to CLL, MM, or breast cancer was found. Interestingly, conventional cytogenetic detected a constitutional t(12;17)(p13;p13). Our data are consistent with distinct genetic landscape of the two tumors which were characterized by specific disease-related abnormalities. CLL cells carried poor prognostic imbalances, i.e. large deletions of the long arm of chromosomes 11 and 13, while in MM cells two functionally linked mutations, i.e. BRAF V600E and a TERT promoter occurred. Although, known germline variations predisposing to MM and/or CLL were ruled out, genetic counseling suggested the proband family was at high risk for MM.

  11. Raman hyperspectral imaging in conjunction with independent component analysis as a forensic tool for explosive analysis: The case of an ATM explosion.

    PubMed

    Almeida, Mariana Ramos; Logrado, Lucio Paulo Lima; Zacca, Jorge Jardim; Correa, Deleon Nascimento; Poppi, Ronei Jesus

    2017-11-01

    In this work, Raman hyperspectral imaging, in conjunction with independent component analysis, was employed as an analytical methodology to detect an ammonium nitrate fuel oil (ANFO) explosive in banknotes after an ATM explosion experiment. The proposed methodology allows for the identification of the ANFO explosive without sample preparation or destroying the sample, at quantities as small as 70μgcm -2 . The explosive was identified following ICA data decomposition by the characteristic nitrate band at 1044cm -1 . The use of Raman hyperspectral imaging and independent component analysis shows great potential for identifying forensic samples by providing chemical and spatial information. Copyright © 2017 Elsevier B.V. All rights reserved.

  12. Enhanced efficiency of solid-state NMR investigations of energy materials using an external automatic tuning/matching (eATM) robot

    NASA Astrophysics Data System (ADS)

    Pecher, Oliver; Halat, David M.; Lee, Jeongjae; Liu, Zigeng; Griffith, Kent J.; Braun, Marco; Grey, Clare P.

    2017-02-01

    We have developed and explored an external automatic tuning/matching (eATM) robot that can be attached to commercial and/or home-built magic angle spinning (MAS) or static nuclear magnetic resonance (NMR) probeheads. Complete synchronization and automation with Bruker and Tecmag spectrometers is ensured via transistor-transistor-logic (TTL) signals. The eATM robot enables an automated "on-the-fly" re-calibration of the radio frequency (rf) carrier frequency, which is beneficial whenever tuning/matching of the resonance circuit is required, e.g. variable temperature (VT) NMR, spin-echo mapping (variable offset cumulative spectroscopy, VOCS) and/or in situ NMR experiments of batteries. This allows a significant increase in efficiency for NMR experiments outside regular working hours (e.g. overnight) and, furthermore, enables measurements of quadrupolar nuclei which would not be possible in reasonable timeframes due to excessively large spectral widths. Additionally, different tuning/matching capacitor (and/or coil) settings for desired frequencies (e.g.7Li and 31P at 117 and 122 MHz, respectively, at 7.05 T) can be saved and made directly accessible before automatic tuning/matching, thus enabling automated measurements of multiple nuclei for one sample with no manual adjustment required by the user. We have applied this new eATM approach in static and MAS spin-echo mapping NMR experiments in different magnetic fields on four energy storage materials, namely: (1) paramagnetic 7Li and 31P MAS NMR (without manual recalibration) of the Li-ion battery cathode material LiFePO4; (2) paramagnetic 17O VT-NMR of the solid oxide fuel cell cathode material La2NiO4+δ; (3) broadband 93Nb static NMR of the Li-ion battery material BNb2O5; and (4) broadband static 127I NMR of a potential Li-air battery product LiIO3. In each case, insight into local atomic structure and dynamics arises primarily from the highly broadened (1-25 MHz) NMR lineshapes that the eATM robot is uniquely

  13. Lentiviral Reprogramming of A-T Patient Fibroblasts to Induced Pluripotent Stem Cells.

    PubMed

    Nayler, Sam; Kozlov, Sergei V; Lavin, Martin F; Wolvetang, Ernst

    2017-01-01

    Reprogramming of cells enables generation of pluripotent stem cells and resulting progeny through directed differentiation, making this technology an invaluable tool for the study of human development and disease. Reprogramming occurs with a wide range of efficiency, a culmination of intrinsic and extrinsic factors including the tissue of origin, the passage number and culture history of the target cells. Another major factor affecting reprogramming is the methodology used and the quality of the reprogramming process itself, including for conventional viral-based approaches viral titer and subsequent viral transduction efficiency, including downstream transgene insertion and stoichiometry. Genetic background is an important parameter affecting the efficiency of the reprogramming process with reports that cells from individuals harboring specific mutations are more difficult to reprogram than control counterparts.Ataxia-Telangiectasia (A-T) fibroblasts underwent reprogramming at reduced efficiency in contrast to their controls. To optimize reprogramming of fibroblasts from patients with A-T, we examined the response of A-T cells to various cell culture conditions after lentiviral transduction with reprogramming factors Oc4/Sox2 (pSIN4-EF2-O2S) and Klf4/c-Myc (pSIN4-CMV-K2M). Parameters included media type (KSR or serum-containing DMEM), treatment with a p53 inhibitor (small-molecule cyclic pifithrin-α), and either a low or high concentration of bFGF. Post-transduction, equivalent numbers of cells from heterozygote and homozygote patients were plated and assessed at regular intervals for survival and proliferation. Our findings indicate that A-T cells responded favorably to the addition of FCS and gradual weaning away from their native media into KSR-containing stem cell media that produced suitable conditions for their reprogramming. We examined a range of properties to identify and isolate good quality iPSCs including the expression status of important stem cell

