WorldWideScience

Sample records for chk1 haploinsufficiency results

  1. Trial Watch: Targeting ATM–CHK2 and ATR–CHK1 pathways for anticancer therapy

    Science.gov (United States)

    Manic, Gwenola; Obrist, Florine; Sistigu, Antonella; Vitale, Ilio

    2015-01-01

    The ataxia telangiectasia mutated serine/threonine kinase (ATM)/checkpoint kinase 2 (CHEK2, best known as CHK2) and the ATM and Rad3-related serine/threonine kinase (ATR)/CHEK1 (best known as CHK1) cascades are the 2 major signaling pathways driving the DNA damage response (DDR), a network of processes crucial for the preservation of genomic stability that act as a barrier against tumorigenesis and tumor progression. Mutations and/or deletions of ATM and/or CHK2 are frequently found in tumors and predispose to cancer development. In contrast, the ATR–CHK1 pathway is often upregulated in neoplasms and is believed to promote tumor growth, although some evidence indicates that ATR and CHK1 may also behave as haploinsufficient oncosuppressors, at least in a specific genetic background. Inactivation of the ATM–CHK2 and ATR–CHK1 pathways efficiently sensitizes malignant cells to radiotherapy and chemotherapy. Moreover, ATR and CHK1 inhibitors selectively kill tumor cells that present high levels of replication stress, have a deficiency in p53 (or other DDR players), or upregulate the ATR–CHK1 module. Despite promising preclinical results, the clinical activity of ATM, ATR, CHK1, and CHK2 inhibitors, alone or in combination with other therapeutics, has not yet been fully demonstrated. In this Trial Watch, we give an overview of the roles of the ATM-CHK2 and ATR-CHK1 pathways in cancer initiation and progression, and summarize the results of clinical studies aimed at assessing the safety and therapeutic profile of regimens based on inhibitors of ATR and CHK1, the only 2 classes of compounds that have so far entered clinics. PMID:27308506

  2. Chk1 suppressed cell death

    Directory of Open Access Journals (Sweden)

    Meuth Mark

    2010-09-01

    Full Text Available Abstract The role of Chk1 in the cellular response to DNA replication stress is well established. However recent work indicates a novel role for Chk1 in the suppression of apoptosis following the disruption of DNA replication or DNA damage. This review will consider these findings in the context of known pathways of Chk1 signalling and potential applications of therapies that target Chk1.

  3. Geldanamycin-induced degradation of Chk1 is mediated by proteasome

    International Nuclear Information System (INIS)

    Nomura, M.; Nomura, N.; Yamashita, J.

    2005-01-01

    Checkpoint kinase 1 (Chk1) is a cell cycle regulator and a heat shock protein 90 (Hsp90) client. It is essential for cell proliferation and survival. In this report, we analyzed the mechanisms of Chk1 regulation in U87MG glioblastoma cells using Geldanamycin (GA), which interferes with the function of Hsp90. GA reduced Chk1 protein level but not its mRNA level in glioblastoma cells. Co-treatment with GA and cycloheximide (CHX), a protein synthesis inhibitor, induced a decrease of half-life of the Chk1 protein to 3 h and resulted in Chk1 down-regulation. CHX alone induced only 32% reduction of Chk1 protein even after 24 h. These findings indicated that reduction of Chk1 by GA was due to destabilization and degradation of the protein. In addition, GA-induced down-regulation of Chk1 was reversed by MG132, a specific proteasome inhibitor. And it was revealed that Chk1 was ubiquitinated by GA. These results have indicated that degradation of Chk1 by GA was mediated by the ubiquitin-proteasome pathway in U87MG glioblastoma cells

  4. Chk1 protects against chromatin bridges by constitutively phosphorylating BLM serine 502 to inhibit BLM degradation.

    Science.gov (United States)

    Petsalaki, Eleni; Dandoulaki, Maria; Morrice, Nick; Zachos, George

    2014-09-15

    Chromatin bridges represent incompletely segregated chromosomal DNA connecting the anaphase poles and can result in chromosome breakage. The Bloom's syndrome protein helicase (BLM, also known as BLMH) suppresses formation of chromatin bridges. Here, we show that cells deficient in checkpoint kinase 1 (Chk1, also known as CHEK1) exhibit higher frequency of chromatin bridges and reduced BLM protein levels compared to controls. Chk1 inhibition leads to BLM ubiquitylation and proteasomal degradation during interphase. Furthermore, Chk1 constitutively phosphorylates human BLM at serine 502 (S502) and phosphorylated BLM localises to chromatin bridges. Mutation of S502 to a non-phosphorylatable alanine residue (BLM-S502A) reduces the stability of BLM, whereas expression of a phospho-mimicking BLM-S502D, in which S502 is mutated to aspartic acid, stabilises BLM and prevents chromatin bridges in Chk1-deficient cells. In addition, wild-type but not BLM-S502D associates with cullin 3, and cullin 3 depletion rescues BLM accumulation and localisation to chromatin bridges after Chk1 inhibition. We propose that Chk1 phosphorylates BLM-S502 to inhibit cullin-3-mediated BLM degradation during interphase. These results suggest that Chk1 prevents deleterious anaphase bridges by stabilising BLM. © 2014. Published by The Company of Biologists Ltd.

  5. Enhancement of hypoxia-activated prodrug TH-302 anti-tumor activity by Chk1 inhibition.

    Science.gov (United States)

    Meng, Fanying; Bhupathi, Deepthi; Sun, Jessica D; Liu, Qian; Ahluwalia, Dharmendra; Wang, Yan; Matteucci, Mark D; Hart, Charles P

    2015-05-21

    The hypoxia-activated prodrug TH-302 is reduced at its nitroimidazole group and selectively under hypoxic conditions releases the DNA cross-linker bromo-isophosphoramide mustard (Br-IPM). Here, we have explored the effect of Chk1 inhibition on TH-302-mediated pharmacological activities. We employed in vitro cell viability, DNA damage, cellular signaling assays and the in vivo HT29 human tumor xenograft model to study the effect of Chk1inhibition on TH-302 antitumor activities. TH-302 cytotoxicity is greatly enhanced by Chk1 inhibition in p53-deficient but not in p53-proficient human cancer cell lines. Chk1 inhibitors reduced TH-302-induced cell cycle arrest via blocking TH-302-induced decrease of phosphorylation of histone H3 and increasing Cdc2-Y15 phosphorylation. Employing the single-cell gel electrophoresis (comet) assay, we observed a potentiation of the TH-302 dependent tail moment. TH-302 induced γH2AX and apoptosis were also increased upon the addition of Chk1 inhibitor. Potentiation of TH-302 cytotoxicity by Chk1 inhibitor was only observed in cell lines proficient in, but not deficient in homology-directed DNA repair. We also show that combination treatment led to lowering of Rad51 expression levels as compared to either agent alone. In vivo data demonstrate that Chk1 inhibitor enhances TH-302 anti-tumor activity in p53 mutant HT-29 human tumor xenografts, supporting the hypothesis that these in vitro results can translate to enhanced in vivo efficacy of the combination. TH-302-mediated in vitro and in vivo anti-tumor activities were greatly enhanced by the addition of Chk1 inhibitors. The preclinical data presented in this study support a new approach for the treatment of p53-deficient hypoxic cancers by combining Chk1 inhibitors with the hypoxia-activated prodrug TH-302.

  6. Chk1 inhibition activates p53 through p38 MAPK in tetraploid cancer cells.

    Science.gov (United States)

    Vitale, Ilio; Senovilla, Laura; Galluzzi, Lorenzo; Criollo, Alfredo; Vivet, Sonia; Castedo, Maria; Kroemer, Guido

    2008-07-01

    We have previously shown that tetraploid cancer cells succumb through a p53-dependent apoptotic pathway when checkpoint kinase 1 (Chk1) is depleted by small interfering RNAs (siRNAs) or inhibited with 7-hydroxystaurosporine (UCN-01). Here, we demonstrate that Chk1 inhibition results in the activating phosphorylation of p38 mitogen-activated protein kinase (p38 MAPK). Depletion of p38 MAPK by transfection with a siRNA targeting the alpha isoform of p38 MAPK (p38alpha MAPK) abolishes the phosphorylation of p53 on serines 15 and 46 that is induced by Chk1 knockdown. The siRNA-mediated downregulation and pharmacological inhibition of p38alpha MAPK (with SB 203580) also reduces cell death induced by Chk1 knockdown or UCN-01. These results underscore the role of p38 MAPK as a pro-apoptotic kinase in the p53-dependant pathway for the therapeutic elimination of polyploidy cells.

  7. dcc Haploinsufficiency results in blunted sensitivity to cocaine enhancement of reward seeking.

    Science.gov (United States)

    Reynolds, Lauren M; Gifuni, Anthony J; McCrea, E Tess; Shizgal, Peter; Flores, Cecilia

    2016-02-01

    Mesocortical dopamine connectivity continues to mature during adolescence. This protracted development confers increased vulnerability for environmental and genetic factors to disrupt mesocortical wiring and subsequently influence responses to drugs of abuse in adulthood. The netrin-1 receptor, DCC, orchestrates medial prefrontal cortex dopamine input during adolescence and dictates the functional organization of local circuitry. Haploinsufficiency of dcc results in increased dopamine innervation to the medial prefrontal cortex, which in turn leads to resilience against the behavioral activating effects of stimulant drugs. However, whether sensitivity to the rewarding effects of drugs of abuse is also altered in dcc haploinsufficiency remains to be resolved. Here, we used the curve-shift method to measure cocaine-induced facilitation of intracranial self-stimulation (ICSS) in adult dcc haploinsufficient mice and wild-type littermates. We found that dcc haploinsufficient mice acquire ICSS behavior at comparable stimulation parameters to wild-type controls. However, cocaine-induced potentiation of ICSS is significantly blunted in dcc haploinsufficient mice. These results are consistent with decreased sensitivity to the rewarding effects of cocaine and/or decreased proclivity to invest effort in the pursuit of reward in dcc haploinsufficient mice. Moreover, these findings suggest that DCC signaling determines adult susceptibility to drug abuse most likely by controlling prefrontal cortex development in adolescence. Copyright © 2015 Elsevier B.V. All rights reserved.

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

    Science.gov (United States)

    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.

  9. The Interaction between Checkpoint Kinase 1 (Chk1) and the Minichromosome Maintenance (MCM) Complex Is Required for DNA Damage-induced Chk1 Phosphorylation*

    Science.gov (United States)

    Han, Xiangzi; Aslanian, Aaron; Fu, Kang; Tsuji, Toshiya; Zhang, Youwei

    2014-01-01

    Chk1 is an essential mediator of the DNA damage response and cell cycle checkpoint. However, how exactly Chk1 transduces the checkpoint signaling is not fully understood. Here we report the identification of the heterohexamic minichromosome maintenance (MCM) complex that interacts with Chk1 by mass spectrometry. The interaction between Chk1 and the MCM complex was reduced by DNA damage treatment. We show that the MCM complex, at least partially, contributes to the chromatin association of Chk1, allowing for immediate phosphorylation of Chk1 by ataxia telangiectasia mutated and Rad3-related (ATR) in the presence of DNA damage. Further, phosphorylation of Chk1 at ATR sites reduces the interaction between Chk1 and the MCM complex, facilitating chromatin release of phosphorylated Chk1, a critical step in the initiation and amplification of cell cycle checkpoint. Together, these data provide novel insights into the activation of Chk1 in response to DNA damage. PMID:25049228

  10. The cell-cycle checkpoint kinase Chk1 is required for mammalian homologous recombination repair

    DEFF Research Database (Denmark)

    Sørensen, Claus Storgaard; Hansen, Lasse Tengbjerg; Dziegielewski, Jaroslaw

    2005-01-01

    repair (HRR) system. Abrogation of Chk1 function with small interfering RNA or chemical antagonists inhibits HRR, leading to persistent unrepaired DNA double-strand breaks (DSBs) and cell death after replication inhibition with hydroxyurea or DNA-damage caused by camptothecin. After hydroxyurea treatment......-depleted cells failed to form RAD51 nuclear foci after exposure to hydroxyurea, and cells expressing a phosphorylation-deficient mutant RAD51(T309A) were hypersensitive to hydroxyurea. These results highlight a crucial role for the Chk1 signalling pathway in protecting cells against lethal DNA lesions...

  11. rad-Dependent response of the chk1-encoded protein kinase at the DNA damage checkpoint

    NARCIS (Netherlands)

    Walworth, N.C.; Bernards, R.A.

    1996-01-01

    Exposure of eukaryotic cells to agents that generate DNA damage results in transient arrest of progression through the cell cycle. In fission yeast, the DNA damage checkpoint associated with cell cycle arrest before mitosis requires the protein kinase p56chk1. DNA damage induced by ultraviolet

  12. Adventures in Scaffold Morphing: Discovery of Fused Ring Heterocyclic Checkpoint Kinase 1 (CHK1) Inhibitors.

    Science.gov (United States)

    Yang, Bin; Vasbinder, Melissa M; Hird, Alexander W; Su, Qibin; Wang, Haixia; Yu, Yan; Toader, Dorin; Lyne, Paul D; Read, Jon A; Breed, Jason; Ioannidis, Stephanos; Deng, Chun; Grondine, Michael; DeGrace, Nancy; Whitston, David; Brassil, Patrick; Janetka, James W

    2018-02-08

    Checkpoint kinase 1 (CHK1) inhibitors are potential cancer therapeutics that can be utilized for enhancing the efficacy of DNA damaging agents. Multiple small molecule CHK1 inhibitors from different chemical scaffolds have been developed and evaluated in clinical trials in combination with chemotherapeutics and radiation treatment. Scaffold morphing of thiophene carboxamide ureas (TCUs), such as AZD7762 (1) and a related series of triazoloquinolines (TZQs), led to the identification of fused-ring bicyclic CHK1 inhibitors, 7-carboxamide thienopyridines (7-CTPs), and 7-carboxamide indoles. X-ray crystal structures reveal a key intramolecular noncovalent sulfur-oxygen interaction in aligning the hinge-binding carboxamide group to the thienopyridine core in a coplanar fashion. An intramolecular hydrogen bond to an indole NH was also effective in locking the carboxamide in the preferred bound conformation to CHK1. Optimization on the 7-CTP series resulted in the identification of lead compound 44, which displayed respectable drug-like properties and good in vitro and in vivo potency.

  13. Inhibition of autophagy enhances DNA damage-induced apoptosis by disrupting CHK1-dependent S phase arrest

    Energy Technology Data Exchange (ETDEWEB)

    Liou, Jong-Shian; Wu, Yi-Chen; Yen, Wen-Yen; Tang, Yu-Shuan [Institute of Cellular and Organismic Biology, Academia Sinica, Taipei 115, Taiwan, ROC (China); Kakadiya, Rajesh B.; Su, Tsann-Long [Institute of Biomedical Sciences, Academia Sinica, Taipei 115, Taiwan, ROC (China); Yih, Ling-Huei, E-mail: lhyih@gate.sinica.edu.tw [Institute of Cellular and Organismic Biology, Academia Sinica, Taipei 115, Taiwan, ROC (China)

    2014-08-01

    DNA damage has been shown to induce autophagy, but the role of autophagy in the DNA damage response and cell fate is not fully understood. BO-1012, a bifunctional alkylating derivative of 3a-aza-cyclopenta[a]indene, is a potent DNA interstrand cross-linking agent with anticancer activity. In this study, BO-1012 was found to reduce DNA synthesis, inhibit S phase progression, and induce phosphorylation of histone H2AX on serine 139 (γH2AX) exclusively in S phase cells. Both CHK1 and CHK2 were phosphorylated in response to BO-1012 treatment, but only depletion of CHK1, but not CHK2, impaired BO-1012-induced S phase arrest and facilitated the entry of γH2AX-positive cells into G2 phase. CHK1 depletion also significantly enhanced BO-1012-induced cell death and apoptosis. These results indicate that BO-1012-induced S phase arrest is a CHK1-dependent pro-survival response. BO-1012 also resulted in marked induction of acidic vesicular organelle (AVO) formation and microtubule-associated protein 1 light chain 3 (LC3) processing and redistribution, features characteristic of autophagy. Depletion of ATG7 or co-treatment of cells with BO-1012 and either 3-methyladenine or bafilomycin A1, two inhibitors of autophagy, not only reduced CHK1 phosphorylation and disrupted S phase arrest, but also increased cleavage of caspase-9 and PARP, and cell death. These results suggest that cells initiate S phase arrest and autophagy as pro-survival responses to BO-1012-induced DNA damage, and that suppression of autophagy enhances BO-1012-induced apoptosis via disruption of CHK1-dependent S phase arrest. - Highlights: • Autophagy inhibitors enhanced the cytotoxicity of a DNA alkylating agent, BO-1012. • BO-1012-induced S phase arrest was a CHK1-dependent pro-survival response. • Autophagy inhibition enhanced BO-1012 cytotoxicity via disrupting the S phase arrest.

  14. Loss of CHK1 function impedes DNA damage-induced FANCD2 monoubiquitination but normalizes the abnormal G2 arrest in Fanconi anemia.

    Science.gov (United States)

    Guervilly, Jean-Hugues; Macé-Aimé, Gaëtane; Rosselli, Filippo

    2008-03-01

    Fanconi anemia (FA) is a cancer-prone hereditary disease resulting from mutations in one of the 13 genes defining the FANC/BRCA pathway. This pathway is involved in the cellular resistance to DNA-cross-linking agents. How the FANC/BRCA pathway is activated and why its deficiency leads to the accumulation of FA cells with a 4N DNA content are still poorly answered questions. We investigated the involvement of ATR pathway members in these processes. We show here that RAD9 and RAD17 are required for DNA interstrand cross-link (ICL) resistance and for the optimal activation of FANCD2. Moreover, we demonstrate that CHK1 and its interacting partner CLASPIN that act downstream in the ATR pathway are required for both FANCD2 monoubiquitination and assembling in subnuclear foci in response to DNA damage. Paradoxically, in the absence of any genotoxic stress, CHK1 or CLASPIN depletion results in an increased basal level of FANCD2 monoubiquitination and focalization. We also demonstrate that the ICL-induced accumulation of FA cells in late S/G2 phase is dependent on ATR and CHK1. In agreement with this, CHK1 phosphorylation is enhanced in FA cells, and chemical inhibition of the ATR/CHK1 axis in FA lymphoblasts decreases their sensitivity to mitomycin C. In conclusion, this work describes a complex crosstalk between CHK1 and the FANC/BRCA pathway: CHK1 activates this pathway through FANCD2 monoubiquitination, whereas FA deficiency leads to a CHK1-dependent G2 accumulation, raising the possibility that the FANC/BRCA pathway downregulates CHK1 activation.

  15. Dnmt1-dependent Chk1 pathway suppression is protective against neuron division.

    Science.gov (United States)

    Oshikawa, Mio; Okada, Kei; Tabata, Hidenori; Nagata, Koh-Ichi; Ajioka, Itsuki

    2017-09-15

    Neuronal differentiation and cell-cycle exit are tightly coordinated, even in pathological situations. When pathological neurons re-enter the cell cycle and progress through the S phase, they undergo cell death instead of division. However, the mechanisms underlying mitotic resistance are mostly unknown. Here, we have found that acute inactivation of retinoblastoma (Rb) family proteins (Rb, p107 and p130) in mouse postmitotic neurons leads to cell death after S-phase progression. Checkpoint kinase 1 (Chk1) pathway activation during the S phase prevented the cell death, and allowed the division of cortical neurons that had undergone acute Rb family inactivation, oxygen-glucose deprivation (OGD) or in vivo hypoxia-ischemia. During neurogenesis, cortical neurons became protected from S-phase Chk1 pathway activation by the DNA methyltransferase Dnmt1, and underwent cell death after S-phase progression. Our results indicate that Chk1 pathway activation overrides mitotic safeguards and uncouples neuronal differentiation from mitotic resistance. © 2017. Published by The Company of Biologists Ltd.

  16. A phospho-proteomic screen identifies substrates of the checkpoint kinase Chk1

    DEFF Research Database (Denmark)

    Blasius, Melanie; Forment, Josep V; Thakkar, Neha

    2011-01-01

    BACKGROUND: The cell-cycle checkpoint kinase Chk1 is essential in mammalian cells due to its roles in controlling processes such as DNA replication, mitosis and DNA-damage responses. Despite its paramount importance, how Chk1 controls these functions remains unclear, mainly because very few Chk1...

  17. The fork and the kinase: a DNA replication tale from a CHK1 perspective.

    Science.gov (United States)

    González Besteiro, Marina A; Gottifredi, Vanesa

    2015-01-01

    Replication fork progression is being continuously hampered by exogenously introduced and naturally occurring DNA lesions and other physical obstacles. Checkpoint kinase 1 (Chk1) is activated at replication forks that encounter damaged DNA. Subsequently, Chk1 inhibits the initiation of new replication factories and stimulates the firing of dormant origins (those in the vicinity of stalled forks). Chk1 also avoids fork collapse into DSBs (double strand breaks) and promotes fork elongation. At the molecular level, the current model considers stalled forks as the site of Chk1 activation and the nucleoplasm as the location where Chk1 phosphorylates target proteins. This model certainly serves to explain how Chk1 modulates origin firing, but how Chk1 controls the fate of stalled forks is less clear. Interestingly, recent reports demonstrating that Chk1 phosphorylates chromatin-bound proteins and even holds kinase-independent functions might shed light on how Chk1 contributes to the elongation of damaged DNA. Indeed, such findings have unveiled a puzzling connection between Chk1 and DNA lesion bypass, which might be central to promoting fork elongation and checkpoint attenuation. In summary, Chk1 is a multifaceted and versatile signaling factor that acts at ongoing forks and replication origins to determine the extent and quality of the cellular response to replication stress. Copyright © 2014 Elsevier B.V. All rights reserved.

  18. Group X hybrid histidine kinase Chk1 is dispensable for stress adaptation, host-pathogen interactions and virulence in the opportunistic yeast Candida guilliermondii.

    Science.gov (United States)

    Navarro-Arias, María J; Dementhon, Karine; Defosse, Tatiana A; Foureau, Emilien; Courdavault, Vincent; Clastre, Marc; Le Gal, Solène; Nevez, Gilles; Le Govic, Yohann; Bouchara, Jean-Philippe; Giglioli-Guivarc'h, Nathalie; Noël, Thierry; Mora-Montes, Hector M; Papon, Nicolas

    2017-09-01

    Hybrid histidine kinases (HHKs) progressively emerge as prominent sensing proteins in the fungal kingdom and as ideal targets for future therapeutics. The group X HHK is of major interest, since it was demonstrated to play an important role in stress adaptation, host-pathogen interactions and virulence in some yeast and mold models, and particularly Chk1, that corresponds to the sole group X HHK in Candida albicans. In the present work, we investigated the role of Chk1 in the low-virulence species Candida guilliermondii, in order to gain insight into putative conservation of the role of group X HHK in opportunistic yeasts. We demonstrated that disruption of the corresponding gene CHK1 does not influence growth, stress tolerance, drug susceptibility, protein glycosylation or cell wall composition in C. guilliermondii. In addition, we showed that loss of CHK1 does not affect C. guilliermondii ability to interact with macrophages and to stimulate cytokine production by human peripheral blood mononuclear cells. Finally, the C. guilliermondii chk1 null mutant was found to be as virulent as the wild-type strain in the experimental model Galleria mellonella. Taken together, our results demonstrate that group X HHK function is not conserved in Candida species. Copyright © 2017 Institut Pasteur. Published by Elsevier Masson SAS. All rights reserved.

  19. Inhibition of Chk1 by CEP-3891 accelerates mitotic nuclear fragmentation in response to ionizing Radiation

    DEFF Research Database (Denmark)

    Syljuåsen, Randi G; Sørensen, Claus Storgaard; Nylandsted, Jesper

    2004-01-01

    The human checkpoint kinase Chk1 has been suggested as a target for cancer treatment. Here, we show that a new inhibitor of Chk1 kinase, CEP-3891, efficiently abrogates both the ionizing radiation (IR)-induced S and G(2) checkpoints. When the checkpoints were abrogated by CEP-3891, the majority (64...

  20. The F box protein Fbx6 regulates Chk1 stability and cellular sensitivity to replication stress.

    Science.gov (United States)

    Zhang, You-Wei; Brognard, John; Coughlin, Chris; You, Zhongsheng; Dolled-Filhart, Marisa; Aslanian, Aaron; Manning, Gerard; Abraham, Robert T; Hunter, Tony

    2009-08-28

    ATR and Chk1 are two key protein kinases in the replication checkpoint. Activation of ATR-Chk1 has been extensively investigated, but checkpoint termination and replication fork restart are less well understood. Here, we report that DNA damage not only activates Chk1, but also exposes a degron-like region at the carboxyl terminus of Chk1 to an Fbx6-containing SCF (Skp1-Cul1-F box) E3 ligase, which mediates the ubiquitination and degradation of Chk1 and, in turn, terminates the checkpoint. The protein levels of Chk1 and Fbx6 showed an inverse correlation in both cultured cancer cells and in human breast tumor tissues. Further, we show that low levels of Fbx6 and consequent impairment of replication stress-induced Chk1 degradation are associated with cancer cell resistance to the chemotherapeutic agent, camptothecin. We propose that Fbx6-dependent Chk1 degradation contributes to S phase checkpoint termination and that a defect in this mechanism might increase tumor cell resistance to certain anticancer drugs.

  1. Berberine, a genotoxic alkaloid, induces ATM-Chk1 mediated G2 arrest in prostate cancer cells

    International Nuclear Information System (INIS)

    Wang Yu; Liu Qiao; Liu Zhaojian; Li Boxuan; Sun Zhaoliang; Zhou Haibin; Zhang Xiyu; Gong Yaoqin; Shao Changshun

    2012-01-01

    Berberine has been shown to possess anti-tumor activity against a wide spectrum of cancer cells. It inhibits cancer cell proliferation by inducing cell cycle arrest, at G1 and/or G2/M, and apoptosis. While it has been documented that berberine induces G1 arrest by activating the p53-p21 cascade, it remains unclear what mechanism underlies the berberine-induced G2/M arrest, which is p53-independent. In this study, we tested the anti-proliferative effect of berberine on murine prostate cancer cell line RM-1 and characterized the underlying mechanisms. Berberine dose-dependently induced DNA double-strand breaks and apoptosis. At low concentrations, berberine was observed to induce G1 arrest, concomitant with the activation of p53-p21 cascade. Upon exposure to berberine at a higher concentration (50 μM) for 24 h, cells exhibited G2/M arrest. Pharmacological inhibition of ATM by KU55933, or Chk1 by UCN-01, could efficiently abrogate the G2/M arrest in berberine-treated cells. Downregulation of Chk1 by RNA interference also abolished the G2/M arrest caused by berberine, confirming the role of Chk1 in the pathway leading to G2/M arrest. Abrogation of G2/M arrest by ATM inhibition forced more cells to undergo apoptosis in response to berberine treatment. Chk1 inhibition by UCN-01, on the other hand, rendered cells more sensitive to berberine only when p53 was inhibited. Our results suggest that combined administration of berberine and caffeine, or other ATM inhibitor, may accelerate the killing of cancer cells.

  2. Berberine, a genotoxic alkaloid, induces ATM-Chk1 mediated G2 arrest in prostate cancer cells

    Energy Technology Data Exchange (ETDEWEB)

    Wang Yu; Liu Qiao; Liu Zhaojian; Li Boxuan; Sun Zhaoliang; Zhou Haibin; Zhang Xiyu; Gong Yaoqin [Ministry of Education Key Laboratory of Experimental Teratology and Institute of Molecular Medicine and Genetics, Shandong University School of Medicine, Jinan (China); Shao Changshun, E-mail: changshun.shao@gmail.com [Ministry of Education Key Laboratory of Experimental Teratology and Institute of Molecular Medicine and Genetics, Shandong University School of Medicine, Jinan (China)

    2012-06-01

    Berberine has been shown to possess anti-tumor activity against a wide spectrum of cancer cells. It inhibits cancer cell proliferation by inducing cell cycle arrest, at G1 and/or G2/M, and apoptosis. While it has been documented that berberine induces G1 arrest by activating the p53-p21 cascade, it remains unclear what mechanism underlies the berberine-induced G2/M arrest, which is p53-independent. In this study, we tested the anti-proliferative effect of berberine on murine prostate cancer cell line RM-1 and characterized the underlying mechanisms. Berberine dose-dependently induced DNA double-strand breaks and apoptosis. At low concentrations, berberine was observed to induce G1 arrest, concomitant with the activation of p53-p21 cascade. Upon exposure to berberine at a higher concentration (50 {mu}M) for 24 h, cells exhibited G2/M arrest. Pharmacological inhibition of ATM by KU55933, or Chk1 by UCN-01, could efficiently abrogate the G2/M arrest in berberine-treated cells. Downregulation of Chk1 by RNA interference also abolished the G2/M arrest caused by berberine, confirming the role of Chk1 in the pathway leading to G2/M arrest. Abrogation of G2/M arrest by ATM inhibition forced more cells to undergo apoptosis in response to berberine treatment. Chk1 inhibition by UCN-01, on the other hand, rendered cells more sensitive to berberine only when p53 was inhibited. Our results suggest that combined administration of berberine and caffeine, or other ATM inhibitor, may accelerate the killing of cancer cells.

  3. Phosphorylation of Minichromosome Maintenance 3 (MCM3) by Checkpoint Kinase 1 (Chk1) Negatively Regulates DNA Replication and Checkpoint Activation.

    Science.gov (United States)

    Han, Xiangzi; Mayca Pozo, Franklin; Wisotsky, Jacob N; Wang, Benlian; Jacobberger, James W; Zhang, Youwei

    2015-05-08

    Mechanisms controlling DNA replication and replication checkpoint are critical for the maintenance of genome stability and the prevention or treatment of human cancers. Checkpoint kinase 1 (Chk1) is a key effector protein kinase that regulates the DNA damage response and replication checkpoint. The heterohexameric minichromosome maintenance (MCM) complex is the core component of mammalian DNA helicase and has been implicated in replication checkpoint activation. Here we report that Chk1 phosphorylates the MCM3 subunit of the MCM complex at Ser-205 under normal growth conditions. Mutating the Ser-205 of MCM3 to Ala increased the length of DNA replication track and shortened the S phase duration, indicating that Ser-205 phosphorylation negatively controls normal DNA replication. Upon replicative stress treatment, the inhibitory phosphorylation of MCM3 at Ser-205 was reduced, and this reduction was accompanied with the generation of single strand DNA, the key platform for ataxia telangiectasia mutated and Rad3-related (ATR) activation. As a result, the replication checkpoint is activated. Together, these data provide significant insights into the regulation of both normal DNA replication and replication checkpoint activation through the novel phosphorylation of MCM3 by Chk1. © 2015 by The American Society for Biochemistry and Molecular Biology, Inc.

  4. Effects of Chk1 inhibition on the temporal duration of radiation-induced G2 arrest in HeLa cells

    International Nuclear Information System (INIS)

    Nahar, Kamrun; Goto, Tatsuaki; Kaida, Atsushi; Deguchi, Shifumi; Miura, Masahiko

    2014-01-01

    Chk1 inhibitor acts as a potent radiosensitizer in p53-deficient tumor cells by abrogating the G2/M check-point. However, the effects of Chk1 inhibitor on the duration of G2 arrest have not been precisely analyzed. To address this issue, we utilized a cell-cycle visualization system, fluorescent ubiquitination-based cell-cycle indicator (Fucci), to analyze the change in the first green phase duration (FGPD) after irradiation. In the Fucci system, G1 and S/G2/M cells emit red and green fluorescence, respectively; therefore, G2 arrest is reflected by an elongated FGPD. The system also allowed us to differentially analyze cells that received irradiation in the red or green phase. Cells irradiated in the green phase exhibited a significantly elongated FGPD relative to cells irradiated in the red phase. In cells irradiated in either phase, Chk1 inhibitor reduced FGPD almost to control levels. The results of this study provide the first clear information regarding the effects of Chk1 inhibition on radiation-induced G2 arrest, with special focus on the time dimension. (author)

  5. Caffeine decreases phospho-Chk1 (Ser317) and increases mitotic cells with cyclin B1 and caspase 3 in tumors from UVB-treated mice.

    Science.gov (United States)

    Lu, Yao-Ping; Lou, You-Rong; Peng, Qing-Yun; Nghiem, Paul; Conney, Allan H

    2011-07-01

    Oral administration of caffeine to mice inhibits UVB-induced carcinogenesis, and these results are paralleled by epidemiology studies indicating that caffeinated coffee and tea intake (but not decaffeinated beverage intake) is associated with decreased incidence of nonmelanoma skin cancer. Topical applications of caffeine to the skin of SKH-1 mice that had previously been treated with UVB inhibited subsequent skin tumor development and stimulated apoptosis in tumors but not in nontumor areas of the epidermis. This study sought to determine the basis of these differential effects on tumor versus nontumor sites that can be induced by caffeine, long after all UVB treatment has ceased. The activation status of the ATR/Chk1 pathway in UVB-induced tumors and uninvolved skin was determined by quantitating phospho-Chk1 (Ser317) and induction of lethal mitosis in vivo in the presence and absence of topical caffeine treatment. In the absence of caffeine, we found that UVB-induced tumors often had islands of phospho-Chk1 (Ser317) staining cells that were not present in nontumor areas of the epidermis. Treatment of mice with topical caffeine significantly diminished phospho-Chk1 (Ser317) staining and increased the number of mitotic cells that expressed cyclin B1 and caspase 3 in tumors, consistent with caffeine-induced lethal mitosis selectively in tumors. We hypothesize that compared with adjacent uninvolved skin, UVB-induced skin tumors have elevated activation of, and dependence on, the ATR/Chk1 pathway long after UVB exposure has ceased and that caffeine can induce apoptosis selectively in tumors by inhibiting this pathway and promoting lethal mitosis.

  6. NSC30049 inhibits Chk1 pathway in 5-FU-resistant CRC bulk and stem cell populations.

    Science.gov (United States)

    Narayan, Satya; Jaiswal, Aruna S; Sharma, Ritika; Nawab, Akbar; Duckworth, Lizette Vila; Law, Brian K; Zajac-Kaye, Maria; George, Thomas J; Sharma, Jay; Sharma, Arun K; Hromas, Robert A

    2017-08-22

    The 5-fluorouracil (5-FU) treatment induces DNA damage and stalling of DNA replication forks. These stalled replication forks then collapse to form one sided double-strand breaks, leading to apoptosis. However, colorectal cancer (CRC) stem cells rapidly repair the stalled/collapsed replication forks and overcome treatment effects. Recent evidence suggests a critical role of checkpoint kinase 1 (Chk1) in preventing the replicative stress. Therefore, Chk1 kinase has been a target for developing mono or combination therapeutic agents. In the present study, we have identified a novel orphan molecule NSC30049 (NSC49L) that is effective alone, and in combination potentiates 5-FU-mediated growth inhibition of CRC heterogeneous bulk and FOLFOX-resistant cell lines in culture with minimal effect on normal colonic epithelial cells. It also inhibits the sphere forming activity of CRC stem cells, and decreases the expression levels of mRNAs of CRC stem cell marker genes. Results showed that NSC49L induces 5-FU-mediated S-phase cell cycle arrest due to increased load of DNA damage and increased γ-H2AX staining as a mechanism of cytotoxicity. The pharmacokinetic analysis showed a higher bioavailability of this compound, however, with a short plasma half-life. The drug is highly tolerated by animals with no pathological aberrations. Furthermore, NSC49L showed very potent activity in a HDTX model of CRC stem cell tumors either alone or in combination with 5-FU. Thus, NSC49L as a single agent or combined with 5-FU can be developed as a therapeutic agent by targeting the Chk1 pathway in 5-FU-resistant CRC heterogeneous bulk and CRC stem cell populations.

  7. Cell Density Affects the Detection of Chk1 Target Engagement by the Selective Inhibitor V158411.

    Science.gov (United States)

    Geneste, Clara C; Massey, Andrew J

    2018-02-01

    Understanding drug target engagement and the relationship to downstream pharmacology is critical for drug discovery. Here we have evaluated target engagement of Chk1 by the small-molecule inhibitor V158411 using two different target engagement methods (autophosphorylation and cellular thermal shift assay [CETSA]). Target engagement measured by these methods was subsequently related to Chk1 inhibitor-dependent pharmacology. Inhibition of autophosphorylation was a robust method for measuring V158411 Chk1 target engagement. In comparison, while target engagement determined using CETSA appeared robust, the V158411 CETSA target engagement EC 50 values were 43- and 19-fold greater than the autophosphorylation IC 50 values. This difference was attributed to the higher cell density in the CETSA assay configuration. pChk1 (S296) IC 50 values determined using the CETSA assay conditions were 54- and 33-fold greater than those determined under standard conditions and were equivalent to the CETSA EC 50 values. Cellular conditions, especially cell density, influenced the target engagement of V158411 for Chk1. The effects of high cell density on apparent compound target engagement potency should be evaluated when using target engagement assays that necessitate high cell densities (such as the CETSA conditions used in this study). In such cases, the subsequent relation of these data to downstream pharmacological changes should therefore be interpreted with care.

  8. Structure-guided evolution of potent and selective CHK1 inhibitors through scaffold morphing.

    Science.gov (United States)

    Reader, John C; Matthews, Thomas P; Klair, Suki; Cheung, Kwai-Ming J; Scanlon, Jane; Proisy, Nicolas; Addison, Glynn; Ellard, John; Piton, Nelly; Taylor, Suzanne; Cherry, Michael; Fisher, Martin; Boxall, Kathy; Burns, Samantha; Walton, Michael I; Westwood, Isaac M; Hayes, Angela; Eve, Paul; Valenti, Melanie; de Haven Brandon, Alexis; Box, Gary; van Montfort, Rob L M; Williams, David H; Aherne, G Wynne; Raynaud, Florence I; Eccles, Suzanne A; Garrett, Michelle D; Collins, Ian

    2011-12-22

    Pyrazolopyridine inhibitors with low micromolar potency for CHK1 and good selectivity against CHK2 were previously identified by fragment-based screening. The optimization of the pyrazolopyridines to a series of potent and CHK1-selective isoquinolines demonstrates how fragment-growing and scaffold morphing strategies arising from a structure-based understanding of CHK1 inhibitor binding can be combined to successfully progress fragment-derived hit matter to compounds with activity in vivo. The challenges of improving CHK1 potency and selectivity, addressing synthetic tractability, and achieving novelty in the crowded kinase inhibitor chemical space were tackled by multiple scaffold morphing steps, which progressed through tricyclic pyrimido[2,3-b]azaindoles to N-(pyrazin-2-yl)pyrimidin-4-amines and ultimately to imidazo[4,5-c]pyridines and isoquinolines. A potent and highly selective isoquinoline CHK1 inhibitor (SAR-020106) was identified, which potentiated the efficacies of irinotecan and gemcitabine in SW620 human colon carcinoma xenografts in nude mice.

  9. NEK11: linking CHK1 and CDC25A in DNA damage checkpoint signaling

    DEFF Research Database (Denmark)

    Sørensen, Claus Storgaard; Melixetian, Marina; Klein, Ditte Kjaersgaard

    2010-01-01

    The DNA damage induced G(2)/M checkpoint is an important guardian of the genome that prevents cell division when DNA lesions are present. The checkpoint prevents cells from entering mitosis by degrading CDC25A, a key CDK activator. CDC25A proteolysis is controlled by direct phosphorylation events...... is required for beta-TrCP mediated CDC25A polyubiquitylation and degradation. The activity of NEK11 is in turn controlled by CHK1 that activates NEK11 via phosphorylation on serine 273. Since inhibition of NEK11 activity forces checkpoint-arrested cells into mitosis and cell death, NEK11 is, like CHK1...

  10. Toxic effect of silica nanoparticles on endothelial cells through DNA damage response via Chk1-dependent G2/M checkpoint.

    Directory of Open Access Journals (Sweden)

    Junchao Duan

    Full Text Available Silica nanoparticles have become promising carriers for drug delivery or gene therapy. Endothelial cells could be directly exposed to silica nanoparticles by intravenous administration. However, the underlying toxic effect mechanisms of silica nanoparticles on endothelial cells are still poorly understood. In order to clarify the cytotoxicity of endothelial cells induced by silica nanoparticles and its mechanisms, cellular morphology, cell viability and lactate dehydrogenase (LDH release were observed in human umbilical vein endothelial cells (HUVECs as assessing cytotoxicity, resulted in a dose- and time- dependent manner. Silica nanoparticles-induced reactive oxygen species (ROS generation caused oxidative damage followed by the production of malondialdehyde (MDA as well as the inhibition of superoxide dismutase (SOD and glutathione peroxidase (GSH-Px. Both necrosis and apoptosis were increased significantly after 24 h exposure. The mitochondrial membrane potential (MMP decreased obviously in a dose-dependent manner. The degree of DNA damage including the percentage of tail DNA, tail length and Olive tail moment (OTM were markedly aggravated. Silica nanoparticles also induced G2/M arrest through the upregulation of Chk1 and the downregulation of Cdc25C, cyclin B1/Cdc2. In summary, our data indicated that the toxic effect mechanisms of silica nanoparticles on endothelial cells was through DNA damage response (DDR via Chk1-dependent G2/M checkpoint signaling pathway, suggesting that exposure to silica nanoparticles could be a potential hazards for the development of cardiovascular diseases.

  11. Sensitization of human cancer cells to gemcitabine by the Chk1 inhibitor MK-8776: cell cycle perturbation and impact of administration schedule in vitro and in vivo

    International Nuclear Information System (INIS)

    Montano, Ryan; Thompson, Ruth; Chung, Injae; Hou, Huagang; Khan, Nadeem; Eastman, Alan

    2013-01-01

    addition of MK-8776 enhances sensitivity to gemcitabine: first, there is an increased number of cells arrested in S phase; and second, the arrested cells have adequate time to initiate recombination and thereby become Chk1 dependent. These results have important implications for the design of clinical trials using this drug combination

  12. A ruthenium polypyridyl intercalator stalls DNA replication forks, radiosensitizes human cancer cells and is enhanced by Chk1 inhibition

    Science.gov (United States)

    Gill, Martin R.; Harun, Siti Norain; Halder, Swagata; Boghozian, Ramon A.; Ramadan, Kristijan; Ahmad, Haslina; Vallis, Katherine A.

    2016-08-01

    Ruthenium(II) polypyridyl complexes can intercalate DNA with high affinity and prevent cell proliferation; however, the direct impact of ruthenium-based intercalation on cellular DNA replication remains unknown. Here we show the multi-intercalator [Ru(dppz)2(PIP)]2+ (dppz = dipyridophenazine, PIP = 2-(phenyl)imidazo[4,5-f][1,10]phenanthroline) immediately stalls replication fork progression in HeLa human cervical cancer cells. In response to this replication blockade, the DNA damage response (DDR) cell signalling network is activated, with checkpoint kinase 1 (Chk1) activation indicating prolonged replication-associated DNA damage, and cell proliferation is inhibited by G1-S cell-cycle arrest. Co-incubation with a Chk1 inhibitor achieves synergistic apoptosis in cancer cells, with a significant increase in phospho(Ser139) histone H2AX (γ-H2AX) levels and foci indicating increased conversion of stalled replication forks to double-strand breaks (DSBs). Normal human epithelial cells remain unaffected by this concurrent treatment. Furthermore, pre-treatment of HeLa cells with [Ru(dppz)2(PIP)]2+ before external beam ionising radiation results in a supra-additive decrease in cell survival accompanied by increased γ-H2AX expression, indicating the compound functions as a radiosensitizer. Together, these results indicate ruthenium-based intercalation can block replication fork progression and demonstrate how these DNA-binding agents may be combined with DDR inhibitors or ionising radiation to achieve more efficient cancer cell killing.

  13. Reconstitution of RPA-covered single-stranded DNA-activated ATR-Chk1 signaling.

    Science.gov (United States)

    Choi, Jun-Hyuk; Lindsey-Boltz, Laura A; Kemp, Michael; Mason, Aaron C; Wold, Marc S; Sancar, Aziz

    2010-08-03

    ATR kinase is a critical upstream regulator of the checkpoint response to various forms of DNA damage. Previous studies have shown that ATR is recruited via its binding partner ATR-interacting protein (ATRIP) to replication protein A (RPA)-covered single-stranded DNA (RPA-ssDNA) generated at sites of DNA damage where ATR is then activated by TopBP1 to phosphorylate downstream targets including the Chk1 signal transducing kinase. However, this critical feature of the human ATR-initiated DNA damage checkpoint signaling has not been demonstrated in a defined system. Here we describe an in vitro checkpoint system in which RPA-ssDNA and TopBP1 are essential for phosphorylation of Chk1 by the purified ATR-ATRIP complex. Checkpoint defective RPA mutants fail to activate ATR kinase in this system, supporting the conclusion that this system is a faithful representation of the in vivo reaction. Interestingly, we find that an alternative form of RPA (aRPA), which does not support DNA replication, can substitute for the checkpoint function of RPA in vitro, thus revealing a potential role for aRPA in the activation of ATR kinase. We also find that TopBP1 is recruited to RPA-ssDNA in a manner dependent on ATRIP and that the N terminus of TopBP1 is required for efficient recruitment and activation of ATR kinase.

  14. Prevalence of SHOX Haploinsufficiency among Short Statured Children

    DEFF Research Database (Denmark)

    Marstrand-Joergensen, Maja Rou; Beck Jensen, Rikke; Aksglaede, Lise

    2017-01-01

    were recorded for patients with SHOX haploinsufficiency. RESULTS: Thirty-two patients were excluded due to Turner syndrome (n=28), SRY-positive 46,XX male karyotype (n=1), or lacked clinical follow-up information (n=3).The prevalence of SHOX haploinsufficiency was nine out of 542 (1.7%). The nine......=0.046, after one year of GH treatment. CONCLUSION: The prevalence of SHOX haploinsufficiency was 1.7%. The clinical findings indicating SHOX haploinsufficiency among the nine children were disproportionate short stature and forearm anomalies....

  15. Activation of CHK1 in Supporting Cells Indirectly Promotes Hair Cell Survival

    Directory of Open Access Journals (Sweden)

    Azadeh Jadali

    2017-05-01

    Full Text Available The sensory hair cells of the inner ear are exquisitely sensitive to ototoxic insults. Loss of hair cells after exposure to ototoxic agents causes hearing loss. Chemotherapeutic agents such as cisplatin causes hair cell loss. Cisplatin forms DNA mono-adducts as well as intra- and inter-strand DNA crosslinks. DNA cisplatin adducts are repaired through the DNA damage response. The decision between cell survival and cell death following DNA damage rests on factors that are involved in determining damage tolerance, cell survival and apoptosis. Cisplatin damage on hair cells has been the main focus of many ototoxic studies, yet the effect of cisplatin on supporting cells has been largely ignored. In this study, the effects of DNA damage response in cochlear supporting cells were interrogated. Supporting cells play a major role in the development, maintenance and oto-protection of hair cells. Loss of supporting cells may indirectly affect hair cell survival or maintenance. Activation of the Phosphoinositide 3-Kinase (PI3K signaling was previously shown to promote hair cell survival. To test whether activating PI3K signaling promotes supporting cell survival after cisplatin damage, cochlear explants from the neural subset (NS Cre Pten conditional knockout mice were employed. Deletion of Phosphatase and Tensin Homolog (PTEN activates PI3K signaling in multiple cell types within the cochlea. Supporting cells lacking PTEN showed increased cell survival after cisplatin damage. Supporting cells lacking PTEN also showed increased phosphorylation of Checkpoint Kinase 1 (CHK1 levels after cisplatin damage. Nearest neighbor analysis showed increased numbers of supporting cells with activated PI3K signaling in close proximity to surviving hair cells in cisplatin damaged cochleae. We propose that increased PI3K signaling promotes supporting cell survival through phosphorylation of CHK1 and increased survival of supporting cells indirectly increases hair cell

  16. The depletion of ATM inhibits colon cancer proliferation and migration via B56γ2-mediated Chk1/p53/CD44 cascades.

    Science.gov (United States)

    Liu, Rui; Tang, Jiajia; Ding, Chaodong; Liang, Weicheng; Zhang, Li; Chen, Tianke; Xiong, Yan; Dai, Xiaowei; Li, Wenfeng; Xu, Yunsheng; Hu, Jin; Lu, Liting; Liao, Wanqin; Lu, Xincheng

    2017-04-01

    Ataxia-telangiectasia mutated (ATM) protein kinase is a major guardian of genomic stability, and its well-established function in cancer is tumor suppression. Here, we report an oncogenic role of ATM. Using two isogenic sets of human colon cancer cell lines that differed only in their ATM status, we demonstrated that ATM deficiency significantly inhibits cancer cell proliferation, migration, and invasion. The tumor-suppressive function of ATM depletion is not modulated by the compensatory activation of ATR, but it is associated with B56γ2-mediated Chk1/p53/CD44 signaling pathways. Under normal growth conditions, the depletion of ATM prevents B56γ2 ubiquitination and degradation, which activates PP2A-mediated Chk1/p53/p21 signaling pathways, leading to senescence and cell cycle arrest. CD44 was validated as a novel ATM target based on its ability to rescue cell migration and invasion defects in ATM-depleted cells. The activation of p53 induced by ATM depletion suppresses CD44 transcription, thus resulting in epithelial-mesenchymal transition (EMT) and cell migration suppression. Our study suggests that ATM has tumorigenic potential in post-formed colon neoplasia, and it supports ATM as an appealing target for improving cancer therapy. Copyright © 2017 Elsevier B.V. All rights reserved.

  17. Circumvention of Mcl-1-dependent drug resistance by simultaneous Chk1 and MEK1/2 inhibition in human multiple myeloma cells.

    Science.gov (United States)

    Pei, Xin-Yan; Dai, Yun; Felthousen, Jessica; Chen, Shuang; Takabatake, Yukie; Zhou, Liang; Youssefian, Leena E; Sanderson, Michael W; Bodie, Wesley W; Kramer, Lora B; Orlowski, Robert Z; Grant, Steven

    2014-01-01

    The anti-apoptotic protein Mcl-1 plays a major role in multiple myeloma (MM) cell survival as well as bortezomib- and microenvironmental forms of drug resistance in this disease. Consequently, there is a critical need for strategies capable of targeting Mcl-1-dependent drug resistance in MM. The present results indicate that a regimen combining Chk1 with MEK1/2 inhibitors effectively kills cells displaying multiple forms of drug resistance stemming from Mcl-1 up-regulation in association with direct transcriptional Mcl-1 down-regulation and indirect disabling of Mcl-1 anti-apoptotic function through Bim up-regulation and increased Bim/Mcl-1 binding. These actions release Bak from Mcl-1, accompanied by Bak/Bax activation. Analogous events were observed in both drug-naïve and acquired bortezomib-resistant MM cells displaying increased Mcl-1 but diminished Bim expression, or cells ectopically expressing Mcl-1. Moreover, concomitant Chk1 and MEK1/2 inhibition blocked Mcl-1 up-regulation induced by IL-6/IGF-1 or co-culture with stromal cells, effectively overcoming microenvironment-related drug resistance. Finally, this regimen down-regulated Mcl-1 and robustly killed primary CD138+ MM cells, but not normal hematopoietic cells. Together, these findings provide novel evidence that this targeted combination strategy could be effective in the setting of multiple forms of Mcl-1-related drug resistance in MM.

  18. Circumvention of Mcl-1-dependent drug resistance by simultaneous Chk1 and MEK1/2 inhibition in human multiple myeloma cells.

    Directory of Open Access Journals (Sweden)

    Xin-Yan Pei

    Full Text Available The anti-apoptotic protein Mcl-1 plays a major role in multiple myeloma (MM cell survival as well as bortezomib- and microenvironmental forms of drug resistance in this disease. Consequently, there is a critical need for strategies capable of targeting Mcl-1-dependent drug resistance in MM. The present results indicate that a regimen combining Chk1 with MEK1/2 inhibitors effectively kills cells displaying multiple forms of drug resistance stemming from Mcl-1 up-regulation in association with direct transcriptional Mcl-1 down-regulation and indirect disabling of Mcl-1 anti-apoptotic function through Bim up-regulation and increased Bim/Mcl-1 binding. These actions release Bak from Mcl-1, accompanied by Bak/Bax activation. Analogous events were observed in both drug-naïve and acquired bortezomib-resistant MM cells displaying increased Mcl-1 but diminished Bim expression, or cells ectopically expressing Mcl-1. Moreover, concomitant Chk1 and MEK1/2 inhibition blocked Mcl-1 up-regulation induced by IL-6/IGF-1 or co-culture with stromal cells, effectively overcoming microenvironment-related drug resistance. Finally, this regimen down-regulated Mcl-1 and robustly killed primary CD138+ MM cells, but not normal hematopoietic cells. Together, these findings provide novel evidence that this targeted combination strategy could be effective in the setting of multiple forms of Mcl-1-related drug resistance in MM.

  19. HMGA2 Inhibits Apoptosis through Interaction with ATR-CHK1 Signaling Complex in Human Cancer Cells

    Directory of Open Access Journals (Sweden)

    Suchitra Natarajan

    2013-03-01

    Full Text Available The non-histone chromatin binding protein high mobility group AT-hook 2 (HMGA2 is expressed in stem cells and many cancer cells, including tumor initiating cells, but not translated in normal human somatic cells. The presence of HMGA2 is correlated with advanced neoplastic disease and poor prognosis for patients. We had previously demonstrated a role of HMGA2 in DNA repair pathways. In the present study, we employed different human tumor cell models with endogenous and exogenous expression of HMGA2 and show that upon DNA damage, the presence of HMGA2 caused an increased and sustained phosphorylation of the ataxia telangiectasia and Rad3-related kinase (ATR and its downstream target checkpoint kinase 1 (CHK1. The presence of activated pCHK1Ser296 coincided with prolonged G2/M block and increased tumor cell survival, which was enhanced further in the presence of HMGA2. Our study, thus, identifies a novel relationship between the ATR-CHK1 DNA damage response pathway and HMGA2, which may support the DNA repair function of HMGA2 in cancer cells. Furthermore, our data provide a rationale for the use of inhibitors to ATR or CHK1 and HMGA2 in the treatment of HMGA2-positive human cancer cells.

  20. Chk1 regulates the S phase checkpoint by coupling the physiological turnover and ionizing radiation-induced accelerated proteolysis of Cdc25A

    DEFF Research Database (Denmark)

    Sørensen, Claus Storgaard; Syljuåsen, Randi G; Falck, Jacob

    2003-01-01

    Chk1 kinase coordinates cell cycle progression and preserves genome integrity. Here, we show that chemical or genetic ablation of human Chk1 triggered supraphysiological accumulation of the S phase-promoting Cdc25A phosphatase, prevented ionizing radiation (IR)-induced degradation of Cdc25A...

  1. Ataxia-telangiectasia-mutated (ATM) and NBS1-dependent phosphorylation of Chk1 on Ser-317 in response to ionizing radiation

    DEFF Research Database (Denmark)

    Gatei, Magtouf; Sloper, Katie; Sørensen, Claus Storgaard

    2003-01-01

    . In mammalian cells, evidence has been presented that Chk1 is devoted to the ATR signaling pathway and is modified by ATR in response to replication inhibition and UV-induced damage, whereas Chk2 functions primarily through ATM in response to ionizing radiation (IR), suggesting that Chk2 and Chk1 might have...

  2. Jaridonin-induced G2/M phase arrest in human esophageal cancer cells is caused by reactive oxygen species-dependent Cdc2-tyr15 phosphorylation via ATM–Chk1/2–Cdc25C pathway

    Energy Technology Data Exchange (ETDEWEB)

    Ma, Yong-Cheng [Clinical Pharmacology Laboratory, Henan Province People' s Hospital, No. 7, Wei Wu Road, Zhengzhou, Henan (China); Su, Nan [Department of Quality Detection and Management, Henan University of Animal Husbandry and Economy, Zhengzhou, Henan (China); Shi, Xiao-Jing; Zhao, Wen; Ke, Yu [School of Pharmaceutical Sciences, Zhengzhou University, No. 100, Science Avenue, Zhengzhou, Henan (China); Zi, Xiaolin [Department of Urology, University of California, Irvine, Orange, CA (United States); Department of Pharmacology, University of California, Irvine, Orange, CA (United States); Department of Pharmaceutical Sciences, University of California, Irvine, Orange, CA (United States); Zhao, Ning-Min; Qin, Yu-Hua; Zhao, Hong-Wei [Clinical Pharmacology Laboratory, Henan Province People' s Hospital, No. 7, Wei Wu Road, Zhengzhou, Henan (China); Liu, Hong-Min, E-mail: liuhm@zzu.edu.cn [School of Pharmaceutical Sciences, Zhengzhou University, No. 100, Science Avenue, Zhengzhou, Henan (China)

    2015-01-15

    Jaridonin, a novel diterpenoid from Isodon rubescens, has been shown previously to inhibit proliferation of esophageal squamous cancer cells (ESCC) through G2/M phase cell cycle arrest. However, the involved mechanism is not fully understood. In this study, we found that the cell cycle arrest by Jaridonin was associated with the increased expression of phosphorylation of ATM at Ser1981 and Cdc2 at Tyr15. Jaridonin also resulted in enhanced phosphorylation of Cdc25C via the activation of checkpoint kinases Chk1 and Chk2, as well as in increased phospho-H2A.X (Ser139), which is known to be phosphorylated by ATM in response to DNA damage. Furthermore, Jaridonin-mediated alterations in cell cycle arrest were significantly attenuated in the presence of NAC, implicating the involvement of ROS in Jaridonin's effects. On the other hand, addition of ATM inhibitors reversed Jaridonin-related activation of ATM and Chk1/2 as well as phosphorylation of Cdc25C, Cdc2 and H2A.X and G2/M phase arrest. In conclusion, these findings identified that Jaridonin-induced cell cycle arrest in human esophageal cancer cells is associated with ROS-mediated activation of ATM–Chk1/2–Cdc25C pathway. - Highlights: • Jaridonin induced G2/M phase arrest through induction of redox imbalance. • Jaridonin increased the level of ROS through depleting glutathione in cell. • ATM–Chk1/2–Cdc25C were involved in Jaridonin-induced cell cycle arrest. • Jaridonin selectively inhibited cancer cell viability and cell cycle progression.

  3. Fisetin induces G2/M phase cell cycle arrest by inactivating cdc25C-cdc2 via ATM-Chk1/2 activation in human endometrial cancer cells

    Directory of Open Access Journals (Sweden)

    Zhan-Ying Wang

    2015-06-01

    Full Text Available Endometrial cancer is one of the most prevalent gynaecological malignancies where, currently available therapeutic options remain limited. Recently phytochemicals are exploited for their efficiency in cancer therapy. The present study investigates the anti-proliferative effect of fisetin, a flavonoid on human endometrial cancer cells (KLE and Hec1 A. Fisetin (20-100 µM effectively reduced the viability of Hec1 A and KLE cells and potentially altered the cell population at G2/M stage. Expression levels of the cell cycle proteins (cyclin B1, p-Cdc2, p-Cdc25C, p-Chk1, Chk2, p-ATM, cyclin B1, H2AX, p21 and p27 were analyzed. Fisetin suppressed cyclin B1 expression and caused inactiva-tion of Cdc25C and Cdc2 by increasing their phosphorylation levels and further activated ATM, Chk1 and Chk2. Increased levels of p21 and p27 were observed as well. These results suggest that fisetin induced G2/M cell cycle arrest via inactivating Cdc25c and Cdc2 through activation of ATM, Chk1 and Chk2.

  4. The kinase domain residue serine 173 of Schizosaccharomyces pombe Chk1 kinase is critical for the response to DNA replication stress

    Directory of Open Access Journals (Sweden)

    Naomi Coulton

    2017-12-01

    Full Text Available While mammalian Chk1 kinase regulates replication origins, safeguards fork integrity and promotes fork progression, yeast Chk1 acts only in G1 and G2. We report here that the mutation of serine 173 (S173A in the kinase domain of fission yeast Chk1 abolishes the G1-M and S-M checkpoints with little impact on the G2-M arrest. This separation-of-function mutation strongly reduces the Rad3-dependent phosphorylation of Chk1 at serine 345 during logarithmic growth, but not when cells experience exogenous DNA damage. Loss of S173 lowers the restrictive temperature of a catalytic DNA polymerase epsilon mutant (cdc20.M10 and is epistatic with a mutation in DNA polymerase delta (cdc6.23 when DNA is alkylated by methyl-methanesulfate (MMS. The chk1-S173A allele is uniquely sensitive to high MMS concentrations where it displays a partial checkpoint defect. A complete checkpoint defect occurs only when DNA replication forks break in cells without the intra-S phase checkpoint kinase Cds1. Chk1-S173A is also unable to block mitosis when the G1 transcription factor Cdc10 (cdc10.V50 is impaired. We conclude that serine 173, which is equivalent to lysine 166 in the activation loop of human Chk1, is only critical in DNA polymerase mutants or when forks collapse in the absence of Cds1.

  5. Mechanistic Distinctions between CHK1 and WEE1 Inhibition Guide the Scheduling of Triple Therapy with Gemcitabine.

    Science.gov (United States)

    Koh, Siang-Boon; Wallez, Yann; Dunlop, Charles R; Bernaldo de Quirós Fernández, Sandra; Bapiro, Tashinga E; Richards, Frances M; Jodrell, Duncan I

    2018-06-01

    Combination of cytotoxic therapy with emerging DNA damage response inhibitors (DDRi) has been limited by tolerability issues. However, the goal of most combination trials has been to administer DDRi with standard-of-care doses of chemotherapy. We hypothesized that mechanism-guided treatment scheduling could reduce the incidence of dose-limiting toxicities and enable tolerable multitherapeutic regimens. Integrative analyses of mathematical modeling and single-cell assays distinguished the synergy kinetics of WEE1 inhibitor (WEE1i) from CHEK1 inhibitor (CHK1i) by potency, spatiotemporal perturbation, and mitotic effects when combined with gemcitabine. These divergent properties collectively supported a triple-agent strategy, whereby a pulse of gemcitabine and CHK1i followed by WEE1i durably suppressed tumor cell growth. In xenografts, CHK1i exaggerated replication stress without mitotic CDK hyperactivation, enriching a geminin-positive subpopulation and intratumoral gemcitabine metabolite. Without overt toxicity, addition of WEE1i to low-dose gemcitabine and CHK1i was most effective in tumor control compared with single and double agents. Overall, our work provides quantitative insights into the mechanisms of DDRi chemosensitization, leading to the rational development of a tolerable multitherapeutic regimen. Significance: Multiple lines of mechanistic insight regarding DNA damage response inhibitors rationally guide the preclinical development of a tolerable multitherapeutic regimen. Graphical Abstract: http://cancerres.aacrjournals.org/content/canres/78/11/3054/F1.large.jpg Cancer Res; 78(11); 3054-66. ©2018 AACR . ©2018 American Association for Cancer Research.

  6. Cytokinetically quiescent (G0/G1) human multiple myeloma cells are susceptible to simultaneous inhibition of Chk1 and MEK1/2.

    Science.gov (United States)

    Pei, Xin-Yan; Dai, Yun; Youssefian, Leena E; Chen, Shuang; Bodie, Wesley W; Takabatake, Yukie; Felthousen, Jessica; Almenara, Jorge A; Kramer, Lora B; Dent, Paul; Grant, Steven

    2011-11-10

    Effects of Chk1 and MEK1/2 inhibition were investigated in cytokinetically quiescent multiple myeloma (MM) and primary CD138(+) cells. Coexposure to the Chk1 and MEK1/2 inhibitors AZD7762 and selumetinib (AZD6244) robustly induced apoptosis in various MM cells and CD138(+) primary samples, but spared normal CD138(-) and CD34(+) cells. Furthermore, Chk1/MEK1/2 inhibitor treatment of asynchronized cells induced G(0)/G(1) arrest and increased apoptosis in all cell-cycle phases, including G(0)/G(1). To determine whether this regimen is active against quiescent G(0)/G(1) MM cells, cells were cultured in low-serum medium to enrich the G(0)/G(1) population. G(0)/G(1)-enriched cells exhibited diminished sensitivity to conventional agents (eg, Taxol and VP-16) but significantly increased susceptibility to Chk1 ± MEK1/2 inhibitors or Chk1 shRNA knock-down. These events were associated with increased γH2A.X expression/foci formation and Bim up-regulation, whereas Bim shRNA knock-down markedly attenuated lethality. Immunofluorescent analysis of G(0)/G(1)-enriched or primary MM cells demonstrated colocalization of activated caspase-3 and the quiescent (G(0)) marker statin, a nuclear envelope protein. Finally, Chk1/MEK1/2 inhibition increased cell death in the Hoechst-positive (Hst(+)), low pyronin Y (PY)-staining (2N Hst(+)/PY(-)) G(0) population and in sorted small side-population (SSP) MM cells. These findings provide evidence that cytokinetically quiescent MM cells are highly susceptible to simultaneous Chk1 and MEK1/2 inhibition.

  7. ATR-Chk1-APC/C-dependent stabilization of Cdc7-ASK (Dbf4) kinase is required for DNA lesion bypass under replication stress

    DEFF Research Database (Denmark)

    Yamada, M.; Watanabe, K.; Mistrik, M.

    2013-01-01

    replication. Stalled DNA replication evoked stabilization of the Cdc7-ASK (Dbf4) complex in a manner dependent on ATR-Chk1-mediated checkpoint signaling and its interplay with the anaphase-promoting complex/cyclosomeCdh1 (APC/C) ubiquitin ligase. Mechanistically, Chk1 kinase inactivates APC/C through...... degradation of Cdh1 upon replication block, thereby stabilizing APC/C substrates, including Cdc7-ASK (Dbf4). Furthermore, motif C of ASK (Dbf4) interacts with the N-terminal region of RAD18 ubiquitin ligase, and this interaction is required for chromatin binding of RAD18. Impaired interaction of ASK (Dbf4...

  8. Synthesis and Profiling of a Novel Potent Selective Inhibitor of CHK1 Kinase Possessing Unusual N-trifluoromethylpyrazole Pharmacophore Resistant to Metabolic N-dealkylation

    Czech Academy of Sciences Publication Activity Database

    Samadder, P.; Suchánková, Tereza; Hylse, O.; Khirsariya, P.; Nikulenkov, F.; Drápela, Stanislav; Straková, Nicol; Vaňhara, P.; Vašíčková, K.; Kolářová, H.; Binó, Lucia; Bittová, M.; Ovesná, P.; Kollár, P.; Fedr, Radek; Esner, M.; Jaros, J.; Hampl, A.; Krejčí, L.; Paruch, K.; Souček, Karel

    2017-01-01

    Roč. 16, č. 9 (2017), s. 1831-1842 ISSN 1535-7163 R&D Projects: GA MZd(CZ) NV15-33999A Institutional support: RVO:68081707 Keywords : therapeutic-efficacy * protein-kinases * targeting chk1 * cancer-therapy Subject RIV: FD - Oncology ; Hematology OBOR OECD: Oncology Impact factor: 5.764, year: 2016

  9. Discovery of pyrazolo[1,5-a]pyrimidine-based CHK1 inhibitors: A template-based approach-Part 2

    Energy Technology Data Exchange (ETDEWEB)

    Labroli, Marc; Paruch, Kamil; Dwyer, Michael P.; Alvarez, Carmen; Keertikar, Kartik; Poker, Cory; Rossman, Randall; Duca, Jose S.; Fischmann, Thierry O.; Madison, Vincent; Parry, David; Davis, Nicole; Seghezzi, Wolfgang; Wiswell, Derek; Guzi, Timothy J. [Merck

    2013-11-20

    Previous efforts by our group have established pyrazolo[1,5-a]pyrimidine as a viable core for the development of potent and selective CDK inhibitors. As part of an effort to utilize the pyrazolo[1,5-a]pyrimidine core as a template for the design and synthesis of potent and selective kinase inhibitors, we focused on a key regulator in the cell cycle progression, CHK1. Continued SAR development of the pyrazolo[1,5-a]pyrimidine core at the C5 and C6 positions, in conjunction with previously disclosed SAR at the C3 and C7 positions, led to the discovery of potent and selective CHK1 inhibitors.

  10. Blocking CHK1 Expression Induces Apoptosis and Abrogates the G2 Checkpoint Mechanism

    Directory of Open Access Journals (Sweden)

    Yan Luo

    2001-01-01

    Full Text Available Checkpoint kinase 1 (Chki is a checkpoint gene that is activated after DNA damage. It phosphorylates and inactivates the Cdc2 activating phosphatase Cdc25C. This in turn inactivates Cdc2, which leads to G2/M arrest. We report that blocking Chki expression by antisense or ribozymes in mammalian cells induces apoptosis and interferes with the G2/M arrest induced by adriamycin. The Chki inhibitor UCN-01 also blocks the G2 arrest after DNA damage and renders cells more susceptible to adriamycin. These results indicate that Chki is an essential gene for the checkpoint mechanism during normal cell proliferation as well as in the DNA damage response.

  11. BRCA1, FANCD2 and Chk1 are potential molecular targets for the modulation of a radiation-induced DNA damage response in bystander cells.

    Science.gov (United States)

    Burdak-Rothkamm, Susanne; Rothkamm, Kai; McClelland, Keeva; Al Rashid, Shahnaz T; Prise, Kevin M

    2015-01-28

    Radiotherapy is an important treatment option for many human cancers. Current research is investigating the use of molecular targeted drugs in order to improve responses to radiotherapy in various cancers. The cellular response to irradiation is driven by both direct DNA damage in the targeted cell and intercellular signalling leading to a broad range of bystander effects. This study aims to elucidate radiation-induced DNA damage response signalling in bystander cells and to identify potential molecular targets to modulate the radiation induced bystander response in a therapeutic setting. Stalled replication forks in T98G bystander cells were visualised via bromodeoxyuridine (BrdU) nuclear foci detection at sites of single stranded DNA. γH2AX co-localised with these BrdU foci. BRCA1 and FANCD2 foci formed in T98G bystander cells. Using ATR mutant F02-98 hTERT and ATM deficient GM05849 fibroblasts it could be shown that ATR but not ATM was required for the recruitment of FANCD2 to sites of replication associated DNA damage in bystander cells whereas BRCA1 bystander foci were ATM-dependent. Phospho-Chk1 foci formation was observed in T98G bystander cells. Clonogenic survival assays showed moderate radiosensitisation of directly irradiated cells by the Chk1 inhibitor UCN-01 but increased radioresistance of bystander cells. This study identifies BRCA1, FANCD2 and Chk1 as potential targets for the modulation of radiation response in bystander cells. It adds to our understanding of the key molecular events propagating out-of-field effects of radiation and provides a rationale for the development of novel molecular targeted drugs for radiotherapy optimisation. Copyright © 2014 Elsevier Ireland Ltd. All rights reserved.

  12. YY1 Haploinsufficiency Causes an Intellectual Disability Syndrome Featuring Transcriptional and Chromatin Dysfunction

    DEFF Research Database (Denmark)

    Gabriele, Michele; Vulto-van Silfhout, Anneke T; Germain, Pierre-Luc

    2017-01-01

    that define a syndrome of cognitive impairment, behavioral alterations, intrauterine growth restriction, feeding problems, and various congenital malformations. Our combined clinical and molecular data define "YY1 syndrome" as a haploinsufficiency syndrome. Through immunoprecipitation of YY1-bound chromatin...... on the YY1-bound enhancers, underscoring a crucial role for YY1 in enhancer regulation. Collectively, these results define a clinical syndrome caused by haploinsufficiency of YY1 through dysregulation of key transcriptional regulators....

  13. MRN- and 9-1-1-Independent Activation of the ATR-Chk1 Pathway during the Induction of the Virulence Program in the Phytopathogen Ustilago maydis.

    Directory of Open Access Journals (Sweden)

    María Tenorio-Gómez

    Full Text Available DNA damage response (DDR leads to DNA repair, and depending on the extent of the damage, to further events, including cell death. Evidence suggests that cell differentiation may also be a consequence of the DDR. During the formation of the infective hypha in the phytopathogenic fungus Ustilago maydis, two DDR kinases, Atr1 and Chk1, are required to induce a G2 cell cycle arrest, which in turn is essential to display the virulence program. However, the triggering factor of DDR in this process has remained elusive. In this report we provide data suggesting that no DNA damage is associated with the activation of the DDR during the formation of the infective filament in U. maydis. We have analyzed bulk DNA replication during the formation of the infective filament, and we found no signs of impaired DNA replication. Furthermore, using RPA-GFP fusion as a surrogate marker of the presence of DNA damage, we were unable to detect any sign of DNA damage at the cellular level. In addition, neither MRN nor 9-1-1 complexes, both instrumental to transmit the DNA damage signal, are required for the induction of the above mentioned cell cycle arrest, as well as for virulence. In contrast, we have found that the claspin-like protein Mrc1, which in other systems serves as scaffold for Atr1 and Chk1, was required for both processes. We discuss possible alternative ways to trigger the DDR, independent of DNA damage, in U. maydis during virulence program activation.

  14. Proteasome activity is important for replication recovery, CHK1 phosphorylation and prevention of G2 arrest after low-dose formaldehyde

    Energy Technology Data Exchange (ETDEWEB)

    Ortega-Atienza, Sara; Green, Samantha E.; Zhitkovich, Anatoly, E-mail: anatoly_zhitkovich@brown.edu

    2015-07-15

    Formaldehyde (FA) is a human carcinogen with numerous sources of environmental and occupational exposures. This reactive aldehyde is also produced endogenously during metabolism of drugs and other processes. DNA–protein crosslinks (DPCs) are considered to be the main genotoxic lesions for FA. Accumulating evidence suggests that DPC repair in high eukaryotes involves proteolysis of crosslinked proteins. Here, we examined a role of the main cellular proteolytic machinery proteasomes in toxic responses of human lung cells to low FA doses. We found that transient inhibition of proteasome activity increased cytotoxicity and diminished clonogenic viability of FA-treated cells. Proteasome inactivation exacerbated suppressive effects of FA on DNA replication and increased the levels of the genotoxic stress marker γ-H2AX in normal human cells. A transient loss of proteasome activity in FA-exposed cells also caused delayed perturbations of cell cycle, which included G2 arrest and a depletion of S-phase populations at FA doses that had no effects in control cells. Proteasome activity diminished p53-Ser15 phosphorylation but was important for FA-induced CHK1 phosphorylation, which is a biochemical marker of DPC proteolysis in replicating cells. Unlike FA, proteasome inhibition had no effect on cell survival and CHK1 phosphorylation by the non-DPC replication stressor hydroxyurea. Overall, we obtained evidence for the importance of proteasomes in protection of human cells against biologically relevant doses of FA. Biochemically, our findings indicate the involvement of proteasomes in proteolytic repair of DPC, which removes replication blockage by these highly bulky lesions. - Highlights: • Proteasome inhibition enhances cytotoxicity of low-dose FA in human lung cells. • Active proteasomes diminish replication-inhibiting effects of FA. • Proteasome activity prevents delayed G2 arrest in FA-treated cells. • Proteasome inhibition exacerbates replication stress by FA in

  15. Reversal of DDK-Mediated MCM Phosphorylation by Rif1-PP1 Regulates Replication Initiation and Replisome Stability Independently of ATR/Chk1.

    Science.gov (United States)

    Alver, Robert C; Chadha, Gaganmeet Singh; Gillespie, Peter J; Blow, J Julian

    2017-03-07

    Dbf4-dependent kinases (DDKs) are required for the initiation of DNA replication, their essential targets being the MCM2-7 proteins. We show that, in Xenopus laevis egg extracts and human cells, hyper-phosphorylation of DNA-bound Mcm4, but not phosphorylation of Mcm2, correlates with DNA replication. These phosphorylations are differentially affected by the DDK inhibitors PHA-767491 and XL413. We show that DDK-dependent MCM phosphorylation is reversed by protein phosphatase 1 (PP1) targeted to chromatin by Rif1. Loss of Rif1 increased MCM phosphorylation and the rate of replication initiation and also compromised the ability of cells to block initiation when challenged with replication inhibitors. We also provide evidence that Rif1 can mediate MCM dephosphorylation at replication forks and that the stability of dephosphorylated replisomes strongly depends on Chk1 activity. We propose that both replication initiation and replisome stability depend on MCM phosphorylation, which is maintained by a balance of DDK-dependent phosphorylation and Rif1-mediated dephosphorylation. Copyright © 2017 The Authors. Published by Elsevier Inc. All rights reserved.

  16. Fibroblast growth factor 10 haploinsufficiency causes chronic obstructive pulmonary disease.

    Science.gov (United States)

    Klar, Joakim; Blomstrand, Peter; Brunmark, Charlott; Badhai, Jitendra; Håkansson, Hanna Falk; Brange, Charlotte Sollie; Bergendal, Birgitta; Dahl, Niklas

    2011-10-01

    Genetic factors influencing lung function may predispose to chronic obstructive pulmonary disease (COPD). The fibroblast growth factor 10 (FGF10) signalling pathway is critical for lung development and lung epithelial renewal. The hypothesis behind this study was that constitutive FGF10 insufficiency may lead to pulmonary disorder. Therefore investigation of the pulmonary functions of patients heterozygous for loss of function mutations in the FGF10 gene was performed. The spirometric measures of lung function from patients and non-carrier siblings were compared and both groups were related to matched reference data for normal human lung function. The patients show a significant decrease in lung function parameters when compared to control values. The average FEV1/IVC quota (FEV1%) for the patients is 0.65 (80% of predicted) and reversibility test using Terbutalin resulted in a 3.7% increase in FEV1. Patients with FGF10 haploinsufficiency have lung function parameters indicating COPD. A modest response to Terbutalin confirms an irreversible obstructive lung disease. These findings support the idea that genetic variants affecting the FGF10 signalling pathway are important determinants of lung function that may ultimately contribute to COPD. Specifically, the results show that FGF10 haploinsufficiency affects lung function measures providing a model for a dosage sensitive effect of FGF10 in the development of COPD.

  17. Dissociation of frontotemporal dementia-related deficits and neuroinflammation in progranulin haploinsufficient mice.

    Science.gov (United States)

    Filiano, Anthony J; Martens, Lauren Herl; Young, Allen H; Warmus, Brian A; Zhou, Ping; Diaz-Ramirez, Grisell; Jiao, Jian; Zhang, Zhijun; Huang, Eric J; Gao, Fen-Biao; Farese, Robert V; Roberson, Erik D

    2013-03-20

    Frontotemporal dementia (FTD) is a neurodegenerative disease with hallmark deficits in social and emotional function. Heterozygous loss-of-function mutations in GRN, the progranulin gene, are a common genetic cause of the disorder, but the mechanisms by which progranulin haploinsufficiency causes neuronal dysfunction in FTD are unclear. Homozygous progranulin knock-out (Grn(-/-)) mice have been studied as a model of this disorder and show behavioral deficits and a neuroinflammatory phenotype with robust microglial activation. However, homozygous GRN mutations causing complete progranulin deficiency were recently shown to cause a different neurological disorder, neuronal ceroid lipofuscinosis, suggesting that the total absence of progranulin may have effects distinct from those of haploinsufficiency. Here, we studied progranulin heterozygous (Grn(+/-)) mice, which model progranulin haploinsufficiency. We found that Grn(+/-) mice developed age-dependent social and emotional deficits potentially relevant to FTD. However, unlike Grn(-/-) mice, behavioral deficits in Grn(+/-) mice occurred in the absence of gliosis or increased expression of tumor necrosis factor-α. Instead, we found neuronal abnormalities in the amygdala, an area of selective vulnerability in FTD, in Grn(+/-) mice. Our findings indicate that FTD-related deficits resulting from progranulin haploinsufficiency can develop in the absence of detectable gliosis and neuroinflammation, thereby dissociating microglial activation from functional deficits and suggesting an important effect of progranulin deficiency on neurons.

  18. Rai1 Haploinsufficiency Is Associated with Social Abnormalities in Mice

    Directory of Open Access Journals (Sweden)

    Nalini R. Rao

    2017-04-01

    Full Text Available Background: Autism is characterized by difficulties in social interaction, communication, and repetitive behaviors; with different degrees of severity in each of the core areas. Haploinsufficiency and point mutations of RAI1 are associated with Smith-Magenis syndrome (SMS, a genetic condition that scores within the autism spectrum range for social responsiveness and communication, and is characterized by neurobehavioral abnormalities, intellectual disability, developmental delay, sleep disturbance, and self-injurious behaviors. Methods: To investigate the relationship between Rai1 and social impairment, we evaluated the Rai1+/− mice with a battery of tests to address social behavior in mice. Results: We found that the mutant mice showed diminished interest in social odors, abnormal submissive tendencies, and increased repetitive behaviors when compared to wild type littermates. Conclusions: These findings suggest that Rai1 contributes to social behavior in mice, and prompt it as a candidate gene for the social behaviors observed in Smith-Magenis Syndrome patients.

  19. Haploinsufficiency of BAZ1B contributes to Williams syndrome through transcriptional dysregulation of neurodevelopmental pathways.

    Science.gov (United States)

    Lalli, Matthew A; Jang, Jiwon; Park, Joo-Hye C; Wang, Yidi; Guzman, Elmer; Zhou, Hongjun; Audouard, Morgane; Bridges, Daniel; Tovar, Kenneth R; Papuc, Sorina M; Tutulan-Cunita, Andreea C; Huang, Yadong; Budisteanu, Magdalena; Arghir, Aurora; Kosik, Kenneth S

    2016-04-01

    Williams syndrome (WS) is a neurodevelopmental disorder caused by a genomic deletion of ∼28 genes that results in a cognitive and behavioral profile marked by overall intellectual impairment with relative strength in expressive language and hypersocial behavior. Advancements in protocols for neuron differentiation from induced pluripotent stem cells allowed us to elucidate the molecular circuitry underpinning the ontogeny of WS. In patient-derived stem cells and neurons, we determined the expression profile of the Williams-Beuren syndrome critical region-deleted genes and the genome-wide transcriptional consequences of the hemizygous genomic microdeletion at chromosome 7q11.23. Derived neurons displayed disease-relevant hallmarks and indicated novel aberrant pathways in WS neurons including over-activated Wnt signaling accompanying an incomplete neurogenic commitment. We show that haploinsufficiency of the ATP-dependent chromatin remodeler, BAZ1B, which is deleted in WS, significantly contributes to this differentiation defect. Chromatin-immunoprecipitation (ChIP-seq) revealed BAZ1B target gene functions are enriched for neurogenesis, neuron differentiation and disease-relevant phenotypes. BAZ1B haploinsufficiency caused widespread gene expression changes in neural progenitor cells, and together with BAZ1B ChIP-seq target genes, explained 42% of the transcriptional dysregulation in WS neurons. BAZ1B contributes to regulating the balance between neural precursor self-renewal and differentiation and the differentiation defect caused by BAZ1B haploinsufficiency can be rescued by mitigating over-active Wnt signaling in neural stem cells. Altogether, these results reveal a pivotal role for BAZ1B in neurodevelopment and implicate its haploinsufficiency as a likely contributor to the neurological phenotypes in WS. © The Author 2016. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oup.com.

  20. Further confirmation of the MED13L haploinsufficiency syndrome

    NARCIS (Netherlands)

    van Haelst, M.M.; Monroe, G.R.; Duran, K.J.; van Binsbergen, E.; Breur, J.M.P.J.; Giltay, J.C.; van Haaften, G.W.

    MED13L haploinsufficiency syndrome has been described in two patients and is characterized by moderate intellectual disability (ID), conotruncal heart defects, facial abnormalities and hypotonia. Missense mutations in MED13L are linked to transposition of the great arteries and non-syndromal

  1. OBSCN Mutations Associated with Dilated Cardiomyopathy and Haploinsufficiency.

    Directory of Open Access Journals (Sweden)

    Steven Marston

    Full Text Available Studies of the functional consequences of DCM-causing mutations have been limited to a few cases where patients with known mutations had heart transplants. To increase the number of potential tissue samples for direct investigation we performed whole exon sequencing of explanted heart muscle samples from 30 patients that had a diagnosis of familial dilated cardiomyopathy and screened for potentially disease-causing mutations in 58 HCM or DCM-related genes.We identified 5 potentially disease-causing OBSCN mutations in 4 samples; one sample had two OBSCN mutations and one mutation was judged to be not disease-related. Also identified were 6 truncating mutations in TTN, 3 mutations in MYH7, 2 in DSP and one each in TNNC1, TNNI3, MYOM1, VCL, GLA, PLB, TCAP, PKP2 and LAMA4. The mean level of obscurin mRNA was significantly greater and more variable in healthy donor samples than the DCM samples but did not correlate with OBSCN mutations. A single obscurin protein band was observed in human heart myofibrils with apparent mass 960 ± 60 kDa. The three samples with OBSCN mutations had significantly lower levels of obscurin immunoreactive material than DCM samples without OBSCN mutations (45±7, 48±3, and 72±6% of control level.Obscurin levels in DCM controls, donor heart and myectomy samples were the same.OBSCN mutations may result in the development of a DCM phenotype via haploinsufficiency. Mutations in the obscurin gene should be considered as a significant causal factor of DCM, alone or in concert with other mutations.

  2. Lung matrix and vascular remodeling in mechanically ventilated elastin haploinsufficient newborn mice

    Science.gov (United States)

    Hilgendorff, Anne; Parai, Kakoli; Ertsey, Robert; Navarro, Edwin; Jain, Noopur; Carandang, Francis; Peterson, Joanna; Mokres, Lucia; Milla, Carlos; Preuss, Stefanie; Alcazar, Miguel Alejandre; Khan, Suleman; Masumi, Juliet; Ferreira-Tojais, Nancy; Mujahid, Sana; Starcher, Barry; Rabinovitch, Marlene

    2014-01-01

    Elastin plays a pivotal role in lung development. We therefore queried if elastin haploinsufficient newborn mice (Eln+/−) would exhibit abnormal lung structure and function related to modified extracellular matrix (ECM) composition. Because mechanical ventilation (MV) has been linked to dysregulated elastic fiber formation in the newborn lung, we also asked if elastin haploinsufficiency would accentuate lung growth arrest seen after prolonged MV of neonatal mice. We studied 5-day-old wild-type (Eln+/+) and Eln+/− littermates at baseline and after MV with air for 8–24 h. Lungs of unventilated Eln+/− mice contained ∼50% less elastin and ∼100% more collagen-1 and lysyl oxidase compared with Eln+/+ pups. Eln+/− lungs contained fewer capillaries than Eln+/+ lungs, without discernible differences in alveolar structure. In response to MV, lung tropoelastin and elastase activity increased in Eln+/+ neonates, whereas tropoelastin decreased and elastase activity was unchanged in Eln+/− mice. Fibrillin-1 protein increased in lungs of both groups during MV, more in Eln+/− than in Eln+/+ pups. In both groups, MV caused capillary loss, with larger and fewer alveoli compared with unventilated controls. Respiratory system elastance, which was less in unventilated Eln+/− compared with Eln+/+ mice, was similar in both groups after MV. These results suggest that elastin haploinsufficiency adversely impacts pulmonary angiogenesis and that MV dysregulates elastic fiber integrity, with further loss of lung capillaries, lung growth arrest, and impaired respiratory function in both Eln+/+ and Eln+/− mice. Paucity of lung capillaries in Eln+/− newborns might help explain subsequent development of pulmonary hypertension previously reported in adult Eln+/− mice. PMID:25539853

  3. Haplo-insufficiency of both BubR1 and SGO1 accelerates cellular senescence

    Directory of Open Access Journals (Sweden)

    Sung-Hyun Park

    2016-02-01

    Full Text Available Abstract Background Spindle assembly checkpoint components BubR1 and Sgo1 play a key role in the maintenance of chromosomal instability during cell division. These proteins function to block the anaphase entry until all condensed chromosomes have been attached by the microtubules emanating from both spindle poles. Haplo-insufficiency of either BubR1 or SGO1 results in enhanced chromosomal instability and tumor development in the intestine. Recent studies show that spindle checkpoint proteins also have a role in slowing down the ageing process. Therefore, we want to study whether haplo-insufficiency of both BubR1 and SGO1 accelerates cellular senescence in mice. Methods We took advantage of the availability of BubR1 and SGO1 knockout mice and generated primary murine embryonic fibroblasts (MEFs with mutations in either BubR1, SGO1, or both and analyzed cellular senescence of the MEFs of various genetic backgrounds. Results We observed that BubR1 +/− SGO +/− MEFs had an accelerated cellular senescence characterized by morphological changes and expressed senescence-associated β-galactosidase. In addition, compared with wild-type MEFs or MEFs with a single gene deficiency, BubR1 +/− SGO1 +/− MEFs expressed enhanced levels of p21 but not p16. Conclusions Taken together, our observations suggest that combined deficiency of BubR1 and Sgo1 accelerates cellular senescence.

  4. Gad67 haploinsufficiency reduces amyloid pathology and rescues olfactory memory deficits in a mouse model of Alzheimer's disease.

    Science.gov (United States)

    Wang, Yue; Wu, Zheng; Bai, Yu-Ting; Wu, Gang-Yi; Chen, Gong

    2017-10-10

    Alzheimer's disease (AD) is the most common age-related neurodegenerative disorder, affecting millions of people worldwide. Although dysfunction of multiple neurotransmitter systems including cholinergic, glutamatergic and GABAergic systems has been associated with AD progression the underlying mechanisms remain elusive. We and others have recently found that GABA content is elevated in AD brains and linked to cognitive deficits in AD mouse models. The glutamic acid decarboxylase 67 (GAD67) is the major enzyme converting glutamate into GABA and has been implied in a number of neurological disorders such as epilepsy and schizophrenia. However, whether Gad67 is involved in AD pathology has not been well studied. Here, we investigate the functional role of GAD67 in an AD mouse model with Gad67 haploinsufficiency that is caused by replacing one allele of Gad67 with green fluorescent protein (GFP) gene during generation of GAD67-GFP mice. To genetically reduce GAD67 in AD mouse brains, we crossed the Gad67 haploinsufficient mice (GAD67-GFP +/- ) with 5xFAD mice (harboring 5 human familial AD mutations in APP and PS1 genes) to generate a new line of bigenic mice. Immunostaining, ELISA, electrophysiology and behavior test were applied to compare the difference between groups. We found that reduction of GAD67 resulted in a significant decrease of amyloid β production in 5xFAD mice. Concurrently, the abnormal astrocytic GABA and tonic GABA currents, as well as the microglial reactivity were significantly reduced in the 5xFAD mice with Gad67 haploinsufficiency. Importantly, the olfactory memory deficit of 5xFAD mice was rescued by Gad67 haploinsufficiency. Our results demonstrate that GAD67 plays an important role in AD pathology, suggesting that GAD67 may be a potential drug target for modulating the progress of AD.

  5. Arid1b haploinsufficient mice reveal neuropsychiatric phenotypes and reversible causes of growth impairment.

    Science.gov (United States)

    Celen, Cemre; Chuang, Jen-Chieh; Luo, Xin; Nijem, Nadine; Walker, Angela K; Chen, Fei; Zhang, Shuyuan; Chung, Andrew S; Nguyen, Liem H; Nassour, Ibrahim; Budhipramono, Albert; Sun, Xuxu; Bok, Levinus A; McEntagart, Meriel; Gevers, Evelien F; Birnbaum, Shari G; Eisch, Amelia J; Powell, Craig M; Ge, Woo-Ping; Santen, Gijs We; Chahrour, Maria; Zhu, Hao

    2017-07-11

    Sequencing studies have implicated haploinsufficiency of ARID1B , a SWI/SNF chromatin-remodeling subunit, in short stature (Yu et al., 2015), autism spectrum disorder (O'Roak et al., 2012), intellectual disability (Deciphering Developmental Disorders Study, 2015), and corpus callosum agenesis (Halgren et al., 2012). In addition, ARID1B is the most common cause of Coffin-Siris syndrome, a developmental delay syndrome characterized by some of the above abnormalities (Santen et al., 2012; Tsurusaki et al., 2012; Wieczorek et al., 2013). We generated Arid1b heterozygous mice, which showed social behavior impairment, altered vocalization, anxiety-like behavior, neuroanatomical abnormalities, and growth impairment. In the brain, Arid1b haploinsufficiency resulted in changes in the expression of SWI/SNF-regulated genes implicated in neuropsychiatric disorders. A focus on reversible mechanisms identified Insulin-like growth factor (IGF1) deficiency with inadequate compensation by Growth hormone-releasing hormone (GHRH) and Growth hormone (GH), underappreciated findings in ARID1B patients. Therapeutically, GH supplementation was able to correct growth retardation and muscle weakness. This model functionally validates the involvement of ARID1B in human disorders, and allows mechanistic dissection of neurodevelopmental diseases linked to chromatin-remodeling.

  6. Lef1 haploinsufficient mice display a low turnover and low bone mass phenotype in a gender- and age-specific manner.

    Directory of Open Access Journals (Sweden)

    Tommy Noh

    Full Text Available We investigated the role of Lef1, one of the four transcription factors that transmit Wnt signaling to the genome, in the regulation of bone mass. Microcomputed tomographic analysis of 13- and 17-week-old mice revealed significantly reduced trabecular bone mass in Lef1(+/- females compared to littermate wild-type females. This was attributable to decreased osteoblast activity and bone formation as indicated by histomorphometric analysis of bone remodeling. In contrast to females, bone mass was unaffected by Lef1 haploinsufficiency in males. Similarly, females were substantially more responsive than males to haploinsufficiency in Gsk3beta, a negative regulator of the Wnt pathway, displaying in this case a high bone mass phenotype. Lef1 haploinsufficiency also led to low bone mass in males lacking functional androgen receptor (AR (tfm mutants. The protective skeletal effect of AR against Wnt-related low bone mass is not necessarily a result of direct interaction between the AR and Wnt signaling pathways, because Lef1(+/- female mice had normal bone mass at the age of 34 weeks. Thus, our results indicate an age- and gender-dependent role for Lef1 in regulating bone formation and bone mass in vivo. The resistance to Lef1 haploinsufficiency in males with active AR and in old females could be due to the reduced bone turnover in these mice.

  7. Tyrosine kinase receptor c-ros-oncogene 1 inhibition alleviates aberrant bone formation of TWIST-1 haploinsufficient calvarial cells from Saethre-Chotzen syndrome patients.

    Science.gov (United States)

    Camp, Esther; Anderson, Peter J; Zannettino, Andrew C W; Glackin, Carlotta A; Gronthos, Stan

    2018-09-01

    Saethre-Chotzen syndrome (SCS), associated with TWIST-1 mutations, is characterized by premature fusion of cranial sutures. TWIST-1 haploinsufficiency, leads to alterations in suture mesenchyme cellular gene expression patterns, resulting in aberrant osteogenesis and craniosynostosis. We analyzed the expression of the TWIST-1 target, Tyrosine kinase receptor c-ros-oncogene 1 (C-ROS-1) in TWIST-1 haploinsufficient calvarial cells derived from SCS patients and calvaria of Twist-1 del/+ mutant mice and found it to be highly expressed when compared to TWIST-1 wild-type controls. Knock-down of C-ROS-1 expression in TWIST-1 haploinsufficient calvarial cells derived from SCS patients was associated with decreased capacity for osteogenic differentiation in vitro. Furthermore, treatment of human SCS calvarial cells with the tyrosine kinase chemical inhibitor, Crizotinib, resulted in reduced C-ROS-1 activity and the osteogenic potential of human SCS calvarial cells with minor effects on cell viability or proliferation. Cultured human SCS calvarial cells treated with Crizotinib exhibited a dose-dependent decrease in alkaline phosphatase activity and mineral deposition, with an associated decrease in expression levels of Runt-related transcription factor 2 and OSTEOPONTIN, with reduced PI3K/Akt signalling in vitro. Furthermore, Crizotinib treatment resulted in reduced BMP-2 mediated bone formation potential of whole Twist-1 del/+ mutant mouse calvaria organotypic cultures. Collectively, these results suggest that C-ROS-1 promotes osteogenic differentiation of TWIST-1 haploinsufficient calvarial osteogenic progenitor cells. Furthermore, the aberrant osteogenic potential of these cells is inhibited by the reduction of C-ROS-1. Therefore, targeting C-ROS-1 with a pharmacological agent, such as Crizotinib, may serve as a novel therapeutic strategy to alleviate craniosynostosis associated with aberrant TWIST-1 function. © 2018 Wiley Periodicals, Inc.