  14. The evolution of protease mutation 76V is associated with protease mutation 46I and gag mutation 431V.

    PubMed

    Knops, Elena; Kemper, Ina; Schülter, Eugen; Pfister, Herbert; Kaiser, Rolf; Verheyen, Jens

    2010-03-13

    Recently, first-line lopinavir failure was observed due to protease mutation 76V. In the present study, we found 76V associated with protease mutation 46I and gag cleavage-site mutation 431V. Longitudinal analysis of patients failing protease inhibitor therapies demonstrated that 76V strictly occurs either together with 46I and/or 431V or in HIV isolates already harbouring one of both mutations. Therefore, all three mutations seem to cooperate in terms of protease inhibitor resistance.

  15. The androgen receptor gene mutations database.

    PubMed

    Patterson, M N; Hughes, I A; Gottlieb, B; Pinsky, L

    1994-09-01

    The androgen receptor gene mutations database is a comprehensive listing of mutations published in journals and meetings proceedings. The majority of mutations are point mutations identified in patients with androgen insensitivity syndrome. Information is included regarding the phenotype, the nature and location of the mutations, as well as the effects of the mutations on the androgen binding activity of the receptor. The current version of the database contains 149 entries, of which 114 are unique mutations. The database is available from EMBL (NetServ@EMBL-Heidelberg.DE) or as a Macintosh Filemaker file (mc33001@musica.mcgill.ca).

  16. Mutation testing in Treacher Collins Syndrome.

    PubMed

    Ellis, P E; Dawson, M; Dixon, M J

    2002-12-01

    To report on a study where 97 subjects were screened for mutations in the Treacher Collins syndrome (TCS) gene TCOF1. Ninety-seven subjects with a clinical diagnosis of TCS were screened for potential mutations in TCOF1, by means of single strand conformation polymorphism (SSCP) analysis. In those subjects where potential mutations were detected, sequence analysis was performed to determine the site and type of mutation present. Thirty-six TCS-specific mutations are reported including 27 deletions, six point mutations, two splice junction mutations, and one insertion/deletion. This brings the total number of mutations reported to date to 105. The importance of detection of these mutations is mainly in postnatal diagnosis and genetic counselling. Knowledge of the family specific mutation may also be used in prenatal diagnosis to confirm whether the foetus is affected or not, and give the parents the choice of whether to continue with the pregnancy.

  17. Solution-phase DNA mutation scanning and SNP genotyping by nanoliter melting analysis.

    PubMed

    Sundberg, Scott O; Wittwer, Carl T; Greer, Jenny; Pryor, Robert J; Elenitoba-Johnson, Oluwole; Gale, Bruce K

    2007-04-01

    Solution-phase, DNA melting analysis for heterozygote scanning and single nucleotide polymorphism (SNP) genotyping was performed in 10 nl volumes on a custom microchip. Human genomic DNA was PCR amplified in the presence of the saturating fluorescent dye, LCGreen Plus, and placed within microfluidic channels that were created between two glass slides. The microchip was heated at 0.1 degrees C/s with a Peltier device and viewed with an inverted fluorescence microscope modified for photomulitiplier tube detection. The melting data was normalized and the negative first derivative plotted against temperature. Mutation scanning for heterozygotes was easily performed by comparing the shape of the melting curve to homozygous standards. Genotyping of homozygotes by melting temperature (T(m)) required absolute temperature comparisons. Mutation scanning of ATM exon 17 and CFTR exon 10 identified single base change heterozygotes in 84 and 201 base-pair (bp) products, respectively. All genotypes at HFE C282Y were distinguished by simple melting analysis of a 40-bp fragment. Sequential analysis of the same sample on the gold-standard, commercial high-resolution melting instrument HR-1, followed by melting in a 10 nl reaction chamber, produced similar results. DNA melting analysis requires only minutes after PCR and is a simple method for genotyping and scanning that can be reduced to nanoliter volumes. Microscale systems for performing DNA melting reduce the reagents/DNA template required with a promise for high throughput analysis in a closed chamber without risk of contamination.