  8. SIX2 haploinsufficiency causes conductive hearing loss with ptosis in humans.

    Science.gov (United States)

    Guan, Jing; Wang, Dayong; Cao, Wenjian; Zhao, Yali; Du, Renqian; Yuan, Hu; Liu, Qiong; Lan, Lan; Zong, Liang; Yang, Ju; Yin, Zifang; Han, Bing; Zhang, Feng; Wang, Qiuju

    2016-11-01

    The ossicles represent one of the most fundamental morphological features in evolutionary biology of the mammalians. The mobile ossicular morphology abnormalities result in the severe conductive hearing loss. Development and patterning of the middle ear malformation depend on genetic and environmental causes. However, the genetic basis for the risk of congenital ossicle malformation is poorly understood. We show here nine affected individuals in a Chinese pedigree who had bilateral conductive hearing loss with ptosis. We performed whole-genome sequencing and array comparative genomic hybridization (CGH) analysis on DNA samples from the Chinese pedigree. We confirmed the presence of a novel 60 kb heterozygous deletion in size, encompassing SIX2 in our family. Mutation screening in 169 sporadic cases with external ear and middle ear malformations identified no pathogenic variant or polymorphism. We suggest SIX2 haploinsufficiency as a potential congenital factor could be attributed to developmental malformation of the middle ear ossicles and upper eyelid. To the best of our knowledge, this is the first report to provide a description of copy number variation in the SIX2 gene resulting in syndromic conductive hearing loss.

  9. Brain size regulations by cbp haploinsufficiency evaluated by in-vivo MRI based volumetry

    Science.gov (United States)

    Ateca-Cabarga, Juan C.; Cosa, Alejandro; Pallarés, Vicente; López-Atalaya, José P.; Barco, Ángel; Canals, Santiago; Moratal, David

    2015-11-01

    The Rubinstein-Taybi Syndrome (RSTS) is a congenital disease that affects brain development causing severe cognitive deficits. In most cases the disease is associated with dominant mutations in the gene encoding the CREB binding protein (CBP). In this work, we present the first quantitative analysis of brain abnormalities in a mouse model of RSTS using magnetic resonance imaging (MRI) and two novel self-developed automated algorithms for image volumetric analysis. Our results quantitatively confirm key syndromic features observed in RSTS patients, such as reductions in brain size (-16.31%, p < 0.05), white matter volume (-16.00%, p < 0.05), and corpus callosum (-12.40%, p < 0.05). Furthermore, they provide new insight into the developmental origin of the disease. By comparing brain tissues in a region by region basis between cbp+/- and cbp+/+ littermates, we found that cbp haploinsufficiency is specifically associated with significant reductions in prosencephalic tissue, such us in the olfactory bulb and neocortex, whereas regions evolved from the embryonic rhombencephalon were spared. Despite the large volume reductions, the proportion between gray-, white-matter and cerebrospinal fluid were conserved, suggesting a role of CBP in brain size regulation. The commonalities with holoprosencephaly and arhinencephaly conditions suggest the inclusion of RSTS in the family of neuronal migration disorders.

  10. MTH1 and RGT1 demonstrate combined haploinsufficiency in regulation of the hexose transporter genes in Saccharomyces cerevisiae

    Directory of Open Access Journals (Sweden)

    Dietzel Kevin L

    2012-12-01

    Full Text Available Abstract Background The SNF3 gene in the yeast Saccharomyces cerevisiae encodes a low glucose sensor that regulates expression of an important subset of the hexose transporter (HXT superfamily. Null mutations of snf3 result in a defect in growth on low glucose concentrations due to the inability to relieve repression of a subset of the HXT genes. The snf3 null mutation phenotype is suppressed by the loss of either one of the downstream co-repressor proteins Rgt1p or Mth1p. The relief of repression allows expression of HXT transporter proteins, the resumption of glucose uptake and therefore of growth in the absence of a functional Snf3 sensor. Results Strains heterozygous for both the RGT1 and MTH1 genes (RGT1/rgt1Δ MTH1/mth1Δ snf3Δ/snf3Δ but homozygous for the snf3∆ were found to grow on low glucose. Since null alleles in the heterozygous state lead to suppression, MTH1 and RGT1 display the phenomenon of combined haploinsufficiency. This observed haploinsufficiency is consistent with the finding of repressor titration as a mechanism of suppression of snf3. Mutants of the STD1 homolog of MTH1 did not display haploinsufficiency singly or in combination with mutations in RGT1. HXT gene reporter fusion assays indicated that the presence of heterozygosity at the MTH1 and RGT1 alleles leads to increased expression of the HXT2 gene. Deletion of the HXT2 gene in a heterozygous diploid, RGT1/rgt1Δ MTH1/mth1Δ snf3Δ/snf3Δ hxt2Δ/hxt2Δ, prevented the suppression of snf3Δ. Conclusions These findings support the model of relief of repression as the mechanism of restoration of growth on low glucose concentrations in the absence of functional Snf3p. Further, the observation that HXT2 is the gene responsible for restoration of growth under these conditions suggests that the numbers of repressor binding domains found in the regulatory regions of members of the HXT family may have biological relevance and enable differential regulation.

  11. High-calorie diet exacerbates prostate neoplasia in mice with haploinsufficiency of Pten tumor suppressor gene

    Directory of Open Access Journals (Sweden)

    Jehnan Liu

    2015-03-01

    Conclusion: High-calorie diet promotes prostate cancer progression in the genetically susceptible Pten haploinsufficient mouse while preserving insulin sensitivity. This appears to be partly due to increased inflammatory response to high-caloric intake in addition to increased ability of insulin to promote lipogenesis.

  12. Dissociation of Frontotemporal Dementia–Related Deficits and Neuroinflammation in Progranulin Haploinsufficient Mice

    Science.gov (United States)

    Filiano, Anthony J.; Martens, Lauren Herl; Young, Allen H.; Warmus, Brian A.; Zhou, Ping; Diaz-Ramirez, Grisell; Jiao, Jian; Zhang, Zhijun; Huang, Eric J.; Gao, Fen-Biao; Farese, Robert V.; Roberson, Erik D.

    2013-01-01

    Frontotemporal dementia (FTD) is a neurodegenerative disease with hallmark deficits in social and emotional function. Heterozygous loss-of-function mutations in GRN, the progranulin gene, are a common genetic cause of the disorder, but the mechanisms by which progranulin haploinsufficiency causes neuronal dysfunction in FTD are unclear. Homozygous progranulin knockout (Grn−/−) mice have been studied as a model of this disorder and show behavioral deficits and a neuroinflammatory phenotype with robust microglial activation. However, homozygous GRN mutations causing complete progranulin deficiency were recently shown to cause a different neurological disorder, neuronal ceroid lipofuscinosis, suggesting that the total absence of progranulin may have effects distinct from those of haploinsufficiency. Here, we studied progranulin heterozygous (Grn+/−) mice, which model progranulin haploinsufficiency. We found that Grn+/− mice developed age-dependent social and emotional deficits potentially relevant to FTD. However, unlike Grn−/− mice, behavioral deficits in Grn+/− mice occurred in the absence of gliosis or increased expression of tumor necrosis factor–α. Instead, we found neuronal abnormalities in the amygdala, an area of selective vulnerability in FTD, in Grn+/− mice. Our findings indicate that FTD-related deficits due to progranulin haploinsufficiency can develop in the absence of detectable gliosis and neuroinflammation, thereby dissociating microglial activation from functional deficits and suggesting an important effect of progranulin deficiency on neurons. PMID:23516300

  13. Adiponectin haploinsufficiency promotes mammary tumor development in MMTV-PyVT mice by modulation of phosphatase and tensin homolog activities.

    Directory of Open Access Journals (Sweden)

    Janice B B Lam

    Full Text Available Adiponectin is an adipokine possessing beneficial effects on obesity-related medical complications. A negative association of adiponectin levels with breast cancer development has been demonstrated. However, the precise role of adiponectin deficiency in mammary carcinogenesis remains elusive.In the present study, MMTV-polyomavirus middle T antigen (MMTV-PyVT transgenic mice with reduced adiponectin expressions were established and the stromal effects of adiponectin haploinsufficiency on mammary tumor development evaluated. In mice from both FVB/N and C57BL/6J backgrounds, insufficient adiponectin production promoted mammary tumor onset and development. A distinctive basal-like subtype of tumors, with a more aggressive phenotype, was derived from adiponectin haplodeficient MMTV-PyVT mice. Comparing with those from control MMTV-PyVT mice, the isolated mammary tumor cells showed enhanced tumor progression in re-implanted nude mice, accelerated proliferation in primary cultures, and hyperactivated phosphatidylinositol-3-kinase (PI3K/Akt/beta-catenin signaling, which at least partly attributed to the decreased phosphatase and tensin homolog (PTEN activities. Further analysis revealed that PTEN was inactivated by a redox-regulated mechanism. Increased association of PTEN-thioredoxin complexes was detected in tumors derived from mice with reduced adiponectin levels. The activities of thioredoxin (Trx1 and thioredoxin reductase (TrxR1 were significantly elevated, whereas treatment with either curcumin, an irreversible inhibitor of TrxR1, or adiponectin largely attenuated their activities and resulted in the re-activation of PTEN in these tumor cells. Moreover, adiponectin could inhibit TrxR1 promoter-mediated transcription and restore the mRNA expressions of TrxR1.Adiponectin haploinsufficiency facilitated mammary tumorigenesis by down-regulation of PTEN activity and activation of PI3K/Akt signalling pathway through a mechanism involving Trx1/TrxR1

  14. Haploinsufficiency of the Sec7 guanine nucleotide exchange factor gea1 impairs septation in fission yeast.

    Directory of Open Access Journals (Sweden)

    Alan M Eckler

    Full Text Available Membrane trafficking is essential to eukaryotic life and is controlled by a complex network of proteins that regulate movement of proteins and lipids between organelles. The GBF1/GEA family of Guanine nucleotide Exchange Factors (GEFs regulates trafficking between the endoplasmic reticulum and Golgi by catalyzing the exchange of GDP for GTP on ADP Ribosylation Factors (Arfs. Activated Arfs recruit coat protein complex 1 (COP-I to form vesicles that ferry cargo between these organelles. To further explore the function of the GBF1/GEA family, we have characterized a fission yeast mutant lacking one copy of the essential gene gea1 (gea1+/-, the Schizosaccharomyces pombe ortholog of GBF1. The haploinsufficient gea1+/- strain was shown to be sensitive to the GBF1 inhibitor brefeldin A (BFA and was rescued from BFA sensitivity by gea1p overexpression. No overt defects in localization of arf1p or arf6p were observed in gea1+/- cells, but the fission yeast homolog of the COP-I cargo sac1 was mislocalized, consistent with impaired COP-I trafficking. Although Golgi morphology appeared normal, a slight increase in vacuolar size was observed in the gea1+/- mutant strain. Importantly, gea1+/- cells exhibited dramatic cytokinesis-related defects, including disorganized contractile rings, an increased septation index, and alterations in septum morphology. Septation defects appear to result from altered secretion of enzymes required for septum dynamics, as decreased secretion of eng1p, a β-glucanase required for septum breakdown, was observed in gea1+/- cells, and overexpression of eng1p suppressed the increased septation phenotype. These observations implicate gea1 in regulation of septum breakdown and establish S. pombe as a model system to explore GBF1/GEA function in cytokinesis.

  15. The contribution of CLIP2 haploinsufficiency to the clinical manifestations of the Williams-Beuren syndrome.

    Science.gov (United States)

    Vandeweyer, Geert; Van der Aa, Nathalie; Reyniers, Edwin; Kooy, R Frank

    2012-06-08

    Williams-Beuren syndrome is a rare contiguous gene syndrome, characterized by intellectual disability, facial dysmorphisms, connective-tissue abnormalities, cardiac defects, structural brain abnormalities, and transient infantile hypercalcemia. Genes lying telomeric to RFC2, including CLIP2, GTF2I and GTF2IRD1, are currently thought to be the most likely major contributors to the typical Williams syndrome cognitive profile, characterized by a better-than-expected auditory rote-memory ability, a relative sparing of language capabilities, and a severe visual-spatial constructive impairment. Atypical deletions in the region have helped to establish genotype-phenotype correlations. So far, however, hardly any deletions affecting only a single gene in the disease region have been described. We present here two healthy siblings with a pure, hemizygous deletion of CLIP2. A putative role in the cognitive and behavioral abnormalities seen in Williams-Beuren patients has been suggested for this gene on the basis of observations in a knock-out mouse model. The presented siblings did not show any of the clinical features associated with the syndrome. Cognitive testing showed an average IQ for both and no indication of the Williams syndrome cognitive profile. This shows that CLIP2 haploinsufficiency by itself does not lead to the physical or cognitive characteristics of the Williams-Beuren syndrome, nor does it lead to the Williams syndrome cognitive profile. Although contribution of CLIP2 to the phenotype cannot be excluded when it is deleted in combination with other genes, our results support the hypothesis that GTF2IRD1 and GTF2I are the main genes causing the cognitive defects associated with Williams-Beuren syndrome. Copyright © 2012 The American Society of Human Genetics. Published by Elsevier Inc. All rights reserved.

  16. Impaired spatial learning strategies and novel object recognition in mice haploinsufficient for the dual specificity tyrosine-regulated kinase-1A (Dyrk1A.

    Directory of Open Access Journals (Sweden)

    Glòria Arqué

    Full Text Available BACKGROUND: Pathogenic aneuploidies involve the concept of dosage-sensitive genes leading to over- and underexpression phenotypes. Monosomy 21 in human leads to mental retardation and skeletal, immune and respiratory function disturbances. Most of the human condition corresponds to partial monosomies suggesting that critical haploinsufficient genes may be responsible for the phenotypes. The DYRK1A gene is localized on the human chromosome 21q22.2 region, and has been proposed to participate in monosomy 21 phenotypes. It encodes a dual-specificity kinase involved in neuronal development and in adult brain physiology, but its possible role as critical haploinsufficient gene in cognitive function has not been explored. METHODOLOGY/PRINCIPAL FINDINGS: We used mice heterozygous for a Dyrk1A targeted mutation (Dyrk1A+/- to investigate the implication of this gene in the cognitive phenotypes of monosomy 21. Performance of Dyrk1A+/- mice was assayed 1/ in a navigational task using the standard hippocampally related version of the Morris water maze, 2/ in a swimming test designed to reveal potential kinesthetic and stress-related behavioral differences between control and heterozygous mice under two levels of aversiveness (25 degrees C and 17 degrees C and 3/ in a long-term novel object recognition task, sensitive to hippocampal damage. Dyrk1A+/- mice showed impairment in the development of spatial learning strategies in a hippocampally-dependent memory task, they were impaired in their novel object recognition ability and were more sensitive to aversive conditions in the swimming test than euploid control animals. CONCLUSIONS/SIGNIFICANCE: The present results are clear examples where removal of a single gene has a profound effect on phenotype and indicate that haploinsufficiency of DYRK1A might contribute to an impairment of cognitive functions and stress coping behavior in human monosomy 21.

  17. Telomere Elongation and Naive Pluripotent Stem Cells Achieved from Telomerase Haplo-Insufficient Cells by Somatic Cell Nuclear Transfer

    Directory of Open Access Journals (Sweden)

    Li-Ying Sung

    2014-12-01

    Full Text Available Summary: Haplo-insufficiency of telomerase genes in humans leads to telomere syndromes such as dyskeratosis congenital and idiopathic pulmonary fibrosis. Generation of pluripotent stem cells from telomerase haplo-insufficient donor cells would provide unique opportunities toward the realization of patient-specific stem cell therapies. Recently, pluripotent human embryonic stem cells (ntESCs have been efficiently achieved by somatic cell nuclear transfer (SCNT. We tested the hypothesis that SCNT could effectively elongate shortening telomeres of telomerase haplo-insufficient cells in the ntESCs with relevant mouse models. Indeed, telomeres of telomerase haplo-insufficient (Terc+/− mouse cells are elongated in ntESCs. Moreover, ntESCs derived from Terc+/− cells exhibit naive pluripotency as evidenced by generation of Terc+/− ntESC clone pups by tetraploid embryo complementation, the most stringent test of naive pluripotency. These data suggest that SCNT could offer a powerful tool to reprogram telomeres and to discover the factors for robust restoration of telomeres and pluripotency of telomerase haplo-insufficient somatic cells. : Sung et al. demonstrate in a mouse model that telomeres of telomerase haplo-insufficient cells can be elongated by somatic cell nuclear transfer. Moreover, ntESCs derived from Terc+/− cells exhibit pluripotency evidenced by generation of Terc+/−ntESC clone pups by tetraploid embryo complementation, the most stringent test of naive pluripotency.

  18. Intermittent fasting uncovers and rescues cognitive phenotypes in PTEN neuronal haploinsufficient mice.

    Science.gov (United States)

    Cabral-Costa, J V; Andreotti, D Z; Mello, N P; Scavone, C; Camandola, S; Kawamoto, E M

    2018-06-05

    Phosphatase and tensin homolog (PTEN) is an important protein with key modulatory functions in cell growth and survival. PTEN is crucial during embryogenesis and plays a key role in the central nervous system (CNS), where it directly modulates neuronal development and synaptic plasticity. Loss of PTEN signaling function is associated with cognitive deficits and synaptic plasticity impairment. Accordingly, Pten mutations have a strong link with autism spectrum disorder. In this study, neuronal Pten haploinsufficient male mice were subjected to a long-term environmental intervention - intermittent fasting (IF) - and then evaluated for alterations in exploratory, anxiety and learning and memory behaviors. Although no significant effects on spatial memory were observed, mutant mice showed impaired contextual fear memory in the passive avoidance test - an outcome that was effectively rescued by IF. In this study, we demonstrated that IF modulation, in addition to its rescue of the memory deficit, was also required to uncover behavioral phenotypes otherwise hidden in this neuronal Pten haploinsufficiency model.

  19. Tsc2 Haploinsufficiency Has Limited Effects on Fetal Brain Cytokine Levels during Gestational Immune Activation

    Directory of Open Access Journals (Sweden)

    Dan Ehninger

    2014-01-01

    Full Text Available Dysregulated TSC/mTOR signaling may play a pathogenetic role in forms of syndromic autism, such as autism associated with tuberous sclerosis, a genetic disorder caused by heterozygous TSC1 or TSC2 mutations. Environmental risk factors, such as gestational viral infections, may, in some cases, also contribute to the pathogenesis of autism and related neuropsychiatric disorders. We have recently found that a heterozygous Tsc2 mutation and the poly I:C model of maternal immune activation (MIA interactively perturb fetal development and adult social behavior in mice, suggesting that these factors converge on shared pathways. TSC/mTOR signaling plays an important role in the modulation of immune responses, raising the possibility that the damage caused by MIA was greater in Tsc2+/− than in wildtype fetuses because of an exacerbated immune response in the mutants. Here, cytokine antibody arrays were employed to measure relative cytokine abundances in the fetal brain and the placenta during MIA. Cytokines were induced by gestational poly I:C but there was no obvious modulatory effect of Tsc2 haploinsufficiency. The data indicate that cytokine exposure during MIA is comparable in Tsc2 haploinsufficient and wildtype control fetuses, suggesting that downstream molecular and cellular processes may account for the interactive effects of Tsc2 haploinsufficiency and MIA.

  20. The inhibition of PARP but not EGFR results in the radiosensitization of HPV/p16-positive HNSCC cell lines

    International Nuclear Information System (INIS)

    Güster, Julian David; Weissleder, Stephanie Valerie; Busch, Chia-Jung; Kriegs, Malte; Petersen, Cordula; Knecht, Rainald; Dikomey, Ekkehard; Rieckmann, Thorsten

    2014-01-01

    Background and purpose: HPV-negative and HPV-positive HNSCC comprise distinct tumor entities with different biological characteristics. Specific regimens for the comparably well curable HPV-positive entity that reduce side effects without compromising outcome have yet to be established. Therefore, we tested here whether the inhibition of EGFR or PARP may be used to specifically enhance the radiosensitivity of HPV-positive HNSCC cells. Materials and methods: Experiments were performed with five HPV/p16-positive HNSCC cell lines. Inhibitors used were cetuximab, olaparib and PF-00477736. The respective inhibition of EGFR, PARP and Chk1 was evaluated by Western blot, immunofluorescence analysis and assessment of cell cycle distribution. Cell survival was assessed by colony formation assay. Results: Inhibition of EGFR by cetuximab failed to radiosensitize any of the HPV-positive HNSCC cell lines tested. In contrast, PARP-inhibition resulted in a substantial radiosensitization of all strains, with the sensitization being further enhanced by the additional inhibition of Chk1. Conclusions: PARP-inhibition effectively radiosensitizes HPV-positive HNSCC cells and may therefore represent a viable alternative to chemotherapy possibly even allowing for a reduction in radiation dose. For the latter, PARP-inhibition may be combined with the inhibition of Chk1. In contrast, the inhibition of EGFR cannot be expected to radiosensitize HPV-positive HNSCC through the modulation of cellular radiosensitivity

  1. Partial Tmem106b reduction does not correct abnormalities due to progranulin haploinsufficiency.

    Science.gov (United States)

    Arrant, Andrew E; Nicholson, Alexandra M; Zhou, Xiaolai; Rademakers, Rosa; Roberson, Erik D

    2018-06-22

    Loss of function mutations in progranulin (GRN) are a major cause of frontotemporal dementia (FTD). Progranulin is a secreted glycoprotein that localizes to lysosomes and is critical for proper lysosomal function. Heterozygous GRN mutation carriers develop FTD with TDP-43 pathology and exhibit signs of lysosomal dysfunction in the brain, with increased levels of lysosomal proteins and lipofuscin accumulation. Homozygous GRN mutation carriers develop neuronal ceroid lipofuscinosis (NCL), an earlier-onset lysosomal storage disorder caused by severe lysosomal dysfunction. Multiple genome-wide association studies have shown that risk of FTD in GRN mutation carriers is modified by polymorphisms in TMEM106B, which encodes a lysosomal membrane protein. Risk alleles of TMEM106B may increase TMEM106B levels through a variety of mechanisms. Brains from FTD patients with GRN mutations exhibit increased TMEM106B expression, and protective TMEM106B polymorphisms are associated with decreased TMEM106B expression. Together, these data raise the possibility that reduction of TMEM106B levels may protect against the pathogenic effects of progranulin haploinsufficiency. We crossed Tmem106b +/- mice with Grn +/- mice, which model the progranulin haploinsufficiency of GRN mutation carriers and develop age-dependent social deficits and lysosomal abnormalities in the brain. We tested whether partial Tmem106b reduction could normalize the social deficits and lysosomal abnormalities of Grn +/- mice. Partial reduction of Tmem106b levels did not correct the social deficits of Grn +/- mice. Tmem106b reduction also failed to normalize most lysosomal abnormalities of Grn +/- mice, except for β-glucuronidase activity, which was suppressed by Tmem106b reduction and increased by progranulin insufficiency. These data do not support the hypothesis that Tmem106b reduction protects against the pathogenic effects of progranulin haploinsufficiency, but do show that Tmem106b reduction normalizes some

  2. Congenital Hyperinsulinism in Infants with Turner Syndrome: Possible Association with Monosomy X and KDM6A Haploinsufficiency.

    Science.gov (United States)

    Gibson, Christopher E; Boodhansingh, Kara E; Li, Changhong; Conlin, Laura; Chen, Pan; Becker, Susan A; Bhatti, Tricia; Bamba, Vaneeta; Adzick, N Scott; De Leon, Diva D; Ganguly, Arupa; Stanley, Charles A

    2018-06-14

    Previous case reports have suggested a possible association of congenital hyperinsulinism with Turner syndrome. We examined the clinical and molecular features in girls with both congenital hyperinsulinism and Turner syndrome seen at The Children's Hospital of Philadelphia (CHOP) between 1974 and 2017. Records of girls with hyperinsulinism and Turner syndrome were reviewed. Insulin secretion was studied in pancreatic islets and in mouse islets treated with an inhibitor of KDM6A, an X chromosome gene associated with hyperinsulinism in Kabuki syndrome. Hyperinsulinism was diagnosed in 12 girls with Turner syndrome. Six were diazoxide-unresponsive; 3 had pancreatectomies. The incidence of Turner syndrome among CHOP patients with hyperinsulinism (10 of 1,050 from 1997 to 2017) was 48 times more frequent than expected. The only consistent chromosomal anomaly in these girls was the presence of a 45,X cell line. Studies of isolated islets from 1 case showed abnormal elevated cytosolic calcium and heightened sensitivity to amino acid-stimulated insulin release; similar alterations were demonstrated in mouse islets treated with a KDM6A inhibitor. These results demonstrate a higher than expected frequency of Turner syndrome among children with hyperinsulinism. Our data suggest that haploinsufficiency for KDM6A due to mosaic X chromosome monosomy may be responsible for hyperinsulinism in Turner syndrome. © 2018 S. Karger AG, Basel.

  3. Haploinsufficiency for Core Exon Junction Complex Components Disrupts Embryonic Neurogenesis and Causes p53-Mediated Microcephaly.

    Directory of Open Access Journals (Sweden)

    Hanqian Mao

    2016-09-01

    Full Text Available The exon junction complex (EJC is an RNA binding complex comprised of the core components Magoh, Rbm8a, and Eif4a3. Human mutations in EJC components cause neurodevelopmental pathologies. Further, mice heterozygous for either Magoh or Rbm8a exhibit aberrant neurogenesis and microcephaly. Yet despite the requirement of these genes for neurodevelopment, the pathogenic mechanisms linking EJC dysfunction to microcephaly remain poorly understood. Here we employ mouse genetics, transcriptomic and proteomic analyses to demonstrate that haploinsufficiency for each of the 3 core EJC components causes microcephaly via converging regulation of p53 signaling. Using a new conditional allele, we first show that Eif4a3 haploinsufficiency phenocopies aberrant neurogenesis and microcephaly of Magoh and Rbm8a mutant mice. Transcriptomic and proteomic analyses of embryonic brains at the onset of neurogenesis identifies common pathways altered in each of the 3 EJC mutants, including ribosome, proteasome, and p53 signaling components. We further demonstrate all 3 mutants exhibit defective splicing of RNA regulatory proteins, implying an EJC dependent RNA regulatory network that fine-tunes gene expression. Finally, we show that genetic ablation of one downstream pathway, p53, significantly rescues microcephaly of all 3 EJC mutants. This implicates p53 activation as a major node of neurodevelopmental pathogenesis following EJC impairment. Altogether our study reveals new mechanisms to help explain how EJC mutations influence neurogenesis and underlie neurodevelopmental disease.

  4. SERCA2 Haploinsufficiency in a Mouse Model of Darier Disease Causes a Selective Predisposition to Heart Failure

    Directory of Open Access Journals (Sweden)

    Vikram Prasad

    2015-01-01

    Full Text Available Null mutations in one copy of ATP2A2, the gene encoding sarco/endoplasmic reticulum Ca2+-ATPase isoform 2 (SERCA2, cause Darier disease in humans, a skin condition involving keratinocytes. Cardiac function appears to be unimpaired in Darier disease patients, with no evidence that SERCA2 haploinsufficiency itself causes heart disease. However, SERCA2 deficiency is widely considered a contributing factor in heart failure. We therefore analyzed Atp2a2 heterozygous mice to determine whether SERCA2 haploinsufficiency can exacerbate specific heart disease conditions. Despite reduced SERCA2a levels in heart, Atp2a2 heterozygous mice resembled humans in exhibiting normal cardiac physiology. When subjected to hypothyroidism or crossed with a transgenic model of reduced myofibrillar Ca2+-sensitivity, SERCA2 deficiency caused no enhancement of the disease state. However, when combined with a transgenic model of increased myofibrillar Ca2+-sensitivity, SERCA2 haploinsufficiency caused rapid onset of hypertrophy, decompensation, and death. These effects were associated with reduced expression of the antiapoptotic Hax1, increased levels of the proapoptotic genes Chop and Casp12, and evidence of perturbations in energy metabolism. These data reveal myofibrillar Ca2+-sensitivity to be an important determinant of the cardiac effects of SERCA2 haploinsufficiency and raise the possibility that Darier disease patients are more susceptible to heart failure under certain conditions.

  5. Short stature caused by isolated SHOX gene haploinsufficiency: update on the diagnosis and treatment.

    Science.gov (United States)

    Jorge, Alexander A L; Funari, Mariana Fa; Nishi, Mirian Y; Mendonca, Berenice B

    2010-12-01

    Heterozygous SHOX defects are observed in about 50 to 90% of patients with Leri-Weill dyschondrosteosis (LWD), a common dominant inherited skeletal dysplasia; and in 2 to 15% of children with idiopathic short stature (ISS), indicating that SHOX defects are the most important monogenetic cause of short stature. In addition, children selected by disproportionate idiopathic short stature had a higher frequency of SHOX mutations (22%). A careful clinical evaluation of family members with short stature is recommended since it usually revealed LWD patients in families first classified as having ISS or familial short stature. SHOX-molecular analysis is indicated in families with LWD and ISS children with disproportionate short stature. Treatment with recombinant human growth hormone is considered an accepted approach to treat short stature associated with isolated SHOX defect. Here we review clinical, molecular and therapeutic aspects of SHOX haploinsufficiency.

  6. IGF-1 receptor haploinsufficiency leads to age-dependent development of metabolic syndrome.

    Science.gov (United States)

    Thakur, Sachin; Garg, Neha; Zhang, Ning; Hussey, Sophie E; Musi, Nicolas; Adamo, Martin L

    2017-05-13

    Individuals born small for gestational age (SGA) are at a higher risk of developing the metabolic syndrome later in life. IGF-1 resistance has been reported in placentae from SGA births and mutations in the Igf1 receptor gene have been reported in several cohorts of SGA subjects. We have used the Igf1r heterozygous (Igf1r +/- ) male mouse as a model to investigate the mechanisms by which Igf1r haploinsufficiency leads to insulin resistance. Despite exhibiting IGF-1 resistance, insulin signaling is enhanced in young Igf1r +/- mice but is attenuated in the muscle of old Igf1r +/- mice. Although smaller than WT (wild type) mice, old-aged Igf1r +/- had increased adiposity and exhibit increased lipogenesis. We hypothesize that IGF-1 resistance initially causes a transient increase in insulin signaling thereby promoting a lipogenic phenotype, which subsequently leads to insulin resistance. Copyright © 2017. Published by Elsevier Inc.

  7. Expanding the phenotypic spectrum of ARID1B-mediated disorders and identification of altered cell-cycle dynamics due to ARID1B haploinsufficiency.

    Science.gov (United States)

    Sim, Joe C H; White, Susan M; Fitzpatrick, Elizabeth; Wilson, Gabrielle R; Gillies, Greta; Pope, Kate; Mountford, Hayley S; Torring, Pernille M; McKee, Shane; Vulto-van Silfhout, Anneke T; Jhangiani, Shalini N; Muzny, Donna M; Leventer, Richard J; Delatycki, Martin B; Amor, David J; Lockhart, Paul J

    2014-03-27

    Mutations in genes encoding components of the Brahma-associated factor (BAF) chromatin remodeling complex have recently been shown to contribute to multiple syndromes characterised by developmental delay and intellectual disability. ARID1B mutations have been identified as the predominant cause of Coffin-Siris syndrome and have also been shown to be a frequent cause of nonsyndromic intellectual disability. Here, we investigate the molecular basis of a patient with an overlapping but distinctive phenotype of intellectual disability, plantar fat pads and facial dysmorphism. High density microarray analysis of the patient demonstrated a heterozygous deletion at 6q25.3, which resulted in the loss of four genes including AT Rich Interactive Domain 1B (ARID1B). Subsequent quantitative real-time PCR analysis revealed ARID1B haploinsufficiency in the patient. Analysis of both patient-derived and ARID1B knockdown fibroblasts after serum starvation demonstrated delayed cell cycle re-entry associated with reduced cell number in the S1 phase. Based on the patient's distinctive phenotype, we ascertained four additional patients and identified heterozygous de novo ARID1B frameshift or nonsense mutations in all of them. This study broadens the spectrum of ARID1B associated phenotypes by describing a distinctive phenotype including plantar fat pads but lacking the hypertrichosis or fifth nail hypoplasia associated with Coffin-Siris syndrome. We present the first direct evidence in patient-derived cells that alterations in cell cycle contribute to the underlying pathogenesis of syndromes associated with ARID1B haploinsufficiency.

  8. Progranulin haploinsufficiency causes biphasic social dominance abnormalities in the tube test.

    Science.gov (United States)

    Arrant, A E; Filiano, A J; Warmus, B A; Hall, A M; Roberson, E D

    2016-07-01

    Loss-of-function mutations in progranulin (GRN) are a major autosomal dominant cause of frontotemporal dementia (FTD), a neurodegenerative disorder in which social behavior is disrupted. Progranulin-insufficient mice, both Grn(+/-) and Grn(-/-) , are used as models of FTD due to GRN mutations, with Grn(+/-) mice mimicking the progranulin haploinsufficiency of FTD patients with GRN mutations. Grn(+/-) mice have increased social dominance in the tube test at 6 months of age, although this phenotype has not been reported in Grn(-/-) mice. In this study, we investigated how the tube test phenotype of progranulin-insufficient mice changes with age, determined its robustness under several testing conditions, and explored the associated cellular mechanisms. We observed biphasic social dominance abnormalities in Grn(+/-) mice: at 6-8 months, Grn(+/-) mice were more dominant than wild-type littermates, while after 9 months of age, Grn(+/-) mice were less dominant. In contrast, Grn(-/-) mice did not exhibit abnormal social dominance, suggesting that progranulin haploinsufficiency has distinct effects from complete progranulin deficiency. The biphasic tube test phenotype of Grn(+/-) mice was associated with abnormal cellular signaling and neuronal morphology in the amygdala and prefrontal cortex. At 6-9 months, Grn(+/-) mice exhibited increased mTORC2/Akt signaling in the amygdala and enhanced dendritic arbors in the basomedial amygdala, and at 9-16 months Grn(+/-) mice exhibited diminished basal dendritic arbors in the prelimbic cortex. These data show a progressive change in tube test dominance in Grn(+/-) mice and highlight potential underlying mechanisms by which progranulin insufficiency may disrupt social behavior. © 2016 John Wiley & Sons Ltd and International Behavioural and Neural Genetics Society.

  9. Genetic Modifiers of Cardiovascular Phenotype Caused by Elastin Haploinsufficiency Act by Extrinsic Noncomplementation*

    Science.gov (United States)

    Kozel, Beth A.; Knutsen, Russell H.; Ye, Li; Ciliberto, Christopher H.; Broekelmann, Thomas J.; Mecham, Robert P.

    2011-01-01

    Elastin haploinsufficiency causes the cardiovascular complications associated with Williams-Beuren syndrome and isolated supravalvular aortic stenosis. Significant variability exists in the vascular pathology in these individuals. Using the Eln+/− mouse, we sought to identify the source of this variability. Following outcrossing of C57Bl/6J Eln+/−, two backgrounds were identified whose cardiovascular parameters deviated significantly from the parental strain. F1 progeny of the C57Bl/6J; Eln+/−x129X1/SvJ were more hypertensive and their arteries less compliant. In contrast, Eln+/− animals crossed to DBA/2J were protected from the pathologic changes associated with elastin insufficiency. Among the crosses, aortic elastin and collagen content did not correlate with quantitative vasculopathy traits. Quantitative trait locus analysis performed on F2 C57; Eln+/−x129 intercrosses identified highly significant peaks on chromosome 1 (LOD 9.7) for systolic blood pressure and on chromosome 9 (LOD 8.7) for aortic diameter. Additional peaks were identified that affect only Eln+/−, including a region upstream of Eln on chromosome 5 (LOD 4.5). Bioinformatic analysis of the quantitative trait locus peaks revealed several interesting candidates, including Ren1, Ncf1, and Nos1; genes whose functions are unrelated to elastic fiber assembly, but whose effects may synergize with elastin insufficiency to predispose to hypertension and stiffer blood vessels. Real time RT-PCR studies show background-specific increased expression of Ncf1 (a subunit of the NOX2 NAPDH oxidase) that parallel the presence of increased oxidative stress in Eln+/− aortas. This finding raises the possibility that polymorphisms in genes affecting the generation of reactive oxygen species alter cardiovascular function in individuals with elastin haploinsufficiency through extrinsic noncomplementation. PMID:22049077

  10. Haploinsufficiency of a spliceosomal GTPase encoded by EFTUD2 causes mandibulofacial dysostosis with microcephaly.

    Science.gov (United States)

    Lines, Matthew A; Huang, Lijia; Schwartzentruber, Jeremy; Douglas, Stuart L; Lynch, Danielle C; Beaulieu, Chandree; Guion-Almeida, Maria Leine; Zechi-Ceide, Roseli Maria; Gener, Blanca; Gillessen-Kaesbach, Gabriele; Nava, Caroline; Baujat, Geneviève; Horn, Denise; Kini, Usha; Caliebe, Almuth; Alanay, Yasemin; Utine, Gulen Eda; Lev, Dorit; Kohlhase, Jürgen; Grix, Arthur W; Lohmann, Dietmar R; Hehr, Ute; Böhm, Detlef; Majewski, Jacek; Bulman, Dennis E; Wieczorek, Dagmar; Boycott, Kym M

    2012-02-10

    Mandibulofacial dysostosis with microcephaly (MFDM) is a rare sporadic syndrome comprising craniofacial malformations, microcephaly, developmental delay, and a recognizable dysmorphic appearance. Major sequelae, including choanal atresia, sensorineural hearing loss, and cleft palate, each occur in a significant proportion of affected individuals. We present detailed clinical findings in 12 unrelated individuals with MFDM; these 12 individuals compose the largest reported cohort to date. To define the etiology of MFDM, we employed whole-exome sequencing of four unrelated affected individuals and identified heterozygous mutations or deletions of EFTUD2 in all four. Validation studies of eight additional individuals with MFDM demonstrated causative EFTUD2 mutations in all affected individuals tested. A range of EFTUD2-mutation types, including null alleles and frameshifts, is seen in MFDM, consistent with haploinsufficiency; segregation is de novo in all cases assessed to date. U5-116kD, the protein encoded by EFTUD2, is a highly conserved spliceosomal GTPase with a central regulatory role in catalytic splicing and post-splicing-complex disassembly. MFDM is the first multiple-malformation syndrome attributed to a defect of the major spliceosome. Our findings significantly extend the range of reported spliceosomal phenotypes in humans and pave the way for further investigation in related conditions such as Treacher Collins syndrome. Copyright © 2012 The American Society of Human Genetics. Published by Elsevier Inc. All rights reserved.

  11. Characterizing haploinsufficiency of SHELL gene to improve fruit form prediction in introgressive hybrids of oil palm.

    Science.gov (United States)

    Teh, Chee-Keng; Muaz, Siti Dalila; Tangaya, Praveena; Fong, Po-Yee; Ong, Ai-Ling; Mayes, Sean; Chew, Fook-Tim; Kulaveerasingam, Harikrishna; Appleton, David

    2017-06-08

    The fundamental trait in selective breeding of oil palm (Eleais guineensis Jacq.) is the shell thickness surrounding the kernel. The monogenic shell thickness is inversely correlated to mesocarp thickness, where the crude palm oil accumulates. Commercial thin-shelled tenera derived from thick-shelled dura × shell-less pisifera generally contain 30% higher oil per bunch. Two mutations, sh MPOB (M1) and sh AVROS (M2) in the SHELL gene - a type II MADS-box transcription factor mainly present in AVROS and Nigerian origins, were reported to be responsible for different fruit forms. In this study, we have tested 1,339 samples maintained in Sime Darby Plantation using both mutations. Five genotype-phenotype discrepancies and eight controls were then re-tested with all five reported mutations (sh AVROS , sh MPOB , sh MPOB2 , sh MPOB3 and sh MPOB4 ) within the same gene. The integration of genotypic data, pedigree records and shell formation model further explained the haploinsufficiency effect on the SHELL gene with different number of functional copies. Some rare mutations were also identified, suggesting a need to further confirm the existence of cis-compound mutations in the gene. With this, the prediction accuracy of fruit forms can be further improved, especially in introgressive hybrids of oil palm. Understanding causative variant segregation is extremely important, even for monogenic traits such as shell thickness in oil palm.

  12. Dkk1 haploinsufficiency requires expression of Bmp2 for bone anabolic activity

    Science.gov (United States)

    Intini, Giuseppe; Nyman, Jeffry S.

    2015-01-01

    Bone fractures remain a serious health burden and prevention and enhanced healing of fractures has been obtained by augmenting either BMP or Wnt signaling. However, whether BMP and Wnt signaling are both required or are self-sufficient for anabolic and fracture healing activities has never been fully elucidated. Mice haploinsufficient for Dkk1 (Dkk1+/−) exhibit a high bone mass phenotype due to an up-regulation of canonical Wnt signaling while mice lacking Bmp2 expression in the limbs (Bmp2c/c;Prx1::cre) succumb to spontaneous fracture and are unable to initiate fracture healing; combined, these mice offer an opportunity to examine the requirement for activated BMP signaling on the anabolic and fracture healing activity of Wnts. When Dkk1+/− mice were crossed with Bmp2c/c;Prx1::cre mice, the offspring bearing both genetic alterations were unable to increase bone mass and heal fractures, indicating that increased canonical Wnt signaling is unable to exploit its activity in absence of Bmp2. Thus, our data suggest that BMP signaling is required for Wnt-mediated anabolic activity and that therapies aimed at preventing fractures and fostering fracture repair may need to target both pathways for maximal efficacy. PMID:25603465

  13. Evidence of Aortopathy in Mice with Haploinsufficiency of Notch1 in Nos3-Null Background

    Directory of Open Access Journals (Sweden)

    Sara N. Koenig

    2015-03-01

    Full Text Available Thoracic aortic aneurysms (TAA are a significant cause of morbidity and mortality in humans. While the exact etiology is unknown, genetic factors play an important role. Mutations in NOTCH1 have been linked to bicuspid aortic valve (BAV and aortopathy in humans. The aim of this study was to determine if haploinsufficiency of Notch1 contributes to aortopathy using Notch1+/−; Nos3−/− mice. Echocardiographic analysis of Notch1+/−; Nos3−/− mice reveals effacement of the sinotubular junction and a trend toward dilation of the aortic sinus. Furthermore, examination of the proximal aorta of Notch1+/−; Nos3−/− mice reveals elastic fiber degradation, a trend toward increased matrix metalloproteinase 2 expression, and increased smooth muscle cell apoptosis, features characteristic of aneurysmal disease. Although at a lower penetrance, we also found features consistent with aortopathic changes in Notch1 heterozygote mice and in Nos3-null mice. Our findings implicate a novel role for Notch1 in aortopathy of the proximal aorta.

  14. Identification of Genes in Saccharomyces cerevisiae that Are Haploinsufficient for Overcoming Amino Acid Starvation

    Directory of Open Access Journals (Sweden)

    Nancy S. Bae

    2017-04-01

    Full Text Available The yeast Saccharomyces cerevisiae responds to amino acid deprivation by activating a pathway conserved in eukaryotes to overcome the starvation stress. We have screened the entire yeast heterozygous deletion collection to identify strains haploinsufficient for growth in the presence of sulfometuron methyl, which causes starvation for isoleucine and valine. We have discovered that cells devoid of MET15 are sensitive to sulfometuron methyl, and loss of heterozygosity at the MET15 locus can complicate screening the heterozygous deletion collection. We identified 138 cases of loss of heterozygosity in this screen. After eliminating the issues of the MET15 loss of heterozygosity, strains isolated from the collection were retested on sulfometuron methyl. To determine the general effect of the mutations for a starvation response, SMM-sensitive strains were tested for the ability to grow in the presence of canavanine, which induces arginine starvation, and strains that were MET15 were also tested for growth in the presence of ethionine, which causes methionine starvation. Many of the genes identified in our study were not previously identified as starvation-responsive genes, including a number of essential genes that are not easily screened in a systematic way. The genes identified span a broad range of biological functions, including many involved in some level of gene expression. Several unnamed proteins have also been identified, giving a clue as to possible functions of the encoded proteins.

  15. Attenuated hypertrophic response to pressure overload in a lamin A/C haploinsufficiency mouse.

    Science.gov (United States)

    Cupesi, Mihaela; Yoshioka, Jun; Gannon, Joseph; Kudinova, Anastacia; Stewart, Colin L; Lammerding, Jan

    2010-06-01

    Inherited mutations cause approximately 30% of all dilated cardiomyopathy cases, with autosomal dominant mutations in the LMNA gene accounting for more than one third of these. The LMNA gene encodes the nuclear envelope proteins lamins A and C, which provide structural support to the nucleus and also play critical roles in transcriptional regulation. Functional deletion of a single allele is sufficient to trigger dilated cardiomyopathy in humans and mice. However, whereas Lmna(-/-) mice develop severe muscular dystrophy and dilated cardiomyopathy and die by 8 weeks of age, heterozygous Lmna(+/-) mice have a much milder phenotype, with changes in ventricular function and morphology only becoming apparent at 1 year of age. Here, we studied 8- to 20-week-old Lmna(+/-) mice and wild-type littermates in a pressure overload model to examine whether increased mechanical load can accelerate or exacerbate myocardial dysfunction in the heterozygotes. While overall survival was similar between genotypes, Lmna(+/-) animals had a significantly attenuated hypertrophic response to pressure overload as evidenced by reduced ventricular mass and myocyte size. Analysis of pressure overload-induced transcriptional changes suggested that the reduced hypertrophy in the Lmna(+/-) mice was accompanied by impaired activation of the mechanosensitive gene Egr-1. In conclusion, our findings provide further support for a critical role of lamins A and C in regulating the cellular response to mechanical stress in cardiomyocytes and demonstrate that haploinsufficiency of lamins A and C alone is sufficient to alter hypertrophic responses and cardiac function in the face of pressure overload in the heart. (c) 2009 Elsevier Ltd. All rights reserved.

  16. Haploinsufficiency of the retinoblastoma protein gene reduces diet-induced obesity, insulin resistance, and hepatosteatosis in mice

    DEFF Research Database (Denmark)

    Mercader, Josep; Ribot, Joan; Murano, Incoronata

    2009-01-01

    Brown adipose tissue activity dissipates energy as heat, and there is evidence that lack of the retinoblastoma protein (pRb) may favor the development of the brown adipocyte phenotype in adipose cells. In this work we assessed the impact of germ-line haploinsufficiency of the pRb gene (Rb) on the...... first evidence that partial deficiency in the Rb gene protects against the development of obesity and associated metabolic disturbances. Key words: brown adipose tissue, white adipose tissue, energy metabolism, genetic animal model....

  17. 1p13.2 deletion displays clinical features overlapping Noonan syndrome, likely related to NRAS gene haploinsufficiency

    Directory of Open Access Journals (Sweden)

    Natália Duarte Linhares

    Full Text Available Abstract Deletion-induced hemizygosity may unmask deleterious autosomal recessive variants and be a cause of the phenotypic variability observed in microdeletion syndromes. We performed complete exome sequencing (WES analysis to examine this possibility in a patient with 1p13.2 microdeletion. Since the patient displayed clinical features suggestive of Noonan Syndrome (NS, we also used WES to rule out the presence of pathogenic variants in any of the genes associated with the different types of NS. We concluded that the clinical findings could be attributed solely to the 1p13.2 haploinsufficiency. Retrospective analysis of other nine reported patients with 1p13.2 microdeletions showed that six of them also presented some characteristics of NS. In all these cases, the deleted segment included the NRAS gene. Gain-of-function mutations of NRAS gene are causally related to NS type 6. Thus, it is conceivable that NRAS haploinsufficiency and gain-of-function mutations may have similar clinical consequences. The same phenomenon has been described for two other genes belonging to the Ras/MAPK pathway: MAP2K2 and SHOC2. In conclusion, we here report genotype-phenotype correlations in patients with chromosome 1p13.2 microdeletions and we propose that NRAS may be a critical gene for the NS characteristics in the patients.

  18. MEF2C Haploinsufficiency features consistent hyperkinesis, variable epilepsy, and has a role in dorsal and ventral neuronal developmental pathways

    Science.gov (United States)

    Paciorkowski, Alex R.; Traylor, Ryan N.; Rosenfeld, Jill A.; Hoover, Jacqueline M.; Harris, Catharine J.; Winter, Susan; Lacassie, Yves; Bialer, Martin; Lamb, Allen N.; Schultz, Roger A.; Berry-Kravis, Elizabeth; Porter, Brenda E.; Falk, Marni; Venkat, Anu; Vanzo, Rena J.; Cohen, Julie S.; Fatemi, Ali; Dobyns, William B.; Shaffer, Lisa G.; Ballif, Blake C.; Marsh, Eric D.

    2013-01-01

    MEF2C haploinsufficiency syndrome is an emerging neurodevelopmental disorder associated with intellectual disability, autistic features, epilepsy, and abnormal movements. We report 16 new patients with MEF2C haploinsufficiency, including the oldest reported patient with MEF2C deletion at 5q14.3. We detail the neurobehavioral phenotype, epilepsy, and abnormal movements, and compare our subjects with those previously reported in the literature. We also investigate Mef2c expression in the developing mouse forebrain. A spectrum of neurofunctional deficits emerges, with hyperkinesis a consistent finding. Epilepsy varied from absent to severe, and included intractable myoclonic seizures and infantile spasms. Subjects with partial MEF2C deletion were statistically less likely to have epilepsy. Finally, we confirm that Mef2c is present both in dorsal primary neuroblasts and ventral gamma-aminobutyric acid(GABA)ergic interneurons in the forebrain of the developing mouse. Given interactions with several key neurodevelopmental genes such as ARX, FMR1, MECP2, and TBR1, it appears that MEF2C plays a role in several developmental stages of both dorsal and ventral neuronal cell types. PMID:23389741

  19. Heterozygous Lmna(delK32) mice develop dilated cardiomyopathy through a combined pathomechanism of haploinsufficiency and peptide toxicity

    DEFF Research Database (Denmark)

    Cattin, M. E.; Bertrand, A. T.; Schlossarek, S.

    2013-01-01

    itself has a clear deleterious effect on engineered heart tissues force of contraction, it also leads to the nuclear aggregation of viral-mediated expression of K32-lamin. In conclusion, Het mice are the first knock-in Lmna model with cardiac-specific phenotype at the heterozygous state. Altogether, our....... The pathomechanisms linking mutations to DCM remain to be elucidated. We investigated the phenotype and associated pathomechanisms of heterozygous Lmna(K32/) (Het) knock-in mice, which carry a human mutation. Het mice developed a cardiac-specific phenotype. Two phases, with two different pathomechanisms, could...... be observed that lead to the development of cardiac dysfunction, DCM and death between 35 and 70 weeks of age. In young Het hearts, there was a clear reduction in lamin A/C level, mainly due to the degradation of toxic K32-lamin. As a side effect, lamin A/C haploinsufficiency probably triggers the cardiac...

  20. Trehalose upregulates progranulin expression in human and mouse models of GRN haploinsufficiency: a novel therapeutic lead to treat frontotemporal dementia.

    Science.gov (United States)

    Holler, Christopher J; Taylor, Georgia; McEachin, Zachary T; Deng, Qiudong; Watkins, William J; Hudson, Kathryn; Easley, Charles A; Hu, William T; Hales, Chadwick M; Rossoll, Wilfried; Bassell, Gary J; Kukar, Thomas

    2016-06-24

    Progranulin (PGRN) is a secreted growth factor important for neuronal survival and may do so, in part, by regulating lysosome homeostasis. Mutations in the PGRN gene (GRN) are a common cause of frontotemporal lobar degeneration (FTLD) and lead to disease through PGRN haploinsufficiency. Additionally, complete loss of PGRN in humans leads to neuronal ceroid lipofuscinosis (NCL), a lysosomal storage disease. Importantly, Grn-/- mouse models recapitulate pathogenic lysosomal features of NCL. Further, GRN variants that decrease PGRN expression increase the risk of developing Alzheimer's disease (AD) and Parkinson's disease (PD). Together these findings demonstrate that insufficient PGRN predisposes neurons to degeneration. Therefore, compounds that increase PGRN levels are potential therapeutics for multiple neurodegenerative diseases. Here, we performed a cell-based screen of a library of known autophagy-lysosome modulators and identified multiple novel activators of a human GRN promoter reporter including several common mTOR inhibitors and an mTOR-independent activator of autophagy, trehalose. Secondary cellular screens identified trehalose, a natural disaccharide, as the most promising lead compound because it increased endogenous PGRN in all cell lines tested and has multiple reported neuroprotective properties. Trehalose dose-dependently increased GRN mRNA as well as intracellular and secreted PGRN in both mouse and human cell lines and this effect was independent of the transcription factor EB (TFEB). Moreover, trehalose rescued PGRN deficiency in human fibroblasts and neurons derived from induced pluripotent stem cells (iPSCs) generated from GRN mutation carriers. Finally, oral administration of trehalose to Grn haploinsufficient mice significantly increased PGRN expression in the brain. This work reports several novel autophagy-lysosome modulators that enhance PGRN expression and identifies trehalose as a promising therapeutic for raising PGRN levels to treat

  1. Haploinsufficiency of the insulin-like growth factor-1 receptor enhances endothelial repair and favorably modifies angiogenic progenitor cell phenotype.

    Science.gov (United States)

    Yuldasheva, Nadira Y; Rashid, Sheikh Tawqeer; Haywood, Natalie J; Cordell, Paul; Mughal, Romana; Viswambharan, Hema; Imrie, Helen; Sukumar, Piruthivi; Cubbon, Richard M; Aziz, Amir; Gage, Matthew; Mbonye, Kamatamu Amanda; Smith, Jessica; Galloway, Stacey; Skromna, Anna; Scott, D Julian A; Kearney, Mark T; Wheatcroft, Stephen B

    2014-09-01

    Defective endothelial regeneration predisposes to adverse arterial remodeling and is thought to contribute to cardiovascular disease in type 2 diabetes mellitus. We recently demonstrated that the type 1 insulin-like growth factor receptor (IGF1R) is a negative regulator of insulin sensitivity and nitric oxide bioavailability. In this report, we examined partial deletion of the IGF1R as a potential strategy to enhance endothelial repair. We assessed endothelial regeneration after wire injury in mice and abundance and function of angiogenic progenitor cells in mice with haploinsufficiency of the IGF1R (IGF1R(+/-)). Endothelial regeneration after arterial injury was accelerated in IGF1R(+/-) mice. Although the yield of angiogenic progenitor cells was lower in IGF1R(+/-) mice, these angiogenic progenitor cells displayed enhanced adhesion, increased secretion of insulin-like growth factor-1, and enhanced angiogenic capacity. To examine the relevance of IGF1R manipulation to cell-based therapy, we transfused IGF1R(+/-) bone marrow-derived CD117(+) cells into wild-type mice. IGF1R(+/-) cells accelerated endothelial regeneration after arterial injury compared with wild-type cells and did not alter atherosclerotic lesion formation. Haploinsufficiency of the IGF1R is associated with accelerated endothelial regeneration in vivo and enhanced tube forming and adhesive potential of angiogenic progenitor cells in vitro. Partial deletion of IGF1R in transfused bone marrow-derived CD117(+) cells enhanced their capacity to promote endothelial regeneration without altering atherosclerosis. Our data suggest that manipulation of the IGF1R could be exploited as novel therapeutic approach to enhance repair of the arterial wall after injury. © 2014 American Heart Association, Inc.

  2. Disruption of murine mp29/Syf2/Ntc31 gene results in embryonic lethality with aberrant checkpoint response.

    Directory of Open Access Journals (Sweden)

    Chia-Hsin Chen

    Full Text Available Human p29 is a putative component of spliceosomes, but its role in pre-mRNA is elusive. By siRNA knockdown and stable overexpression, we demonstrated that human p29 is involved in DNA damage response and Fanconi anemia pathway in cultured cells. In this study, we generated p29 knockout mice (mp29(GT/GT using the mp29 gene trap embryonic stem cells to study the role of mp29 in DNA damage response in vivo. Interruption of mp29 at both alleles resulted in embryonic lethality. Embryonic abnormality occurred as early as E6.5 in mp29(GT/GT mice accompanied with decreased mRNA levels of α-tubulin and Chk1. The reduction of α-tubulin and Chk1 mRNAs is likely due to an impaired post-transcriptional event. An aberrant G2/M checkpoint was found in mp29 gene trap embryos when exposed to aphidicolin and UV light. This embryonic lethality was rescued by crossing with mp29 transgenic mice. Additionally, the knockdown of zfp29 in zebrafish resulted in embryonic death at 72 hours of development postfertilization (hpf. A lower level of acetylated α-tubulin was also observed in zfp29 morphants. Together, these results illustrate an indispensable role of mp29 in DNA checkpoint response during embryonic development.

  3. Genetic and biochemical evidence that haploinsufficiency of the Nf1 tumor suppressor gene modulates melanocyte and mast cell fates in vivo.

    Science.gov (United States)

    Ingram, D A; Yang, F C; Travers, J B; Wenning, M J; Hiatt, K; New, S; Hood, A; Shannon, K; Williams, D A; Clapp, D W

    2000-01-03

    Neurofibromatosis type 1 (NF1) is a common autosomal-dominant disorder characterized by cutaneous neurofibromas infiltrated with large numbers of mast cells, melanocyte hyperplasia, and a predisposition to develop malignant neoplasms. NF1 encodes a GTPase activating protein (GAP) for Ras. Consistent with Knudson's "two hit" model of tumor suppressor genes, leukemias and malignant solid tumors in NF1 patients frequently demonstrate somatic loss of the normal NF1 allele. However, the phenotypic and biochemical consequences of heterozygous inactivation of Nf1 are largely unknown. Recently neurofibromin, the protein encoded by NF1, was shown to negatively regulate Ras activity in Nf1-/- murine myeloid hematopoietic cells in vitro through the c-kit receptor tyrosine kinase (dominant white spotting, W). Since the W and Nf1 locus appear to function along a common developmental pathway, we generated mice with mutations at both loci to examine potential interactions in vivo. Here, we show that haploinsufficiency at Nf1 perturbs cell fates in mast cells in vivo, and partially rescues coat color and mast cell defects in W(41) mice. Haploinsufficiency at Nf1 also increased mast cell proliferation, survival, and colony formation in response to Steel factor, the ligand for c-kit. Furthermore, haploinsufficiency was associated with enhanced Ras-mitogen-activated protein kinase activity, a major downstream effector of Ras, via wild-type and mutant (W(41)) c-kit receptors. These observations identify a novel interaction between c-kit and neurofibromin in vivo, and offer experimental evidence that haploinsufficiency of Nf1 alters both cellular and biochemical phenotypes in two cell lineages that are affected in individuals with NF1. Collectively, these data support the emerging concept that heterozygous inactivation of tumor suppressor genes may have profound biological effects in multiple cell types.

  4. Human NF-κB1 Haploinsufficiency and Epstein-Barr Virus-Induced Disease-Molecular Mechanisms and Consequences.

    Science.gov (United States)

    Hoeger, Birgit; Serwas, Nina Kathrin; Boztug, Kaan

    2017-01-01

    Nuclear factor kappa-light-chain-enhancer of activated B cells 1 (NF-κB1)-related human primary immune deficiencies have initially been characterized as defining a subgroup of common variable immunodeficiencies (CVIDs), representing intrinsic B-cell disorders with antibody deficiency and recurrent infections of various kind. Recent evidence indicates that NF-κB1 haploinsufficiency underlies a variable type of combined immunodeficiency (CID) affecting both B and T lymphocyte compartments, with a broadened spectrum of disease manifestations, including Epstein-Barr virus (EBV)-induced lymphoproliferative disease and immediate life-threatening consequences. As part of this review series focused on EBV-related primary immunodeficiencies, we discuss the current clinical and molecular understanding of monoallelic NFKB1 germline mutations with special focus on the emerging context of EBV-associated disease. We outline mechanistic implications of dysfunctional NF-κB1 in B and T cells and discuss the fatal relation of impaired T-cell function with the inability to clear EBV infections. Finally, we compare common and suggested treatment angles in the context of this complex disease.

  5. CHCHD10 mutations p.R15L and p.G66V cause motoneuron disease by haploinsufficiency.

    Science.gov (United States)

    Brockmann, Sarah J; Freischmidt, Axel; Oeckl, Patrick; Müller, Kathrin; Ponna, Srinivas K; Helferich, Anika M; Paone, Christoph; Reinders, Jörg; Kojer, Kerstin; Orth, Michael; Jokela, Manu; Auranen, Mari; Udd, Bjarne; Hermann, Andreas; Danzer, Karin M; Lichtner, Peter; Walther, Paul; Ludolph, Albert C; Andersen, Peter M; Otto, Markus; Kursula, Petri; Just, Steffen; Weishaupt, Jochen H

    2018-02-15

    Mutations in the mitochondrially located protein CHCHD10 cause motoneuron disease by an unknown mechanism. In this study, we investigate the mutations p.R15L and p.G66V in comparison to wild-type CHCHD10 and the non-pathogenic variant p.P34S in vitro, in patient cells as well as in the vertebrate in vivo model zebrafish. We demonstrate a reduction of CHCHD10 protein levels in p.R15L and p.G66V mutant patient cells to approximately 50%. Quantitative real-time PCR revealed that expression of CHCHD10 p.R15L, but not of CHCHD10 p.G66V, is already abrogated at the mRNA level. Altered secondary structure and rapid protein degradation are observed with regard to the CHCHD10 p.G66V mutant. In contrast, no significant differences in expression, degradation rate or secondary structure of non-pathogenic CHCHD10 p.P34S are detected when compared with wild-type protein. Knockdown of CHCHD10 expression in zebrafish to about 50% causes motoneuron pathology, abnormal myofibrillar structure and motility deficits in vivo. Thus, our data show that the CHCHD10 mutations p.R15L and p.G66V cause motoneuron disease primarily based on haploinsufficiency of CHCHD10. © The Author(s) 2018. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oup.com.

  6. Impaired associative fear learning in mice with complete loss or haploinsufficiency of AMPA GluR1 receptors

    Directory of Open Access Journals (Sweden)

    Michael Feyder

    2007-12-01

    Full Text Available There is compelling evidence that L-alpha-amino-3-hydroxy-5-methylisoxazole-4-propionate (AMPA glutamate receptors containing the GluR1 subunit contribute to the molecular mechanisms associated with learning. AMPA GluR1 glutamate receptor knockout mice (KO exhibit abnormal hippocampal and amygdala plasticity, and deficits on various assays for cognition including Pavlovian fear conditioning. Here we examined associative fear learning in mice with complete absence (KO or partial loss (heterozygous mutant, HET of GluR1 on multiple fear conditioning paradigms. After multi-trial delay or trace conditioning, KO displayed impaired tone and context fear recall relative to WT, whereas HET were normal. After one-trial delay conditioning, both KO and HET showed impaired tone and context recall. HET and KO showed normal nociceptive sensitivity in the hot plate and tail flick tests. These data demonstrate that the complete absence of GluR1 subunit-containing receptors prevents the formation of associative fear memories, while GluR1 haploinsufficiency is sufficient to impair one-trial fear learning. These findings support growing evidence of a major role for GluR1-containing AMPA receptors in amygdalamediated forms of learning and memory.

  7. Haploinsufficiency of KDM6A is associated with severe psychomotor retardation, global growth restriction, seizures and cleft palate.

    Science.gov (United States)

    Lindgren, Amelia M; Hoyos, Tatiana; Talkowski, Michael E; Hanscom, Carrie; Blumenthal, Ian; Chiang, Colby; Ernst, Carl; Pereira, Shahrin; Ordulu, Zehra; Clericuzio, Carol; Drautz, Joanne M; Rosenfeld, Jill A; Shaffer, Lisa G; Velsher, Lea; Pynn, Tania; Vermeesch, Joris; Harris, David J; Gusella, James F; Liao, Eric C; Morton, Cynthia C

    2013-05-01

    We describe a female subject (DGAP100) with a 46,X,t(X;5)(p11.3;q35.3)inv(5)(q35.3q35.1)dn, severe psychomotor retardation with hypotonia, global postnatal growth restriction, microcephaly, globally reduced cerebral volume, seizures, facial dysmorphia and cleft palate. Fluorescence in situ hybridization and whole-genome sequencing demonstrated that the X chromosome breakpoint disrupts KDM6A in the second intron. No genes were directly disrupted on chromosome 5. KDM6A is a histone 3 lysine 27 demethylase and a histone 3 lysine 4 methyltransferase. Expression of KDM6A is significantly reduced in DGAP100 lymphoblastoid cells compared to control samples. We identified nine additional cases with neurodevelopmental delay and various other features consistent with the DGAP100 phenotype with copy number variation encompassing KDM6A from microarray databases. We evaluated haploinsufficiency of kdm6a in a zebrafish model. kdm6a is expressed in the pharyngeal arches and ethmoid plate of the developing zebrafish, while a kdm6a morpholino knockdown exhibited craniofacial defects. We conclude KDM6A dosage regulation is associated with severe and diverse structural defects and developmental abnormalities.

  8. Autosomal dominant inheritance of Williams-Beuren syndrome in a father and son with haploinsufficiency for FKBP6.

    Science.gov (United States)

    Metcalfe, Kay; Simeonov, Emil; Beckett, William; Donnai, Dian; Tassabehji, May

    2005-04-01

    Williams-Beuren syndrome (WBS) is a neurodevelopmental microdeletion disorder that usually occurs sporadically due to its location within a highly repetitive genomic region that is unstable and prone to unequal cross-over during meiosis. The consequential loss of chromosomal material includes approximately 1.5 Mb of DNA at 7q11.23. Whilst cases of dominant inheritance have been described in the literature, there have been few reports of molecular confirmation and none have carried out detailed genotyping. We describe a Bulgarian father and son with WBS detected by fluorescent in situ hybridisation (with an elastin gene probe) and loss of heterozygosity mapping using microsatellite markers located in the critical region. These individuals appear to have a common WBS heterozygous deletion, confirming the expected dominant transmission and adding to the few familial cases reported. The deletion includes the gene FKBP6 which has recently been shown to play a role in homologous chromosome pairing in meiosis and male fertility in mouse models. Homozygous Fkbp6 -/- male mice are infertile and our data suggests that haploinsufficiency for FKBP6 does not appear to preclude male fertility in WBS, although male infertility involving this gene has the potential to follow the mouse model as a human autosomal recessive condition.

  9. Human Pluripotent Stem Cell-derived Cortical Neurons for High Throughput Medication Screening in Autism: A Proof of Concept Study in SHANK3 Haploinsufficiency Syndrome

    Directory of Open Access Journals (Sweden)

    Hélène Darville

    2016-07-01

    Full Text Available Autism spectrum disorders affect millions of individuals worldwide, but their heterogeneity complicates therapeutic intervention that is essentially symptomatic. A versatile yet relevant model to rationally screen among hundreds of therapeutic options would help improving clinical practice. Here we investigated whether neurons differentiated from pluripotent stem cells can provide such a tool using SHANK3 haploinsufficiency as a proof of principle. A library of compounds was screened for potential to increase SHANK3 mRNA content in neurons differentiated from control human embryonic stem cells. Using induced pluripotent stem cell technology, active compounds were then evaluated for efficacy in correcting dysfunctional networks of neurons differentiated from individuals with deleterious point mutations of SHANK3. Among 202 compounds tested, lithium and valproic acid showed the best efficacy at corrected SHANK3 haploinsufficiency associated phenotypes in cellulo. Lithium pharmacotherapy was subsequently provided to one patient and, after one year, an encouraging decrease in autism severity was observed. This demonstrated that pluripotent stem cell-derived neurons provide a novel cellular paradigm exploitable in the search for specific disease-modifying treatments.

  10. Haploinsufficiency of the 22q11.2 microdeletion gene Mrpl40 disrupts short-term synaptic plasticity and working memory through dysregulation of mitochondrial calcium.

    Science.gov (United States)

    Devaraju, P; Yu, J; Eddins, D; Mellado-Lagarde, M M; Earls, L R; Westmoreland, J J; Quarato, G; Green, D R; Zakharenko, S S

    2017-09-01

    Hemizygous deletion of a 1.5- to 3-megabase region on chromosome 22 causes 22q11.2 deletion syndrome (22q11DS), which constitutes one of the strongest genetic risks for schizophrenia. Mouse models of 22q11DS have abnormal short-term synaptic plasticity that contributes to working-memory deficiencies similar to those in schizophrenia. We screened mutant mice carrying hemizygous deletions of 22q11DS genes and identified haploinsufficiency of Mrpl40 (mitochondrial large ribosomal subunit protein 40) as a contributor to abnormal short-term potentiation (STP), a major form of short-term synaptic plasticity. Two-photon imaging of the genetically encoded fluorescent calcium indicator GCaMP6, expressed in presynaptic cytosol or mitochondria, showed that Mrpl40 haploinsufficiency deregulates STP via impaired calcium extrusion from the mitochondrial matrix through the mitochondrial permeability transition pore. This led to abnormally high cytosolic calcium transients in presynaptic terminals and deficient working memory but did not affect long-term spatial memory. Thus, we propose that mitochondrial calcium deregulation is a novel pathogenic mechanism of cognitive deficiencies in schizophrenia.

  11. results

    Directory of Open Access Journals (Sweden)

    Salabura Piotr

    2017-01-01

    Full Text Available HADES experiment at GSI is the only high precision experiment probing nuclear matter in the beam energy range of a few AGeV. Pion, proton and ion beams are used to study rare dielectron and strangeness probes to diagnose properties of strongly interacting matter in this energy regime. Selected results from p + A and A + A collisions are presented and discussed.

  12. Microcephalin and pericentrin regulate mitotic entry via centrosome-associated Chk1

    DEFF Research Database (Denmark)

    Tibelius, Alexandra; Marhold, Joachim; Zentgraf, Hanswalter

    2009-01-01

    Primary microcephaly, Seckel syndrome, and microcephalic osteodysplastic primordial dwarfism type II (MOPD II) are disorders exhibiting marked microcephaly, with small brain sizes reflecting reduced neuron production during fetal life. Although primary microcephaly can be caused by mutations...

  13. Endoglin haploinsufficiency attenuates radiation-induced deterioration of kidney function in mice

    International Nuclear Information System (INIS)

    Scharpfenecker, Marion; Floot, Ben; Russell, Nicola S.; Coppes, Rob P.; Stewart, Fiona A.

    2013-01-01

    Background and Purpose: Endoglin is a transforming growth receptor beta (TGF-β) co-receptor, which plays a crucial role in the development of late normal tissue damage. Mice with halved endoglin levels (Eng +/- mice) develop less inflammation, vascular damage and fibrosis after kidney irradiation compared to their wild type littermates (Eng +/+ mice). This study was aimed at investigating whether reduced tissue damage in Eng +/- mice also results in superior kidney function. Material and Methods: Kidneys of Eng +/+ and Eng +/- mice were irradiated with a single dose of 14 Gy. Functional kidney parameters and kidney histology were analysed at 20, 30 and 40 weeks after irradiation. Results: Eng +/- mice displayed improved kidney parameters (haematocrit, BUN) compared to Eng +/+ mice at 40 weeks after irradiation. Irradiation of Eng +/+ kidneys damaged the vascular network and led to an increase in PDGFR-β positive cells, indicative of fibrosis-promoting myofibroblasts. Compared to Eng +/+ kidneys, vascular perfusion and number of PDGFR-β positive cells were reduced in Eng +/- control mice; however, this did not further deteriorate after irradiation. Conclusions: Taken together, we show that not only kidney morphology, but also kidney function is improved after irradiation in Eng +/- compared to Eng +/+ mice

  14. Haploinsufficient Bmp4 ocular phenotypes include anterior segment dysgenesis with elevated intraocular pressure

    Directory of Open Access Journals (Sweden)

    Nusinowitz Steven

    2001-11-01

    Full Text Available Abstract Background Glaucoma is a blinding disease usually associated with high intraocular pressure (IOP. In some families, abnormal anterior segment development contributes to glaucoma. The genes causing anterior segment dysgenesis and glaucoma in most of these families are not identified and the affected developmental processes are poorly understood. Bone morphogenetic proteins (BMPs participate in various developmental processes. We tested the importance of Bmp4 gene dosage for ocular development and developmental glaucoma. Results Bmp4+/- mice have anterior segment abnormalities including malformed, absent or blocked trabecular meshwork and Schlemm's canal drainage structures. Mice with severe drainage structure abnormalities, over 80% or more of their angle's extent, have elevated IOP. The penetrance and severity of abnormalities is strongly influenced by genetic background, being most severe on the C57BL/6J background and absent on some other backgrounds. On the C57BL/6J background there is also persistence of the hyaloid vasculature, diminished numbers of inner retinal cells, and absence of the optic nerve. Conclusions We demonstrate that heterozygous deficiency of BMP4 results in anterior segment dysgenesis and elevated IOP. The abnormalities are similar to those in human patients with developmental glaucoma. Thus, BMP4 is a strong candidate to contribute to Axenfeld-Rieger anomaly and other developmental conditions associated with human glaucoma. BMP4 also participates in posterior segment development and wild-type levels are usually critical for optic nerve development on the C57BL/6J background. Bmp4+/- mice are useful for studying various components of ocular development, and may allow identification of strain specific modifiers affecting a variety of ocular phenotypes.

  15. Induction of B-cell lymphoma by UVB Radiation in p53 Haploinsufficient Mice

    Directory of Open Access Journals (Sweden)

    Ullrich Stephen E

    2011-01-01

    Full Text Available Abstract Background The incidence of non-Hodgkin's lymphoma has increased over recent years. The exact etiology of lymphoma remains unknown. Ultraviolet light exposure has been associated with the development of internal lymphoid malignancies and some reports suggest that it may play a role in the development of lymphoma in humans. Here we describe the characterization and progression of lymphoma in p53 heterozygous mice exposed to UVB irradiation. Methods UVB-irradiated p53+/- mice developed enlargement of the spleen. Isolated spleen cells were transplanted into Rag deficient hosts. The UV-induced tumor cells were analyzed by flow cytometry. The tumor cells were tagged with GFP to study their metastatic potential. SKY and karyotypic analysis were carried out for the detection of chromosomal abnormalities. Functional assays included in vitro class switch recombination assay, immunoglobulin rearrangement assay, as well as cytokine profiling. Results UVB-exposed mice showed enlargement of the spleen and lymph nodes. Cells transplanted into Rag deficient mice developed aggressive tumors that infiltrated the lymph nodes, the spleen and the bone marrow. The tumor cells did not grow in immune competent syngeneic C57Bl/6 mice yet showed a modest growth in UV-irradiated B6 mice. Phenotypic analysis of these tumor cells revealed these cells are positive for B cell markers CD19+, CD5+, B220+, IgM+ and negative for T cell, NK or dendritic cell markers. The UV-induced tumor cells underwent robust in vitro immunoglobulin class switch recombination in response to lipopolysaccharide. Cytogenetic analysis revealed a t(14;19 translocation and trisomy of chromosome 6. These tumor cells secret IL-10, which can promote tumor growth and cause systemic immunosuppression. Conclusion UV-irradiated p53+/- mice developed lymphoid tumors that corresponded to a mature B cell lymphoma. Our results suggest that an indirect mechanism is involved in the development of internal

  16. Exercise does not protect against MPTP-induced neurotoxicity in BDNF haploinsufficient mice.

    Directory of Open Access Journals (Sweden)

    Kim M Gerecke

    Full Text Available Exercise has been demonstrated to potently protect substantia nigra pars compacta (SN dopaminergic neurons from 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP-induced neurotoxicity. One mechanism proposed to account for this neuroprotection is the upregulation of neurotrophic factors. Several neurotrophic factors, including Brain Derived Neurotrophic Factor (BDNF, have been shown to upregulate in response to exercise. In order to determine if exercise-induced neuroprotection is dependent upon BDNF, we compared the neuroprotective effects of voluntary exercise in mice heterozygous for the BDNF gene (BDNF+/- with strain-matched wild-type (WT mice. Stereological estimates of SNpc DA neurons from WT mice allowed 90 days exercise via unrestricted running demonstrated complete protection against the MPTP-induced neurotoxicity. However, BDNF+/- mice allowed 90 days of unrestricted exercise were not protected from MPTP-induced SNpc DA neuron loss. Proteomic analysis comparing SN and striatum from 90 day exercised WT and BDNF+/- mice showed differential expression of proteins related to energy regulation, intracellular signaling and trafficking. These results suggest that a full genetic complement of BDNF is critical for the exercise-induced neuroprotection of SNpc DA neurons.

  17. VDR haploinsufficiency impacts body composition and skeletal acquisition in a gender-specific manner.

    Science.gov (United States)

    de Paula, Francisco J A; Dick-de-Paula, Ingrid; Bornstein, Sheila; Rostama, Bahman; Le, Phuong; Lotinun, Sutada; Baron, Roland; Rosen, Clifford J

    2011-09-01

    The vitamin D receptor (VDR) is crucial for virtually all of vitamin D's actions and is thought to be ubiquitously expressed. We hypothesized that disruption of one allele of the VDR gene would impact bone development and would have metabolic consequences. Body composition and bone mass (BMD) in VDR heterozygous (VDR HET) mice were compared to those obtained in male and female VDR KO and WT mice at 8 weeks of age. Male mice were also evaluated at 16 weeks, and bone marrow mesenchymal stem cell (MSC) differentiation was evaluated in VDR female mice. Additionally, female VDR HET and WT mice received intermittent PTH treatment or vehicle (VH) for 4 weeks. BMD was determined at baseline and after treatment. MRI was done in vivo at the end of treatment; μCT and bone histomorphometry were performed after killing the animals. VDR HET male mice had normal skeletal development until 16 weeks of age but showed significantly less gain in fat mass than WT mice. In contrast, female VDR HET mice showed decreased total-body BMD at age 8 weeks but had a normal skeletal response to PTH. MSC differentiation was also impaired in VDR HET female mice. Thus, female VDR HET mice show early impairment in bone acquisition, while male VDR HET mice exhibit a lean phenotype. Our results indicate that the VDR HET mouse is a useful model for studying the metabolic and skeletal impact of decreased vitamin D sensitivity.

  18. Induction of B-cell lymphoma by UVB Radiation in p53 Haploinsufficient Mice

    International Nuclear Information System (INIS)

    Puebla-Osorio, Nahum; Miyahara, Yasuko; Coimbatore, Sreevidya; Limón-Flores, Alberto Y; Kazimi, Nasser; Ullrich, Stephen E; Zhu, Chengming

    2011-01-01

    The incidence of non-Hodgkin's lymphoma has increased over recent years. The exact etiology of lymphoma remains unknown. Ultraviolet light exposure has been associated with the development of internal lymphoid malignancies and some reports suggest that it may play a role in the development of lymphoma in humans. Here we describe the characterization and progression of lymphoma in p53 heterozygous mice exposed to UVB irradiation. UVB-irradiated p53 +/- mice developed enlargement of the spleen. Isolated spleen cells were transplanted into Rag deficient hosts. The UV-induced tumor cells were analyzed by flow cytometry. The tumor cells were tagged with GFP to study their metastatic potential. SKY and karyotypic analysis were carried out for the detection of chromosomal abnormalities. Functional assays included in vitro class switch recombination assay, immunoglobulin rearrangement assay, as well as cytokine profiling. UVB-exposed mice showed enlargement of the spleen and lymph nodes. Cells transplanted into Rag deficient mice developed aggressive tumors that infiltrated the lymph nodes, the spleen and the bone marrow. The tumor cells did not grow in immune competent syngeneic C57Bl/6 mice yet showed a modest growth in UV-irradiated B6 mice. Phenotypic analysis of these tumor cells revealed these cells are positive for B cell markers CD19 + , CD5 + , B220 + , IgM + and negative for T cell, NK or dendritic cell markers. The UV-induced tumor cells underwent robust in vitro immunoglobulin class switch recombination in response to lipopolysaccharide. Cytogenetic analysis revealed a t(14;19) translocation and trisomy of chromosome 6. These tumor cells secret IL-10, which can promote tumor growth and cause systemic immunosuppression. UV-irradiated p53 +/- mice developed lymphoid tumors that corresponded to a mature B cell lymphoma. Our results suggest that an indirect mechanism is involved in the development of internal tumors after chronic exposure to UV light. The

  19. EPHA4 haploinsufficiency is responsible for the short stature of a patient with 2q35-q36.2 deletion and Waardenburg syndrome.

    Science.gov (United States)

    Li, Chuan; Chen, Rongyu; Fan, Xin; Luo, Jingsi; Qian, Jiale; Wang, Jin; Xie, Bobo; Shen, Yiping; Chen, Shaoke

    2015-04-11

    Waardenburg syndrome type I (WS1), an auditory-pigmentary genetic disorder, is caused by heterozygous loss-of-function mutations in PAX3. Abnormal physical signs such as dystopia canthorum, patchy hypopigmentation and sensorineural hearing loss are common, but short stature is not associated with WS1. We reported a 4-year and 6 month-old boy with a rare combination of WS1 and severe short stature (83.5 cm (-5.8SD)). His facial features include dystopia canthorum, mild synophrys, slightly up-slanted palpebral fissure, posteriorly rotated ears, alae nasi hypoplasia and micrognathia. No heterochromia was noticed. He had a normal intelligence quotient and hearing. Insulin-like growth factor-1 (IGF-1) was 52.7 ng/ml, lower than the normal range (55 ~ 452 ng/ml) and the peak growth hormone level was 7.57 ng/ml at 90 minutes after taking moderate levodopa and pyridostigmine bromide. The patient exhibited a good response to human growth hormone (rhGH) replacement therapy, showing a 9.2 cm/year growth rate and an improvement of 1 standard deviation (SD) of height after one year treatment. CMA test of patient's DNA revealed a 4.46 Mb de novo deletion at 2q35-q36.2 (hg19; chr2:221,234,146-225,697,363). PAX3 haploinsufficiency is known to cause Waardenburg syndrome. Examining overlapping deletions in patients led to the conclusion that EPHA4 is a novel short stature gene. The finding is supported by the splotch-retarded and epha4 knockout mouse models which both showed growth retardation. We believe this rare condition is caused by the haploinsufficiency of both PAX3 and EPH4 genes. We further reported a growth response to recombinant human growth hormone treatment in this patient.

  20. The HSP90 inhibitor NVP-AUY922 radiosensitizes by abrogation of homologous recombination resulting in mitotic entry with unresolved DNA damage.

    Directory of Open Access Journals (Sweden)

    Shane Zaidi

    Full Text Available Heat shock protein 90 (HSP90 is a molecular chaperone responsible for the conformational maintenance of a number of client proteins that play key roles in cell cycle arrest, DNA damage repair and apoptosis following radiation. HSP90 inhibitors exhibit antitumor activity by modulating the stabilisation and activation of HSP90 client proteins. We sought to evaluate NVP-AUY922, the most potent HSP90 inhibitor yet reported, in preclinical radiosensitization studies.NVP-AUY922 potently radiosensitized cells in vitro at low nanomolar concentrations with a concurrent depletion of radioresistance-linked client proteins. Radiosensitization by NVP-AUY922 was verified for the first time in vivo in a human head and neck squamous cell carcinoma xenograft model in athymic mice, as measured by delayed tumor growth and increased surrogate end-point survival (p = <0.0001. NVP-AUY922 was shown to ubiquitously inhibit resolution of dsDNA damage repair correlating to delayed Rad51 foci formation in all cell lines tested. Additionally, NVP-AUY922 induced a stalled mitotic phenotype, in a cell line-dependent manner, in HeLa and HN5 cell lines irrespective of radiation exposure. Cell cycle analysis indicated that NVP-AUY922 induced aberrant mitotic entry in all cell lines tested in the presence of radiation-induced DNA damage due to ubiquitous CHK1 depletion, but resultant downstream cell cycle effects were cell line dependent.These results identify NVP-AUY922 as the most potent HSP90-mediated radiosensitizer yet reported in vitro, and for the first time validate it in a clinically relevant in vivo model. Mechanistic analysis at clinically achievable concentrations demonstrated that radiosensitization is mediated by the combinatorial inhibition of cell growth and survival pathways, ubiquitous delay in Rad51-mediated homologous recombination and CHK1-mediated G(2/M arrest, but that the contribution of cell cycle perturbation to radiosensitization may be cell line

  1. A Transition Zone Showing Highly Discontinuous or Alternating Levels of Stem Cell and Proliferation Markers Characterizes the Development of PTEN-Haploinsufficient Colorectal Cancer.

    Science.gov (United States)

    Arvai, Kevin J; Hsu, Ya-Hsuan; Lee, Lobin A; Jones, Dan

    2015-01-01

    Stepwise acquisition of oncogene mutations and deletion/inactivation of tumor suppressor genes characterize the development of colorectal cancer (CRC). These genetic events interact with discrete morphologic transitions from hyperplastic mucosa to adenomatous areas, followed by in situ malignant transformation and finally invasive carcinoma. The goal of this study was to identify tissue markers of the adenoma-carcinoma morphogenetic transitions in CRC. We analyzed the patterns of expression of growth regulatory and stem cell markers across these distinct morphologic transition zones in 735 primary CRC tumors. In 202 cases with preserved adenoma-adenocarcinoma transition, we identified, in 37.1% of cases, a zone of adenomatous epithelium, located immediately adjacent to the invasive component, that showed rapidly alternating intraglandular stretches of PTEN+ and PTEN- epithelium. This zone exactly overlapped with similar alternating expression of Ki-67 and inversely with the transforming growth factor-beta (TGF-β) growth regulator SMAD4. These zones also show parallel alternating levels and/or subcellular localization of multiple cancer stem/progenitor cell (CSC) markers, including β-catenin/CTNNB1, ALDH1, and CD44. PTEN was always re-expressed in the invasive tumor in these cases, unlike those with complete loss of PTEN expression. Genomic microarray analysis of CRC with prominent CSC-like expansions demonstrated a high frequency of PTEN genomic deletion/haploinsufficiency in tumors with CSC-like transition zones (62.5%) but not in tumors with downregulated but non-alternating PTEN expression (14.3%). There were no significant differences in the levels of KRAS mutation or CTNNB1 mutation in CSC-like tumors as compared to unselected CRC cases. In conclusion, we have identified a distinctive CSC-like pre-invasive transition zone in PTEN-haploinsufficient CRC that shows convergent on-off regulation of the PTEN/AKT, TGF-β/SMAD and Wnt/β-catenin pathways. This

  2. A Transition Zone Showing Highly Discontinuous or Alternating Levels of Stem Cell and Proliferation Markers Characterizes the Development of PTEN-Haploinsufficient Colorectal Cancer.

    Directory of Open Access Journals (Sweden)

    Kevin J Arvai

    Full Text Available Stepwise acquisition of oncogene mutations and deletion/inactivation of tumor suppressor genes characterize the development of colorectal cancer (CRC. These genetic events interact with discrete morphologic transitions from hyperplastic mucosa to adenomatous areas, followed by in situ malignant transformation and finally invasive carcinoma. The goal of this study was to identify tissue markers of the adenoma-carcinoma morphogenetic transitions in CRC.We analyzed the patterns of expression of growth regulatory and stem cell markers across these distinct morphologic transition zones in 735 primary CRC tumors. In 202 cases with preserved adenoma-adenocarcinoma transition, we identified, in 37.1% of cases, a zone of adenomatous epithelium, located immediately adjacent to the invasive component, that showed rapidly alternating intraglandular stretches of PTEN+ and PTEN- epithelium. This zone exactly overlapped with similar alternating expression of Ki-67 and inversely with the transforming growth factor-beta (TGF-β growth regulator SMAD4. These zones also show parallel alternating levels and/or subcellular localization of multiple cancer stem/progenitor cell (CSC markers, including β-catenin/CTNNB1, ALDH1, and CD44. PTEN was always re-expressed in the invasive tumor in these cases, unlike those with complete loss of PTEN expression. Genomic microarray analysis of CRC with prominent CSC-like expansions demonstrated a high frequency of PTEN genomic deletion/haploinsufficiency in tumors with CSC-like transition zones (62.5% but not in tumors with downregulated but non-alternating PTEN expression (14.3%. There were no significant differences in the levels of KRAS mutation or CTNNB1 mutation in CSC-like tumors as compared to unselected CRC cases.In conclusion, we have identified a distinctive CSC-like pre-invasive transition zone in PTEN-haploinsufficient CRC that shows convergent on-off regulation of the PTEN/AKT, TGF-β/SMAD and Wnt

  3. Haploinsufficiency of MeCP2-interacting transcriptional co-repressor SIN3A causes mild intellectual disability by affecting the development of cortical integrity.

    Science.gov (United States)

    Witteveen, Josefine S; Willemsen, Marjolein H; Dombroski, Thaís C D; van Bakel, Nick H M; Nillesen, Willy M; van Hulten, Josephus A; Jansen, Eric J R; Verkaik, Dave; Veenstra-Knol, Hermine E; van Ravenswaaij-Arts, Conny M A; Wassink-Ruiter, Jolien S Klein; Vincent, Marie; David, Albert; Le Caignec, Cedric; Schieving, Jolanda; Gilissen, Christian; Foulds, Nicola; Rump, Patrick; Strom, Tim; Cremer, Kirsten; Zink, Alexander M; Engels, Hartmut; de Munnik, Sonja A; Visser, Jasper E; Brunner, Han G; Martens, Gerard J M; Pfundt, Rolph; Kleefstra, Tjitske; Kolk, Sharon M

    2016-08-01

    Numerous genes are associated with neurodevelopmental disorders such as intellectual disability and autism spectrum disorder (ASD), but their dysfunction is often poorly characterized. Here we identified dominant mutations in the gene encoding the transcriptional repressor and MeCP2 interactor switch-insensitive 3 family member A (SIN3A; chromosome 15q24.2) in individuals who, in addition to mild intellectual disability and ASD, share striking features, including facial dysmorphisms, microcephaly and short stature. This phenotype is highly related to that of individuals with atypical 15q24 microdeletions, linking SIN3A to this microdeletion syndrome. Brain magnetic resonance imaging showed subtle abnormalities, including corpus callosum hypoplasia and ventriculomegaly. Intriguingly, in vivo functional knockdown of Sin3a led to reduced cortical neurogenesis, altered neuronal identity and aberrant corticocortical projections in the developing mouse brain. Together, our data establish that haploinsufficiency of SIN3A is associated with mild syndromic intellectual disability and that SIN3A can be considered to be a key transcriptional regulator of cortical brain development.

  4. LETM1 haploinsufficiency causes mitochondrial defects in cells from humans with Wolf-Hirschhorn syndrome: implications for dissecting the underlying pathomechanisms in this condition

    Directory of Open Access Journals (Sweden)

    Lesley Hart

    2014-05-01

    Full Text Available Wolf-Hirschhorn syndrome (WHS represents an archetypical example of a contiguous gene deletion disorder – a condition comprising a complex set of developmental phenotypes with a multigenic origin. Epileptic seizures, intellectual disability, growth restriction, motor delay and hypotonia are major co-morbidities in WHS. Haploinsufficiency of LETM1, which encodes a mitochondrial inner-membrane protein functioning in ion transport, has been proposed as an underlying pathomechanism, principally for seizures but also for other core features of WHS, including growth and motor delay. Growing evidence derived from several model organisms suggests that reduced LETM1 expression is associated with some element of mitochondrial dysfunction. Surprisingly, LETM1-dependent mitochondrial functional deficits have not previously been described in cells from individuals with WHS. Here, using a unique panel of WHS-patient-derived cell lines with deletions of differing sizes, incorporating LETM1 or not, we show, for the first time, that LETM1 expression is reduced in mitochondria isolated from WHS-patient cells. Furthermore, we show that this is associated with distinct mitochondrial phenotypes, including altered intracellular [Ca2+] levels, dysfunctional mitochondrial transition-pore opening, hyperpolarization and superoxide leakage from resting mitochondria. Interestingly, we find that these phenotypes segregate with seizures in our WHS cohort. Our findings identify novel cellular phenotypes in WHS attributable to a 50% reduction in LETM1 expression level; these phenotypes could underlie and/or contribute to some of the core clinical features of this condition.

  5. LETM1 haploinsufficiency causes mitochondrial defects in cells from humans with Wolf-Hirschhorn syndrome: implications for dissecting the underlying pathomechanisms in this condition.

    Science.gov (United States)

    Hart, Lesley; Rauch, Anita; Carr, Antony M; Vermeesch, Joris R; O'Driscoll, Mark

    2014-05-01

    Wolf-Hirschhorn syndrome (WHS) represents an archetypical example of a contiguous gene deletion disorder - a condition comprising a complex set of developmental phenotypes with a multigenic origin. Epileptic seizures, intellectual disability, growth restriction, motor delay and hypotonia are major co-morbidities in WHS. Haploinsufficiency of LETM1, which encodes a mitochondrial inner-membrane protein functioning in ion transport, has been proposed as an underlying pathomechanism, principally for seizures but also for other core features of WHS, including growth and motor delay. Growing evidence derived from several model organisms suggests that reduced LETM1 expression is associated with some element of mitochondrial dysfunction. Surprisingly, LETM1-dependent mitochondrial functional deficits have not previously been described in cells from individuals with WHS. Here, using a unique panel of WHS-patient-derived cell lines with deletions of differing sizes, incorporating LETM1 or not, we show, for the first time, that LETM1 expression is reduced in mitochondria isolated from WHS-patient cells. Furthermore, we show that this is associated with distinct mitochondrial phenotypes, including altered intracellular [Ca(2+)] levels, dysfunctional mitochondrial transition-pore opening, hyperpolarization and superoxide leakage from resting mitochondria. Interestingly, we find that these phenotypes segregate with seizures in our WHS cohort. Our findings identify novel cellular phenotypes in WHS attributable to a 50% reduction in LETM1 expression level; these phenotypes could underlie and/or contribute to some of the core clinical features of this condition.

  6. Toxicology and Carcinogenesis Study of Senna in the C3B6.129F1-Trp53tm1Brd N12 haploinsufficient mice

    Science.gov (United States)

    Surh, Inok; Brix, Amy; French, John E.; Collins, Bradley J.; Sanders, J. Michael; Vallant, Molly; Dunnick, June K.

    2013-01-01

    Senna is a pod or leaf of Senna alexandrina P. Mill and is used as a stimulant laxative. In the large intestine, bacterial enzymes break sennosides and release rhein-9-anthrone, the active form for the laxative effect. To determine potential toxic effects of senna, a 5-week dose range finding study in the C57BL/6N mouse and a 40-week toxicology and carcinogenesis study in the C3B6.129F1-Trp53tm1Brd N12 haploinsufficient (p53+/−) mouse were conducted. In the 5-week study, C57BL/6N mice were exposed up to 10,000 ppm senna in feed. Increased incidences of epithelial hyperplasia of the cecum and colon were observed in males and females exposed to 5,000 or 10,000 ppm senna. These intestinal lesions were not considered to be of sufficient severity to cause mortality and, thus, in the p53+/− mouse 40-week study, the high dose of 10,000 ppm was selected. Significant increases in the incidences of epithelial hyperplasia of the colon and cecum were observed at 10,000 ppm in p53(+/−) males and females, and the incidence of hyperplasia of the colon was significantly increased at 3,000 ppm in females. In conclusion, the large intestine was the major target of senna-induced toxicity in both wild-type and the p53+/− mouse model. There was no neoplastic change, when senna was administered to p53 +/− mouse. PMID:23125117

  7. Toxicology and carcinogenesis study of senna in C3B6.129F1-Trp53 tm1Brd N12 haploinsufficient mice.

    Science.gov (United States)

    Surh, Inok; Brix, Amy; French, John E; Collins, Bradley J; Sanders, J Michael; Vallant, Molly; Dunnick, June K

    2013-07-01

    Senna is a pod or leaf of Senna alexandrina P. Mill and is used as a stimulant laxative. In the large intestine, bacterial enzymes reduce sennosides to rhein-9-anthrone, the active form for the laxative effect. To determine the potential toxic effects of senna, a 5-week dose range finding study in the C57BL/6N mouse and a 40-week toxicology and carcinogenesis study in the C3B6.129F1-Trp53 (tm1Brd) N12 haploinsufficient (p53(+/-)) mouse were conducted. In the 5-week study, C57BL/6N mice were exposed to up to 10,000 ppm senna in feed. Increased incidences of epithelial hyperplasia of the cecum and colon were observed in males and females exposed to 5,000 or 10,000 ppm senna. These intestinal lesions were not considered to be of sufficient severity to cause mortality and, thus, in the p53(+/-) mouse 40-week study, the high dose of 10,000 ppm was selected. Significant increases in the incidences of epithelial hyperplasia of the colon and cecum were observed at 10,000 ppm in p53(+/-) males and females, and the incidence of hyperplasia of the colon was significantly increased at 3,000 ppm in females. In conclusion, the large intestine was the major target of senna-induced toxicity in both wild-type and the p53(+/-) mouse model. There was no neoplastic change when senna was administered to p53(+/-) mouse.