  18. Mutational Profile of Homozygous β-Thalassemia in Rio de Janeiro, Brazil.

    PubMed

    Carrocini, Gisele C S; Venancio, Larissa P R; Pessoa, Viviani L R; Lobo, Clarisse L C; Bonini-Domingos, Claudia R

    2017-01-01

    β-Thalassemia (β-thal) is a hemolytic anemia that is caused by point mutations in most cases. The Brazilian population is highly heterogeneous and knowledge of the mutations that make up the genotypic profile of individuals can contribute information about the formation of the population and clinical condition of patients. In this study, we evaluated the mutations present in homozygous β-thal patients from Rio de Janeiro, Brazil. We analyzed 24 samples of peripheral blood of patients with homozygous β-thal. To identify the mutations, we carried out allele-specific-polymerase chain reaction (AS-PCR) and DNA sequencing. We found 11 different mutations on the β-globin gene. Among the most frequent mutations observed were HBB: c.92 + 6T>C, followed by HBB: c.93-21G>A, HBB: c.118C>T and HBB: c.92 + 1G>A. We also identified the rare mutation HBB: c.75T>A that was reported in an individual carrying Hb S (HBB: c.20A>T)/β-thal (HBB: c.75T>A) but not in Brazilian thalassemic patients, thus, this is the first report of this mutation in Brazilian β-thal patients. For its multiethnic character, Brazil has different mutations that cause β-thal and that are distributed with different frequencies according to the regions of the country. Our findings contribute to the description of the mutational profile of Brazilian thalassemic patients, showing wide heterogeneity and genetic variability.

  19. [Application of gene capture technology on mutation screening of RB1 gene in retinoblastoma patients].

    PubMed

    Meng, Q Y; Huang, L Z; Wang, B; Li, X X; Liang, J H

    2017-06-11

    Objectives: To analyze RB1 gene mutation in retinoblastoma (RB) patients using gene capture technology. Methods: Experimental research. The clinical data of 17 RB patients were collected at Department of Ophthalmology, Peking University People's Hospital from June 2010 to Jun 2014. Peripheral blood samples of seventeen RB patients and their parents were collected and genomic DNA were extracted. DNA library from RB patients was mixed with designed gene capture probe of RB1 exons and its flanking sequences. The data were analyzed using bioinformatics software. To avoid the false positive, the abnormal sites were verified using the Sanger sequencing method. Results: Totally, there were 17 RB patients, including 12 males and 5 females, from 0.5 to 23 years old, average ages were (3.2±5.2) years old. Both eyes were involved in 6 patients. The other 11 cases were only one eye was attacked. Four RB patients were found to have germline mutations, among whom 2 had bilateral tumors and 2 had unilateral tumors. 2 novel missense mutations were identified, including 15(th) exon c.1408A>T (p. Ile470Phe) and c.1960G>C (p. Val654Leu) at 19(th) exon. No RB1 mutation was identified in any of their parents. We also identified 2 mutations reported previously. One is c.1030C>T termination mutation at 10(th) exon in a bilateral RB patients and his father, who was diagnosed with unilateral RB. The other is c.371-372delTA frame shift mutation at 3(rd) exon. No mutation was found in their parents. Conclusions: Two novel germline RB1 mutations were found using gene capture technology, which enriched RB1 mutations library. (Chin J Ophthalmol, 2017, 53: 455-459) .

  20. Individual patient data meta-analysis shows a significant association between the ATM rs1801516 SNP and toxicity after radiotherapy in 5456 breast and prostate cancer patients.

    PubMed

    Andreassen, Christian Nicolaj; Rosenstein, Barry S; Kerns, Sarah L; Ostrer, Harry; De Ruysscher, Dirk; Cesaretti, Jamie A; Barnett, Gillian C; Dunning, Alison M; Dorling, Leila; West, Catharine M L; Burnet, Neil G; Elliott, Rebecca; Coles, Charlotte; Hall, Emma; Fachal, Laura; Vega, Ana; Gómez-Caamaño, Antonio; Talbot, Christopher J; Symonds, R Paul; De Ruyck, Kim; Thierens, Hubert; Ost, Piet; Chang-Claude, Jenny; Seibold, Petra; Popanda, Odilia; Overgaard, Marie; Dearnaley, David; Sydes, Matthew R; Azria, David; Koch, Christine Anne; Parliament, Matthew; Blackshaw, Michael; Sia, Michael; Fuentes-Raspall, Maria J; Ramon Y Cajal, Teresa; Barnadas, Agustin; Vesprini, Danny; Gutiérrez-Enríquez, Sara; Mollà, Meritxell; Díez, Orland; Yarnold, John R; Overgaard, Jens; Bentzen, Søren M; Alsner, Jan

    2016-12-01

    Several small studies have indicated that the ATM rs1801516 SNP is associated with risk of normal tissue toxicity after radiotherapy. However, the findings have not been consistent. In order to test this SNP in a well-powered study, an individual patient data meta-analysis was carried out by the International Radiogenomics Consortium. The analysis included 5456 patients from 17 different cohorts. 2759 patients were given radiotherapy for breast cancer and 2697 for prostate cancer. Eight toxicity scores (overall toxicity, acute toxicity, late toxicity, acute skin toxicity, acute rectal toxicity, telangiectasia, fibrosis and late rectal toxicity) were analyzed. Adjustments were made for treatment and patient related factors with potential impact on the risk of toxicity. For all endpoints except late rectal toxicity, a significantly increased risk of toxicity was found for carriers of the minor (Asn) allele with odds ratios of approximately 1.5 for acute toxicity and 1.2 for late toxicity. The results were consistent with a co-dominant pattern of inheritance. This study convincingly showed a significant association between the ATM rs1801516 Asn allele and increased risk of radiation-induced normal tissue toxicity. Copyright © 2016 Elsevier Ireland Ltd. All rights reserved.