  8. Role of MCT1 and CAII in skeletal muscle pH homeostasis, energetics, and function: in vivo insights from MCT1 haploinsufficient mice

    KAUST Repository

    Chatel, Benjamin; Bendahan, David; Hourdé , Christophe; Pellerin, Luc; Lengacher, Sylvain; Magistretti, Pierre J.; Le Fur, Yann; Vilmen, Christophe; Bernard, Monique; Messonnier, Laurent A.

    2017-01-01

    The purpose of this study was to investigate the effects of a partial suppression of monocarboxylate transporter (MCT)-1 on skeletal muscle pH, energetics, and function (MCT1(+/-) mice). Twenty-four MCT1(+/-) and 13 wild-type (WT) mice were subjected to a rest-exercise-recovery protocol, allowing assessment of muscle energetics (by magnetic resonance spectroscopy) and function. The study included analysis of enzyme activities and content of protein involved in pH regulation. Skeletal muscle of MCT1(+/-) mice had lower MCT1 (-61%; P < 0.05) and carbonic anhydrase (CA)-II (-54%; P < 0.05) contents. Although intramuscular pH was higher in MCT1(+/-) mice at rest (P < 0.001), the mice showed higher acidosis during the first minute of exercise (P < 0.01). Then, the pH time course was similar among groups until exercise completion. MCT1(+/-) mice had higher specific peak (P < 0.05) and maximum tetanic (P < 0.01) forces and lower fatigability (P < 0.001) when compared to WT mice. We conclude that both MCT1 and CAII are involved in the homeostatic control of pH in skeletal muscle, both at rest and at the onset of exercise. The improved muscle function and resistance to fatigue in MCT1(+/-) mice remain unexplained.-Chatel, B., Bendahan, D., Hourdé, C., Pellerin, L., Lengacher, S., Magistretti, P., Fur, Y. L., Vilmen, C., Bernard, M., Messonnier, L. A. Role of MCT1 and CAII in skeletal muscle pH homeostasis, energetics, and function: in vivo insights from MCT1 haploinsufficient mice.

  9. Association of brain-derived neurotrophic factor (BDNF) haploinsufficiency with lower adaptive behaviour and reduced cognitive functioning in WAGR/11p13 deletion syndrome.

    Science.gov (United States)

    Han, Joan C; Thurm, Audrey; Golden Williams, Christine; Joseph, Lisa A; Zein, Wadih M; Brooks, Brian P; Butman, John A; Brady, Sheila M; Fuhr, Shannon R; Hicks, Melanie D; Huey, Amanda E; Hanish, Alyson E; Danley, Kristen M; Raygada, Margarita J; Rennert, Owen M; Martinowich, Keri; Sharp, Stephen J; Tsao, Jack W; Swedo, Susan E

    2013-01-01

    In animal studies, brain-derived neurotrophic factor (BDNF) is an important regulator of central nervous system development and synaptic plasticity. WAGR (Wilms tumour, Aniridia, Genitourinary anomalies, and mental Retardation) syndrome is caused by 11p13 deletions of variable size near the BDNF locus and can serve as a model for studying human BDNF haploinsufficiency (+/-). We hypothesized that BDNF+/- would be associated with more severe cognitive impairment in subjects with WAGR syndrome. Twenty-eight subjects with WAGR syndrome (6-28 years), 12 subjects with isolated aniridia due to PAX6 mutations/microdeletions (7-54 years), and 20 healthy controls (4-32 years) received neurocognitive assessments. Deletion boundaries for the subjects in the WAGR group were determined by high-resolution oligonucleotide array comparative genomic hybridization. Within the WAGR group, BDNF+/- subjects (n = 15), compared with BDNF intact (+/+) subjects (n = 13), had lower adaptive behaviour (p = .02), reduced cognitive functioning (p = .04), higher levels of reported historical (p = .02) and current (p = .02) social impairment, and higher percentage meeting cut-off score for autism (p = .047) on Autism Diagnostic Interview-Revised. These differences remained nominally significant after adjusting for visual acuity. Using diagnostic measures and clinical judgement, 3 subjects (2 BDNF+/- and 1 BDNF+/+) in the WAGR group (10.7%) were classified with autism spectrum disorder. A comparison group of visually impaired subjects with isolated aniridia had cognitive functioning comparable to that of healthy controls. In summary, among subjects with WAGR syndrome, BDNF+/- subjects had a mean Vineland Adaptive Behaviour Compose score that was 14-points lower and a mean intelligence quotient (IQ) that was 20-points lower than BDNF+/+ subjects. Our findings support the hypothesis that BDNF plays an important role in human neurocognitive development. Published by Elsevier Ltd.

  10. Role of MCT1 and CAII in skeletal muscle pH homeostasis, energetics, and function: in vivo insights from MCT1 haploinsufficient mice

    KAUST Repository

    Chatel, Benjamin

    2017-03-03

    The purpose of this study was to investigate the effects of a partial suppression of monocarboxylate transporter (MCT)-1 on skeletal muscle pH, energetics, and function (MCT1(+/-) mice). Twenty-four MCT1(+/-) and 13 wild-type (WT) mice were subjected to a rest-exercise-recovery protocol, allowing assessment of muscle energetics (by magnetic resonance spectroscopy) and function. The study included analysis of enzyme activities and content of protein involved in pH regulation. Skeletal muscle of MCT1(+/-) mice had lower MCT1 (-61%; P < 0.05) and carbonic anhydrase (CA)-II (-54%; P < 0.05) contents. Although intramuscular pH was higher in MCT1(+/-) mice at rest (P < 0.001), the mice showed higher acidosis during the first minute of exercise (P < 0.01). Then, the pH time course was similar among groups until exercise completion. MCT1(+/-) mice had higher specific peak (P < 0.05) and maximum tetanic (P < 0.01) forces and lower fatigability (P < 0.001) when compared to WT mice. We conclude that both MCT1 and CAII are involved in the homeostatic control of pH in skeletal muscle, both at rest and at the onset of exercise. The improved muscle function and resistance to fatigue in MCT1(+/-) mice remain unexplained.-Chatel, B., Bendahan, D., Hourdé, C., Pellerin, L., Lengacher, S., Magistretti, P., Fur, Y. L., Vilmen, C., Bernard, M., Messonnier, L. A. Role of MCT1 and CAII in skeletal muscle pH homeostasis, energetics, and function: in vivo insights from MCT1 haploinsufficient mice.

  11. Toxicology study of senna (CAS No. 8013-11-4) in C57BL/6NTAC Mice and toxicology and carcinogenesis study of senna in genetically modified C3B6.129F1/Tac-Trp53tm1Brd haploinsufficient mice (Feed Studies).

    Science.gov (United States)

    2012-04-01

    Senna is used as a stimulant laxative in the management of constipation resulting from opioid use or when treatment with bulking or osmotic agents has failed. Increased use of senna was expected due to the removal of the stimulant laxatives danthron and phenolphthalein from the market. Senna was nominated for study by the Center for Drug Evaluation and Research, United States Food and Drug Administration (FDA) due to the wide use of laxative preparations, positive genotoxicity in vitro for some senna components or metabolites, and unknown carcinogenic potential. Because a 2-year rat study was ongoing by the manufacturer, the FDA requested that the NTP conduct a senna study in the p53(+/-) mouse. In this study, the potential for carcinogenic effects of senna was studied in the C3B6.129F1/Tac-Trp53tm1Brd N12 haploinsufficient (heterozygous F1 p53(+/-)) mouse model as an ongoing goal of the NTP to develop and test model systems for toxicology and carcinogenesis studies, especially those that can provide mechanistic information relative to understanding an agents mode of action. C57BL/6NTac mice were exposed to senna in feed for 5 weeks; heterozygous F1 p53(+/-) mice were exposed to senna in feed for 40 weeks. Genetic toxicology studies were conducted in Salmonella typhimurium, Escherichia coli, and mouse peripheral blood erythrocytes.

  12. Mice haploinsufficient for Map2k7, a gene involved in neurodevelopment and risk for schizophrenia, show impaired attention, a vigilance decrement deficit and unstable cognitive processing in an attentional task: impact of minocycline.

    Science.gov (United States)

    Openshaw, R L; Thomson, D M; Penninger, J M; Pratt, J A; Morris, B J

    2017-01-01

    Members of the c-Jun N-terminal kinase (JNK) family of mitogen-activated protein (MAP) kinases, and the upstream kinase MKK7, have all been strongly linked with synaptic plasticity and with the development of the neocortex. However, the impact of disruption of this pathway on cognitive function is unclear. In the current study, we test the hypothesis that reduced MKK7 expression is sufficient to cause cognitive impairment. Attentional function in mice haploinsufficient for Map2k7 (Map2k7 +/- mice) was investigated using the five-choice serial reaction time task (5-CSRTT). Once stable performance had been achieved, Map2k7 +/- mice showed a distinctive attentional deficit, in the form of an increased number of missed responses, accompanied by a more pronounced decrement in performance over time and elevated intra-individual reaction time variability. When performance was reassessed after administration of minocycline-a tetracycline antibiotic currently showing promise for the improvement of attentional deficits in patients with schizophrenia-signs of improvement in attentional performance were detected. Overall, Map2k7 haploinsufficiency causes a distinctive pattern of cognitive impairment strongly suggestive of an inability to sustain attention, in accordance with those seen in psychiatric patients carrying out similar tasks. This may be important for understanding the mechanisms of cognitive dysfunction in clinical populations and highlights the possibility of treating some of these deficits with minocycline.

  13. RanBP2 modulates Cox11 and hexokinase I activities and haploinsufficiency of RanBP2 causes deficits in glucose metabolism.

    Directory of Open Access Journals (Sweden)

    Azamat Aslanukov

    2006-10-01

    Full Text Available The Ran-binding protein 2 (RanBP2 is a large multimodular and pleiotropic protein. Several molecular partners with distinct functions interacting specifically with selective modules of RanBP2 have been identified. Yet, the significance of these interactions with RanBP2 and the genetic and physiological role(s of RanBP2 in a whole-animal model remain elusive. Here, we report the identification of two novel partners of RanBP2 and a novel physiological role of RanBP2 in a mouse model. RanBP2 associates in vitro and in vivo and colocalizes with the mitochondrial metallochaperone, Cox11, and the pacemaker of glycolysis, hexokinase type I (HKI via its leucine-rich domain. The leucine-rich domain of RanBP2 also exhibits strong chaperone activity toward intermediate and mature folding species of Cox11 supporting a chaperone role of RanBP2 in the cytosol during Cox11 biogenesis. Cox11 partially colocalizes with HKI, thus supporting additional and distinct roles in cell function. Cox11 is a strong inhibitor of HKI, and RanBP2 suppresses the inhibitory activity of Cox11 over HKI. To probe the physiological role of RanBP2 and its role in HKI function, a mouse model harboring a genetically disrupted RanBP2 locus was generated. RanBP2(-/- are embryonically lethal, and haploinsufficiency of RanBP2 in an inbred strain causes a pronounced decrease of HKI and ATP levels selectively in the central nervous system. Inbred RanBP2(+/- mice also exhibit deficits in growth rates and glucose catabolism without impairment of glucose uptake and gluconeogenesis. These phenotypes are accompanied by a decrease in the electrophysiological responses of photosensory and postreceptoral neurons. Hence, RanBP2 and its partners emerge as critical modulators of neuronal HKI, glucose catabolism, energy homeostasis, and targets for metabolic, aging disorders and allied neuropathies.

  14. RanBP2 modulates Cox11 and hexokinase I activities and haploinsufficiency of RanBP2 causes deficits in glucose metabolism.

    Science.gov (United States)

    Aslanukov, Azamat; Bhowmick, Reshma; Guruju, Mallikarjuna; Oswald, John; Raz, Dorit; Bush, Ronald A; Sieving, Paul A; Lu, Xinrong; Bock, Cheryl B; Ferreira, Paulo A

    2006-10-01

    The Ran-binding protein 2 (RanBP2) is a large multimodular and pleiotropic protein. Several molecular partners with distinct functions interacting specifically with selective modules of RanBP2 have been identified. Yet, the significance of these interactions with RanBP2 and the genetic and physiological role(s) of RanBP2 in a whole-animal model remain elusive. Here, we report the identification of two novel partners of RanBP2 and a novel physiological role of RanBP2 in a mouse model. RanBP2 associates in vitro and in vivo and colocalizes with the mitochondrial metallochaperone, Cox11, and the pacemaker of glycolysis, hexokinase type I (HKI) via its leucine-rich domain. The leucine-rich domain of RanBP2 also exhibits strong chaperone activity toward intermediate and mature folding species of Cox11 supporting a chaperone role of RanBP2 in the cytosol during Cox11 biogenesis. Cox11 partially colocalizes with HKI, thus supporting additional and distinct roles in cell function. Cox11 is a strong inhibitor of HKI, and RanBP2 suppresses the inhibitory activity of Cox11 over HKI. To probe the physiological role of RanBP2 and its role in HKI function, a mouse model harboring a genetically disrupted RanBP2 locus was generated. RanBP2(-/-) are embryonically lethal, and haploinsufficiency of RanBP2 in an inbred strain causes a pronounced decrease of HKI and ATP levels selectively in the central nervous system. Inbred RanBP2(+/-) mice also exhibit deficits in growth rates and glucose catabolism without impairment of glucose uptake and gluconeogenesis. These phenotypes are accompanied by a decrease in the electrophysiological responses of photosensory and postreceptoral neurons. Hence, RanBP2 and its partners emerge as critical modulators of neuronal HKI, glucose catabolism, energy homeostasis, and targets for metabolic, aging disorders and allied neuropathies.

  15. Inhibition of human Chk1 causes increased initiation of DNA replication, phosphorylation of ATR targets, and DNA breakage

    DEFF Research Database (Denmark)

    Syljuåsen, Randi G; Sørensen, Claus Storgaard; Hansen, Lasse Tengbjerg

    2005-01-01

    by increased amounts of nonextractable RPA protein, formation of single-stranded DNA, and induction of DNA strand breaks. Moreover, these responses were prevented by siRNA-mediated downregulation of Cdk2 or the replication initiation protein Cdc45, or by addition of the CDK inhibitor roscovitine. We propose...

  16. Truncating Plakophilin-2 Mutations in Arrhythmogenic Cardiomyopathy Are Associated with Protein Haploinsufficiency in Both Myocardium and Epidermis

    DEFF Research Database (Denmark)

    Rasmussen, Torsten Bloch; Nissen, Peter H; Palmfeldt, Johan

    2014-01-01

    BACKGROUND: Arrhythmogenic cardiomyopathy (AC) is a hereditary cardiac condition associated with ventricular arrhythmias, heart failure, and sudden death. The disease is most often caused by mutations in the desmosomal gene for plakophilin-2 (PKP2), which is expressed in both myocardial...... and epidermal tissue. This study aimed to investigate protein expression in myocardial tissue of patients with AC carrying PKP2 mutations and elucidate whether keratinocytes of the same individuals exhibited a similar pattern of protein expression. METHODS AND RESULTS: Direct sequencing of 5 AC genes in 71...... unrelated patients with AC identified 10 different PKP2 mutations in 12 index patients. One patient, heterozygous for a PKP2 nonsense mutation, developed severe heart failure and underwent cardiac transplantation. Western blotting and immunohistochemistry of the explanted heart showed a significant decrease...

  17. Haploinsufficiency of myostatin protects against aging-related declines in muscle function and enhances the longevity of mice.

    Science.gov (United States)

    Mendias, Christopher L; Bakhurin, Konstantin I; Gumucio, Jonathan P; Shallal-Ayzin, Mark V; Davis, Carol S; Faulkner, John A

    2015-08-01

    The molecular mechanisms behind aging-related declines in muscle function are not well understood, but the growth factor myostatin (MSTN) appears to play an important role in this process. Additionally, epidemiological studies have identified a positive correlation between skeletal muscle mass and longevity. Given the role of myostatin in regulating muscle size, and the correlation between muscle mass and longevity, we tested the hypotheses that the deficiency of myostatin would protect oldest-old mice (28-30 months old) from an aging-related loss in muscle size and contractility, and would extend the maximum lifespan of mice. We found that MSTN(+/-) and MSTN(-/-) mice were protected from aging-related declines in muscle mass and contractility. While no differences were detected between MSTN(+/+) and MSTN(-/-) mice, MSTN(+/-) mice had an approximately 15% increase in maximal lifespan. These results suggest that targeting myostatin may protect against aging-related changes in skeletal muscle and contribute to enhanced longevity. © 2015 The Authors. Aging Cell published by the Anatomical Society and John Wiley & Sons Ltd.

  18. GABAergic neuron deficit as an idiopathic generalized epilepsy mechanism: the role of BRD2 haploinsufficiency in juvenile myoclonic epilepsy.

    Directory of Open Access Journals (Sweden)

    Libor Velíšek

    Full Text Available Idiopathic generalized epilepsy (IGE syndromes represent about 30% of all epilepsies. They have strong, but elusive, genetic components and sex-specific seizure expression. Multiple linkage and population association studies have connected the bromodomain-containing gene BRD2 to forms of IGE. In mice, a null mutation at the homologous Brd2 locus results in embryonic lethality while heterozygous Brd2+/- mice are viable and overtly normal. However, using the flurothyl model, we now show, that compared to the Brd2+/+ littermates, Brd2+/- males have a decreased clonic, and females a decreased tonic-clonic, seizure threshold. Additionally, long-term EEG/video recordings captured spontaneous seizures in three out of five recorded Brd2+/- female mice. Anatomical analysis of specific regions of the brain further revealed significant differences in Brd2+/- vs +/+ mice. Specifically, there were decreases in the numbers of GABAergic (parvalbumin- or GAD67-immunopositive neurons along the basal ganglia pathway, i.e., in the neocortex and striatum of Brd2+/- mice, compared to Brd2+/+ mice. There were also fewer GABAergic neurons in the substantia nigra reticulata (SNR, yet there was a minor, possibly compensatory increase in the GABA producing enzyme GAD67 in these SNR cells. Further, GAD67 expression in the superior colliculus and ventral medial thalamic nucleus, the main SNR outputs, was significantly decreased in Brd2+/- mice, further supporting GABA downregulation. Our data show that the non-channel-encoding, developmentally critical Brd2 gene is associated with i sex-specific increases in seizure susceptibility, ii the development of spontaneous seizures, and iii seizure-related anatomical changes in the GABA system, supporting BRD2's involvement in human IGE.

  19. Radiation-induced hyperproliferation of intestinal crypts results in elevated genome instability with inactive p53-related genomic surveillance.

    Science.gov (United States)

    Zhou, Xin; Ma, Xiaofei; Wang, Zhenhua; Sun, Chao; Wang, Yupei; He, Yang; Zhang, Hong

    2015-12-15

    Radiation-induced hyperproliferation of intestinal crypts is well documented, but its potential tumorigenic effects remain elusive. Here we aim to determine the genomic surveillance process during crypt hyperproliferation, and its consequential outcome after ionizing radiation. Crypt regeneration in the intestine was induced by a single dose of 12Gy abdominal irradiation. γ-H2AX, 53BP1 and DNA-PKcs were used as DNA repair surrogates to investigate the inherent ability of intestinal crypt cells to recognize and repair double-strand breaks. Ki67 staining and the 5-bromo-2'-deoxyuridine incorporation assay were used to study patterns of cell proliferation in regenerating crypts. Staining for ATM, p53, Chk1 and Chk2 was performed to study checkpoint activation and release. Apoptosis was evaluated through H&E staining and terminal deoxynucleotidyl transferase (dUTP) nick-end labeling. The ATM-p53 pathway was immediately activated after irradiation. A second wave of DSBs in crypt cells was observed in regenerating crypts, accompanied with significantly increased chromosomal bridges. The p53-related genomic surveillance pathway was not active during the regeneration phase despite DSBs and chromosomal bridges in the cells of regenerating crypts. Non-homologous end joining (NHEJ) DSBs repair was involved in the DSBs repair process, as indicated by p-DNA-PKcs staining. Intestinal crypt cells retained hyperproliferation with inactive p53-related genomic surveillance system. NHEJ was involved in the resultant genomic instability during hyperproliferation. Copyright © 2015 Elsevier Inc. All rights reserved.

  20. Inhibition of checkpoint kinase 1 sensitizes lung cancer brain metastases to radiotherapy

    International Nuclear Information System (INIS)

    Yang, Heekyoung; Yoon, Su Jin; Jin, Juyoun; Choi, Seung Ho; Seol, Ho Jun; Lee, Jung-Il

    2011-01-01

    Research highlights: → The most important therapeutic tool in brain metastasis is radiation therapy. → Radiosensitivity of cancer cells was enhanced with treatment of Chk1 inhibitor. → Depletion of Chk1 in cancer cells showed an enhancement of sensitivity to radiation. → Chk1 can be a good target for enhancement of radiosensitivity. -- Abstract: The most important therapeutic tool in brain metastasis is radiation therapy. However, resistance to radiation is a possible cause of recurrence or treatment failure. Recently, signal pathways about DNA damage checkpoints after irradiation have been noticed. We investigated the radiosensitivity can be enhanced with treatment of Chk1 inhibitor, AZD7762 in lung cancer cell lines and xenograft models of lung cancer brain metastasis. Clonogenic survival assays showed enhancement of radiosensitivity with AZD7762 after irradiation of various doses. AZD7762 increased ATR/ATM-mediated Chk1 phosphorylation and stabilized Cdc25A, suppressed cyclin A expression in lung cancer cell lines. In xenograft models of lung cancer (PC14PE6) brain metastasis, AZD7762 significantly prolonged the median survival time in response to radiation. Depletion of Chk1 using shRNA also showed an enhancement of sensitivity to radiation in PC14PE6 cells. The results of this study support that Chk1 can be a good target for enhancement of radiosensitivity.

  1. The dwarf phenotype in GH240B mice, haploinsufficient for the autism candidate gene Neurobeachin, is caused by ectopic expression of recombinant human growth hormone.

    Science.gov (United States)

    Nuytens, Kim; Tuand, Krizia; Fu, Quili; Stijnen, Pieter; Pruniau, Vincent; Meulemans, Sandra; Vankelecom, Hugo; Creemers, John W M

    2014-01-01

    Two knockout mouse models for the autism candidate gene Neurobeachin (Nbea) have been generated independently. Although both models have similar phenotypes, one striking difference is the dwarf phenotype observed in the heterozygous configuration of the GH240B model that is generated by the serendipitous insertion of a promoterless human growth hormone (hGH) genomic fragment in the Nbea gene. In order to elucidate this discrepancy, the dwarfism present in this Nbea mouse model was investigated in detail. The growth deficiency in Nbea+/- mice coincided with an increased percentage of fat mass and a decrease in bone mineral density. Low but detectable levels of hGH were detected in the pituitary and hypothalamus of Nbea+/- mice but not in liver, hippocampus nor in serum. As a consequence, several members of the mouse growth hormone (mGH) signaling cascade showed altered mRNA levels, including a reduction in growth hormone-releasing hormone mRNA in the hypothalamus. Moreover, somatotrope cells were less numerous in the pituitary of Nbea+/- mice and both contained and secreted significantly less mGH resulting in reduced levels of circulating insulin-like growth factor 1. These findings demonstrate that the random integration of the hGH transgene in this mouse model has not only inactivated Nbea but has also resulted in the tissue-specific expression of hGH causing a negative feedback loop, mGH hyposecretion and dwarfism.

  2. The dwarf phenotype in GH240B mice, haploinsufficient for the autism candidate gene Neurobeachin, is caused by ectopic expression of recombinant human growth hormone.

    Directory of Open Access Journals (Sweden)

    Kim Nuytens

    Full Text Available Two knockout mouse models for the autism candidate gene Neurobeachin (Nbea have been generated independently. Although both models have similar phenotypes, one striking difference is the dwarf phenotype observed in the heterozygous configuration of the GH240B model that is generated by the serendipitous insertion of a promoterless human growth hormone (hGH genomic fragment in the Nbea gene. In order to elucidate this discrepancy, the dwarfism present in this Nbea mouse model was investigated in detail. The growth deficiency in Nbea+/- mice coincided with an increased percentage of fat mass and a decrease in bone mineral density. Low but detectable levels of hGH were detected in the pituitary and hypothalamus of Nbea+/- mice but not in liver, hippocampus nor in serum. As a consequence, several members of the mouse growth hormone (mGH signaling cascade showed altered mRNA levels, including a reduction in growth hormone-releasing hormone mRNA in the hypothalamus. Moreover, somatotrope cells were less numerous in the pituitary of Nbea+/- mice and both contained and secreted significantly less mGH resulting in reduced levels of circulating insulin-like growth factor 1. These findings demonstrate that the random integration of the hGH transgene in this mouse model has not only inactivated Nbea but has also resulted in the tissue-specific expression of hGH causing a negative feedback loop, mGH hyposecretion and dwarfism.

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

    Science.gov (United States)

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

    2014-01-01

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

  4. Chk1 Inhibitor SCH900776 Effectively Potentiates the Cytotoxic Effects of Platinum-Based Chemotherapeutic Drugs in Human Colon Cancer Cells

    Czech Academy of Sciences Publication Activity Database

    Herudková, Jarmila; Paruch, K.; Khirsariya, P.; Souček, Karel; Krkoška, Martin; Blanářová, Olga; Sova, P.; Kozubík, Alois; Vaculová, Alena

    2017-01-01

    Roč. 19, č. 10 (2017), s. 830-841 ISSN 1476-5586 R&D Projects: GA ČR GA15-06650S Institutional support: RVO:68081707 Keywords : dna-damaging agents * in-vitro * replication checkpoint Subject RIV: EB - Genetics ; Molecular Biology OBOR OECD: Biochemistry and molecular biology Impact factor: 5.006, year: 2016

  5. Upregulation of Haploinsufficient Gene Expression in the Brain by Targeting a Long Non-coding RNA Improves Seizure Phenotype in a Model of Dravet Syndrome.

    Science.gov (United States)

    Hsiao, J; Yuan, T Y; Tsai, M S; Lu, C Y; Lin, Y C; Lee, M L; Lin, S W; Chang, F C; Liu Pimentel, H; Olive, C; Coito, C; Shen, G; Young, M; Thorne, T; Lawrence, M; Magistri, M; Faghihi, M A; Khorkova, O; Wahlestedt, C

    2016-07-01

    Dravet syndrome is a devastating genetic brain disorder caused by heterozygous loss-of-function mutation in the voltage-gated sodium channel gene SCN1A. There are currently no treatments, but the upregulation of SCN1A healthy allele represents an appealing therapeutic strategy. In this study we identified a novel, evolutionary conserved mechanism controlling the expression of SCN1A that is mediated by an antisense non-coding RNA (SCN1ANAT). Using oligonucleotide-based compounds (AntagoNATs) targeting SCN1ANAT we were able to induce specific upregulation of SCN1A both in vitro and in vivo, in the brain of Dravet knock-in mouse model and a non-human primate. AntagoNAT-mediated upregulation of Scn1a in postnatal Dravet mice led to significant improvements in seizure phenotype and excitability of hippocampal interneurons. These results further elucidate the pathophysiology of Dravet syndrome and outline a possible new approach for the treatment of this and other genetic disorders with similar etiology. Copyright © 2016 The Authors. Published by Elsevier B.V. All rights reserved.

  6. Upregulation of Haploinsufficient Gene Expression in the Brain by Targeting a Long Non-coding RNA Improves Seizure Phenotype in a Model of Dravet Syndrome

    Directory of Open Access Journals (Sweden)

    J. Hsiao

    2016-07-01

    Full Text Available Dravet syndrome is a devastating genetic brain disorder caused by heterozygous loss-of-function mutation in the voltage-gated sodium channel gene SCN1A. There are currently no treatments, but the upregulation of SCN1A healthy allele represents an appealing therapeutic strategy. In this study we identified a novel, evolutionary conserved mechanism controlling the expression of SCN1A that is mediated by an antisense non-coding RNA (SCN1ANAT. Using oligonucleotide-based compounds (AntagoNATs targeting SCN1ANAT we were able to induce specific upregulation of SCN1A both in vitro and in vivo, in the brain of Dravet knock-in mouse model and a non-human primate. AntagoNAT-mediated upregulation of Scn1a in postnatal Dravet mice led to significant improvements in seizure phenotype and excitability of hippocampal interneurons. These results further elucidate the pathophysiology of Dravet syndrome and outline a possible new approach for the treatment of this and other genetic disorders with similar etiology.

  7. Collagen V haploinsufficiency in a murine model of classic Ehlers-Danlos syndrome is associated with deficient structural and mechanical healing in tendons.

    Science.gov (United States)

    Johnston, Jessica M; Connizzo, Brianne K; Shetye, Snehal S; Robinson, Kelsey A; Huegel, Julianne; Rodriguez, Ashley B; Sun, Mei; Adams, Sheila M; Birk, David E; Soslowsky, Louis J

    2017-12-01

    Classic Ehlers-Danlos syndrome (EDS) patients suffer from connective tissue hyperelasticity, joint instability, skin hyperextensibility, tissue fragility, and poor wound healing due to heterozygous mutations in COL5a1 or COL5a2 genes. This study investigated the roles of collagen V in establishing structure and function in uninjured patellar tendons as well as in the injury response using a Col5a1 +/- mouse, a model for classic EDS. These analyses were done comparing tendons from a classic EDS model (Col5a1 +/- ) with wild-type controls. Tendons were subjected to mechanical testing, histological, and fibril analysis before injury as well as 3 and 6 weeks after injury. We found that Col5a1 +/- tendons demonstrated diminished recovery of mechanical competency after injury as compared to normal wild-type tendons, which recovered their pre-injury values by 6 weeks post injury. Additionally, the Col5a1 +/- tendons demonstrated altered fibril morphology and diameter distributions compared to the wild-type tendons. This study indicates that collagen V plays an important role in regulating collagen fibrillogenesis and the associated recovery of mechanical integrity in tendons after injury. In addition, the dysregulation with decreased collagen V expression in EDS is associated with a diminished injury response. The results presented herein have the potential to direct future targeted therapeutics for classic EDS patients. © 2017 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. J Orthop Res 35:2707-2715, 2017. © 2017 Orthopaedic Research Society. Published by Wiley Periodicals, Inc.

  8. Haploinsufficiency of the E3 ubiquitin ligase C-terminus of heat shock cognate 70 interacting protein (CHIP produces specific behavioral impairments.

    Directory of Open Access Journals (Sweden)

    Bethann McLaughlin

    Full Text Available The multifunctional E3 ubiquitin ligase CHIP is an essential interacting partner of HSP70, which together promote the proteasomal degradation of client proteins. Acute CHIP overexpression provides neuroprotection against neurotoxic mitochondrial stress, glucocorticoids, and accumulation of toxic amyloid fragments, as well as genetic mutations in other E3 ligases, which have been shown to result in familial Parkinson's disease. These studies have created a great deal of interest in understanding CHIP activity, expression and modulation. While CHIP knockout mice have the potential to provide essential insights into the molecular control of cell fate and survival, the animals have been difficult to characterize in vivo due to severe phenotypic and behavioral dysfunction, which have thus far been poorly characterized. Therefore, in the present study we conducted a battery of neurobehavioral and physiological assays of adult CHIP heterozygotic (HET mutant mice to provide a better understanding of the functional consequence of CHIP deficiency. We found that CHIP HET mice had normal body and brain weight, body temperature, muscle tone and breathing patterns, but do have a significant elevation in baseline heart rate. Meanwhile basic behavioral screens of sensory, motor, emotional and cognitive functions were normative. We observed no alterations in performance in the elevated plus maze, light-dark preference and tail suspension assays, or two simple cognitive tasks: novel object recognition and spontaneous alternation in a Y maze. Significant deficits were found, however, when CHIP HET mice performed wire hang, inverted screen, wire maneuver, and open field tasks. Taken together, our data indicate a clear subset of behaviors that are altered at baseline in CHIP deficient animals, which will further guide whole animal studies of the effects of CHIP dysregulation on cardiac function, brain circuitry and function, and responsiveness to environmental and

  9. Haploinsufficiency of Dmxl2, encoding a synaptic protein, causes infertility associated with a loss of GnRH neurons in mouse.

    Directory of Open Access Journals (Sweden)

    Brooke Tata

    2014-09-01

    Full Text Available Characterization of the genetic defects causing gonadotropic deficiency has made a major contribution to elucidation of the fundamental role of Kisspeptins and Neurokinin B in puberty onset and reproduction. The absence of puberty may also reveal neurodevelopmental disorders caused by molecular defects in various cellular pathways. Investigations of these neurodevelopmental disorders may provide information about the neuronal processes controlling puberty onset and reproductive capacity. We describe here a new syndrome observed in three brothers, which involves gonadotropic axis deficiency, central hypothyroidism, peripheral demyelinating sensorimotor polyneuropathy, mental retardation, and profound hypoglycemia, progressing to nonautoimmune insulin-dependent diabetes mellitus. High-throughput sequencing revealed a homozygous in-frame deletion of 15 nucleotides in DMXL2 in all three affected patients. This homozygous deletion was associated with lower DMXL2 mRNA levels in the blood lymphocytes of the patients. DMXL2 encodes the synaptic protein rabconnectin-3α, which has been identified as a putative scaffold protein for Rab3-GAP and Rab3-GEP, two regulators of the GTPase Rab3a. We found that rabconnectin-3α was expressed in exocytosis vesicles in gonadotropin-releasing hormone (GnRH axonal extremities in the median eminence of the hypothalamus. It was also specifically expressed in cells expressing luteinizing hormone (LH and follicle-stimulating hormone (FSH within the pituitary. The conditional heterozygous deletion of Dmxl2 from mouse neurons delayed puberty and resulted in very low fertility. This reproductive phenotype was associated with a lower number of GnRH neurons in the hypothalamus of adult mice. Finally, Dmxl2 knockdown in an insulin-secreting cell line showed that rabconnectin-3α controlled the constitutive and glucose-induced secretion of insulin. In conclusion, this study shows that low levels of DMXL2 expression cause a

  10. Checkpoint kinase 1-induced phosphorylation of O-linked β-N-acetylglucosamine transferase regulates the intermediate filament network during cytokinesis.

    Science.gov (United States)

    Li, Zhe; Li, Xueyan; Nai, Shanshan; Geng, Qizhi; Liao, Ji; Xu, Xingzhi; Li, Jing

    2017-12-01

    Checkpoint kinase 1 (Chk1) is a kinase instrumental for orchestrating DNA replication, DNA damage checkpoints, the spindle assembly checkpoint, and cytokinesis. Despite Chk1's pivotal role in multiple cellular processes, many of its substrates remain elusive. Here, we identified O- linked β- N -acetylglucosamine ( O -GlcNAc)-transferase (OGT) as one of Chk1's substrates. We found that Chk1 interacts with and phosphorylates OGT at Ser-20, which not only stabilizes OGT, but also is required for cytokinesis. Phospho-specific antibodies of OGT-pSer-20 exhibited specific signals at the midbody of the cell, consistent with midbody localization of OGT as reported previously. Moreover, phospho-deficient OGT (S20A) cells attenuated cellular O -GlcNAcylation levels and also reduced phosphorylation of Ser-71 in the cytoskeletal protein vimentin, a modification critical for severing vimentin filament during cytokinesis. Consequently, elongated vimentin bridges were observed in cells depleted of OGT via an si OGT- based approach. Lastly, expression of plasmids resistant to si OGT efficiently rescued the vimentin bridge phenotype, but the OGT-S20A rescue plasmids did not. Our results suggest a Chk1-OGT-vimentin pathway that regulates the intermediate filament network during cytokinesis. © 2017 by The American Society for Biochemistry and Molecular Biology, Inc.

  11. Disruption of the Sec24d gene results in early embryonic lethality in the mouse.

    Directory of Open Access Journals (Sweden)

    Andrea C Baines

    Full Text Available Transport of newly synthesized proteins from the endoplasmic reticulum (ER to the Golgi is mediated by the coat protein complex COPII. The inner coat of COPII is assembled from heterodimers of SEC23 and SEC24. Though mice with mutations in one of the four Sec24 paralogs, Sec24b, exhibit a neural tube closure defect, deficiency in humans or mice has not yet been described for any of the other Sec24 paralogs. We now report characterization of mice with targeted disruption of Sec24d. Early embryonic lethality is observed in mice completely deficient in SEC24D, while a hypomorphic Sec24d allele permits survival to mid-embryogenesis. Mice haploinsufficient for Sec24d exhibit no phenotypic abnormality. A BAC transgene containing Sec24d rescues the embryonic lethality observed in Sec24d-null mice. These results demonstrate an absolute requirement for SEC24D expression in early mammalian development that is not compensated by the other three Sec24 paralogs. The early embryonic lethality resulting from loss of SEC24D in mice contrasts with the previously reported mild skeletal phenotype of SEC24D deficiency in zebrafish and restricted neural tube phenotype of SEC24B deficiency in mice. Taken together, these observations suggest that the multiple Sec24 paralogs have developed distinct functions over the course of vertebrate evolution.

  12. 1998 results

    International Nuclear Information System (INIS)

    Gadonneix, P.

    1998-01-01

    This document presents the financial and commercial results of Gaz de France (GdF) company for 1998. The following points are presented successively: financial results (budget results, turnover, self-financing capacity, investments, debt situation), commercial results (some remarkable numbers and records, the tertiary and residential market, the industrial market, cogeneration and natural gas for vehicles), the strategy, 1998 realizations and perspectives (the natural gas energy in the 21. century, the development of GdF, the gas distribution and services (development of the French distribution system, export of the know-how, development of services), the transportation and storage systems threw Europe (densification of the pipeline network, the key-position of France, the north-south equilibrium of the distribution network), the natural gas production by GdF, the diversification of supplies, and the main daughter companies abroad). (J.S.)

  13. Extraordinary results

    International Nuclear Information System (INIS)

    Cicova, V.

    2012-01-01

    For the first time in the history, Slovenske elektrarne became the first winner in a new category Business and Biodiversity in the competition of European companies aimed at the environment protection. Excellent results were achieved by a long-term co-operation with the Tatras National Park, in particular in saving the endangered animals.

  14. Ganil results

    International Nuclear Information System (INIS)

    Tamain, B.

    1992-06-01

    Recent Ganil results are presented: hot nuclei properties and multifragmentation, study of flow change around the inversion energy. Mesons and hard photons production are also briefly discussed. Correlations with studies that have been led in Saturne energy range, and the developments that can be foreseen in the future have been discussed

  15. SAGE results

    International Nuclear Information System (INIS)

    Gavrin, V.N.

    1996-01-01

    The Russian-American Gallium solar neutrino Experiment (SAGE) is described. The solar neutrino flux measured by 31 extractions through October, 1993 is presented. The result of 69+/-10(stat)+5/-7(syst) SNU is to be compared with a Standard Solar Model prediction of 132 SNU. The initial results of a measurement of experimental efficiencies are also discussed by exposing the gallium target to neutrinos from an artificial source. The capture rate of neutrinos from this source is very close to that which is expected. The result can be expressed as a ratio of the measured capture rate to the anticipated rate from the source activity. This ratio is 0.93+0.15, -0.17 where the systematic and statistical errors have been combined. To first order the experimental efficiencies are in agreement with those determined during solar neutrino measurements and in previous auxiliary measurements. One must conclude that the discrepancy between the measured solar neutrino flux and that predicted by the solar models can not arise from an experimental artifact. (author)

  16. Mutations in Mll2, an H3K4 Methyltransferase, Result in Insulin Resistance and Impaired Glucose Tolerance in Mice

    Science.gov (United States)

    Schröter, David; Matthews, Helen C.; Bogani, Debora; Moir, Lee; Long, Anna; Church, Christopher; Hugill, Alison; Anstee, Quentin M.; Goldin, Rob; Thursz, Mark; Hollfelder, Florian; Cox, Roger D.

    2013-01-01

    We employed a random mutagenesis approach to identify novel monogenic determinants of type 2 diabetes. Here we show that haplo-insufficiency of the histone methyltransferase myeloid-lineage leukemia (Mll2/Wbp7) gene causes type 2 diabetes in the mouse. We have shown that mice heterozygous for two separate mutations in the SET domain of Mll2 or heterozygous Mll2 knockout mice were hyperglycaemic, hyperinsulinaemic and developed non-alcoholic fatty liver disease. Consistent with previous Mll2 knockout studies, mice homozygous for either ENU mutation (or compound heterozygotes) died during embryonic development at 9.5–14.5 days post coitum. Heterozygous deletion of Mll2 induced in the adult mouse results in a normal phenotype suggesting that changes in chromatin methylation during development result in the adult phenotype. Mll2 has been shown to regulate a small subset of genes, a number of which Neurod1, Enpp1, Slc27a2, and Plcxd1 are downregulated in adult mutant mice. Our results demonstrate that histone H3K4 methyltransferase Mll2 is a component of the genetic regulation necessary for glucose homeostasis, resulting in a specific disease pattern linking chromatin modification with causes and progression of type 2 diabetes, providing a basis for its further understanding at the molecular level. PMID:23826075

  17. Mutations in Mll2, an H3K4 methyltransferase, result in insulin resistance and impaired glucose tolerance in mice.

    Directory of Open Access Journals (Sweden)

    Michelle Goldsworthy

    Full Text Available We employed a random mutagenesis approach to identify novel monogenic determinants of type 2 diabetes. Here we show that haplo-insufficiency of the histone methyltransferase myeloid-lineage leukemia (Mll2/Wbp7 gene causes type 2 diabetes in the mouse. We have shown that mice heterozygous for two separate mutations in the SET domain of Mll2 or heterozygous Mll2 knockout mice were hyperglycaemic, hyperinsulinaemic and developed non-alcoholic fatty liver disease. Consistent with previous Mll2 knockout studies, mice homozygous for either ENU mutation (or compound heterozygotes died during embryonic development at 9.5-14.5 days post coitum. Heterozygous deletion of Mll2 induced in the adult mouse results in a normal phenotype suggesting that changes in chromatin methylation during development result in the adult phenotype. Mll2 has been shown to regulate a small subset of genes, a number of which Neurod1, Enpp1, Slc27a2, and Plcxd1 are downregulated in adult mutant mice. Our results demonstrate that histone H3K4 methyltransferase Mll2 is a component of the genetic regulation necessary for glucose homeostasis, resulting in a specific disease pattern linking chromatin modification with causes and progression of type 2 diabetes, providing a basis for its further understanding at the molecular level.

  18. Impact of MCT1 Haploinsufficiency on the Mouse Retina

    KAUST Repository

    Peachey, Neal S.

    2018-05-02

    The monocarboxylate transporter 1 (MCT1) is highly expressed in the outer retina, suggesting that it plays a critical role in photoreceptors. We examined MCT1+/− heterozygotes, which express half of the normal complement of MCT1. The MCT1+/− retina developed normally and retained normal function, indicating that MCT1 is expressed at sufficient levels to support outer retinal metabolism.

  19. Impact of MCT1 Haploinsufficiency on the Mouse Retina

    KAUST Repository

    Peachey, Neal S.; Yu, Minzhong; Han, John Y. S.; Lengacher, Sylvain; Magistretti, Pierre J.; Pellerin, Luc; Philp, Nancy J.

    2018-01-01

    The monocarboxylate transporter 1 (MCT1) is highly expressed in the outer retina, suggesting that it plays a critical role in photoreceptors. We examined MCT1+/− heterozygotes, which express half of the normal complement of MCT1. The MCT1+/− retina developed normally and retained normal function, indicating that MCT1 is expressed at sufficient levels to support outer retinal metabolism.

  20. Haploinsufficiency of TAB2 causes congenital heart defects in humans

    DEFF Research Database (Denmark)

    Thienpont, Bernard; Zhang, Litu; Postma, Alex V

    2010-01-01

    . To definitively confirm the role of this candidate gene in CHDs, we performed mutation analysis of TAB2 in 402 patients with a CHD, which revealed two evolutionarily conserved missense mutations. Finally, a balanced translocation was identified, cosegregating with familial CHD. Mapping of the breakpoints...... demonstrated that this translocation disrupts TAB2. Taken together, these data clearly demonstrate a role for TAB2 in human cardiac development....

  1. In Silico Exploration of 1,7-Diazacarbazole Analogs as Checkpoint Kinase 1 Inhibitors by Using 3D QSAR, Molecular Docking Study, and Molecular Dynamics Simulations

    Directory of Open Access Journals (Sweden)

    Xiaodong Gao

    2016-05-01

    Full Text Available Checkpoint kinase 1 (Chk1 is an important serine/threonine kinase with a self-protection function. The combination of Chk1 inhibitors and anti-cancer drugs can enhance the selectivity of tumor therapy. In this work, a set of 1,7-diazacarbazole analogs were identified as potent Chk1 inhibitors through a series of computer-aided drug design processes, including three-dimensional quantitative structure–activity relationship (3D-QSAR modeling, molecular docking, and molecular dynamics simulations. The optimal QSAR models showed significant cross-validated correlation q2 values (0.531, 0.726, fitted correlation r2 coefficients (higher than 0.90, and standard error of prediction (less than 0.250. These results suggested that the developed models possess good predictive ability. Moreover, molecular docking and molecular dynamics simulations were applied to highlight the important interactions between the ligand and the Chk1 receptor protein. This study shows that hydrogen bonding and electrostatic forces are key interactions that confer bioactivity.

  2. [Molecular pathogenesis of Waardenburg syndrome type II resulting from SOX10 gene mutation].

    Science.gov (United States)

    Zhang, Hua; Chen, Hongsheng; Feng, Yong; Qian, Minfei; Li, Jiping; Liu, Jun; Zhang, Chun

    2016-08-01

    To explore the molecular mechanism of Waardenburg syndrome type II (WS2) resulting from SOX10 gene mutation E248fs through in vitro experiment. 293T cells were transiently transfected with wild type (WT) SOX10 and mutant type (MT) E248fs plasmids. The regulatory effect of WT/MT SOX10 on the transcriptional activity of MITF gene and influence of E248fs on WT SOX10 function were determined with a luciferase activity assay. The DNA binding capacity of the WT/MT SOX10 with the promoter of the MITF gene was determined with a biotinylated double-stranded oligonucleotide probe containing the SOX10 binding sequence cattgtc to precipitate MITF and E248fs, respectively. The stability of SOX10 and E248fs were also analyzed. As a loss-of-function mutation, the E248fs mutant failed to transactivate the MITF promoter as compared with the WT SOX10 (P<0.01), which also showed a dominant-negative effect on WT SOX10. The WT SOX10 and E248fs mutant were also able to bind specifically to the cattgtc motif in the MITF promoter, whereas E248fs had degraded faster than WT SOX10. Despite the fact that the E248fs has a dominant-negative effect on SOX10, its reduced stability may down-regulate the transcription of MITF and decrease the synthesis of melanin, which may result in haploinsufficiency of SOX10 protein and cause the milder WS2 phenotype.

  3. DW-MRI as a Predictive Biomarker of Radiosensitization of GBM through Targeted Inhibition of Checkpoint Kinases.

    Science.gov (United States)

    Williams, Terence M; Galbán, Stefanie; Li, Fei; Heist, Kevin A; Galbán, Craig J; Lawrence, Theodore S; Holland, Eric C; Thomae, Tami L; Chenevert, Thomas L; Rehemtulla, Alnawaz; Ross, Brian D

    2013-04-01

    The inherent treatment resistance of glioblastoma (GBM) can involve multiple mechanisms including checkpoint kinase (Chk1/2)-mediated increased DNA repair capability, which can attenuate the effects of genotoxic chemotherapies and radiation. The goal of this study was to evaluate diffusion-weighted magnetic resonance imaging (DW-MRI) as a biomarker for Chk1/2 inhibitors in combination with radiation for enhancement of treatment efficacy in GBM. We evaluated a specific small molecule inhibitor of Chk1/2, AZD7762, in combination with radiation using in vitro human cell lines and in vivo using a genetically engineered GBM mouse model. DW-MRI and T1-contrast MRI were used to follow treatment effects on intracranial tumor cellularity and growth rates, respectively. AZD7762 inhibited clonal proliferation in a panel of GBM cell lines and increased radiosensitivity in p53-mutated GBM cell lines to a greater extent compared to p53 wild-type cells. In vivo efficacy of AZD7762 demonstrated a dose-dependent inhibitory effect on GBM tumor growth rate and a reduction in tumor cellularity based on DW-MRI scans along with enhancement of radiation efficacy. DW-MRI was found to be a useful imaging biomarker for the detection of radiosensitization through inhibition of checkpoint kinases. Chk1/2 inhibition resulted in antiproliferative activity, prevention of DNA damage-induced repair, and radiosensitization in preclinical GBM tumor models, both in vitro and in vivo. The effects were found to be maximal in p53-mutated GBM cells. These results provide the rationale for integration of DW-MRI in clinical translation of Chk1/2 inhibition with radiation for the treatment of GBM.

  4. Piperine causes G1 phase cell cycle arrest and apoptosis in melanoma cells through checkpoint kinase-1 activation.

    Directory of Open Access Journals (Sweden)

    Neel M Fofaria

    Full Text Available In this study, we determined the cytotoxic effects of piperine, a major constituent of black and long pepper in melanoma cells. Piperine treatment inhibited the growth of SK MEL 28 and B16 F0 cells in a dose and time-dependent manner. The growth inhibitory effects of piperine were mediated by cell cycle arrest of both the cell lines in G1 phase. The G1 arrest by piperine correlated with the down-regulation of cyclin D1 and induction of p21. Furthermore, this growth arrest by piperine treatment was associated with DNA damage as indicated by phosphorylation of H2AX at Ser139, activation of ataxia telangiectasia and rad3-related protein (ATR and checkpoint kinase 1 (Chk1. Pretreatment with AZD 7762, a Chk1 inhibitor not only abrogated the activation of Chk1 but also piperine mediated G1 arrest. Similarly, transfection of cells with Chk1 siRNA completely protected the cells from G1 arrest induced by piperine. Piperine treatment caused down-regulation of E2F1 and phosphorylation of retinoblastoma protein (Rb. Apoptosis induced by piperine was associated with down-regulation of XIAP, Bid (full length and cleavage of Caspase-3 and PARP. Furthermore, our results showed that piperine treatment generated ROS in melanoma cells. Blocking ROS by tiron protected the cells from piperine mediated cell cycle arrest and apoptosis. These results suggest that piperine mediated ROS played a critical role in inducing DNA damage and activation of Chk1 leading to G1 cell cycle arrest and apoptosis.

  5. The Checkpoint Kinase 1 Inhibitor Prexasertib Induces Regression of Preclinical Models of Human Neuroblastoma.

    Science.gov (United States)

    Lowery, Caitlin D; VanWye, Alle B; Dowless, Michele; Blosser, Wayne; Falcon, Beverly L; Stewart, Julie; Stephens, Jennifer; Beckmann, Richard P; Bence Lin, Aimee; Stancato, Louis F

    2017-08-01

    Purpose: Checkpoint kinase 1 (CHK1) is a key regulator of the DNA damage response and a mediator of replication stress through modulation of replication fork licensing and activation of S and G 2 -M cell-cycle checkpoints. We evaluated prexasertib (LY2606368), a small-molecule CHK1 inhibitor currently in clinical testing, in multiple preclinical models of pediatric cancer. Following an initial assessment of prexasertib activity, this study focused on the preclinical models of neuroblastoma. Experimental Design: We evaluated the antiproliferative activity of prexasertib in a panel of cancer cell lines; neuroblastoma cell lines were among the most sensitive. Subsequent Western blot and immunofluorescence analyses measured DNA damage and DNA repair protein activation. Prexasertib was investigated in several cell line-derived xenograft mouse models of neuroblastoma. Results: Within 24 hours, single-agent prexasertib promoted γH2AX-positive double-strand DNA breaks and phosphorylation of DNA damage sensors ATM and DNA-PKcs, leading to neuroblastoma cell death. Knockdown of CHK1 and/or CHK2 by siRNA verified that the double-strand DNA breaks and cell death elicited by prexasertib were due to specific CHK1 inhibition. Neuroblastoma xenografts rapidly regressed following prexasertib administration, independent of starting tumor volume. Decreased Ki67 and increased immunostaining of endothelial and pericyte markers were observed in xenografts after only 6 days of exposure to prexasertib, potentially indicating a swift reduction in tumor volume and/or a direct effect on tumor vasculature. Conclusions: Overall, these data demonstrate that prexasertib is a specific inhibitor of CHK1 in neuroblastoma and leads to DNA damage and cell death in preclinical models of this devastating pediatric malignancy. Clin Cancer Res; 23(15); 4354-63. ©2017 AACR . ©2017 American Association for Cancer Research.

  6. DNA damage by X-rays and their impact on replication processes

    International Nuclear Information System (INIS)

    Parplys, Ann Christin; Petermann, Eva; Petersen, Cordula; Dikomey, Ekkehard; Borgmann, Kerstin

    2012-01-01

    Background: Replication-dependent radiosensitization of tumors ranks among the most promising tools for future improvements in tumor therapy. However, cell cycle checkpoint signaling during S phase is a key for maintaining genomic stability after ionizing irradiation allowing DNA damage repair by stabilizing replication forks, inhibiting new origin firing and recruiting DNA repair proteins. As the impact of the different types of DNA damage induced by ionizing radiation on replication fork functionality has not been investigated, this study was performed in tumor cells treated with various agents that induce specific DNA lesions. Methods: U2OS cells were exposed to methyl methanesulfonate (MMS) to induce base damage, low or high concentrations of hydrogen peroxide for the induction of SSBs, Topotecan to induce DSBs at replication, Mitomycin C (MMC) to induce interstrand cross-links or ionizing irradiation to analyze all damages. Chk1 phosphorylation, origin firing and replication fork progression, and cell cycle distribution were analyzed. Results: In our system, the extent of Chk1 phosphorylation was dependent on the type of damage induced and prolonged Chk1 phosphorylation correlated with the inhibition of replication initiation. Ionizing radiation, high concentrations of hydrogen peroxide, and Topotecan affected replication elongation much more strongly that the other agents. Almost all agents induced a slight increase in the S phase population but subsequent G2 arrest was only observed in response to those agents that strongly inhibited replication elongation and caused prolonged Chk1 phosphorylation. Conclusions: Our data suggest that to improve radiotherapy, radiosensitivity in S phase could be increased by combining irradiation with agents that induce secondary DSB or inhibit checkpoint signaling, such as inhibitors of PARP or Chk1.

  7. Cell cycle G2/M arrest through an S phase-dependent mechanism by HIV-1 viral protein R

    Directory of Open Access Journals (Sweden)

    Liang Dong

    2010-07-01

    Full Text Available Abstract Background Cell cycle G2 arrest induced by HIV-1 Vpr is thought to benefit viral proliferation by providing an optimized cellular environment for viral replication and by skipping host immune responses. Even though Vpr-induced G2 arrest has been studied extensively, how Vpr triggers G2 arrest remains elusive. Results To examine this initiation event, we measured the Vpr effect over a single cell cycle. We found that even though Vpr stops the cell cycle at the G2/M phase, but the initiation event actually occurs in the S phase of the cell cycle. Specifically, Vpr triggers activation of Chk1 through Ser345 phosphorylation in an S phase-dependent manner. The S phase-dependent requirement of Chk1-Ser345 phosphorylation by Vpr was confirmed by siRNA gene silencing and site-directed mutagenesis. Moreover, downregulation of DNA replication licensing factors Cdt1 by siRNA significantly reduced Vpr-induced Chk1-Ser345 phosphorylation and G2 arrest. Even though hydroxyurea (HU and ultraviolet light (UV also induce Chk1-Ser345 phosphorylation in S phase under the same conditions, neither HU nor UV-treated cells were able to pass through S phase, whereas vpr-expressing cells completed S phase and stopped at the G2/M boundary. Furthermore, unlike HU/UV, Vpr promotes Chk1- and proteasome-mediated protein degradations of Cdc25B/C for G2 induction; in contrast, Vpr had little or no effect on Cdc25A protein degradation normally mediated by HU/UV. Conclusions These data suggest that Vpr induces cell cycle G2 arrest through a unique molecular mechanism that regulates host cell cycle regulation in an S-phase dependent fashion.

  8. A retrotransposon insertion in the 5' regulatory domain of Ptf1a results in ectopic gene expression and multiple congenital defects in Danforth's short tail mouse.

    Directory of Open Access Journals (Sweden)

    Francesca Lugani

    Full Text Available Danforth's short tail mutant (Sd mouse, first described in 1930, is a classic spontaneous mutant exhibiting defects of the axial skeleton, hindgut, and urogenital system. We used meiotic mapping in 1,497 segregants to localize the mutation to a 42.8-kb intergenic segment on chromosome 2. Resequencing of this region identified an 8.5-kb early retrotransposon (ETn insertion within the highly conserved regulatory sequences upstream of Pancreas Specific Transcription Factor, 1a (Ptf1a. This mutation resulted in up to tenfold increased expression of Ptf1a as compared to wild-type embryos at E9.5 but no detectable changes in the expression levels of other neighboring genes. At E9.5, Sd mutants exhibit ectopic Ptf1a expression in embryonic progenitors of every organ that will manifest a developmental defect: the notochord, the hindgut, and the mesonephric ducts. Moreover, at E 8.5, Sd mutant mice exhibit ectopic Ptf1a expression in the lateral plate mesoderm, tail bud mesenchyme, and in the notochord, preceding the onset of visible defects such as notochord degeneration. The Sd heterozygote phenotype was not ameliorated by Ptf1a haploinsufficiency, further suggesting that the developmental defects result from ectopic expression of Ptf1a. These data identify disruption of the spatio-temporal pattern of Ptf1a expression as the unifying mechanism underlying the multiple congenital defects in Danforth's short tail mouse. This striking example of an enhancer mutation resulting in profound developmental defects suggests that disruption of conserved regulatory elements may also contribute to human malformation syndromes.

  9. A novel frameshift GRN mutation results in frontotemporal lobar degeneration with a distinct clinical phenotype in two siblings: case report and literature review.

    Science.gov (United States)

    Hosaka, Takashi; Ishii, Kazuhiro; Miura, Takeshi; Mezaki, Naomi; Kasuga, Kensaku; Ikeuchi, Takeshi; Tamaoka, Akira

    2017-09-15

    Progranulin gene (GRN) mutations are major causes of frontotemporal lobar degeneration. To date, 68 pathogenic GRN mutations have been identified. However, very few of these mutations have been reported in Asians. Moreover, some GRN mutations manifest with familial phenotypic heterogeneity. Here, we present a novel GRN mutation resulting in frontotemporal lobar degeneration with a distinct clinical phenotype, and we review reports of GRN mutations associated with familial phenotypic heterogeneity. We describe the case of a 74-year-old woman with left frontotemporal lobe atrophy who presented with progressive anarthria and non-fluent aphasia. Her brother had been diagnosed with corticobasal syndrome (CBS) with right-hand limb-kinetic apraxia, aphasia, and a similar pattern of brain atrophy. Laboratory blood examinations did not reveal abnormalities that could have caused cognitive dysfunction. In the cerebrospinal fluid, cell counts and protein concentrations were within normal ranges, and concentrations of tau protein and phosphorylated tau protein were also normal. Since similar familial cases due to mutation of GRN and microtubule-associated protein tau gene (MAPT) were reported, we performed genetic analysis. No pathological mutations of MAPT were identified, but we identified a novel GRN frameshift mutation (c.1118_1119delCCinsG: p.Pro373ArgX37) that resulted in progranulin haploinsufficiency. This is the first report of a GRN mutation associated with familial phenotypic heterogeneity in Japan. Literature review of GRN mutations associated with familial phenotypic heterogeneity revealed no tendency of mutation sites. The role of progranulin has been reported in this and other neurodegenerative diseases, and the analysis of GRN mutations may lead to the discovery of a new therapeutic target.

  10. Activation of DNA damage repair pathways by murine polyomavirus

    Energy Technology Data Exchange (ETDEWEB)

    Heiser, Katie; Nicholas, Catherine; Garcea, Robert L., E-mail: Robert.Garcea@Colorado.edu

    2016-10-15

    Nuclear replication of DNA viruses activates DNA damage repair (DDR) pathways, which are thought to detect and inhibit viral replication. However, many DNA viruses also depend on these pathways in order to optimally replicate their genomes. We investigated the relationship between murine polyomavirus (MuPyV) and components of DDR signaling pathways including CHK1, CHK2, H2AX, ATR, and DNAPK. We found that recruitment and retention of DDR proteins at viral replication centers was independent of H2AX, as well as the viral small and middle T-antigens. Additionally, infectious virus production required ATR kinase activity, but was independent of CHK1, CHK2, or DNAPK signaling. ATR inhibition did not reduce the total amount of viral DNA accumulated, but affected the amount of virus produced, indicating a defect in virus assembly. These results suggest that MuPyV may utilize a subset of DDR proteins or non-canonical DDR signaling pathways in order to efficiently replicate and assemble. -- Highlights: •Murine polyomavirus activates and recruits DNA damage repair (DDR) proteins to replication centers. •Large T-antigen mediates recruitment of DDR proteins to viral replication centers. •Inhibition or knockout of CHK1, CHK2, DNA-PK or H2AX do not affect viral titers. •Inhibition of ATR activity reduces viral titers, but not viral DNA accumulation.

  11. Total 2004 results

    International Nuclear Information System (INIS)

    2005-02-01

    This document presents the 2004 results of Total Group: consolidated account, special items, number of shares, market environment, adjustment for amortization of Sanofi-Aventis merger-related intangibles, 4. quarter 2004 results (operating and net incomes, cash flow), upstream (results, production, reserves, recent highlights), downstream (results, refinery throughput, recent highlights), chemicals (results, recent highlights), Total's full year 2004 results (operating and net income, cash flow), 2005 sensitivities, Total SA parent company accounts and proposed dividend, adoption of IFRS accounting, summary and outlook, main operating information by segment for the 4. quarter and full year 2004: upstream (combined liquids and gas production by region, liquids production by region, gas production by region), downstream (refined product sales by region, chemicals), Total financial statements: consolidated statement of income, consolidated balance sheet (assets, liabilities and shareholder's equity), consolidated statements of cash flows, business segments information. (J.S.)

  12. Total 2004 results

    Energy Technology Data Exchange (ETDEWEB)

    NONE

    2005-02-01

    This document presents the 2004 results of Total Group: consolidated account, special items, number of shares, market environment, adjustment for amortization of Sanofi-Aventis merger-related intangibles, 4. quarter 2004 results (operating and net incomes, cash flow), upstream (results, production, reserves, recent highlights), downstream (results, refinery throughput, recent highlights), chemicals (results, recent highlights), Total's full year 2004 results (operating and net income, cash flow), 2005 sensitivities, Total SA parent company accounts and proposed dividend, adoption of IFRS accounting, summary and outlook, main operating information by segment for the 4. quarter and full year 2004: upstream (combined liquids and gas production by region, liquids production by region, gas production by region), downstream (refined product sales by region, chemicals), Total financial statements: consolidated statement of income, consolidated balance sheet (assets, liabilities and shareholder's equity), consolidated statements of cash flows, business segments information. (J.S.)

  13. Recent results from TASSO

    International Nuclear Information System (INIS)

    Foster, B.

    1982-03-01

    Results are presented on the inclusive production of π 0 , K 0 and antiK 0 and lambda and antilambda in e + e - annihilation. These results, together with those on inclusive charged hadron production are used to obtain information on fragmentation mechanisms and the production of heavy quark flavours in e + e - annihilation. (author)

  14. Recent results from TRISTAN

    Energy Technology Data Exchange (ETDEWEB)

    Enomoto, Ryoji [National Laboratory for High Energy Physics, Ibaraki (Japan)

    1997-01-01

    TRISTAN results on {gamma}{gamma} physics from 1994 to 1995 are reviewed in this report. We have systematically investigated jet production, the {gamma}-structure function, and charm pair production in {gamma}{gamma} processes. The results are discussed, and future prospects are presented.

  15. Annual results 2004

    International Nuclear Information System (INIS)

    2005-01-01

    This 2004 annual evaluation of the french RTE company (electric power transport network) provides information on the 2004 results on: institutional information, financial results, customers and market, industrial resources, environment and consultation, human resources and international aspects. (A.L.B.)

  16. Tevatron physics results

    CERN Multimedia

    CERN. Geneva

    2007-01-01

    I will summarize the physics results from the Tevatron experiments with particular emphasis on the experimental methods used in different kinds of analysis. In particular, the Tevatron is a proton-antiproton collider that has now accumulated more than 2 fb^-1 of luminosity in the two experiments, called CDF and D0. In this lecture I will review the results on inclusive productions of jets, W- and Z-bosons, the results in the flavor sector, the measurements of top production, searches for Higgs boson production and searches for physics beyond the Standard Model. In each case I will explain the basic experimental concepts and methods needed for making the measurement.

  17. CMS Higgs boson results

    CERN Document Server

    Bluj, Michal Jacek

    2018-01-01

    In this report we review recent Higgs boson results obtained with pp collisions at $\\sqrt{s}=\\,$13 TeV recorded by the CMS detector in 2016 for an integrated luminosity of 35.9fb$^{\\text{-1}}$. The 2016 data allowed the observation of the $H \\to \\tau\\tau$ and $H \\to WW$ decays with high significance. We also present a combined measurement based on a full set of CMS analyses performed with 2016 data. These results are compatible with the standard model predictions with precision of several measurements exceeding results from combination of ATLAS and CMS data collected in 2011 and 2012.

  18. Arsenic speciation results

    Data.gov (United States)

    U.S. Environmental Protection Agency — Linear combination fitting results of synchrotron data to determine arsenic speciation in soil samples. This dataset is associated with the following publication:...

  19. Haiti DevResults

    Data.gov (United States)

    US Agency for International Development — DevResults is a web-based portfolio management system that tracks program data for the Haiti Mission that was awarded in April of 2013. (The Mozambique and/or...

  20. ATLAS soft QCD results

    CERN Document Server

    Sykora, Tomas; The ATLAS collaboration

    2018-01-01

    Recent results of soft QCD measurements performed by the ATLAS collaboration are reported. The measurements include total, elastic and inelastic cross sections, inclusive spectra, underlying event and particle correlations in p-p and p-Pb collisions.

  1. Atmospheric Deposition Modeling Results

    Data.gov (United States)

    U.S. Environmental Protection Agency — This asset provides data on model results for dry and total deposition of sulfur, nitrogen and base cation species. Components include deposition velocities, dry...

  2. Transacsys PLC - Final Results

    CERN Multimedia

    2002-01-01

    Final results from Transacsys PLC. A subsidary of this company was set up to develop the CERN EDH system into a commercial product but incurred too much financial loss so the project was cancelled (1/2 page).

  3. New particles: experimental results

    International Nuclear Information System (INIS)

    Augustin, J.E.

    The results of studies on production and properties of psi(3100) and psi(3700) resonances are presented, particular attention being given to spin, parity, g-parity and isospin determination. Evidence obtained in the SPEAR and DORIS storage rings in psi'→γ chi and psi→γX intermediate states are presented, together with SPEAR results on e-μ events and high energy jet production. (39 references) [fr

  4. Antares: preliminary demonstrator results

    International Nuclear Information System (INIS)

    Kouchner, A.

    2000-05-01

    The ANTARES collaboration is building an undersea neutrino telescope off Toulon (Mediterranean sea) with effective area ∼ 0.1 km 2 . An extensive study of the site properties has been achieved together with software analysis in order to optimize the performance of the detector. Results are summarized here. An instrumented line, linked to shore for first time via an electro-optical cable, has been immersed late 1999. The preliminary results of this demonstrator line are reported. (author)

  5. Chapter 5: Monitoring results

    DEFF Research Database (Denmark)

    Poel, Bart; Thomsen, Kirsten Engelund; Schultz, Jørgen Munthe

    2003-01-01

    The monitoring results from the IEA Task 13 project "Advanced solar low energy houses" are described in this chapter. The underlying information was collected in the form of questionnaires. The questionnaires were formulated in such a way that participants are provided with a uniform lay......-out to fill in their particular results. Thus it is possible to compare the performances measured, calculated or predicted for the different houses....

  6. Compilation of results 1987

    International Nuclear Information System (INIS)

    1987-01-01

    A compilation is carried out which in concentrated form presents reports on research and development within the nuclear energy field covering a two and a half years period. The foregoing report was edited in December 1984. The projects are presendted with title, project number, responsible unit, person to contact and short result reports. The result reports consist of short summaries over each project. (L.F.)

  7. Higgs results from ATLAS

    International Nuclear Information System (INIS)

    Chen, Xin

    2016-01-01

    The updated Higgs measurements in various search channels with ATLAS Run 1 data are reviewed. Both the Standard Model (SM) Higgs results, such as H → γγ, ZZ, WW, ττ, μμ, bb-bar, and Beyond Standard Model (BSM) results, such as the charged Higgs, Higgs invisible decay and tensor couplings, are summarized. Prospects for future Higgs searches are briefly discussed

  8. Unfavorable results in replantation

    Directory of Open Access Journals (Sweden)

    Abraham G Thomas

    2013-01-01

    Full Text Available Reattachment of amputated parts of the body (Replantation has become a reality since the first arm replant was carried out six decades ago. Failures were not uncommon in the beginning, leading on to the analysis of the problem and refinements in technique. Improvements in sutures, instrumentation and better microscopes further helped the surgeons to do replantation with better finesse and functional results. Evaluation of results and particularly failure and long term results help the younger surgeons to learn from the difficulties faced earlier to do better in the future. An attempt is made to list various aspects of replantation experienced by the author during the past 30 years, particularly in reference to unfavorable results, which had been occasionally total failure, or a partial failure, with poor function and cosmesis due to infection. An insensate limb with poor function is the result of inadequate or improper nerve coaptation or infection destroying the whole repair. It is apt to mention that infection is mostly the result of poor vascularity due to devitalized tissue. Difficulties arise often in identifying the viable tissue, particularly while debriding in the distal amputated part since there is no bleeding. Experience counts in this, specifically to identify the viable muscle. The factors that may lead to complications are listed with remarks to avoid them.

  9. Total 2003 Results

    International Nuclear Information System (INIS)

    2003-01-01

    This document presents the 2003 results of Total Group: consolidated account, special items, number of shares, market environment, 4. quarter 2003 results, full year 2003 results, upstream (key figures, proved reserves), downstream key figures, chemicals key figures, parent company accounts and proposed dividends, 2004 sensitivities, summary and outlook, operating information by segment for the 4. quarter and full year 2003: upstream (combined liquids and gas production by region, liquids production by region, gas production by region), downstream (refinery throughput by region, refined product sales by region, chemicals), impact of allocating contribution of Cepsa to net operating income by business segment: equity in income (loss) and affiliates and other items, Total financial statements: consolidated statement of income, consolidated balance sheet (assets, liabilities and shareholder's equity), consolidated statements of cash flows, business segments information. (J.S.)

  10. Results from EQAS 2002

    DEFF Research Database (Denmark)

    Petersen, A.; Aarestrup, Frank Møller; Jensen, A.B.

    An international external quality assurance program on serotyping and antimicrobial susceptibility testing of eight Salmonella enterica strains was performed to enhance the capacity of national and regional reference laboratories in WHO Global Salm-Surv (WHO GSS). In 2002 a total of 117 laborator......An international external quality assurance program on serotyping and antimicrobial susceptibility testing of eight Salmonella enterica strains was performed to enhance the capacity of national and regional reference laboratories in WHO Global Salm-Surv (WHO GSS). In 2002 a total of 117...... laboratories from 67 countries participated. For serotyping, almost 90 % of the results were correct. For susceptibility testing, 91 % of the results were in agreement with the expected results, and 86 % of the performed tests with the reference strain E. coli ATCC 25922 were inside the quality control range...

  11. RTE - 2012 financial results

    International Nuclear Information System (INIS)

    Ricour, Olivia; Marguier, Marina; Lartigau, Thierry

    2013-01-01

    The mission of RTE, the French electricity Transportation grid, a public service assignment, is to balance the electricity supply and demand in real time. This report presents RTE's financial results for 2012: increase of investments for services to clients, performance results, financial balance, stability of the economical model. RTE's regulated economical model, main financial indicators, 2007-2012 investments, 2012 investments by category, 2012 turnover, 2012 costs structure, taxes, financial balance sheet at the end of 2012, and the share of electricity transport in the electricity price are presented in appendixes

  12. Geochemical investigations and results

    International Nuclear Information System (INIS)

    Herbert, H.J.; Sander, W.

    1986-01-01

    The following information can be derived from results so far for a final store: - With known mineralogy, precise information can be given on the solution metamorphosis processes to be expected. The previous results of this in-situ experiment have confirmed the theoretical considerations. - Sensors were developed and tested, which make possible continuous monitoring under hydrostatic pressure in a final store in the case of incoming solution, i.e. for exploration bores. - The collection of physical and chemical parameters in open sections and shafts creates the basis for assessing the effect of backfilling from the chemical point of view. (orig./PW) [de

  13. Results from SAGE II

    International Nuclear Information System (INIS)

    Nico, J.S.

    1994-01-01

    The Russian-American Gallium solar neutrino Experiment (SAGE) began the second phase of operation (SAGE II) in September of 1992. Monthly measurements of the integral flux of solar neutrinos have been made with 55 tonnes of gallium. The K-peak results of the first nine runs of SAGE II give a capture rate of 66 -13 +18 (stat) -7 +5 (sys) SNU. Combined with the SAGE I result of 73 -16 +18 (stat) -7 5 (sys) SNU, the capture rate is 69 -11 +11 (stat) -7 +5 (sys) SNU. This represents only 52%--56% of the capture rate predicted by different Standard Solar Models

  14. First AFP results

    CERN Document Server

    Staszewski, Rafal; The ATLAS collaboration

    2017-01-01

    ATLAS Forward Proton (AFP) are detectors dedicated to measurements of protons scattered diffractively or electromagnetically at small angles in inelastic processes. The first arm of AFP was installed in 2016. The installation of the full system was finished in 2017. Since 2016 AFP has collected data is special and standard runs. The presentation shows the first results obtained with data collected by AFP.

  15. Recent results of BABAR

    International Nuclear Information System (INIS)

    Bernard, D.

    2001-01-01

    The BABAR detector at SLAC's PEP-II storage ring has collected data amounting to about 30.4 fb -1 until june 2001. Results on CP violation, and in particular search for direct CP violation, and measurement of rare B decays are presented

  16. Roadmap of Infinite Results

    DEFF Research Database (Denmark)

    Srba, Jiří

    2002-01-01

    This paper provides a comprehensive summary of equivalence checking results for infinite-state systems. References to the relevant papers will be updated continuously according to the development in the area. The most recent version of this document is available from the web-page http://www.brics.dk/~srba/roadmap....

  17. IRU Results and Perspectives

    NARCIS (Netherlands)

    Bronswijk, van J.E.M.H.

    2003-01-01

    This chapter is devoted to the disciplines within USOBuilt Graduate School as organized in International Research and Design Units, the fora where research and design at a (post)doctorate level is performed and taught. A fixed template was used to self-assess results and perspectives, consisting of

  18. Results of CPLEAR

    International Nuclear Information System (INIS)

    Rickenbach, R.; Adler, R.; Alhalel, T.; Angelopoulos, A.; Apostolakis, A.; Aslanides, E.; Backenstoss, G.; Bargassa, P.; Bee, C.P.; Behnke, O.; Benelli, A.; Bertin, V.; Blanc, F.; Bloch, P.; Carlson, P.; Carroll, M.; Carvalho, J.; Cawley, E.; Charalambous, S.; Chardin, G.; Chertok, M.B.; Cody, A.; Danielsson, M.; Dejardin, M.; Derre, J.; Ealet, A.; Eckart, B.; Eleftheriadis, C.; Evangelou, I.; Faravel, L.; Fassnacht, P.; Felder, C.; Ferreira-Marques, R.; Fetscher, W.; Fidecaro, M.; Filipcic, A.; Francis, D.; Fry, J.; Gabathuler, E.; Gamet, R.; Garreta, D.; Gerber, H.-J.; Go, A.; Guyot, C.; Haselden, A.; Hayman, P.J.; Henry-Couannier, F.; Hollander, R.W.; Hubert, E.; Jon-And, K.; Kettle, P.-R.; Kochowski, C.; Kokkas, P.; Kreuger, R.; Le Gac, R.; Leimgruber, F.; Liolios, A.; Machado, E.; Mandic, I.; Manthos, N.; Marel, G.; Mikuz, M.; Miller, J.; Montanet, F.; Nakada, T.; Pagels, B.; Papadopoulos, I.; Pavlopoulos, P.; Pinto da Cunha, J.; Policarpo, A.; Polivka, G.; Roberts, B.L.; Ruf, T.; Sakeliou, L.; Sanders, P.; Santoni, C.; Schaefer, M.; Schaller, L.A.; Schietinger, T.; Schopper, A.; Schune, P.; Soares, A.; Tauscher, L.; Thibault, C.; Touchard, F.; Touramanis, C.; Triantis, F.; Van Beveren, E.; Van Eijk, C.W.E.; Vlachos, S.; Weber, P.; Wigger, O.; Wolter, M.; Yeche, C.; Zavrtanik, D.; Zimmerman, D.

    1997-01-01

    The CPLEAR experiment uses tagged K 0 and K 0 produced in pp annihilation at rest to measure CP-, T- and CPT-violation parameters in the neutral kaon system. The results of these measurements and some implications are reported. (orig.)

  19. Same query - different results

    International Nuclear Information System (INIS)

    Nevyjel, A.

    1983-10-01

    On behalf of a case study a simple truncated adjacency phrase search was executed in the online versions of Chemical Abstracts on five different host computers (DATA-STAR, DIALOG, ESA, SDC, TELESYSTEMES). The reasons for the differences in the appearing results are discussed. (Author) [de

  20. Management Values Survey Results.

    Science.gov (United States)

    Duffy, Barbara; Payne, Ron

    1988-01-01

    Describes results of a survey conducted to compare values of members of the Association for Educational Communications and Technology (AECT) with managers in business and industry. Issues discussed include job satisfaction, opportunities for advancement, attitudes toward management, and salary; a summary of each value system is provided. (LRW)

  1. Plan Merging : Experimental results

    NARCIS (Netherlands)

    De Weerdt, M.M.; Van der Krogt, R.P.J.; Zutt, J.

    2003-01-01

    In this paper we discuss the results of a plan merging algorithm. This algorithm coordinates the plans of multiple, autonomous agents, each able to independently find a plan. This algorithm is evaluated using realistic data from a taxi company. We show that when we allow passengers to be a few

  2. First results at GSI

    International Nuclear Information System (INIS)

    Bock, R.

    1977-01-01

    UNILAC, and accelerator for heavy ions up to uranium with energies up to 10 MeV/nucleon became operational January 1976. A report is given on results so far in various fields of heavy ion physics, in particular on search for new nuclides, deep-inelastic collisions, spectroscopy of high-spin states and some selected topics of atomic physics. (orig.) [de

  3. Communicating research results

    Science.gov (United States)

    Jan Fryk

    1999-01-01

    A research finding is of little value until it is known and applied. Hence) communication of results should be regarded as a natural, integrated part of research) and thus addressed in the research plans from the very beginning. A clearly defined information strategy and operational goals for information activities are needed for successful communication. For maximum...

  4. Review of LEP results

    CERN Document Server

    Parodi, F

    2001-01-01

    I present a review of the results obtained during 10 years of activity in b-physics at LEP. Special emphasis is put on measurements that attained precisions not even envisaged at the beginning of the LEP programme (V/sub ub/ and Delta m/sub s/). Finally the impact of these measurements on the CKM parameters determination is presented. (16 refs).

  5. [The applicability of results].

    Science.gov (United States)

    Marín-León, I

    2015-11-01

    The ultimate aim of the critical reading of medical literature is to use the scientific advances in clinical practice or for innovation. This requires an evaluation of the applicability of the results of the studies that have been published, which begins with a clear understanding of these results. When the studies do not provide sufficient guarantees of rigor in design and analysis, the conditions necessary for the applicability of the results are not met; however, the fact that the results are reliable is not enough to make it worth trying to use their conclusions. This article explains how carrying out studies in experimental or artificial conditions often moves them away from the real conditions in which they claim to apply their conclusions. To evaluate this applicability, the article proposes evaluating a set of items that will enable the reader to determine the likelihood that the benefits and risks reported in the studies will yield the least uncertainty in the clinical arena where they aim to be applied. Copyright © 2015 SERAM. Published by Elsevier España, S.L.U. All rights reserved.

  6. Radio-sensitization of WRN helicase deficient cancer cells by targeting homologous recombination pathway

    International Nuclear Information System (INIS)

    Gupta, Pooja; Saha, Bhaskar; Patro, Birija Sankar; Chattopadhyay, Subrata

    2016-01-01

    Ionizing radiation (IR) induced DNA double-strand breaks (DSBs) are primarily repaired by non-homologous end joining (NHEJ). However, it is well established that a subset DSBs which are accumulated in IR-induced G2 phase are dependent on homologous recombination (HR). DNA repair deficient tumor cells have been shown to accumulate high levels of DNA damage. Consequently, these cells become hyperdependent on DNA damage response pathways, including the CHK1-kinase-mediated HR-repair. These observations suggest that DNA repair deficient tumors should exhibit increased radio-sensitivity under HR inhibition. Genetic defects leading to functional loss of werner (WRN) protein is associated with genomic instability and increased cancer incidence. WRN function is known to be abrogated in several human cancer cells due to hypermethylation of CpGisland-promoter and transcriptional silencing of WRN gene. In the current investigation, using isogenic pairs of cell lines differing only in the WRN function, we showed that WRN-deficient cell lines were hyper-radiosensitive to CHK1 pharmacologic inhibition. Here, we found that unrepaired DSB was drastically increased in WRN-deficient cells vis-à-vis WRN-proficient cells in response to IR and CHK1 inhibitor (CHK1i). Our results revealed a marginal role of NHEJ pathway accountable for the radio-sensitivity of WRN-deficient cells. Interestingly, silencing CTIP, a HR protein required for RAD51 loading, significantly abrogated the CHK1i-mediated radiosensitivity in WRN-deficient cells. Silencing of WRN or CTIP individually led to no significant difference in the extent of DNA end resection, as required during HR pathway. Imperatively, our results revealed that WRN and CTIP together play a complementary role in executing DNA end resection during HR-mediated repair of IR induced DSBs. Altogether, our data indicated that inhibition of IR-induced HR pathway at RAD51 loading, but not at DSB end resection, make the WRN-deficient cancer cells

  7. Neutrino mass: Recent results

    International Nuclear Information System (INIS)

    Robertson, R.G.H.

    1989-01-01

    Some recent developments in the experimental search for neutrino mass are discussed. Simpson and Hime report finding new evidence for a 17-keV neutrino in the β decay of 3 H and 35 S. New data from Los Alamos on the electron neutrino mass as measured in tritium beta decay give an upper limit of 13.5 eV at the 95% confidence level. This result is not consistent with the long-standing ITEP result of 26(5) eV within a ''model-independent'' range of 17 to 40 eV. It now appears that the electron neutrino is not sufficiently massive to close the universe by itself. 38 refs., 1 figs., 2 tabs

  8. Experimental results from Stripa

    International Nuclear Information System (INIS)

    Hood, M.

    1979-06-01

    The results indicate that the temperature fields in a rock mass containing geologic discontinuities can be predicted accurately using the simple theory of heat conduction. Geologic discontinuities appear to introduce significant nonlinear thermomechanical deformation into the rock mass, as a result of which the thermally induced displacements are much less than those predicted by the simple theory of thermo-elasticity. In addition, the assumption that the rock properties are temperature independent appears to increase the values predicted for these displacements significantly. Therefore, it is important that the temperature dependence of these properties is known and that these values be used in the calculations. The onset of significant thermal spalling along the walls of the heater boreholes appears to be related to conditions where the maximum induced compressive stress exceeds the uniaxial compressive strength of the rock. 7 figures

  9. Envirhom: stakes and results

    International Nuclear Information System (INIS)

    2006-01-01

    After a recall of the evolution of the international system for the protection against ionizing radiations, this report discusses the evolution of a new societal context (evolution of risk perception, concern about accidental situations). It also discusses the emerging scientific issues and challenges regarding the knowledge about biological and health effects of ionizing radiations, which requires investigations on the ecosystems, the effects of chronic low level exposures, and the propagation of effects at different biological levels (cells, tissue, individual, population, communities, and ecosystems). Then, it presents the IRSN environment-health research program, ENVIRHOM, its objectives, and its results concerning the environment on the one side, and health on the other side. The 'environment' side and the 'health' side of this program are then more precisely presented as well as their results

  10. Solar results purchasing

    International Nuclear Information System (INIS)

    Sanders, J.

    2001-01-01

    Solar Thermal water heating has made little market penetration in some European countries. The main barriers to market development are: Long payback periods for the technology; Difficulties for the end-user in meeting the initial capital costs of the installation; Lack of confidence in the delivered energy that can be expected from the technology. The third barrier has been addressed using the concept of Guaranteed Solar Results (GSR). This project has addressed the other two main barriers using the concept of Solar Results Purchasing, (SRP) which combines GSR with Third Party Financing. The work was carried out in the UK, France, and Spain. The project used a uniform approach across the three countries. Each team calculated solar performance using an English version of the SOLO programme developed by TECSOL in France to encode the methodology for GSR model contracts. (author)

  11. Final NOMAD results on $\

    CERN Document Server

    Astier, P.; Baldisseri, A.; Baldo-Ceolin, M.; Banner, M.; Bassompierre, G.; Benslama, K.; Besson, N.; Bird, I.; Blumenfeld, Barry J.; Bobisut, F.; Bouchez, J.; Boyd, S.; Bueno, A.; Bunyatov, S.; Camilleri, L.; Cardini, A.; Cattaneo, P.W.; Cavasinni, V.; Cervera-Villanueva, A.; Chukanov, A.; Collazuol, G.; Conforto, G.; Conta, C.; Contalbrigo, M.; Cousins, R.; Daniels, D.; Degaudenzi, H.; Del Prete, T.; De Santo, A.; Dignan, T.; Di Lella, L.; do Couto e Silva, E.; Dumarchez, J.; Ellis, Malcolm; Feldman, G.J.; Ferrari, R.; Ferrere, D.; Flaminio, V.; Fraternali, M.; Gaillard, J.M.; Gangler, E.; Geiser, A.; Geppert, D.; Gibin, D.; Gninenko, S.; Godley, A.; Gomez-Cadenas, J.J.; Gosset, J.; Gossling, C.; Gouanere, M.; Grant, A.; Graziani, G.; Guglielmi, A.; Hagner, C.; Hernando, J.; Hubbard, D.; Hurst, P.; Hyett, N.; Iacopini, E.; Joseph, C.; Juget, F.; Kirsanov, M.; Klimov, O.; Kokkonen, J.; Kovzelev, A.; Krasnoperov, A.; Kustov, D.; Kuznetsov, V.E.; Lacaprara, S.; Lachaud, C.; Lakic, B.; Lanza, A.; La Rotonda, L.; Laveder, M.; Letessier-Selvon, A.; Levy, J.M.; Linssen, L.; Ljubicic, A.; Long, J.; Lupi, A.; Marchionni, A.; Martelli, F.; Mechain, X.; Mendiburu, J.P.; Meyer, J.P.; Mezzetto, M.; Mishra, S.R.; Moorhead, G.F.; Naumov, D.; Nedelec, P.; Nefedov, Yu.; Nguyen-Mau, C.; Orestano, D.; Pastore, F.; Peak, L.S.; Pennacchio, E.; Pessard, H.; Petti, R.; Placci, A.; Polesello, G.; Pollmann, D.; Polyarush, A.; Popov, B.; Poulsen, C.; Rico, J.; Riemann, P.; Roda, C.; Rubbia, A.; Salvatore, F.; Schahmaneche, K.; Schmidt, B.; Schmidt, T.; Sconza, A.; Sevior, M.; Sillou, D.; Soler, F.J.P.; Sozzi, G.; Steele, D.; Stiegler, U.; Stipcevic, M.; Stolarczyk, T.; Tareb-Reyes, M.; Taylor, G.N.; Tereshchenko, V.; Toropin, A.; Touchard, A.M.; Tovey, S.N.; Tran, M.T.; Tsesmelis, E.; Ulrichs, J.; Vacavant, L.; Valdata-Nappi, M.; Valuev, V.; Vannucci, F.; Varvell, K.E.; Veltri, M.; Vercesi, V.; Vidal-Sitjes, G.; Vieira, J.M.; Vinogradova, T.; Weber, F.V.; Weisse, T.; Wilson, F.F.; Winton, L.J.; Yabsley, Bruce D.; Zaccone, H.; Zuber, K.; Zuccon, P.; Krasnoperov, A V

    2001-01-01

    Results from the nu_tau appearance search in a neutrino beam using the full NOMAD data sample are reported. A new analysis unifies all the hadronic tau decays, significantly improving the overall sensitivity of the experiment to oscillations. The "blind analysis" of all topologies yields no evidence for an oscillation signal. In the two-family oscillation scenario, this sets a 90% C.L. allowed region in the sin^2(2theta)-Delta m^2 plane which includes sin^2(2theta)nu_tau oscillation hypothesis results in sin^2(2theta)<1.5 x 10^{-2} at large Delta m^2 and Delta m^2 < 5.9 eV^2/c^4 at sin^2(2theta)=1. We also derive limits on effective couplings of the tau lepton to nu_mu or nu_e.

  12. Results from LEP

    International Nuclear Information System (INIS)

    Pohl, M.

    1995-01-01

    Selected results from LEP on electroweak neutral currents and strong interactions are reviewed. In the first part, total cross sections, angular and polarization symmetries are interpreted in terms of basic electroweak parameters, like the mass, total and partial widths of the Z and neutral current couplings. Special attention is given to two apparent problems: the discrepancy between the measurements with final state vs. initial state polarization; and the deviation of the measured width of the Z into heavy quarks from Standard Model expectations. These discrepancies are not very significant, but they are the only ones observed at this point and thus deserve attention. In the second part, I outline results on final state strong interactions, namely measurements pertaining to differences between quark and gluon jets and the QCD group structure. (author) 19 figs., 4 tabs., 21 refs

  13. EPA's radon study results

    International Nuclear Information System (INIS)

    Dowd, R.M.

    1988-01-01

    Last winter, in cooperation with agencies in 10 states and two metropolitan area counties, EPA measured the indoor air radon concentrations of 14,000 houses, some chosen statistically at random and some by request of the homeowner. Passive measurement methodologies were used, such as exposing a charcoal canister to the air for a few days and allowing the air to migrate in to the charcoal naturally. To reduce dilution of radon by the outside air, the protocol required that the house be shut up; therefore, the study was conducted during winter. The measuring device was placed in the lowest livable area (usually the basement) of each house to maximize potential concentration. It should be noted that these procedures are generally considered to be screening tests because they result in a worst-case measurement rather than a best value. The results of these findings are presented

  14. Solar results purchasing

    Energy Technology Data Exchange (ETDEWEB)

    Sanders, J.

    2001-07-01

    Solar Thermal water heating has made little market penetration in some European countries. The main barriers to market development are: Long payback periods for the technology; Difficulties for the end-user in meeting the initial capital costs of the installation; Lack of confidence in the delivered energy that can be expected from the technology. The third barrier has been addressed using the concept of Guaranteed Solar Results (GSR). This project has addressed the other two main barriers using the concept of Solar Results Purchasing, (SRP) which combines GSR with Third Party Financing. The work was carried out in the UK, France, and Spain. The project used a uniform approach across the three countries. Each team calculated solar performance using an English version of the SOLO programme developed by TECSOL in France to encode the methodology for GSR model contracts. (author)

  15. Results from SAGE

    International Nuclear Information System (INIS)

    Abdurashitov, J.N.; Gavrin, V.N.; Girin, S.V.

    1996-01-01

    The Russian-American Gallium Solar Neutrino Experiment (SAGE) is described. Beginning in September 1992, SAGE II data were taken with 55 tons of Ga and with significantly reduced backgrounds. The solar neutrino flux measured by 31 extractions through October 1993 is presented. The result of 69 ± 10 +5/-7 SNU is to be compared with a Standard Solar Model prediction of 132 SNU

  16. Statistical mechanics rigorous results

    CERN Document Server

    Ruelle, David

    1999-01-01

    This classic book marks the beginning of an era of vigorous mathematical progress in equilibrium statistical mechanics. Its treatment of the infinite system limit has not been superseded, and the discussion of thermodynamic functions and states remains basic for more recent work. The conceptual foundation provided by the Rigorous Results remains invaluable for the study of the spectacular developments of statistical mechanics in the second half of the 20th century.

  17. Recent results from JADE

    International Nuclear Information System (INIS)

    Nozaki, M.

    1983-01-01

    Recent results from JADE are reported. The JADE experiment is being carried out by a collaboration of DESY, Universities of Hamburg, Heidelburg, Lancaseter and Manchester, Rutherford Laboratory and University of Tokyo. It was proposed in 1976 and after 3 years construction, the JADE started data taking at the e/sup +/e/sup -/ colliding beam facility PETRA with a complete set of detector components in June 1979

  18. Assessing ultrasonic examination results

    International Nuclear Information System (INIS)

    Deutsch, V.; Vogt, M.

    1977-01-01

    Amongst nondestructive examination methods, the ultrasonic examination plays an important role. The reason why its scope of application is so wide is because the sound conducting capacity is the only property the material of a test specimen has to have. As the fields are so manifold, only main aspects can be described briefly. The list of references, however, is very extensive and gives plenty of information of all the problems concerning the assessment of ultrasonic examination results. (orig./RW) [de

  19. Recent results from LHCb

    CERN Document Server

    Oblakowska-Mucha, A

    2016-01-01

    The LHCb detector is a single-arm forward spectrometer that collects data at the LHC. In this review, a few of recent results in the field of $b$-hadron decays performed by the LHCb Collaboration are presented. The analyses use proton-proton collision data corresponding to 3 fb$^{-1}$ collected by the LHCb detector during 2011 and 2012 physics runs with the center-of-mass energies of 7 and 8 TeV.

  20. ATM and checkpoint responses to DNA double strand breaks

    International Nuclear Information System (INIS)

    Khanna, K.K.