  1. Patients with chronic lymphocytic leukemia and complex karyotype show an adverse outcome even in absence of TP53/ATM FISH deletions

    PubMed Central

    Puiggros, Anna; Collado, Rosa; Calasanz, Maria José; Ortega, Margarita; Ruiz-Xivillé, Neus; Rivas-Delgado, Alfredo; Luño, Elisa; González, Teresa; Navarro, Blanca; García-Malo, MaDolores; Valiente, Alberto; Hernández, José Ángel; Ardanaz, María Teresa; Piñan, María Ángeles; Blanco, María Laura; Hernández-Sánchez, María; Batlle-López, Ana; Salgado, Rocío; Salido, Marta; Ferrer, Ana; Abrisqueta, Pau; Gimeno, Eva; Abella, Eugènia; Ferrá, Christelle; Terol, María José; Ortuño, Francisco; Costa, Dolors; Moreno, Carol; Carbonell, Félix; Bosch, Francesc; Delgado, Julio; Espinet, Blanca

    2017-01-01

    Genomic complexity identified by chromosome banding analysis (CBA) predicts a worse clinical outcome in CLL patients treated either with standard or new treatments. Herein, we analyzed the clinical impact of complex karyotypes (CK) with or without high-risk FISH deletions (ATM and/or TP53, HR-FISH) in a cohort of 1045 untreated MBL/CLL patients. In all, 99/1045 (9.5%) patients displayed a CK. Despite ATM and TP53 deletions were more common in CK (25% vs 7%; P < 0.001; 40% vs 5%; P < 0.001, respectively), only 44% (40/90) patients with TP53 deletions showed a CK. CK group showed a significant higher two-year cumulative incidence of treatment (48% vs 20%; P < 0.001), as well as a shorter overall survival (OS) (79 mo vs not reached; P < 0.001). When patients were categorized regarding CK and HR-FISH, those with both characteristics showed the worst median OS (52 mo) being clearly distinct from those non-CK and non-HR-FISH (median not reached), but no significant differences were detected between cases with only CK or HR-FISH. Both CK and TP53 deletion remained statistically significant in the multivariate analysis for OS. In conclusion, CK group is globally associated with advanced disease and poor prognostic markers. Further investigation in larger cohorts with CK lacking HR-FISH is needed to elucidate which mechanisms underlie the poor outcome of this subgroup. PMID:28903342

  2. Pathway Model of the Kinetics of the TGFbeta Antagonist Smad7 and Cross-Talk with the ATM and WNT Pathways

    NASA Technical Reports Server (NTRS)

    Carra, Claudio; Wang, Minli; Huff, Janice L.; Hada, Megumi; ONeill, Peter; Cucinotta, Francis A.

    2010-01-01

    Signal transduction controls cellular and tissue responses to radiation. Transforming growth factor beta (TGFbeta) is an important regulator of cell growth and differentiation and tissue homeostasis, and is often dis-regulated in tumor formation. Mathematical models of signal transduction pathways can be used to elucidate how signal transduction varies with radiation quality, and dose and dose-rate. Furthermore, modeling of tissue specific responses can be considered through mechanistic based modeling. We developed a mathematical model of the negative feedback regulation by Smad7 in TGFbeta-Smad signaling and are exploring possible connections to the WNT/beta -catenin, and ATM/ATF2 signaling pathways. A pathway model of TGFbeta-Smad signaling that includes Smad7 kinetics based on data in the scientific literature is described. Kinetic terms included are TGFbeta/Smad transcriptional regulation of Smad7 through the Smad3-Smad4 complex, Smad7-Smurf1 translocation from nucleus to cytoplasm, and Smad7 negative feedback regulation of the TGFO receptor through direct binding to the TGFO receptor complex. The negative feedback controls operating in this pathway suggests non-linear responses in signal transduction, which are described mathematically. We then explored possibilities for cross-talk mediated by Smad7 between DNA damage responses mediated by ATM, and with the WNT pathway and consider the design of experiments to test model driven hypothesis. Numerical comparisons of the mathematical model to experiments and representative predictions are described.

  3. Novel Connections Between DNA Replication, Telomere Homeostasis, and the DNA Damage Response Revealed by a Genome-Wide Screen for TEL1/ATM Interactions in Saccharomyces cerevisiae

    PubMed Central

    Piening, Brian D.; Huang, Dongqing; Paulovich, Amanda G.

    2013-01-01

    Tel1 is the budding yeast ortholog of the mammalian tumor suppressor and DNA damage response (DDR) kinase ATM. However, tel1-Δ cells, unlike ATM-deficient cells, do not exhibit sensitivity to DNA-damaging agents, but do display shortened (but stably maintained) telomere lengths. Neither the extent to which Tel1p functions in the DDR nor the mechanism by which Tel1 contributes to telomere metabolism is well understood. To address the first question, we present the results from a comprehensive genome-wide screen for genetic interactions with tel1-Δ that cause sensitivity to methyl methanesulfonate (MMS) and/or ionizing radiation, along with follow-up characterizations of the 13 interactions yielded by this screen. Surprisingly, many of the tel1-Δ interactions that confer DNA damage sensitivity also exacerbate the short telomere phenotype, suggesting a connection between these two phenomena. Restoration of normal telomere length in the tel1-Δ xxx-Δ mutants results in only minor suppression of the DNA damage sensitivity, demonstrating that the sensitivity of these mutants must also involve mechanisms independent of telomere length. In support of a model for increased replication stress in the tel1-Δ xxx-Δ mutants, we show that depletion of dNTP pools through pretreatment with hydroxyurea renders tel1-Δ cells (but not wild type) MMS-sensitive, demonstrating that, under certain conditions, Tel1p does indeed play a critical role in the DDR. PMID:23378069

  4. Accelerating Mutational Load Is Not Due to Synergistic Epistasis or Mutator Alleles in Mutation Accumulation Lines of Yeast

    PubMed Central

    Jasmin, Jean-Nicolas; Lenormand, Thomas

    2016-01-01

    Much of our knowledge about the fitness effects of new mutations has been gained from mutation accumulation (MA) experiments. Yet the fitness effect of single mutations is rarely measured in MA experiments. This raises several issues, notably for inferring epistasis for fitness. The acceleration of fitness decline in MA lines has been taken as evidence for synergistic epistasis, but establishing the role of epistasis requires measuring the fitness of genotypes carrying known numbers of mutations. Otherwise, accelerating fitness loss could be explained by increased genetic mutation rates. Here we segregated mutations accumulated over 4800 generations in haploid and diploid MA lines of the yeast Saccharomyces cerevisiae. We found no correspondence between an accelerated fitness decline and synergistic epistasis among deleterious mutations in haploid lines. Pairs of mutations showed no overall epistasis. Furthermore, several lines of evidence indicate that genetic mutation rates did not increase in the MA lines. Crucially, segregant fitness analyses revealed that MA accelerated in both haploid and diploid lines, even though the fitness of diploid lines was nearly constant during the MA experiment. This suggests that the accelerated fitness decline in haploids was caused by cryptic environmental factors that increased mutation rates in all lines during the last third of the lines’ transfers. In addition, we provide new estimates of deleterious mutation rates, including lethal mutations, and highlight that nearly all the mutational load we observed was due to one or two mutations having a large effect on fitness. PMID:26596348

  5. X-ray-induced mutations in Escherichia coli K-12 strains with altered DNA polymerase I activities.

    PubMed

    Nagata, Yuki; Kawata, Masakado; Komura, Jun-ichiro; Ono, Tetsuya; Yamamoto, Kazuo

    2003-07-25

    Spectra of ionizing radiation mutagenesis were determined by sequencing X-ray-induced endogenous tonB gene mutations in Escherichia coli polA strains. We used two polA alleles, the polA1 mutation, defective for Klenow domain, and the polA107 mutation, defective for flap domain. We demonstrated that irradiation of 75 and 50 Gy X-rays could induce 3.8- and 2.6-fold more of tonB mutation in polA1 and polA107 strains, respectively, than spontaneous level. The radiation induced spectrum of 51 tonB mutations in polA1 and 51 in polA107 indicated that minus frameshift, A:T-->T:A transversion and G:C-->T:A transversion were the types of mutations increased. Previously, we have reported essentially the same X-ray-induced tonB mutation spectra in the wild-type strain. These results indicate that (1) X-rays can induce minus frameshift, A:T-->T:A transversion and G:C-->T:A transversion in E. coli and (2) presence or absence of polymerase I (PolI) of E. coli does not have any effects on the process of X-ray mutagenesis.

  6. Mutational effects of γ-rays and carbon ion beams on Arabidopsis seedlings.

    PubMed

    Yoshihara, Ryouhei; Nozawa, Shigeki; Hase, Yoshihiro; Narumi, Issay; Hidema, Jun; Sakamoto, Ayako N

    2013-11-01

    To assess the mutational effects of radiation on vigorously proliferating plant tissue, the mutation spectrum was analyzed with Arabidopsis seedlings using the plasmid-rescue method. Transgenic plants containing the Escherichia coli rpsL gene were irradiated with γ-rays and carbon ion beams (320-MeV (12)C(6+)), and mutations in the rpsL gene were analyzed. Mutant frequency increased significantly following irradiation by γ-rays, but not by 320-MeV (12)C(6+). Mutation spectra showed that both radiations increased the frequency of frameshifts and other mutations, including deletions and insertions, but only γ-rays increased the frequency of total base substitutions. These results suggest that the type of DNA lesions which cause base substitutions were less often induced by 320-MeV (12)C(6+) than by γ-rays in Arabidopsis seedlings. Furthermore, γ-rays never increased the frequencies of G:C to T:A or A:T to C:G transversions, which are caused by oxidized guanine; 320-MeV (12)C(6+), however, produced a slight increase in both transversions. Instead, γ-rays produced a significant increase in the frequency of G:C to A:T transitions. These results suggest that 8-oxoguanine has little effect on mutagenesis in Arabidopsis cells.