    2003-01-01

    DNA damage checkpoints can be classified into G1/S, intra-S and G2/M checkpoints, so named according to the cell cycle transitions that they regulate. DNA damage incurred during the G1 or G2 phase of the cell cycle leads to growth arrest at the G1/S and G2/M phase boundaries, respectively, whereas genotoxic stress during S phase results in the transient suppression of DNA synthesis. In mammals, ATM (ataxia-telangiectasia mutated) is a protein kinase that controls all checkpoint responses to DNA damage. ATM is a versatile kinase which uses various means to regulate a given checkpoint pathway. It has been shown to act upon several proteins within the same pathway, many times controlling several different modifications of the same protein or using several different targets to arrive at the same end point. Some of the ATM targets act as adaptors by recruiting additional substrates for ATM. ATM controls two types of responses in G1. The p53-dependent responses inhibit Cyclin/Cdk activity by transcriptional induction of p21, whereas p53-independent responses inhibit CDKs through degradation of Cdc25A to maintain CdK2 inhibitory phosphorylation. In regulating p53, ATM directly phosphorylates p53 on Ser15, which likely causes p53 transcriptional activation, concurrently activating other kinases that phosphorylate p53 at other sites such as Ser20, which reduces the ability of MDM2 to bind p53, thus promoting its stability. ATM further ensures p53 stability by phosphorylating MDM2. At least six ATM targets, namely CHK2, CHK1, NBS1, BRCA1, SMC1 and FANCD2, have been implicated in the control of S-phase checkpoint. Cdc25A is the downstream effector of CHK1 and CHK2, though the underlying mechanism for control of intra S-phase checkpoint by other targets remain obscure. G2 checkpoint prevents mitotic entry solely through inhibitory phosphorylation of Cdc2/Cdk1. Several ATM targets including CHK1, CHK2, BRCA1, MDC1 and p53BP1 have been implicated in the control of G2/M

  1. Pressure locking test results

    Energy Technology Data Exchange (ETDEWEB)

    DeWall, K.G.; Watkins, J.C.; McKellar, M.G.; Bramwell, D. [Idaho National Engineering Lab., Idaho Falls, ID (United States)] [and others

    1996-12-01

    The U.S. Nuclear Regulatory Commission (NRC), Office of Nuclear Regulatory Research, is funding the Idaho National Engineering Laboratory (INEL) in performing research to provide technical input for their use in evaluating responses to Generic Letter 95-07, {open_quotes}Pressure Locking and Thermal Binding of Safety-Related Power-Operated Gate Valves.{close_quotes} Pressure locking and thermal binding are phenomena that make a closed gate valve difficult to open. This paper discusses only the pressure locking phenomenon in a flexible-wedge gate valve; the authors will publish the results of their thermal binding research at a later date. Pressure locking can occur when operating sequences or temperature changes cause the pressure of the fluid in the bonnet (and, in most valves, between the discs) to be higher than the pressure on the upstream and downstream sides of the disc assembly. This high fluid pressure presses the discs against both seats, making the disc assembly harder to unseat than anticipated by the typical design calculations, which generally consider friction at only one of the two disc/seat interfaces. The high pressure of the bonnet fluid also changes the pressure distribution around the disc in a way that can further contribute to the unseating load. If the combined loads associated with pressure locking are very high, the actuator might not have the capacity to open the valve. The results of the NRC/INEL research discussed in this paper show that the relationship between bonnet pressure and pressure locking stem loads appears linear. The results also show that for this valve, seat leakage affects the bonnet pressurization rate when the valve is subjected to thermally induced pressure locking conditions.

  2. Pressure locking test results

    International Nuclear Information System (INIS)

    DeWall, K.G.; Watkins, J.C.; McKellar, M.G.; Bramwell, D.

    1996-01-01

    The U.S. Nuclear Regulatory Commission (NRC), Office of Nuclear Regulatory Research, is funding the Idaho National Engineering Laboratory (INEL) in performing research to provide technical input for their use in evaluating responses to Generic Letter 95-07, open-quotes Pressure Locking and Thermal Binding of Safety-Related Power-Operated Gate Valves.close quotes Pressure locking and thermal binding are phenomena that make a closed gate valve difficult to open. This paper discusses only the pressure locking phenomenon in a flexible-wedge gate valve; we will publish the results of our thermal binding research at a later date. Pressure locking can occur when operating sequences or temperature changes cause the pressure of the fluid in the bonnet (and, in most valves, between the discs) to be higher than the pressure on the upstream and downstream sides of the disc assembly. This high fluid pressure presses the discs against both seats, making the disc assembly harder to unseat than anticipated by the typical design calculations, which generally consider friction at only one of the two disc/seat interfaces. The high pressure of the bonnet fluid also changes the pressure distribution around the disc in a way that can further contribute to the unseating load. If the combined loads associated with pressure locking are very high, the actuator might not have the capacity to open the valve. The results of the NRC/INEL research discussed in this paper show that the relationship between bonnet pressure and pressure locking stem loads appears linear. The results also show that for this valve, seat leakage affects the bonnet pressurization rate when the valve is subjected to thermally induced pressure locking conditions

  3. Scientific results report 1980

    International Nuclear Information System (INIS)

    1981-01-01

    The report describes in concise form the research tasks and results of the work groups pulsed irradiation, reaction kinematics and insulators and plastics in the field of 'radiation chemistry' of the Hahn-Meitner Institute, Berlin. The main topic of investigation was the kinetics and dynamics of fast chemical processes, the setting-up of chemical reaction mechanisms and research of chemical physical properties of highly reactive species (radicals, ions, electrons). A list of publications and lectures as well as teaching contributions of the institute's scientists, diploma and doctor theses performed in the institute and guest lectures held there is also given. (RB) [de

  4. Recent CLEO Results

    International Nuclear Information System (INIS)

    Ecklund, Karl M.

    2004-01-01

    I report B physics results from the CLEO collaboration, highlighting measurements of the Cabibbo-Kobayashi-Maskawa matrix elements vertical bar Vcb vertical bar and vertical bar Vub vertical bar. I report a recent measurement of vertical bar Vub vertical bar through study of the q2 dependence of B-bar → πlv-bar and B-bar → ρlv-bar. I also describe new measurements of the inclusive semileptonic branching fraction B(B-bar → Xev-bar) and of moments of the hadronic invariant mass spectrum in B-bar → Xlv-bar, with impact on vertical bar Vcb vertical bar

  5. New results from CERES

    CERN Document Server

    Adamova, D; Appelshäuser, H; Belaga, V V; Braun-Munzinger, P; Cherlin, A; Damjanovic, S; Dietel, T; Dietrich, L; Drees, A; Esumi, S C; Filimonov, K; Fomenko, K; Fraenkel, Zeev; Garabatos, C; Glässel, P; Hering, G; Holender, J M; Kushpil, V; Lenkeit, B C; Maas, A; Marin, A; Messer, F; Milosevic, J; Milov, A; Miskowiec, D; Panebratsev, Yu A; Petchenova, O Yu; Petracek, V; Pfeiffer, A; Rak, J; Ravinovich, I; Rehak, P; Sako, H; Schmitz, W; Schükraft, Jürgen; Sedykh, S N; Seipp, W; Shimansky, S S; Slivova, J; Specht, H J; Stachel, J; Sumbera, M; Tilsner, H; Tserruya, Itzhak; Wessels, J P; Wienold, T; Windelband, B; Wurm, J P; Xie, W; Yurevich, S; Yurevich, V I

    2002-01-01

    We will focus here on results from the 1999 data taking period, where 8 M Pb+Au events at 40 AGeV were recorded. Since the new readout system of the TPC was not yet properly working, this data set is limited in terms of statistics, and momentum resolution. Nevertheless, this data sample at lower beam energy allows to study initial conditions different from the ones at top SPS energy. This can be very useful to disentangle temperature and baryon density driven modifications of the dilepton spectrum. (15 refs).

  6. Latest results from JET

    International Nuclear Information System (INIS)

    Bickerton, R.J.

    1989-01-01

    The Joint European Torus (JET) is a large tokamak designed with the essential objective of obtaining and studying plasmas with parameters close to those envisaged for an eventual power-generating, nuclear-fusion reactor. JET is situated on a site near Abingdon, Oxon, UK. JET is the largest single project of the nuclear fusion research programme of the European Atomic Energy Community (EURATOM). The tokamak started operation in mid 1983 after a five year construction period. The scientific and technical results achieved so far are summarised in this article. (orig.)

  7. Recent results from SPEAR

    International Nuclear Information System (INIS)

    Wacker, K.

    1983-09-01

    The first part of this talk is an experimental review of the properties of the THETA meson. Results or upper limits come from radiative j/psi decays and γγ scattering for the final states eta eta, ππ, K anti K and rho rho. In the second part, an upper limit is given for the production of low-mass particles in radiative J/psi decays. Constraints for the existence of low-mass gluonic and Higgs mesons are derived

  8. Results of railgun experiments

    International Nuclear Information System (INIS)

    Hawke, R.S.; Brooks, A.L.; Fowler, C.M.; Peterson, D.R.

    1983-04-01

    During the 1979 Megagauss II conference the hypervelocity potential of railguns and the pulsed power technology needed to power them were discussed. Since then, many laboratories have initiated railgun R and D projects for a variety of potential applications. Los Alamos and Lawrence Livermore National Laboratories initiated a collaborative experimental railgun project which resulted in several successes in accelerating projectiles to high velocities, emphasized the limits on railgun operation, and indicated that the numerical modeling of railgun operation was in good agreement with the experiments

  9. Results from neutrino experiments

    International Nuclear Information System (INIS)

    Smirnov, A.Yu.

    1993-11-01

    Recent (first or/and the best) results from the neutrino experiments are reviewed and their implications for the theory are discussed. The sense of the experiments is the searching for neutrino masses, mixing and interactions beyond the standard model. Present laboratory experiments give upper bounds on the masses and the mixing which are at the level of predictions of the ''electroweak see-saw''. Positive indications of nonzero lepton mixing follow from studies of the solar and atmospheric neutrinos. (author). 95 refs, 11 figs

  10. Results from AMANDA

    CERN Document Server

    Wiebusch, C; Bai, X; Barwick, S W; Becka, T; Becker, K H; Bertrand, D; Bernadini, E; Binon, Freddy G; Biron, A; Boser, S; Botner, O; Bouchta, A; Bouhali, O; Burgess, T; Carius, S; Castermans, T; Chen, A; Chirkin, D; Conrad, J; Cooley, J; Cowen, D F; Davour, A; De Clercq, C; De Young, T R; Desiati, P; Dewulf, J P; Doksus, P; Ekstrom, P; Feser, T; Gaisser, T K; Gaug, M; Gerhardt, L; Goldschmidt, A; Hallgren, A; Halzen, F; Hanson, K; Hardtke, R; Hauschildt, T; Hellwig, M; Herquet, P; Hill, G C; Hulth, P O; Hundertmark, S; Jacobsen, J; Karle, A; Koci, B; Köpke, L; Kowalski, M; Kühn, K; Lamoureux, J I; Leich, H; Leuthold, M J; Lindahl, P; Liubarsky, I; Madsen, J; Marciniewski, P; Matis, H S; McParland, C P; Minaeva, Y; Minocinovic, P; Mock, P C; Morse, R; Nahnhauer, R; Neunhoffer, T; Niessen, P; Nygren, D R; Ögelman, H B; Olbrechts, P; Pérez de los Heros, C; Pohl, A C; Price, P B; Przybylski, G T; Rawlins, K; Resconi, E; Rhode, W; Ribordy, M; Richter, S; Rodríguez-Martino, J; Ross, D; Sander, H G; Schmidt, T; Schneider, D; Schwarz, R; Silvestri, A; Solarz, M; Spiczak, G M; Spiering, C; Steele, D; Steffen, P; Stokstad, R G; Sudhoff, P; Sulanke, K H; Taboada, I; Thollander, L; Tilav, S; Walck, C; Weinheimer, C; Wiebusch, C; Wiedemann, C; Wischnewski, R; Wissing, H; Woschnagg, K; Yodh, G B; Young, S

    2002-01-01

    The Antarctic Muon and Neutrino Detector Array (AMANDA) is a high- energy neutrino telescope operating at the geographic South Pole. It is a lattice of photomultiplier tubes buried deep in the polar ice. The primary goal of this detector is to discover astrophysical sources of high energy neutrinos. We describe the detector methods of operation and present results from the AMANDA-B10 prototype. We demonstrate the improved sensitivity of the current AMANDA-II detector. We conclude with an outlook to the envisioned sensitivity of the future IceCube detector. (37 refs).

  11. Results from PAMELA

    International Nuclear Information System (INIS)

    Mocchiutti, E.; Adriani, O.; Barbarino, G.C.; Bazilevskaya, G.A.; Bellotti, R.; Boezio, M.; Bogomolov, E.A.; Bonechi, L.; Bongi, M.; Bonvicini, V.; Borisov, S.; Bottai, S.; Bruno, A.; Cafagna, F.; Campana, D.

    2011-01-01

    The PAMELA satellite experiment was launched into low earth orbit on June 15th 2006. The combination of a permanent magnet silicon strip spectrometer and a silicon-tungsten imaging calorimeter allows precision studies of the charged cosmic radiation to be conducted over a wide energy range (100 MeV - several hundred GeV). A primary scientific goal is to search for dark matter particle annihilation by measuring the energy spectra of cosmic ray antiparticles. Latest results from the PAMELA experiment are presented with a particular focus on cosmic ray antiprotons and positrons.

  12. Overview of Tokamak Results

    International Nuclear Information System (INIS)

    Unterberg, Bernhard; Samm, Ulrich

    2004-01-01

    An overview is given of recent results obtained in tokamak devices. We introduce basic confinement scenarios as L-mode, H-mode and plasmas with an internal transport barrier and discuss methods for profile control. Important findings in DT-experiments at JET as α-particle heating are described. Methods for power exhaust like plasma regimes with a radiating mantle and radiative divertor scenarios are discussed. The overall impact of plasma edge conditions on the general plasma performance in tokamaks is illustrated by describing the impact of wall conditions on confinement and the edge operational diagram of H-mode plasmas

  13. Recent CDF results

    International Nuclear Information System (INIS)

    Conway, J.S.

    1996-07-01

    Preliminary results form the CDF detector, based on analysis of data collected in Run 1a and Run 1b at the Tevatron, totaling 110 pb - 1 integrated luminosity, place new limits on the masses and couplings of new particles including charged Higgs bosons, supersymmetric gauge particles and quarks, and new vector bosons. One of the observed events, having an e + e - pair, two photons, and large missing energy would not occur with significant rate in the Standard Model, leading to speculation regarding its origin and the possible existence of related events

  14. Recent BABAR Results

    Energy Technology Data Exchange (ETDEWEB)

    Eigen, Gerald [University of Bergen, Bergen (Norway). Dept. of Physics

    2015-04-29

    We present herein the most recent BABAR results on direct CP asymmetry measurements in B → Xsγ, on partial branching fraction and CP asymmetry measurements in B → Xs+-, on a search for B → π/ηℓ+- decays, on a search for lepton number violation in B+ → X-+ℓ'+ modes and a study of B0 →ωω and B0 → ωφ decays.

  15. Spacelab Science Results Study

    Science.gov (United States)

    Naumann, R. J.; Lundquist, C. A.; Tandberg-Hanssen, E.; Horwitz, J. L.; Germany, G. A.; Cruise, J. F.; Lewis, M. L.; Murphy, K. L.

    2009-01-01

    Beginning with OSTA-1 in November 1981 and ending with Neurolab in March 1998, a total of 36 Shuttle missions carried various Spacelab components such as the Spacelab module, pallet, instrument pointing system, or mission peculiar experiment support structure. The experiments carried out during these flights included astrophysics, solar physics, plasma physics, atmospheric science, Earth observations, and a wide range of microgravity experiments in life sciences, biotechnology, materials science, and fluid physics which includes combustion and critical point phenomena. In all, some 764 experiments were conducted by investigators from the U.S., Europe, and Japan. The purpose of this Spacelab Science Results Study is to document the contributions made in each of the major research areas by giving a brief synopsis of the more significant experiments and an extensive list of the publications that were produced. We have also endeavored to show how these results impacted the existing body of knowledge, where they have spawned new fields, and if appropriate, where the knowledge they produced has been applied.

  16. Results from TOTEM

    Directory of Open Access Journals (Sweden)

    Eggert Karsten

    2013-06-01

    Full Text Available The TOTEM experiment at the CERN LHC is focussed on the measurement of the elastic proton-proton scattering, the total pp cross-section, and all kinds of diffractive phenomena. Detectors housed in “Roman Pots” which can be moved close to the outgoing proton beams allow to trigger on elastic and diffractive protons and to determine their parameters like the momentum loss and the transverse momentum transfer. In addition, charged particle detectors in the forward regions detect almost all inelastic events. Together with the CMS detector, a large solid angle is covered enabling precise studies of Min. Bias as well as Single Diffractive and Double Pomeron Interactions. The results will considerably help the interpretation of the Cosmic Ray Showers at highest energies and will give insight into the proton structure and the QCD theory of strong interactions. TOTEM measured the elastic pp- scattering over a large range of t (the squared momentum transfer from 10-3 – 4 GeV2. Noneof the considered models could yield a satisfactory fit over the complete range. However, the exponential slope at low |t|-values and the position of the diffractiveminimum are well within the extrapolation from lower energies. The total pp cross-section has been determined in different ways from the extrapolation of the elasticscattering to t=0 (optical point and the inelastic rate: (i From the elastic scattering using the optical theorem and the CMS, (ii luminosity independently, usingthe inelastic rate, elastic scattering and the optical theorem, (iiiρ independently, by using elastic scattering, inelastic rate and the CMS luminosity. The results for the total crosssection obtained from the different methods are in excellent agreement with each other. First studies of the data on diffractive phenomena havebeen performed by correlating the momentum loss of the forward protons with the topology of the particle flux. The data look very promising and further studies will

  17. EIGER characterization results

    International Nuclear Information System (INIS)

    Dinapoli, Roberto; Bergamaschi, Anna; Greiffenberg, Dominic; Henrich, Beat; Horisberger, Roland; Johnson, Ian; Mozzanica, Aldo; Radicci, Valeria; Schmitt, Bernd; Shi, Xintian; Tinti, Gemma

    2013-01-01

    Characterization and performance measurements have been done on several EIGER detector systems, produced with chips coming from two different lots, both with a lab X-ray source and at the Swiss Light Source (SLS). Results on the detector calibration, electronic noise, threshold dispersion, minimum achievable energy threshold, maximum detectable incoming photon flux and maximum frame rate are presented. An EIGER module is constructed from a ∼4×8cm 2 monolithic silicon sensor bump-bonded to 2 ×4 readout chips and contains 0.5 Mpixel. The first EIGER 500 K systems have been produced and images taken with these detectors are shown. Modules can be tiled together to form large area detectors; both a 9 Mpixel and a 16 Mpixel systems are at present under development for the coherent small angle X-ray scattering and protein crystallography beamlines of the SLS

  18. EIGER characterization results

    Energy Technology Data Exchange (ETDEWEB)

    Dinapoli, Roberto, E-mail: roberto.dinapoli@psi.ch [Paul Scherrer Institut, 5232 Villigen PSI (Switzerland); Bergamaschi, Anna; Greiffenberg, Dominic; Henrich, Beat; Horisberger, Roland; Johnson, Ian; Mozzanica, Aldo [Paul Scherrer Institut, 5232 Villigen PSI (Switzerland); Radicci, Valeria [Paul Scherrer Institut, 5232 Villigen PSI (Switzerland); ESRF, 6 Rue Horowitz, 38043 Grenoble (France); Schmitt, Bernd; Shi, Xintian [Paul Scherrer Institut, 5232 Villigen PSI (Switzerland); Tinti, Gemma [Paul Scherrer Institut, 5232 Villigen PSI (Switzerland); ESRF, 6 Rue Horowitz, 38043 Grenoble (France)

    2013-12-11

    Characterization and performance measurements have been done on several EIGER detector systems, produced with chips coming from two different lots, both with a lab X-ray source and at the Swiss Light Source (SLS). Results on the detector calibration, electronic noise, threshold dispersion, minimum achievable energy threshold, maximum detectable incoming photon flux and maximum frame rate are presented. An EIGER module is constructed from a ∼4×8cm{sup 2} monolithic silicon sensor bump-bonded to 2 ×4 readout chips and contains 0.5 Mpixel. The first EIGER 500 K systems have been produced and images taken with these detectors are shown. Modules can be tiled together to form large area detectors; both a 9 Mpixel and a 16 Mpixel systems are at present under development for the coherent small angle X-ray scattering and protein crystallography beamlines of the SLS.

  19. Recent results from CMS

    CERN Multimedia

    CERN. Geneva

    2016-01-01

    With the increase in center-of-mass energy, a new energy frontier has been opened by the Large Hadron Collider. More than 25 fb^-1 of proton-proton collisions at sqrt(s)=13 TeV have been delivered to both ATLAS and CMS experiments during 2016. This enormous dataset can be used to test the Standard Model in a complete new regime with tremendous precision and it has the potential to unveil new physics or set strong bounds on it. In this talk some of the most recent results made public by the CMS Collaboration will be presented. The focus will mainly be on searches for physics beyond the Standard Model, with particular emphasis on searches for dark matter candidates.

  20. Scientific results - report 1981

    International Nuclear Information System (INIS)

    1982-01-01

    During the year under report 1981, five working groups were active in the field of nuclear chemistry: neutron diffraction, radiation damage in solids, reactor chemistry, trace element research in bio-medicine and geo-chemistry. The objectives of the R+D projects ranged from the more basic research to the development of technological processes. Nuclear inspection methodes that have already been developed (e.g. neutron diffraction, trace element analysis) have increasingly been used in an interdisciplinary way. Besides these R+D projects the project of increase of power of the BER II was pursued also in 1981, and further planning documents on the extension of the BER II have been established. The report informs about the most important results of the single sections. A list of the publications (with abstracts) and lectures, also by guest scientists, is attached. (RB) [de

  1. Payment by Results

    Directory of Open Access Journals (Sweden)

    Brendan A. Rapple

    1994-01-01

    Full Text Available Today the public is demanding that it exercise more control over how tax dollars are spent in the educational sphere, with multitudes also canvassing that education become closely aligned to the marketplace's economic forces. In this paper I examine an historical precedent for such demands, i.e. the comprehensive 19th century system of accountability, "Payment by Results," which endured in English and Welsh elementary schools from 1862 until 1897. Particular emphasis is focused on the economic market-driven aspect of the system whereby every pupil was examined annually by an Inspector, the amount of the governmental grant being largely dependent on the answering. I argue that this was a narrow, restrictive system of educational accountability though one totally in keeping with the age's pervasive utilitarian belief in laissez-faire. I conclude by observing that this Victorian system might be suggestive to us today when calls for analogous schemes of educational accountability are shrill.

  2. Latest results from LUNA

    Science.gov (United States)

    Depalo, Rosanna; LUNA Collaboration

    2018-01-01

    A precise knowledge of the cross section of nuclear fusion reactions is a crucial ingredient in understanding stellar evolution and nucleosynthesis. At stellar temperatures, fusion cross sections are extremely small and difficult to measure. Measuring nuclear cross sections at astrophysical energies is a challenge that triggered a huge amount of experimental work. A breakthrough in this direction was the first operation of an underground accelerator at the Laboratory for Underground Nuclear Astrophysics (LUNA) in Gran Sasso, Italy. The 1400 meters of rocks above the laboratory act as a natural shield against cosmic radiation, suppressing the background by orders of magnitude. The latest results achieved at LUNA are discussed, with special emphasis on the 22Ne(p,γ)23Na reaction. Future perspectives of the LUNA experiment are also illustrated.

  3. Overview of HERMES results

    Directory of Open Access Journals (Sweden)

    Van Hulse Charlotte

    2016-01-01

    Full Text Available The HERMES experiment has collected a wealth of deep-inelastic scattering data using the 27.6 GeV polarized lepton beam at HERA and various pure gas targets, both unpolarized and polarized. This allowed for a series of diverse and unique measurements. Among them are measurements that provide information on the threedimensional structure of the nucleon, both in momentum space and in position space. Results of measurements of exclusive ω production on an unpolarized and transversely polarized nucleon target, sensitive to the distribution in transverse-position and longitudinalmomentum space, are discussed as well as the three-dimensional extraction of azimuthal asymmetries measured in semi-inclusive deep-inelastic scattering, sensitive to twist-2 and twist-3 distributions in three-dimensional momentum space.

  4. Latest results from ALICE

    CERN Document Server

    Scapparone, Eugenio

    2011-01-01

    In this paper selected results obtained by the ALICE experiment at the LHC will be presented. Data collected during the pp runs taken at sqrt(s)=0.9, 2.76 and 7 TeV and Pb-Pb runs at sqrt(s_NN)=2.76 TeV allowed interesting studies on the properties of the hadronic and nuclear matter: proton runs gave us the possibility to explore the ordinary matter at very high energy and up to very low pt, while Pb-Pb runs provided spectacular events where several thousands of particles produced in the interaction revealed how a very dense medium behaves, providing a deeper picture on the quark gluon plasma(QGP) chemical composition and dynamics.

  5. Recent Results from Phobos

    Science.gov (United States)

    García, Edmundo; Back, B. B.; Baker, M. D.; Ballintijn, M.; Barton, D. S.; Betts, R. R.; Bickley, A. A.; Bindel, R.; Busza, W.; Carroll, A.; Chai, Z.; Decowski, M. P.; García, E.; Gburek, T.; George, N.; Gulbrandsen, K.; Halliwell, C.; Hamblen, J.; Hauer, M.; Henderson, C.; Hofman, D. J.; Hollis, R. S.; Hołyński, R.; Holzman, B.; Iordanova, A.; Johnson, E.; Kane, J. L.; Khan, N.; Kulinich, P.; Kuo, C. M.; Lin, W. T.; Manly, S.; Mignerey, A. C.; Nouicer, R.; Olszewski, A.; Pak, R.; Reed, C.; Roland, C.; Roland, G.; Sagerer, J.; Seals, H.; Sedykh, I.; Smith, C. E.; Stankiewicz, M. A.; Steinberg, P.; Stephans, G. S. F.; Sukhanov, A.; Tonjes, M. B.; Trzupek, A.; Vale, C.; van Nieuwenhuizen, G. J.; Vaurynovich, S. S.; Verdier, R.; Veres, G. I.; Wenger, E.; Wolfs, F. L. H.; Wosiek, B.; Woźniak, K.; Wysłouch, B.

    2007-02-01

    The PHOBOS detector is one of four heavy ion experiments at the Relativistic Heavy Ion Collider at Brookhaven National Laboratory. In this paper we will review some of the results of PHOBOS from the data collected in p+p, d+Au and Au+Au collisions at nucleon-nucleon center-of-mass energies up to 200 GeV. Evidence is found of the formation of a very high energy density and highly interactive system, which can not be described in terms of hadrons, and has a relatively low baryon density. There is evidence that the system formed is thermalized to a certain degree. Scaling with the number of participants and extended longitudinal scaling behavior are also observed in distributions of produced charged particles.

  6. Recent results from LHCf

    Directory of Open Access Journals (Sweden)

    Menjo H.

    2015-01-01

    Full Text Available The LHCf experiment is one of the LHC forward experiments. The aim of LHCf is to provide critical calibration data of hadronic intraction models used in air shower simulations. The LHCf has completed the operations for p-p collisions with a collision energy of √s = 0.9 and 7 TeV p-p in 2010 and for p-Pb collisions with a collision energy per nucleon of √sNN = 5.02. The recent LHCf result of forward neutron energy spectra at 7 TeV p-p collision and forward π0 spectra at p-Pb collisions are presented in this paper.

  7. Results and discussion

    International Nuclear Information System (INIS)

    1998-01-01

    The author deals with the experimental study of sorption, desorption and vertical migration of radionuclides in Sr-85 and Cs-137 in selected soil samples from around of NPP Bohunice and NPP Mochovce and other localities of the Slovakia. The influence of different materials [concurrent ions (K + , Ca 2+ , NH 4 + , pH), organic matter (peat) and zeolite, humidity] on kinetic of sorption and desorption of strontium and cesium as well as distribution coefficient (K D ) and transfer coefficients in followed samples of soils were followed. Obtained adsorption isotherm are presented and discussed. Using the Tessiere's sequential extraction analysis a gross variability in binding of radionuclides on soils was found. The obtained results were processed with the correlation analysis and the compartment model

  8. Areva - 2011 Annual results

    International Nuclear Information System (INIS)

    Marie, Patricia; Briand, Pauline; Michaut, Maxime; Scorbiac, Marie de; Repaire, Philippine du

    2012-01-01

    Areva's backlog established at 45.6 billion euros at the end of 2011, significantly increasing at the end of a year marked by the Fukushima accident, confirms the commercial dynamism of the group alongside its customers and reinforces the visibility on its future business level. In a difficult context, the slight decline in revenue in 2011 demonstrates the robustness of Areva's integrated model, resting mainly on recurring business generated in relation to Areva's customers' nuclear installed base, and benefiting from the development of Areva's renewable energies operations. Free operating cash flow before tax, although down over the whole year in 2011, improved in the second half, showing the first effects of Areva's stronger focus on cash generation and debt management. After the success of Areva's bond issue in September 2011, the Group's liquidity remains high at the end of 2011. The Areva teams are now dedicating all of their efforts to the deployment of the 'Action 2016' strategic action plan, which had already yielded its first positive results at the end of 2011, with an improvement in the cost structure of Areva's operations, an increase in order intake, and the launch of several disposals of minority interests. Summary of the 2011 financial results: - Backlog: euro 45.6 bn, +3.1% vs. 2010, i.e +6.7% over 3 months; - Revenue: euro 8.872 bn, i.e -2.6% vs. 2010; - Operating income: - euro 1.923 bn; - Net income attributable to equity owners of the parent: - euro 2.424 bn; - EBITDA: euro 1.068 bn ( euro 420 m excluding Siemens impact); - Free operating cash flow before tax: - euro 2.397 bn (- euro 1.366 bn excluding Siemens impacts), improvement over the second half; - Decrease in net debt of euro 124 m for the year; - Significant drop in general and administrative expenses, with a noticeable reduction between the first and the second half; - Launch of several disposals of minority interests

  9. Report on Results 2000

    Energy Technology Data Exchange (ETDEWEB)

    NONE

    2001-07-01

    This report discusses work being carried out in Norway to promote energy efficiency and the production of new renewable energy. An overall review of the quantifiable results of last year's activities at national level is available. It will serve to initiate an annual reporting tradition. The report represents a step towards an ongoing process for improved targeting and management of national efforts. During the course of the year 2000, NVE has evaluated and adjusted its activities and established a system involving indicators and reporting procedures. It is also important to take notice of the long-term work being undertaken to influence people's attitudes, even though this work is difficult to assess. NVE is investing in i.a. measures aimed at children and young people. Apart from directly influencing future energy users, this investment is also having an effect due to the children's encouragement of their parents to engage in more energy and environment-friendly behaviour. Published in 2000, the IEA report ''Trends in Norwegian Stationary Energy Use'' shows that total Norwegian energy consumption per GDP is not much higher than in other IEA countries, when adjusted for cold climate and industrial structure. However, Norwegians do stand out as intensive users of electricity. The IEA report shows a reduction of 10 TWh in energy usage when compared to the projected post 1990 figures. Energy efficiency activities have contributed towards this reduction. However, the potential for a more rational use of energy in Norway is still substantial and well documented. Based on experience most enterprises could save around 10% of energy used just by making changes to their operations, i.e. without major investments. Furthermore, the potential is growing because of massive technological developments in respect of energy usage, production and distribution. With this in mind, it is necessary to take full advantage of the extensive knowledge

  10. URAT South Parallax Results

    Science.gov (United States)

    Finch, Charlie T.; Zacharias, Norbert; Jao, Wei-Chun

    2018-04-01

    We present 916 trigonometric parallaxes and proper motions of newly discovered nearby stars from the United States Naval Observatory Robotic Astrometric Telescope (URAT). Observations were taken at the Cerro Tololo Interamerican Observatory over a 2-year period from 2015 to 2017 October covering the entire sky south of about +25° decl. SPM4 and UCAC4 early epoch catalog data were added to extend the temporal coverage for the parallax and proper motion fit up to 48 years. Using these new URAT parallaxes, optical and near-IR photometry from the AAVSO Photometric All-Sky Survey and Two Micron All-Sky Survey catalogs, we identify possible new nearby dwarfs, young stars, low-metallicity subdwarfs and white dwarfs. Comparison to known trigonometric parallaxes shows a high quality of the URAT-based results confirming the error in parallax of the URAT south parallaxes reported here to be between 2 and 13 mas. We also include additional 729 trigonometric parallaxes from the URAT north 25 pc sample published in Finch & Zacharias here after applying the same criterion as for the southern sample to have a complete URAT 25 pc sample presented in this paper.

  11. ESR teleradiology survey: results.

    Science.gov (United States)

    2016-08-01

    With recent developments of teleradiology technology and services, it has become necessary to better evaluate its extent and use among different countries in Europe. With this goal in mind, the ESR launched two specific surveys intended to gather the current state of adoption and implementation of teleradiology in clinical practice. A special focus on differentiating between insourcing teleradiology services among partners of the same organisation and outsourcing to external services was an essential part of the design of these surveys. The first survey was addressed to 44 national societies of different countries in Europe, while the second survey was intended for all practicing radiologist ESR members. While the results of these surveys reported here may provide a wealth of information to better understand the trends in adoption of teleradiology in Europe, they only represent a snapshot at a certain point in time. The rapid development of telecommunication tools as well as a fundamental change in practice and healthcare economics will certainly influence these observations in the upcoming years. These data, however, will provide objective and relevant parameters for supporting the efforts of experts and policy makers in promoting appropriate criteria and guidelines for adequate use of teleradiology in clinical practice. Main Messages • Understand concepts and challenges of teleradiology • Provide insight into current trends and solutions for teleradiology • Compare differences in teleradiolgy strategies between countries in Europe • Establish a reference on statistical data of usage of teleradiology in Europe.

  12. [Maraviroc: clinical trials results].

    Science.gov (United States)

    Chidiac, C; Katlama, C; Yeni, P

    2008-03-01

    Just over a decade after identification of chemokine receptors CCR5 and CXCR4 as coreceptors for HIV, maraviroc (Celsentri), the first CCR5 antagonist, has recently obtained its Marketing Authorization in the United States and Europe, for treatment of treatment-experienced adult patients infected with only CCR5-tropic HIV-1 detectable. CCR5 antagonists, after fusion inhibitor enfuvirtide available since 2003, also belong to entry inhibitors. These molecules, unlike previous antiretrovirals, do not target the virus but its target cell by blocking viral penetration. Maraviroc has shown its clinical efficacy in patients failing other antiretroviral classes. Its safety profile was similar to placebo in two large phase III trials. However, careful assessment of both hepatic and immunologic safety of this new therapeutic class is needed. Viral tropism testing has to be investigated before using maraviroc in the clinic, because CCR5 antagonists are not active against CXCR4 viruses. For the moment indicated for the treatment-experienced patient population, maraviroc could in the future benefit to other types of patients, depending on ongoing trials results.

  13. COBE observations and results

    International Nuclear Information System (INIS)

    Smoot, G.F.

    1999-01-01

    This paper summarizes the results from the COBE satellite mission. Nine years have passed since the launch of COBE and six years since the announcement of the discovery of cosmic microwave background anisotropies by the COBE DMR instrument. This is still a relatively short time to look back and understand the implications of COBE and the anisotropy discovery; however, this 3K Cosmology Conference provides some context. The Cosmic Background Explorer (COBE) satellite has made a major contribution to the field of cosmology and has help create the confidence and high level of interest that propels the field today. Two major CMB observations, the thermal spectrum of the CMB and the CMB anisotropies, plus a host of other observations and conclusions are the basis and a major but not exclusive portion of the legacy of COBE. The recent detection and observation of the cosmic infrared background (CIB) are also part of COBE close-quote s major contribution to cosmology. copyright 1999 American Institute of Physics

  14. esophageal cancer: preliminary results

    Directory of Open Access Journals (Sweden)

    Afsaneh Maddah Safaei

    2017-01-01

    Full Text Available Purpose: Dysphagia is a common initial presentation in locally advanced esophageal cancer and negatively impacts patient quality of life and treatment compliance. To induce fast relief of dysphagia in patients with potentially operable esophageal cancer high-dose-rate (HDR brachytherapy was applied prior to definitive radiochemotherapy. Material and methods : In this single arm phase II clinical trial between 2013 to 2014 twenty patients with locally advanced esophageal cancer (17 squamous cell and 3 adenocarcinoma were treated with upfront 10 Gy HDR brachytherapy, followed by 50.4 Gy external beam radiotherapy (EBRT and concurrent chemotherapy with cisplatin/5-fluorouracil. Results : Tumor response, as measured by endoscopy and/or computed tomography scan, revealed complete remission in 16 and partial response in 4 patients (overall response rate 100%. Improvement of dysphagia was induced by brachytherapy within a few days and maintained up to the end of treatment in 80% of patients. No differences in either response rate or dysphagia resolution were found between squamous cell and adenocarcinoma histology. The grade 2 and 3 acute pancytopenia or bicytopenia reported in 4 patients, while sub-acute adverse effects with painful ulceration was seen in five patients, occurring after a median of 2 months. A perforation developed in one patient during the procedure of brachytherapy that resolved successfully with immediate surgery. Conclusions : Brachytherapy before EBRT was a safe and effective procedure to induce rapid and durable relief from dysphagia, especially when combined with EBRT.

  15. Results from SNO

    International Nuclear Information System (INIS)

    Chan, Yuen-dat

    2001-01-01

    The Sudbury Neutrino Observatory (SNO) is an underground heavy water Cherenkov detector for studying solar neutrinos. SNO is capable of performing both flavor sensitive and flavor blind measurements of the solar neutrino flux. The first charged current (CC) measurement is found to be: ψ SNO CC (ν e ) = 1.75 ± 0.07(stat.) -0.11 +0.12 (sys.) ± 0.05 (theor.) x 10 6 cm -2 s -1 and the elastic scattering fluxes (ES) is: ψ SNO ES (ν x ) = 2.39 ± 0.34(stat.) -0.14 +0.16 (sys.) x 10 6 cm -2 s -1 . The ψ SNO CC (ν e ) result, when combined with the high statistics elastic scattering (ES) measurement from Super-Kamiokande, provide a strong evidence for solar neutrino flavor transformation (3.3σ). The deduced total solar neutrino flux is in good agreement with standard solar model predictions. No significant distortion in the energy spectrum is observed

  16. Results from VENUS

    International Nuclear Information System (INIS)

    Ogawa, K.

    1990-01-01

    Recent results from VENUS experiments on e + e - reactions at energies between 52 and 60.8 GeV are presented. The R-values, the ratio of the total hadronic cross section to that of μ pair production, look slightly high within the present energy region. To understand this observation, a detailed study was carried out on the production of a heavy quark with |Q|=e/3. By using a next-to-leading log. approximation, the QCD cut-off parameter, Λ MS , was obtained as being Λ MS =208 MeV(+80MeV, -62MeV). The differential cross sections for e + e - → e + e - , γγ, μ + μ - , and τ + τ - were found to be consistent with predictions of the standard model. The average charge asymmetry for e + e - → qq-bar was also measured and found to be consistent with the prediction of the standard model. No evidence was observed indicating new particle production. No single photon production was observed and the upper limit of the number of light neutrino types was set to be N ν < 17.8 (90 % CL). (author)

  17. Results from SNO

    Energy Technology Data Exchange (ETDEWEB)

    Chan, Yuen-dat

    2001-10-01

    The Sudbury Neutrino Observatory (SNO) is an underground heavy water Cherenkov detector for studying solar neutrinos. SNO is capable of performing both flavor sensitive and flavor blind measurements of the solar neutrino flux. The first charged current (CC) measurement is found to be: {psi}{sub SNO}{sup CC}({nu}{sub e}) = 1.75 {+-} 0.07(stat.){sub -0.11}{sup +0.12}(sys.) {+-} 0.05 (theor.) x 10{sup 6} cm{sup -2}s{sup -1} and the elastic scattering fluxes (ES) is: {psi}{sub SNO}{sup ES}({nu}{sub x}) = 2.39 {+-} 0.34(stat.){sub -0.14}{sup +0.16} (sys.) x 10{sup 6} cm{sup -2}s{sup -1}. The {psi}{sub SNO}{sup CC}({nu}{sub e}) result, when combined with the high statistics elastic scattering (ES) measurement from Super-Kamiokande, provide a strong evidence for solar neutrino flavor transformation (3.3{sigma}). The deduced total solar neutrino flux is in good agreement with standard solar model predictions. No significant distortion in the energy spectrum is observed.

  18. Overview of MAGIC results

    Science.gov (United States)

    Rico, Javier; MAGIC Collaboration

    2016-04-01

    MAGIC is a system of two 17-m diameter Cherenkov telescopes, located at the Observatorio del Roque de los Muchachos, in the Canary island La Palma (Spain). MAGIC performs astronomical observations of gamma-ray sources in the energy range between 50 GeV and 10 TeV. The first MAGIC telescope has been operating since 2004, and in 2009 the system was completed with the second one. During 2011 and 2012 the electronics for the readout system were fully upgraded, and the camera of the first telescope replaced. After that, no major hardware interventions are foreseen in the next years, and the experiment has undertaken a final period of steady astronomical observations. MAGIC studies particle acceleration in the most violent cosmic environments, such as active galactic nuclei, gamma-ray bursts, pulsars, supernova remnants or binary systems. In addition, it addresses some fundamental questions of Physics, such as the origin of Galactic cosmic rays and the nature of dark matter. Moreover, by observing the gamma-ray emission from sources at cosmological distances, we measure the intensity and evolution of the extragalactic background radiation, and perform tests of Lorentz Invariance. In this paper I present the status and some of the latest results of the MAGIC gamma-ray telescopes.

  19. Results from LHCf Experiment

    CERN Document Server

    Tricomi, Alessia

    2012-01-01

    The LHCf experiment has taken data in 2009 and 2010 p-p collisions at LHC at $\\sqrt{s} = 0.9$ TeV and $\\sqrt{s} = 7$ TeV. The measurement of the forward neutral particle spectra produced in proton-proton collisions at LHC up to an energy of 14 TeV in the center of mass system are of fundamental importance to calibrate the Monte Carlo models widely used in the high energy cosmic ray (HECR) field, up to an equivalent laboratory energy of the order of $10^{17}$ eV. In this paper the first results on the inclusive photon spectrum measured by LHCf is reported. Comparison of this spectrum with the model expectations show significant discrepancies, mainly in the high energy region. In addition, perspectives for future analyses as well as the program for the next data taking period, in particular the possibility to take data in p-Pb collisions, will be discussed.

  20. Climax granite test results

    Energy Technology Data Exchange (ETDEWEB)

    Ramspott, L.D.

    1980-01-15

    The Lawrence Livermore Laboratory (LLL), as part of the Nevada Nuclear Waste Storage Investigations (NNWSI) program, is carrying out in situ rock mechanics testing in the Climax granitic stock at the Nevada Test Site (NTS). This summary addresses only those field data taken to date that address thermomechanical modeling for a hard-rock repository. The results to be discussed include thermal measurements in a heater test that was conducted from October 1977 through July 1978, and stress and displacement measurements made during and after excavation of the canister storage drift for the Spent Fuel Test (SFT) in the Climax granite. Associated laboratory and field measurements are summarized. The rock temperature for a given applied heat load at a point in time and space can be adequately modeled with simple analytic calculations involving superposition and integration of numerous point source solutions. The input, for locations beyond about a meter from the source, can be a constant thermal conductivity and diffusivity. The value of thermal conductivity required to match the field data is as much as 25% different from laboratory-measured values. Therefore, unless we come to understand the mechanisms for this difference, a simple in situ test will be required to obtain a value for final repository design. Some sensitivity calculations have shown that the temperature field is about ten times more sensitive to conductivity than to diffusivity under the test conditions. The orthogonal array was designed to detect anisotropy. After considering all error sources, anisotropic efforts in the thermal field were less than 5 to 10%.

  1. Areva: 2014 annual results

    International Nuclear Information System (INIS)

    Repaire, Philippine du

    2015-01-01

    The scale of the net loss for 2014 illustrates the twofold challenge confronting AREVA: continuing stagnation of the nuclear operations, lack of competitiveness and difficulties in managing the risks inherent in large projects. The group understands how serious this situation is. A comprehensive strategic review of operations was undertaken beginning in November 2014 and is being carried out without compromise. As a result, AREVA is now able to announce a solid transformation plan that sets a challenging but economically realistic course for its teams. First, AREVA will refocus on its core business: mastery of key nuclear processes essential to operators around the globe. This strategic redeployment will lead to the revision of certain goals, whether in the management of new reactor projects or in renewable energies. AREVA's objective is to achieve excellence as a high value-added supplier of products and services. Secondly, AREVA, whose resources had been marshaled to support a spurt of growth in nuclear power, must now adapt to new market realities and become competitive once again. The group's most urgent task is recovery and securing its future by immediately launching a far-reaching competitiveness plan founded on organizational simplification, quality of operations, and a completely revamped approach to managing risk in large projects. Last but not least, AREVA must ensure sustainable financing for its activities. A financing plan will be clarified before publication of the half-year financial statements. This document presents the key financial data of the group, its strategic road-map and its operating and financing plans

  2. PDX experimental results

    International Nuclear Information System (INIS)

    Meade, D.; Arunasalam, V.; Barnes, C.

    1981-01-01

    During the initial period of operation PDX has obtained the following results: (a) Production of macroscopically stable poloidal divertor configurations with dee, inverse-dee and single null plasma shapes. (b) Determined vertical positional instability growth rates for passively stabilized elongated dee-shaped plasmas with surface elongations from 1 to 1.4. (c) Production of Z approximately equal to 1 plasmas in a diverted dee configuration with confinement times approaching 80 ms for plasmas with Isub(p) approximately equal to 300 kA, Bsub(T)=17 kG, a=38 cm, q approximately equal to 3 and anti nsub(e) approximately equal to 4x10 13 cm -3 . (d) Extended the Ohmic heating regime to q approximately equal to 2 at nsub(e)R/Bsub(T) approximately equal to 10 15 cm -2 T -1 and q approximately equal to 3 at anti nsub(e)R/Bsub(T) approximately equal to 4.5x10 15 cm -2 T -1 . Neutral beam injection has extended anti nsub(e)R/Bsub(T) to approximately 6x10 15 cm -2 T -1 . (e) Initial neutral beam injection experiments with 1-2 MW injected perpendicularly have been used to study ion and electron heating with divertor control of density and impurities. (f) Divertor physics studies indicate that the divertor captures approximately 70% of the input power, while approximately 30% of the power is radiated. (g) Particle and energy flow onto the divertor neutralizer plate is in qualitative agreement with a simple sheath model. (author)

  3. AREVA annual results 2009

    International Nuclear Information System (INIS)

    2009-01-01

    AREVA expanded its backlog and increased its revenues compared with 2008, on strong installed base business and dynamic major projects, fostering growth in operating income of 240 million euros. As announced previously, Areva is implementing a financing plan suited to its objectives of profitable growth. The plan was implemented successfully in 2009, including the conclusion of an agreement, under very satisfactory terms, to sell its Transmission and Distribution business for 4 billion euros, asset sales for more than 1.5 billion euros, and successful bond issues of 3 billion euros. The plan will continue in 2010 with a capital increase, the completion of asset disposals and cost reduction and continued operational performance improvement programs. Areva bolstered its Renewable Energies business segment by supplementing its offshore wind power and biomass businesses with the acquisition of Ausra, a California-based leader in concentrated solar power technology. Despite the sale of T and D, Areva is maintaining its financial performance outlook for 2012: 12% average annual revenue growth to 12 billion euros in 2012, double digit operating margin and substantially positive free operating cash flow. Annual results 2009: - For the group as a whole, including Transmission and Distribution: Backlog: euros 49.4 bn (+2.5%), Revenues: euros 14 bn (+6.4%), Operating income: euros 501 m (+20.1%); - Nuclear and Renewable Energies perimeter: Backlog: euros 43.3 bn (+1.8%), Strong revenue growth: +5.4% to euros 8.5 bn, Operating income before provision for the Finnish project in the first half of 2009: euros 647 m, Operating income: euros 97 m, for a euros 240 m increase from 2008; - Net income attributable to equity holders of the parent: euros 552 m, i.e. euros 15.59 per share; - Net debt: euros 6,193 m; - Pro-forma net debt, including net cash to be received from the sale of T and D in 2010: euros 3,022 m; - Dividend of euros 7.06 per share to be proposed during the Annual

  4. Overview of MAST results

    International Nuclear Information System (INIS)

    Counsell, G.F.; Akers, R.J.; Appel, L.C.

    2005-01-01

    field. Early edge localized mode activity on MAST is associated with the formation of narrow filamentary structures following field lines in the edge. These filaments rotate toroidally with the edge plasma and, away from the X-points, accelerate radially outwards from the edge up to 20 cm. Studies of disruptions on MAST demonstrate a complex evolution of core energy loss and resultant divertor power loads, including phases where the target heat flux width is broadened by a factor of 8. Observations of energetic particle modes driven by super-Alfvenic beam ions provide support for a model for the non-linear evolution of toroidal Alfven eigenmodes (AEs) forming Bernstein-Green-Krushal waves. The AE activity reduces to low levels with increasing β. Plasma start-up without a central solenoid and in a manner compatible with future large spherical tokamak (ST) devices has been demonstrated using breakdown at a quadrupole magnetic null. Closed flux surface plasmas with peak plasma currents up to 370 kA have been generated and sustained for 0.3 s. New error field correction coils have extended the operational space for low density plasmas and enabled scaling studies of error field induced locked mode formation in the ST

  5. Overview of MAST results

    International Nuclear Information System (INIS)

    Counsell, G.F.; Akers, R.J.; Appel, L.C.