  7. Mutational effects of γ-rays and carbon ion beams on Arabidopsis seedlings

    PubMed Central

    Yoshihara, Ryouhei; Nozawa, Shigeki; Hase, Yoshihiro; Narumi, Issay; Hidema, Jun; Sakamoto, Ayako N.

    2013-01-01

    To assess the mutational effects of radiation on vigorously proliferating plant tissue, the mutation spectrum was analyzed with Arabidopsis seedlings using the plasmid-rescue method. Transgenic plants containing the Escherichia coli rpsL gene were irradiated with γ-rays and carbon ion beams (320-MeV 12C6+), and mutations in the rpsL gene were analyzed. Mutant frequency increased significantly following irradiation by γ-rays, but not by 320-MeV 12C6+. Mutation spectra showed that both radiations increased the frequency of frameshifts and other mutations, including deletions and insertions, but only γ-rays increased the frequency of total base substitutions. These results suggest that the type of DNA lesions which cause base substitutions were less often induced by 320-MeV 12C6+ than by γ-rays in Arabidopsis seedlings. Furthermore, γ-rays never increased the frequencies of G:C to T:A or A:T to C:G transversions, which are caused by oxidized guanine; 320-MeV 12C6+, however, produced a slight increase in both transversions. Instead, γ-rays produced a significant increase in the frequency of G:C to A:T transitions. These results suggest that 8-oxoguanine has little effect on mutagenesis in Arabidopsis cells. PMID:23728320

  8. Expanding the spectrum of HEXA mutations in Indian patients with Tay-Sachs disease.

    PubMed

    Sheth, Jayesh; Mistri, Mehul; Datar, Chaitanya; Kalane, Umesh; Patil, Shekhar; Kamate, Mahesh; Shah, Harshuti; Nampoothiri, Sheela; Gupta, Sarita; Sheth, Frenny

    2014-01-01

    Tay-Sachs disease is an autosomal recessive neurodegenerative disorder occurring due to impaired activity of β-hexosaminidase-A (EC 3.2.1.52), resulting from the mutation in HEXA gene. Very little is known about the molecular pathology of TSD in Indian children except for a few mutations identified by us. The present study is aimed to determine additional mutations leading to Tay-Sachs disease in nine patients confirmed by the deficiency of β-hexosaminidase-A (< 2% of total hexosaminidase activity for infantile patients) in leucocytes. The enzyme activity was assessed by using substrates 4-methylumbelliferyl-N-acetyl-β-d-glucosamine and 4-methylumbelliferyl-N-acetyl-β-d-glucosamine-6-sulfate for total-hexosaminidase and hexosaminidase-A respectively, and heat inactivation method for carrier detection. The exons and exon-intron boundaries of the HEXA gene were bi-directionally sequenced on an automated sequencer. 'In silico' analyses for novel mutations were carried out using SIFT, Polyphen2 and MutationT@ster software programs. The structural study was carried out by UCSF Chimera software using the crystallographic structure of β-hexosaminidase-A (PDB-ID: 2GJX) as the template. Our study identified four novel mutations in three cases. These include a compound heterozygous missense mutation c.524A>C (D175A) and c.805G>C (p.G269R) in one case; and one small 1 bp deletion c.426delT (p.F142LfsX57) and one splice site mutation c.459+4A>C in the other two cases respectively. None of these mutations were detected in 100 chromosomes from healthy individuals of the same ethnic group. Three previously reported missense mutations, (i) c.532C>T (p.R178C), (ii) c.964G>T (p.D322Y), and (iii) c.1385A>T (p.E462V); two nonsense mutations (i) c.709C>T (p.Q237X) and (ii) c.1528C>T (p.R510X), one 4 bp insertion c.1277_1278insTATC (p.Y427IfsX5) and one splice site mutation c.459+5G>A were also identified in six cases. We observe from this study that novel mutations are more

  9. Calpain-3 mutations in Turkey.

    PubMed

    Balci, Burcu; Aurino, Stefania; Haliloglu, Göknur; Talim, Beril; Erdem, Sevim; Akcören, Zuhal; Tan, Ersin; Caglar, Melda; Richard, Isabelle; Nigro, Vincenzo; Topaloglu, Haluk; Dincer, Pervin

    2006-05-01

    Autosomal recessive limb-girdle muscular dystrophies (LGMD2s) are a clinically and genetically heterogeneous group of disorders, characterized by progressive involvement of the proximal limb girdle muscles; the group includes at least 10 different genetic entities. The calpainopathies (LGMD2A), a subgroup of LGMD2s, are estimated to be the most common forms of LGMD2 in all populations so far investigated. LGMD2A is usually characterized by symmetrical and selective atrophy of pelvic, scapular and trunk muscles and a moderate to gross elevation of serum CK. However, the course is highly variable. It is caused by mutations in the CAPN3 gene, which encodes for the calpain-3 protein. Until now, 161 pathogenic mutations have been found in the CAPN3 gene. In the present study, through screening of 93 unrelated LGMD2 families, we identified 29 families with LGMD2A, 21 (22.6%) of which were identified as having CAPN3 gene mutations. We detected six novel (p.K211N, p.D230G, p.Y322H, p.R698S, p.Q738X, c.2257delGinsAA) and nine previously reported mutations (c.550delA, c.19_23del, c.1746-20C>G, p.R49H, p.R490Q, p.Y336N, p.A702V, p.Y537X, p.R541Q) in the CAPN3 gene. There may be a wide variety of mutations, but clustering of specific mutations (c.550delA: 40%, p.R490Q: 10%) could be used in the diagnostic scheme in Turkey.

  10. Feedback regulation of methyl methanesulfonate and ultraviolet-sensitive gene clone 81 via ATM/Chk2 pathway contributes to the resistance of MCF-7 breast cancer cells to cisplatin.

    PubMed

    Lv, Juan; Qian, Ying; Ni, Xiaoyan; Xu, Xiuping; Dong, Xuejun

    2017-03-01

    The methyl methanesulfonate and ultraviolet-sensitive gene clone 81 protein is a structure-specific nuclease that plays important roles in DNA replication and repair. Knockdown of methyl methanesulfonate and ultraviolet-sensitive gene clone 81 has been found to sensitize cancer cells to chemotherapy. However, the underlying molecular mechanism is not well understood. We found that methyl methanesulfonate and ultraviolet-sensitive gene clone 81 was upregulated and the ATM/Chk2 pathway was activated at the same time when MCF-7 cells were treated with cisplatin. By using lentivirus targeting methyl methanesulfonate and ultraviolet-sensitive gene clone 81 gene, we showed that knockdown of methyl methanesulfonate and ultraviolet-sensitive gene clone 81 enhanced cell apoptosis and inhibited cell proliferation in MCF-7 cells under cisplatin treatment. Abrogation of ATM/Chk2 pathway inhibited cell viability in MCF-7 cells in response to cisplatin. Importantly, we revealed that ATM/Chk2 was required for the upregulation of methyl methanesulfonate and ultraviolet-sensitive gene clone 81, and knockdown of methyl methanesulfonate and ultraviolet-sensitive gene clone 81 resulted in inactivation of ATM/Chk2 pathway in response to cisplatin. Meanwhile, knockdown of methyl methanesulfonate and ultraviolet-sensitive gene clone 81 activated the p53/Bcl-2 pathway in response to cisplatin. These data suggest that the ATM/Chk2 may promote the repair of DNA damage caused by cisplatin by sustaining methyl methanesulfonate and ultraviolet-sensitive gene clone 81, and the double-strand breaks generated by methyl methanesulfonate and ultraviolet-sensitive gene clone 81 may activate the ATM/Chk2 pathway in turn, which provide a novel mechanism of how methyl methanesulfonate and ultraviolet-sensitive gene clone 81 modulates DNA damage response and repair.

  11. Contribution of germline mutations in cancer predisposition genes to tumor etiology in young women diagnosed with invasive breast cancer.

    PubMed

    Rummel, Seth K; Lovejoy, Leann; Shriver, Craig D; Ellsworth, Rachel E

    2017-08-01

    Although breast cancer in young women accounts for <10% of diagnoses annually, tumors in young patients exhibit more aggressive characteristics and higher mortality rates. Determination of the frequency of germline mutations in cancer predisposition genes is needed to improve the understanding of breast cancer etiology in young women. All female patients enrolled in the Clinical Breast Cancer Project between 2001 and 2015 and diagnosed with invasive breast cancer before age 40 were included in this study. Family history was classified using the NCCN Familial Risk Assessment guidelines. Targeted sequencing of 94 cancer predisposition genes was performed using peripheral blood DNA. Variants were detected using VariantStudio and classified using ClinVar. Seven percent (141/1980) of patients were young women and 44 had a significant family history. Sequencing was completed for 118 women with genomic DNA. Pathogenic mutations were present in 27 patients: BRCA1 (n = 10), BRCA2 (n = 12), TP53 (n = 1), and CHEK2 (n = 4). Mutations classified as pathogenic were also detected in APC (n = 1) and MUTYH (n = 2). Variants of uncertain significance (VUS) were detected in an additional 17 patients in ten genes. Pathogenic mutations in high- and moderate-risk breast cancer genes were detected in 23% of young women with an additional 3% having pathogenic mutations in colon cancer predisposition genes. VUS were observed in 14% of women in genes such as ATM, BRCA2, CDH1, CHEK2, and PALB2. Identification of those non-genetic factors is critical to reduce the burden of breast cancer in this population.

  12. A founder mutation causing a severe methylenetetrahydrofolate reductase (MTHFR) deficiency in Bukharian Jews.

    PubMed

    Ben-Shachar, Shay; Zvi, Tal; Rolfs, Arndt; Breda Klobus, Andrea; Yaron, Yuval; Bar-Shira, Anat; Orr-Urtreger, Avi

    2012-11-01

    Methylenetetrahydrofolate reductase (MTHFR) deficiency is a rare autosomal recessive disorder. A novel homozygous MTHFR c.474A>T (p.G158G) mutation was detected in two unrelated children of Jewish Bukharian origin. This mutation generates an abnormal splicing and early termination codon. A carrier frequency of 1:39 (5/196) was determined among unrelated healthy Bukharian Jews. Given the disease severity and allele frequency, a population screening for individuals of this ancestry is warranted in order to allow prenatal, or preimplantation diagnosis. Copyright © 2012 Elsevier Inc. All rights reserved.

  13. Cystic fibrosis mutation testing in Italy.

    PubMed

    Bombieri, C; Pignatti, P F

    2001-01-01

    In Italy, Cystic fibrosis (CF) mutation frequency differences have been observed in different regions. In the northeastern Veneto and Trentino Alto Adige regions, a complete cystic fibrosis transmembrane conductance regulator (CFTR) gene screening in CF patients detected through a newborn screening program has identified about 90% of the mutations. In these two regions, the current detection rate using a CF screening panel containing the 16 most common mutations is 86.6%. CF mutations in some other Italian regions have not been so thoroughly analysed. Available data indicate that a more general national screening panel comprising 31 mutations may detect about 75% of all CF mutations in Italy.

  14. Inhibitory signaling potential of a T cell receptor-like molecule in lamprey

    PubMed Central

    Yu, Cuiling; Ehrhardt, Götz R.A.; Alder, Matthew N.; Cooper, Max D.; Xu, Anlong

    2010-01-01

    Summary A T-cell receptor-like molecule (TCRL) with two canonical ITIM motifs has been identified in the sea lamprey. We show here that TCRL is preferentially expressed by lymphocytes bearing variable lymphocyte receptors. To examine the potential of the TCRL inhibitory motifs, chimeric proteins comprised by the FcγRIIb extracellular and transmembrane domains and the TCRL intracellular domain were expressed in a mouse B cell line. BCR co-ligation with the wild type version of the FcγRIIb/TCRL chimeric protein resulted in its tyrosine phosphorylation and the inhibition of BCR-induced calcium mobilization, whole cell protein tyrosine phosphorylation and Erk/Akt/JNK activation. Tyrosine to phenylalanine mutations in either or both ITIM compromised the inhibitory capacity of this receptor chimera. Analysis of receptor associated proteins indicated that the inhibition is mediated by recruitment of the protein tyrosine kinases, SHP1 and SHP2. These findings demonstrate the inhibitory potential of TCRL and its expression by clonally-diverse lymphocytes bearing the variable lymphocyte receptors, thereby implying an immunomodulatory role for this ancestral TCR relative in a jawless vertebrate. PMID:19130486

  15. Common variants at 9q22.33, 14q13.3, and ATM loci, and risk of differentiated thyroid cancer in the French Polynesian population.

    PubMed

    Maillard, Stéphane; Damiola, Francesca; Clero, Enora; Pertesi, Maroulio; Robinot, Nivonirina; Rachédi, Frédérique; Boissin, Jean-Louis; Sebbag, Joseph; Shan, Larrys; Bost-Bezeaud, Frédérique; Petitdidier, Patrick; Doyon, Françoise; Xhaard, Constance; Rubino, Carole; Blanché, Hélène; Drozdovitch, Vladimir; Lesueur, Fabienne; de Vathaire, Florent

    2015-01-01

    French Polynesia has one of the highest incidence rates of thyroid cancer worldwide. Relationships with the atmospheric nuclear weapons tests and other environmental, biological, or behavioral factors have already been reported, but genetic susceptibility has yet to be investigated. We assessed the contribution of polymorphisms at the 9q22.33 and 14q13.3 loci identified by GWAS, and within the DNA repair gene ATM, to the risk of differentiated thyroid cancer (DTC) in 177 cases and 275 matched controls from the native population. For the GWAS SNP rs965513 near FOXE1, an association was found between genotypes G/A and A/A, and risk of DTC. A multiplicative effect of allele A was even noted. An excess risk was also observed in individuals carrying two long alleles of the poly-alanine tract expansion in FOXE1, while no association was observed with rs1867277 falling in the promoter region of the gene. In contrast, the GWAS SNP rs944289 (NKX2-1) did not show any significant association. Although the missense substitution D1853N (rs1801516) in ATM was rare in the population, carriers of the minor allele (A) also showed an excess risk. The relationships between these five polymorphisms and the risk of DTC were not contingent on the body surface area, body mass index, ethnicity or dietary iodine intake. However, an interaction was evidenced between the thyroid radiation dose and rs944289. A clear link could not be established between the high incidence in French Polynesia and the studied polymorphisms, involved in susceptibility to DTC in other populations. Important variation in allele frequencies was observed in the Polynesian population as compared to the European populations. For FOXE1 rs965513, the direction of association and the effect size was similar to that observed in other populations, whereas for ATM rs1801516, the minor allele was associated to an increased risk in the Polynesian population and with a decreased risk in the European population.