    2005-01-01

    filamentary structures following field lines in the edge. These filaments rotate toroidally with the edge plasma and, away from the X-points, accelerate radially outwards from the edge up to 20cm. Studies of disruptions on MAST demonstrate a complex evolution of core energy loss and resultant divertor power loads, including phases where the target heat flux width is broadened by a factor 8. Observations of energetic particle modes driven by super-Alfvenic beam ions provide support for a model for the non-linear evolution of toroidal Alfven eigenmodes (AE) forming BGK waves. AE activity reduces to low levels with increasing β. Plasma start-up without a central solenoid and in a manner compatible with future large ST devices has been demonstrated using breakdown at a quadrupole magnetic null. Closed flux surface plasmas with peak plasma currents up to 370 kA have been generated and sustained for 0.3s. New error field correction coils have extended the operational space for low density plasmas and enabled scaling studies of error field induced locked mode formation in the ST. (author)

  6. Promising pesticide results

    International Nuclear Information System (INIS)

    Wallace, Paula

    2012-01-01

    of DDT in soil. Given its 'sticky' quality, DDT is difficult to isolate and treat in the solid matrix of soil. “Our ViroFlow Technology has been designed to overcome both these problems by using a chemical, not bacterial, agent and by separating DDT from the structure of the soil matrix, thereby making it vulnerable to decomposition,” said Barros. As a result of these findings, Virotec is conducting a series of tests in conjunction with the NSW EPA and Department of Primary Industries to examine ways its solution can be applied to treating DDT in soil.

  7. Result

    Indian Academy of Sciences (India)

    With reference to the detailed evaluation of bids submitted the following agencies has been selected to award the contract on L1 ( lowest bidder) basis. 1. M/s . CITO INFOTECH, Bengaluru ( for procurement of desktop computers). 2. M/s. MCCANNINFO SOLUTION, Mumbai ( for procurement of laptops computers)

  8. Result

    African Journals Online (AJOL)

    Tsinuel

    BACKGROUND: Neonatal deaths in general, early neonatal deaths in particular now represent two- third of infant deaths and one-third of under-five deaths worldwide. Therefore, improving newborn survival is a major priority in child health today. Negotiation of improved neonatal health care practice into the community ...

  9. Rescue of TET2 Haploinsufficiency in Myelodysplastic Syndrome Patients Using Turbo Cosubstrate

    Science.gov (United States)

    2017-07-01

    prevalent in a number of myeloid malignancies such as MDS-myeloproliferative neoplasms (MDS-MPN) and acute myeloid leukemia derived from MDS and MDS...Myelodysplastic syndromes (MDS), MDS-myeloproliferative neoplasms (MDS-MPN), Acute myeloid leukemia (AML), 5-methylcytosine (5mC), Mutation...normal initially, with age, develop diverse myeloid malignancies similar to humans. The objective in this project is to develop effective strategies

  10. Resistance to diet-induced obesity and associated metabolic perturbations in haploinsufficient monocarboxylate transporter 1 mice.

    OpenAIRE

    Lengacher Sylvain; Nehiri-Sitayeb Touria; Steiner Nadia; Carneiro Lionel; Favrod Céline; Preitner Frédéric; Thorens Bernard; Stehle Jean-Christophe; Dix Laure; Pralong François; Magistretti Pierre J; Pellerin Luc

    2013-01-01

    The monocarboxylate transporter 1 (MCT1 or SLC16A1) is a carrier of short-chain fatty acids, ketone bodies, and lactate in several tissues. Genetically modified C57BL/6J mice were produced by targeted disruption of the mct1 gene in order to understand the role of this transporter in energy homeostasis. Null mutation was embryonically lethal, but MCT1(+/-) mice developed normally. However, when fed high fat diet (HFD), MCT1(+/-) mice displayed resistance to development of diet-induced obesity ...

  11. Characterizing haploinsufficiency of SHELL gene to improve fruit form prediction in introgressive hybrids of oil palm

    OpenAIRE

    Teh, Chee Keng; Muaz, Siti Dalila; Tangaya, Praveena; Fong, Po-Yee; Ong, Ai Ling; Mayes, Sean; Chew, Fook Tim; Kulaveerasingam, Harikrishna; Appleton, David Ross

    2017-01-01

    The fundamental trait in selective breeding of oil palm (Eleais guineensis Jacq.) is the shell thickness surrounding the kernel. The monogenic shell thickness is inversely correlated to mesocarp thickness, where the crude palm oil accumulates. Commercial thin-shelled tenera derived from thick-shelled dura???shell-less pisifera generally contain 30% higher oil per bunch. Two mutations, sh MPOB (M1) and sh AVROS (M2) in the SHELL gene ? a type II MADS-box transcription factor mainly present in ...

  12. Deletion mutagenesis identifies a haploinsufficient role for gamma-zein in opaque-2 endosperm modification

    Science.gov (United States)

    Quality Protein Maize (QPM) is a hard kernel variant of the high-lysine mutant, opaque-2. Using gamma irradiation, we created opaque QPM variants to identify opaque-2 modifier genes and to investigate deletion mutagenesis combined with Illumina sequencing as a maize functional genomics tool. A K0326...

  13. Attenuated hypertrophic response to pressure overload in a lamin A/C haploinsufficiency mouse

    OpenAIRE

    Cupesi, Mihaela; Yoshioka, Jun; Gannon, Joseph; Kudinova, Anastacia; Stewart, Colin L.; Lammerding, Jan

    2009-01-01

    Inherited mutations cause approximately 30% of all dilated cardiomyopathy cases, with autosomal dominant mutations in the LMNA gene accounting for more than one third of these. The LMNA gene encodes the nuclear envelope proteins lamins A and C, which provide structural support to the nucleus and also play critical roles in transcriptional regulation. Functional deletion of a single allele is sufficient to trigger dilated cardiomyopathy in humans and mice. However, whereas Lmna−/− mice develop...

  14. A genotype-first approach identifies an intellectual disability-overweight syndrome caused by PHIP haploinsufficiency

    DEFF Research Database (Denmark)

    Jansen, Sandra; Hoischen, Alexander; Coe, Bradley P

    2018-01-01

    Genotype-first combined with reverse phenotyping has shown to be a powerful tool in human genetics, especially in the era of next generation sequencing. This combines the identification of individuals with mutations in the same gene and linking these to consistent (endo)phenotypes to establish di...

  15. Cornelia de Lange Syndrome: NIPBL haploinsufficiency downregulates canonical Wnt pathway in zebrafish embryos and patients fibroblasts.

    Science.gov (United States)

    Pistocchi, A; Fazio, G; Cereda, A; Ferrari, L; Bettini, L R; Messina, G; Cotelli, F; Biondi, A; Selicorni, A; Massa, V

    2013-10-17

    Cornelia de Lange Syndrome is a severe genetic disorder characterized by malformations affecting multiple systems, with a common feature of severe mental retardation. Genetic variants within four genes (NIPBL (Nipped-B-like), SMC1A, SMC3, and HDAC8) are believed to be responsible for the majority of cases; all these genes encode proteins that are part of the 'cohesin complex'. Cohesins exhibit two temporally separated major roles in cells: one controlling the cell cycle and the other involved in regulating the gene expression. The present study focuses on the role of the zebrafish nipblb paralog during neural development, examining its expression in the central nervous system, and analyzing the consequences of nipblb loss of function. Neural development was impaired by the knockdown of nipblb in zebrafish. nipblb-loss-of-function embryos presented with increased apoptosis in the developing neural tissues, downregulation of canonical Wnt pathway genes, and subsequent decreased Cyclin D1 (Ccnd1) levels. Importantly, the same pattern of canonical WNT pathway and CCND1 downregulation was observed in NIPBL-mutated patient-specific fibroblasts. Finally, chemical activation of the pathway in nipblb-loss-of-function embryos rescued the adverse phenotype and restored the physiological levels of cell death.

  16. Carriers with functional null mutations in LAMA3 have localized enamel abnormalities due to haploinsufficiency

    NARCIS (Netherlands)

    Gostynska, Katarzyna B.; Yuen, Wing Yan; Pasmooij, Anna Maria Gerdina; Stellingsma, Cornelius; Pas, Hendri H.; Lemmink, Henny; Jonkman, Marcel F.

    2017-01-01

    The hereditary blistering disease junctional epidermolysis bullosa (JEB) is always accompanied by structural enamel abnormalities of primary and secondary dentition, characterized as amelogenesis imperfecta. Autosomal recessive mutations in LAMA3, LAMB3 and LAMC2 encoding the heterotrimer laminin

  17. Angiogenesis and Therapeutic Approaches to NF1 Tumors

    National Research Council Canada - National Science Library

    Muir, David F

    2007-01-01

    .... Invivo and in vitro models were used to firmly conclude that Nf1 haploinsufficiency in endothelial cells results inexaggerated proliferation and angiogenesis in response to key pro-angiogenic factors...

  18. LHC physics results and prospects

    CERN Document Server

    Kono, Takanori; The ATLAS collaboration

    2018-01-01

    This talk presents the latest results from LHC Run-2 as of May 2018 which include Standard Model measurements, Higgs boson properties and beyond Standard Model search results. The prospects for future LHC runs are also shown.

  19. Recent SUSY Results from CMS

    CERN Multimedia

    CERN. Geneva

    2012-01-01

    We present a summary of the recent results of searches for supersymmetry conducted by the CMS experiment. Several searches are reported using complementary final states and methods. The results presented include searches for stops and sbottoms, production of charginos and neutralinos, and R-parity violating signatures. Several of them are the first results of their kind from CMS, while others increased the mass reach significantly over previously published results from the LHC.

  20. An overview of JET results

    International Nuclear Information System (INIS)

    Adams, J.M.; Alladio, F.; Altmann, H.

    1989-01-01

    An overview is given of experimental results obtained on JET during 1988, and in particular of results at high total power input into plasmas with various configurations. An account is given of the various interpretations of these results and some of the difficulties encountered are related. The progress is summarised in terms of the projected D-T performance. (author)

  1. Comparison of checkpoint responses triggered by DNA polymerase inhibition versus DNA damaging agents

    International Nuclear Information System (INIS)

    Liu, J.-S.; Kuo, S.-R.; Melendy, Thomas

    2003-01-01

    To better understand the different cellular responses to replication fork pausing versus blockage, early DNA damage response markers were compared after treatment of cultured mammalian cells with agents that either inhibit DNA polymerase activity (hydroxyurea (HU) or aphidicolin) or selectively induce S-phase DNA damage responses (the DNA alkylating agents, methyl methanesulfonate (MMS) and adozelesin). These agents were compared for their relative abilities to induce phosphorylation of Chk1, H2AX, and replication protein A (RPA), and intra-nuclear focalization of γ-H2AX and RPA. Treatment by aphidicolin and HU resulted in phosphorylation of Chk1, while HU, but not aphidicolin, induced focalization of γ-H2AX and RPA. Surprisingly, pre-treatment with aphidicolin to stop replication fork progression, did not abrogate HU-induced γ-H2AX and RPA focalization. This suggests that HU may act on the replication fork machinery directly, such that fork progression is not required to trigger these responses. The DNA-damaging fork-blocking agents, adozelesin and MMS, both induced phosphorylation and focalization of H2AX and RPA. Unlike adozelesin and HU, the pattern of MMS-induced RPA focalization did not match the BUdR incorporation pattern and was not blocked by aphidicolin, suggesting that MMS-induced damage is not replication fork-dependent. In support of this, MMS was the only reagent used that did not induce phosphorylation of Chk1. These results indicate that induction of DNA damage checkpoint responses due to adozelesin is both replication fork and fork progression dependent, induction by HU is replication fork dependent but progression independent, while induction by MMS is independent of both replication forks and fork progression

  2. Comparison of checkpoint responses triggered by DNA polymerase inhibition versus DNA damaging agents

    Energy Technology Data Exchange (ETDEWEB)

    Liu, J.-S.; Kuo, S.-R.; Melendy, Thomas

    2003-11-27

    To better understand the different cellular responses to replication fork pausing versus blockage, early DNA damage response markers were compared after treatment of cultured mammalian cells with agents that either inhibit DNA polymerase activity (hydroxyurea (HU) or aphidicolin) or selectively induce S-phase DNA damage responses (the DNA alkylating agents, methyl methanesulfonate (MMS) and adozelesin). These agents were compared for their relative abilities to induce phosphorylation of Chk1, H2AX, and replication protein A (RPA), and intra-nuclear focalization of {gamma}-H2AX and RPA. Treatment by aphidicolin and HU resulted in phosphorylation of Chk1, while HU, but not aphidicolin, induced focalization of {gamma}-H2AX and RPA. Surprisingly, pre-treatment with aphidicolin to stop replication fork progression, did not abrogate HU-induced {gamma}-H2AX and RPA focalization. This suggests that HU may act on the replication fork machinery directly, such that fork progression is not required to trigger these responses. The DNA-damaging fork-blocking agents, adozelesin and MMS, both induced phosphorylation and focalization of H2AX and RPA. Unlike adozelesin and HU, the pattern of MMS-induced RPA focalization did not match the BUdR incorporation pattern and was not blocked by aphidicolin, suggesting that MMS-induced damage is not replication fork-dependent. In support of this, MMS was the only reagent used that did not induce phosphorylation of Chk1. These results indicate that induction of DNA damage checkpoint responses due to adozelesin is both replication fork and fork progression dependent, induction by HU is replication fork dependent but progression independent, while induction by MMS is independent of both replication forks and fork progression.

  3. Mechanisms of caffeine-induced inhibition of UVB carcinogenesis

    Directory of Open Access Journals (Sweden)

    Allan H Conney

    2013-06-01

    Full Text Available Sunlight-induced nonmelanoma skin cancer is the most prevalent cancer in the United States with more than 2 million cases per year. Several studies have shown an inhibitory effect of caffeine administration on UVB-induced skin cancer in mice, and these studies are paralleled by epidemiology studies that indicate an inhibitory effect of coffee drinking on nonmelanoma skin cancer in humans. Strikingly, decaffeinated coffee consumption had no such inhibitory effect.Mechanism studies indicate that caffeine has a sunscreen effect that inhibits UVB-induced formation of thymine dimers and sunburn lesions in the epidermis of mice. In addition, caffeine administration has a biological effect that enhances UVB-induced apoptosis thereby enhancing the elimination of damaged precancerous cells, and caffeine administration also enhances apoptosis in tumors. Caffeine administration enhances UVB-induced apoptosis by p53-dependent and p53-independent mechanisms. Exploration of the p53-independent effect indicated that caffeine administration enhanced UVB-induced apoptosis by inhibiting the UVB-induced increase in ATR-mediated formation of phospho-Chk1 (Ser345 and abolishing the UVB-induced decrease in cyclin B1 which resulted in caffeine-induced premature and lethal mitosis in mouse skin. In studies with cultured primary human keratinocytes, inhibition of ATR with siRNA against ATR inhibited Chk1 phosphorylation and enhanced UVB-induced apoptosis. Transgenic mice with decreased epidermal ATR function that were irradiated chronically with UVB had 69% fewer tumors at the end of the study compared with irradiated littermate controls with normal ATR function. These results, which indicate that genetic inhibition of ATR (like pharmacologic inhibition of ATR via caffeine inhibits UVB-induced carcinogenesis and supports the concept that ATR-mediated phosphorylation of Chk1 is an important target for caffeine’s inhibitory effect on UVB-induced carcinogenesis.

  4. Aesthetic rhinoplasty: Avoiding unfavourable results

    Directory of Open Access Journals (Sweden)

    Kulwant S Bhangoo

    2013-01-01

    Full Text Available Rhinoplasty is one of the most challenging surgical procedures in plastic surgery. It is not surprising that a significant number of patients end up with unfavourable outcomes. Many of these unfavourable outcomes could be the result of poor judgment and wrong decision making. Most frequently, the unfavourable outcome is the result of errors in surgical technique. In this paper, unfavourable outcomes resulting from errors in surgical technique are discussed under the heading of each operative step. Poor placement of intra-nasal incision can result in internal valve obstruction. Bad columellar scars can result from errors during open rhinoplasty. Unfavourable results associated with skeletonisation are mentioned. Tip plasty, being the most difficult part of rhinoplasty, can result in lack of tip projection, asymmetry and deformities associated with placement of tip grafts. Over-resection of the lower lateral cartilages during tip plasty can also result in pinched nose, alar collapse causing external valve obstruction and other alar rim deformities. Humpectomy can result in open roof deformity, inverted V deformity and over-resection resulting in saddle nose. The so-called poly beak deformity is also a preventable unfavourable outcome when dealing with a large dorsal hump. Complications resulting from osteotomies include narrowing of nasal airway, open roof deformity, inverted V deformity and asymmetry of the bony wall resulting from incomplete or green stick fractures. Judicious use of grafts can be very rewarding. By the same token, grafts also carry with them the risk of complications. Allografts can result in recurrent infection, atrophy of the overlying skin and extrusion resulting in crippling deformities. Autografts are recommended by the author. Unfavourable results from autografts include displacement of graft, visibility of the graft edges, asymmetry, warping, and resorption.

  5. Solar neutrino results from SAGE

    International Nuclear Information System (INIS)

    Gavrin, V.N.

    2001-01-01

    The results of ten years of solar neutrino observation by the Russian-American gallium solar neutrino experiment (SAGE) are reported. The overall result of 70 runs during the measurement period from January 1990 to October 1999 is 75.4 -6.8 +7.0 (stat.) -3.0 +3.5 (syst) SNU. This represents only slightly more than half of the predicted standard solar model rate of 129 SNU. The individual results on each run, and the results of combined analysis of all runs during each year, as well as the results of combined analysis of all runs during monthly and bimonthly periods are presented

  6. Solar neutrino results from SAGE

    International Nuclear Information System (INIS)

    Gavrin, V.N.

    2000-01-01

    We report the results of ten years of solar neutrino observation by the Russian-American Gallium solar neutrino Experiment (SAGE). The overall result of 70 runs during the measurement period January 1990 to October 1999 is 75.4 + 7.0/-6.8 (stat.) +3.5/-3.0 (syst.) SNU. This represents only slightly more than half of the predicted standard solar model rate of 129 SNU. The individual results of each run, and the results of combined analysis of all runs during each year, as well as the results of combined analysis of all runs during monthly and bimonthly periods are presented

  7. CCTF CORE I test results

    International Nuclear Information System (INIS)

    Murao, Yoshio; Sudoh, Takashi; Akimoto, Hajime; Iguchi, Tadashi; Sugimoto, Jun; Fujiki, Kazuo; Hirano, Kenmei

    1982-07-01

    This report presents the results of the following CCTF CORE I tests conducted in FY. 1980. (1) Multi-dimensional effect test, (2) Evaluation model test, (3) FLECHT coupling test. On the first test, one-dimensional treatment of the core thermohydrodynamics was discussed. On the second and third tests, the test results were compared with the results calculated by the evaluation model codes and the results of the corresponding FLECHT-SET test (Run 2714B), respectively. The work was performed under contracts with the Atomic Energy Bureau of Science and Technology Agency of Japan. (author)

  8. New results from NA49

    CERN Document Server

    Afanasiev, S V; Bächler, J; Barna, D; Barnby, L S; Bartke, Jerzy; Barton, R A; Behler, M; Betev, L; Bialkowska, H; Billmeier, A; Blume, C; Blyth, C O; Boimska, B; Botje, M; Bracinik, J; Brady, F P; Bramm, R; Brun, R; Buncic, P; Carr, L; Cebra, D; Cerny, V; Cooper, G E; Cramer, J G; Csató, P; Dinkelaker, P; Eckardt, V; Eckhardt, F; Ferenc, D; Filip, P; Fischer, H G; Foder, Z; Foka, P Y; Freund, P; Friese, V; Gál, J; Ganz, R E; Gazdzicki, M; Georgopoulos, G; Gladysz-Dziadus, E; Harris, J W; Hegyi, S; Höhne, C; Igo, G; Jacobs, P; Jones, P G; Kadija, K; Kolesnikov, V I; Kollegger, T; Kowalski, M; Kraus, I; Kreps, M; Lasiuk, B; Van Leeuwen, M; Lévai, Peter; Malakhov, A I; Margetis, S; Markert, C; Mayes, B W; Melkumov, G L; Mischke, A; Molnár, J; Nelson, J M; Odyniec, Grazyna Janina; Oldenburg, M; Pálla, G; Panagiotou, A D; Perl, K; Petridis, A; Pikna, M; Pinsky, L; Poskanzer, A M; Prindle, D J; Pühlhofer, F; Putschke, J; Reid, J G; Renfordt, A; Retyk, W; Ritter, H G; Röhrich, D; Roland, C; Roland, G; Rybicki, A; Sammer, T; Sann, H; Schäfer, E; Schmitz, N; Seyboth, P; Siklér, F; Sitár, B; Skrzypczak, E; Snellings, R; Squier, G T A; Stock, Reinhard; Ströbele, H; Susa, T; Szentpétery, I; Sziklai, J; Toy, M; Trainor, T A; Trentalange, S; Ullrich, T S; Varga, D; Vassiliou, Maria; Veres, G I; Vesztergombi, G; Voloshin, S A; Vranic, D; Wang, F; Weerasundara, D D; Wenig, S; Wetzler, A; Whitten, C; Xu, N; Yates, T A; Koo, I K; Zaranek, J; Zimányi, J

    2002-01-01

    Recent results of the NA49 experiment are presented. These cover first results on pion and kaon production, HBT, and charge fluctuations from Pb+Pb reactions at 40 AGeV and their comparison to 158 AGeV beam energy. Furthermore a study on baryon number transfer in p+p, centrality selected p+Pb and Pb+Pb collisions at 158 AGeV and new results on the system size dependence of kaon yields, including C+C and Si+Si data, are presented. Additionally, a first result on Lambda Lambda correlations is shown. (11 refs).

  9. Retirement Applicant Satisfaction Survey Results

    Data.gov (United States)

    Social Security Administration — This dataset contains information about the Retirement Applicant Survey (RAS). The survey measured satisfaction results with the retirement application process. The...

  10. Recent physics results from LEP

    International Nuclear Information System (INIS)

    Augustin, J.E.

    1990-12-01

    The LEP machine operations, the recent observation of transverse beam polarization, and the luminosity measurements are summarized. The results obtained up to now on the tests of the electroweak sector of the Standard Model are reviewed. This includes the Z neutral boson excitation curve parameters in hadronic and leptonic modes, the forward-backward asymmetries of the leptons, the detection of the polarization of the taus, and the corresponding results on the number of light neutrinos, on the electroweak coupling constants and mixing angle, and on the top quark mass. Some hadronic physics results and QCD studies are reported. The results for particle searches, notably the Higgs boson are summarized

  11. Heavy ion results from ATLAS

    CERN Document Server

    AUTHOR|(INSPIRE)INSPIRE-00241915; The ATLAS collaboration

    2017-01-01

    These proceedings provide an overview of the new results obtained with the ATLAS Detector at the LHC, which are presented in the Quark Matter 2017 conference. These results are covered in twelve parallel talks, one flash talk and eleven posters, and they are grouped into five areas: initial state, jet quenching, quarkonium production, longitudinal flow dynamics, and collectivity in small systems.

  12. FORWARD PHYSICS AND BRAHMS RESULTS.

    Energy Technology Data Exchange (ETDEWEB)

    DEBBE, R.; (FOR THE BRAHMS COLLABORATION)

    2005-02-03

    We report here the BRAHMS measurements of particle production in d+Au and p+p collisions at RHIC. The results presented here are compared to previous p+A measurements at lower energies in fixed target mode. Some preliminary results on abundances of identified particles at high rapidity are also presented.

  13. Possible distortion of autoradiographic results

    Energy Technology Data Exchange (ETDEWEB)

    Kozlov, A.A.; Tumanushvili, G.D. (AN Gruzinskoj SSR, Tbilisi. Inst. Ehksperimental' noj Morfologii)

    1980-01-01

    The effect of radioactive labelling (H/sup 3/-thymidine) on the infusorian division is studied. The presented results show that introduction of labelled compounds results in accelerating infusorian cell division v. Thorough investigation of labelled compound effect with low activity on the parameters of cell division and the search of methods to eliminate distortions able to appear in autoradiographic experiments is expedient.

  14. CDF results on B decays

    International Nuclear Information System (INIS)

    Skarha, J.E.

    1995-05-01

    The authors present recent CDF results on B lifetimes, B meson mass measurements, ratios of branching ratios, and rare decays. In addition, they present the first measurement of time-dependent B d mixing at CDF. Several results have been updated and a few new ones included since the workshop

  15. RESULTS, RESPONSIBILITY, FAULT AND CONTROL

    Directory of Open Access Journals (Sweden)

    Evgeniy Stoyanov

    2016-09-01

    Full Text Available The paper focuses on the responsibility arising from the registered financial results. The analysis of this responsibility presupposes its evaluation and determination of the role of fault in the formation of negative results. The search for efficiency in this whole process is justified by the understanding of the mechanisms that regulate the behavior of economic actors.

  16. First neutron results from SNS

    International Nuclear Information System (INIS)

    Leadbetter, A.J.; Abbley, D.; Bailey, I.F.

    1985-05-01

    The report summarises the analyses of the first neutron results on the pulsed spallation source SNS. The source parameters; aspects of the instrumentation; and experimental results particular to a given beamline; are all discussed. General conclusions based on these data, the detectors and the computing system, are also examined. (U.K.)

  17. Graphical presentation of participants' results

    International Nuclear Information System (INIS)

    Anon.

    1991-01-01

    The results obtained by 19 participating dosimetry systems are presented in this section. Section 3 of the preceding report, ''Evaluation of the Results of the First IAEA Coordinated Research Program on Intercomparison for Individual Monitoring'', explains the format and conventions used for the graphical presentation. The system number appearing in the upper left hand corner of each page can be used to correlate the dosimeter design information found in Table 2 of the preceding report with the results. However, care should be used in drawing inferences from this correlation, since system performance depends on a number of factors other than detector selection and design characteristics. (orig.)

  18. Customer interruption cost and results

    Energy Technology Data Exchange (ETDEWEB)

    Eua-Arporn, B.; Bisarnbutra, S. [Chulalongkorn Univ., Bangkok (Thailand)

    1997-12-31

    Results of a comprehensive study on short-term direct impacts and consumer interruption costs, incurred as a result of power supply interruption, were discussed. The emphasis was on questionnaire development, general responses and the average customer damage function of some selected sectors. The customer damage function was established for each category of customers (agriculture, industry, mining, wholesale, retail merchandising, residential, etc) as well as for different locations. Results showed that the average customer damage function depended mostly on customer category. Size and location were not significant factors. 5 refs., 7 tabs.

  19. Solar neutrino results from SAGE

    International Nuclear Information System (INIS)

    Gavrin, V.N.

    1999-01-01

    We report the status of the Russian-American Gallium solar neutrino Experiment (SAGE). The solar neutrino result for SAGE III, 20 runs during the measuring period May 1995 through December 1997, is 56.7 +9.3/-8.7(stat.)+4.6/-4.8(syst.) SNU. The combined result for 57 measurements from 1990 through 1997 (SAGE I+II+III) is 66.9 +7.1/-6.8 (stat) +5.4/-5.7 (syst) SNU. The final result of the SAGE 51 Cr experiment to check the response of SAGE to low energy neutrinos is also presented

  20. Cell emulation and preliminary results.

    Science.gov (United States)

    2016-07-01

    This report details preliminary results of the testing plan implemented by the Hawaii Natural Energy Institute to evaluate Electric Vehicle (EV) battery durability and reliability under electric utility grid operations. Commercial EV battery cells ar...

  1. New results from old spectroscopy

    International Nuclear Information System (INIS)

    Hemingway, R.J.

    1977-01-01

    A report is presented of some of the major experimental results during the last year in the field of old spectroscopy. Included are properties, quark model, multiplets, particle interactions, and cross sections. 34 references

  2. Electroweak results from the tevatron

    International Nuclear Information System (INIS)

    Wood, D.

    1997-01-01

    Electroweak results are presented from the CDF and DO experiments based on data collected in recent runs of the Fermilab Tevatron Collider. The measurements include the mass and width of the W boson, the production cross sections of the W and Z bosons, and the W charge asymmetry. Additional results come from studies of events with pairs of electroweak gauge bosons and include limits on anomalous couplings

  3. Electroweak results from the tevatron

    Energy Technology Data Exchange (ETDEWEB)

    Wood, D. [Fermi National Accelerator Laboratory, Batavia, IL (United States)

    1997-01-01

    Electroweak results are presented from the CDF and DO experiments based on data collected in recent runs of the Fermilab Tevatron Collider. The measurements include the mass and width of the W boson, the production cross sections of the W and Z bosons, and the W charge asymmetry. Additional results come from studies of events with pairs of electroweak gauge bosons and include limits on anomalous couplings.

  4. Consolidated results 2000. Forecasts 2001

    International Nuclear Information System (INIS)

    2001-01-01

    This document presents an economic analysis of the Group Gaz De France consolidated results for the year 2000. The main topics are the evolution of the energy market, the great economic growth for the five businesses of the Group (exploration-production, trade, transport, distribution and services), financial results affected by the supply costs increase, the position reinforcement among the gas leaders in Europe and the highlights of 2000. (A.L.B.)

  5. Planck 2013 results. I. Overview of products and scientific results

    CERN Document Server

    Ade, P.A.R.; Armitage-Caplan, C.; Arnaud, M.; Ashdown, M.; Atrio-Barandela, F.; Aumont, J.; Baccigalupi, C.; Banday, A.J.; Barreiro, R.B.; Bartelmann, M.; Bartlett, J.G.; Battaner, E.; Benabed, K.; Benoit, A.; Benoit-Levy, A.; Bernard, J.P.; Bersanelli, M.; Bielewicz, P.; Bobin, J.; Bock, J.J.; Bonaldi, A.; Bond, J.R.; Borrill, J.; Bouchet, F.R.; Boulanger, F.; Bowyer, J.W.; Bridges, M.; Bucher, M.; Burigana, C.; Butler, R.C.; Cappellini, B.; Cardoso, J.F.; Carr, R.; Casale, M.; Catalano, A.; Challinor, A.; Chamballu, A.; Chary, R.R.; Chen, X.; Chiang, L.Y.; Chiang, H.C.; Christensen, P.R.; Church, S.; Clements, D.L.; Colombi, S.; Colombo, L.P.L.; Couchot, F.; Coulais, A.; Crill, B.P.; Curto, A.; Cuttaia, F.; Danese, L.; Davies, R.D.; Davis, R.J.; de Bernardis, P.; de Rosa, A.; de Zotti, G.; Delabrouille, J.; Delouis, J.M.; Desert, F.X.; Dickinson, C.; Diego, J.M.; Dole, H.; Donzelli, S.; Dore, O.; Douspis, M.; Dunkley, J.; Dupac, X.; Efstathiou, G.; Ensslin, T.A.; Eriksen, H.K.; Falgarone, E.; Finelli, F.; Foley, S.; Forni, O.; Frailis, M.; Franceschi, E.; Freschi, M.; Fromenteau, S.; Gaier, T.C.; Galeotta, S.; Gallegos, J.; Gandolfo, B.; Ganga, K.; Giard, M.; Giardino, G.; Giraud-Heraud, Y.; Gonzalez-Nuevo, J.; Gorski, K.M.; Gratton, S.; Gregorio, A.; Gruppuso, A.; Haissinski, J.; Hansen, F.K.; Hanson, D.; Harrison, D.; Helou, G.; Henrot-Versille, S.; Hernandez-Monteagudo, C.; Herranz, D.; Hildebrandt, S.R.; Hivon, E.; Hobson, M.; Holmes, W.A.; Hornstrup, A.; Hovest, W.; Huffenberger, K.M.; Jaffe, T.R.; Jaffe, A.H.; Jewell, J.; Jones, W.C.; Juvela, M.; Kangaslahti, P.; Keihanen, E.; Keskitalo, R.; Kisner, T.S.; Kneissl, R.; Knoche, J.; Knox, L.; Kunz, M.; Kurki-Suonio, H.; Lagache, G.; Lahteenmaki, A.; Lamarre, J.M.; Lasenby, A.; Laureijs, R.J.; Lawrence, C.R.; Le Jeune, M.; Leach, S.; Leahy, J.P.; Leonardi, R.; Leon-Tavares, J.; Leroy, C.; Lesgourgues, J.; Liguori, M.; Lilje, P.B.; Linden-Vornle, M.; Lopez-Caniego, M.; Lowe, S.; Lubin, P.M.; Macias-Perez, J.F.; Maffei, B.; Maino, D.; Mandolesi, N.; Maris, M.; Marshall, D.J.; Martin, P.G.; Martinez-Gonzalez, E.; Masi, S.; Matarrese, S.; Matthai, F.; Mazzotta, P.; McDonald, A.; McGehee, P.; Meinhold, P.R.; Melchiorri, A.; Melin, J.B.; Mendes, L.; Mennella, A.; Migliaccio, M.; Miniscalco, R.; Mitra, S.; Miville-Deschenes, M.A.; Moneti, A.; Montier, L.; Morgante, G.; Mortlock, D.; Moss, A.; Munshi, D.; Murphy, J.A.; Naselsky, P.; Nati, F.; Natoli, P.; Netterfield, C.B.; Norgaard-Nielsen, H.U.; North, C.; Noviello, F.; Novikov, D.; Novikov, I.; O'Dwyer, I.J.; Osborne, S.; Oxborrow, C.A.; Paci, F.; Pagano, L.; Pajot, F.; Paladini, R.; Paoletti, D.; Partridge, B.; Pasian, F.; Patanchon, G.; Pearson, D.; Pearson, T.J.; Perdereau, O.; Perotto, L.; Perrotta, F.; Piacentini, F.; Piat, M.; Pierpaoli, E.; Pietrobon, D.; Plaszczynski, S.; Platania, P.; Pointecouteau, E.; Polenta, G.; Ponthieu, N.; Popa, L.; Poutanen, T.; Pratt, G.W.; Prezeau, G.; Prunet, S.; Puget, J.L.; Rachen, J.P.; Reach, W.T.; Rebolo, R.; Reinecke, M.; Remazeilles, M.; Renault, C.; Ricciardi, S.; Riller, T.; Ringeval, C.; Ristorcelli, I.; Rocha, G.; Rosset, C.; Rossetti, M.; Roudier, G.; Rowan-Robinson, M.; Rubino-Martin, J.A.; Rusholme, B.; Salerno, E.; Sandri, M.; Santos, D.; Savini, G.; Scott, D.; Seiffert, M.D.; Shellard, E.P.S.; Smoot, G.F.; Spencer, L.D.; Starck, J.L.; Stolyarov, V.; Stompor, R.; Sudiwala, R.; Sunyaev, R.; Sureau, F.; Sutton, D.; Suur-Uski, A.S.; Sygnet, J.F.; Tauber, J.A.; Tavagnacco, D.; Taylor, D.; Terenzi, L.; Texier, D.; Toffolatti, L.; Tomasi, M.; Tristram, M.; Tucci, M.; Tuovinen, J.; Turler, M.; Tuttlebee, M.; Umana, G.; Valenziano, L.; Valiviita, J.; Van Tent, B.; Varis, J.; Vibert, L.; Vielva, P.; Villa, F.; Vittorio, N.; Wade, L.A.; Wandelt, B.D.; Watson, R.; Watson, C.; White, M.; White, S.D.M.; Wilkinson, A.; Yvon, D.; Zacchei, A.; Zonca, A.

    2014-01-01

    The ESA's Planck satellite, dedicated to studying the early universe, was launched on May 2009 and has been surveying the microwave and submillimetre sky since August 2009. In March 2013, ESA and the Planck Collaboration publicly released the initial cosmology products based on the first 15.5 months of Planck operations, along with a set of scientific and technical papers and a web-based explanatory supplement. This paper describes the mission and its performance, and gives an overview of the processing and analysis of the data, the characteristics of the data, the main scientific results, and the science data products and papers in the release. Scientific results include robust support for the standard, six parameter LCDM model of cosmology and improved measurements for the parameters that define this model, including a highly significant deviation from scale invariance of the primordial power spectrum. The Planck values for some of these parameters and others derived from them are significantly different fr...

  6. Planck 2015 results: I. Overview of products and scientific results

    DEFF Research Database (Denmark)

    Adam, R.; Ade, P. A R; Aghanim, N.

    2016-01-01

    Collaboration released the second set of cosmology products based ondata from the entire Planck mission, including both temperature and polarization, along with a set of scientific and technical papers and a web-based explanatory supplement. This paper gives an overview of the main characteristics of the data...... and the data products in the release, as well as the associated cosmological and astrophysical science results and papers. The data products include maps of the cosmic microwave background (CMB), the thermal Sunyaev-Zeldovich effect, diffuse foregrounds in temperature and polarization, catalogues of compact...... against the Planck data is described, along with a CMB lensing likelihood. Scientific results include cosmological parameters derived from CMB power spectra, gravitational lensing, and cluster counts, as well as constraints on inflation, non-Gaussianity, primordial magnetic fields, dark energy...

  7. Planck 2013 results. I. Overview of products and scientific results

    DEFF Research Database (Denmark)

    Planck Collaboration,; Ade, P. A. R.; Aghanim, N.

    2013-01-01

    , and the science data products and papers in the release. Scientific results include robust support for the standard, six parameter LCDM model of cosmology and improved measurements for the parameters that define this model, including a highly significant deviation from scale invariance of the primordial power......The ESA's Planck satellite, dedicated to studying the early universe, was launched on May 2009 and has been surveying the microwave and submillimetre sky since August 2009. In March 2013, ESA and the Planck Collaboration publicly released the initial cosmology products based on the first 15.......5 months of Planck operations, along with a set of scientific and technical papers and a web-based explanatory supplement. This paper describes the mission and its performance, and gives an overview of the processing and analysis of the data, the characteristics of the data, the main scientific results...

  8. Automated, computer interpreted radioimmunoassay results

    International Nuclear Information System (INIS)

    Hill, J.C.; Nagle, C.E.; Dworkin, H.J.; Fink-Bennett, D.; Freitas, J.E.; Wetzel, R.; Sawyer, N.; Ferry, D.; Hershberger, D.

    1984-01-01

    90,000 Radioimmunoassay results have been interpreted and transcribed automatically using software developed for use on a Hewlett Packard Model 1000 mini-computer system with conventional dot matrix printers. The computer program correlates the results of a combination of assays, interprets them and prints a report ready for physician review and signature within minutes of completion of the assay. The authors designed and wrote a computer program to query their patient data base for radioassay laboratory results and to produce a computer generated interpretation of these results using an algorithm that produces normal and abnormal interpretives. Their laboratory assays 50,000 patient samples each year using 28 different radioassays. Of these 85% have been interpreted using our computer program. Allowances are made for drug and patient history and individualized reports are generated with regard to the patients age and sex. Finalization of reports is still subject to change by the nuclear physician at the time of final review. Automated, computerized interpretations have realized cost savings through reduced personnel and personnel time and provided uniformity of the interpretations among the five physicians. Prior to computerization of interpretations, all radioassay results had to be dictated and reviewed for signing by one of the resident or staff physicians. Turn around times for reports prior to the automated computer program generally were two to three days. Whereas, the computerized interpret system allows reports to generally be issued the day assays are completed

  9. Presentation of economic evaluation results.

    Science.gov (United States)

    Chaikledkaew, Usa

    2014-05-01

    The first HTA guidelines for Thailand included a chapter outlining a set of guidelines on how best to report the findings of health economic evaluations, based on a review of best practice and existing guidelines on the presentation of economic evaluation results from around the world. In this second edition of HTA guidelines for Thailand, the recommendations build on the first edition by using a case study to illustrate how the guidelines can be applied in a real research context. The guidelines propose that all reporting include ten key elements: defining the scope of the study, selection of comparator(s), defining the type of economic evaluation, measurement of costs, measurement of clinical effects, handling time in economic evaluation studies, handling uncertainty and sensitivity analysis, presentation of the results, discussion of the results, and disclosure of funding and authors conflict of interest.

  10. Recent results from hadron colliders

    International Nuclear Information System (INIS)

    Frisch, H.J.

    1990-01-01

    This is a summary of some of the many recent results from the CERN and Fermilab colliders, presented for an audience of nuclear, medium-energy, and elementary particle physicists. The topics are jets and QCD at very high energies, precision measurements of electroweak parameters, the remarkably heavy top quark, and new results on the detection of the large flux of B mesons produced at these machines. A summary and some comments on the bright prospects for the future of hadron colliders conclude the talk. 39 refs., 44 figs., 3 tabs

  11. First results from SAGE II

    International Nuclear Information System (INIS)

    Abdurashitov, J.N.; Faizov, E.L.; Gavrin, V.N.

    1994-01-01

    The Russian-American Gallium solar neutrino Experiment (SAGE) began the second phase of operation (SAGE II) in September of 1992. Monthly measurements of the integral flux of solar neutrinos have been made with 55 tonnes of gallium. The K-peak results of the first five runs of SAGE II give a capture rate of 76 -18 +21 (stat) -7 +5 (sys) SNU. combined with the SAGE I result, the capture rate is 74 -12 +13 (stat) -7 +5 (sys) SNU. This represents only 56%--60% of the capture rate predicted by different Standard Solar Models

  12. Impossibility results for distributed computing

    CERN Document Server

    Attiya, Hagit

    2014-01-01

    To understand the power of distributed systems, it is necessary to understand their inherent limitations: what problems cannot be solved in particular systems, or without sufficient resources (such as time or space). This book presents key techniques for proving such impossibility results and applies them to a variety of different problems in a variety of different system models. Insights gained from these results are highlighted, aspects of a problem that make it difficult are isolated, features of an architecture that make it inadequate for solving certain problems efficiently are identified

  13. Turning Science Results into News

    Science.gov (United States)

    Wanjek, Christopher

    2006-09-01

    Do you want to get into the New York Times? Aside from writing an angry letter or robbing a bank, getting into the news (with your science result) requires a well-crafted press release. Reaching out to reporters is very different from reaching out to fellow scientists. Scientific significance is not the same as newsworthiness, but many science results can be molded into interesting stories that reporters can relate to their audience. This presentation will present examples of science stories that made it big and some that flopped. We will also examine what makes a story attractive to newspaper and magazine editors.

  14. Communicating Performance Assessments Results - 13609

    International Nuclear Information System (INIS)

    Layton, Mark

    2013-01-01

    The F-Area Tank Farms (FTF) and H-Area Tank Farm (HTF) are owned by the U.S. Department of Energy (DOE) and operated by Savannah River Remediation LLC (SRR), Liquid Waste Operations contractor at DOE's Savannah River Site (SRS). The FTF and HTF are active radioactive waste storage and treatment facilities consisting of 51 carbon steel waste tanks and ancillary equipment such as transfer lines, evaporators and pump tanks. Performance Assessments (PAs) for each Tank Farm have been prepared to support the eventual closure of the underground radioactive waste tanks and ancillary equipment. PAs provide the technical bases and results to be used in subsequent documents to demonstrate compliance with the pertinent requirements for final closure of the Tank Farms. The Tank Farms are subject to a number of regulatory requirements. The State regulates Tank Farm operations through an industrial waste water permit and through a Federal Facility Agreement approved by the State, DOE and the Environmental Protection Agency (EPA). Closure documentation will include State-approved Tank Farm Closure Plans and tank-specific closure modules utilizing information from the PAs. For this reason, the State of South Carolina and the EPA must be involved in the performance assessment review process. The residual material remaining after tank cleaning is also subject to reclassification prior to closure via a waste determination pursuant to Section 3116 of the Ronald W. Reagan National Defense Authorization Act of Fiscal Year 2005. PAs are performance-based, risk-informed analyses of the fate and transport of FTF and HTF residual wastes following final closure of the Tank Farms. Since the PAs serve as the primary risk assessment tools in evaluating readiness for closure, it is vital that PA conclusions be communicated effectively. In the course of developing the FTF and HTF PAs, several lessons learned have emerged regarding communicating PA results. When communicating PA results it is

  15. Experimental results surprise quantum theory

    International Nuclear Information System (INIS)

    White, C.

    1986-01-01

    Interest in results from Darmstadt that positron-electron pairs are created in nuclei with high atomic numbers (in the Z range from 180-188) lies in the occurrence of a quantized positron kinetic energy peak at 300. The results lend substance to the contention of Erich Bagge that the traditionally accepted symmetries in positron-electron emission do not exist and, therefore, there is no need to posit the existence of the neutrino. The search is on for the decay of a previously unknown boson to account for the findings, which also points to the need for a major revision in quantum theory. 1 figure

  16. First results from SAGE II

    International Nuclear Information System (INIS)

    Aburashitov, J.N.; Faizov, E.L.; Gavrin, V.N.; Gusev, A.O.; Kalikhov, A.V.; Knodel, T.V.; Knyshenko, I.I.; Kornoukhov, V.N.; Mirmov, I.N.; Pshukov, A.M.; Shalagin, A.M.; Shikhin, A.A.; Timofeyev, P.V.; Veretenkin, E.P.; Vermul, V.M.; Zatsepin, G.T.; Bowles, T.J.; Nico, J.S.; Teasdale, W.A.; Wark, D.L.; Wilkerson, J.F.; Cleveland, B.T.; Daily, T.; Davis, R. Jr.; Lande, K.; Lee, C.K.; Wildenhain, P.W.; Elliott, S.R.; Cherry, M.L.

    1995-01-01

    The Russian-American Gallium solar neutrino Experiment (SAGE) began the second phase of operation (SAGE II) in September of 1992. Monthly measurements of the integral flux of solar neutrinos have been made with 55 tonnes of gallium. The K-peak results of the first five runs of SAGE II give a capture rate of 76 +21 -18 (stat) +5 -7 (sys) SNU. Combined with the SAGE I result, the capture rate is 74 +13 -12 (stat) +5 -7 (sys) SNU. This represents only 56%--60% of the capture rate predicted by different Standard Solar Models. copyright 1995 American Institute of Physics

  17. Results from Numerical General Relativity

    Science.gov (United States)

    Baker, John G.

    2011-01-01

    For several years numerical simulations have been revealing the details of general relativity's predictions for the dynamical interactions of merging black holes. I will review what has been learned of the rich phenomenology of these mergers and the resulting gravitational wave signatures. These wave forms provide a potentially observable record of the powerful astronomical events, a central target of gravitational wave astronomy. Asymmetric radiation can produce a thrust on the system which may accelerate the single black hole resulting from the merger to high relative velocity.

  18. Recent Results from the Tevatron

    International Nuclear Information System (INIS)

    Demorden, L.

    1998-06-01

    We review recent results from fixed-target and collider experiments at the Fermilab Tevatron. Among the topics discussed are jet production rates, α S measurements, the anti d/anti u ratio in the proton sea, diffraction, heavy quark physics and leptoquark searches

  19. New ATLAS Higgs physics results

    CERN Multimedia

    CERN. Geneva

    2014-01-01

    New Higgs physics results from the ATLAS experiment using the full Run-1 LHC dataset, corresponding to an integrated luminosity of approximately 25 fb-1, of proton-proton collisions at 7 TeV and 8 TeV, will be presented.

  20. FFTF startup: status and results

    International Nuclear Information System (INIS)

    Noordhoff, B.H.; Moore, C.E.

    1980-03-01

    Startup testing on the Fast Flux Test Facility (FFTF) during the past three years has progressed beyond initial criticality toward the principal goal of power demonstration in 1980. An overview is presented of technical results to date and project plans to achieve power demonstration and complete the startup test program

  1. Recent results on howard's algorithm

    DEFF Research Database (Denmark)

    Miltersen, P.B.

    2012-01-01

    is generally recognized as fast in practice, until recently, its worst case time complexity was poorly understood. However, a surge of results since 2009 has led us to a much more satisfactory understanding of the worst case time complexity of the algorithm in the various settings in which it applies...

  2. Latest results from EXO-200

    International Nuclear Information System (INIS)

    TOSI, D.

    2014-01-01

    The Enriched Xenon Observatory (EXO) is an experimental program searching for neutrino-less double beta decay in xenon-136. The first stage of this program, EXO-200, has been in operation since early 2011. I present here the latest physics results from the experiment.

  3. LHCb time-dependent results

    OpenAIRE

    Calvi, Marta

    2011-01-01

    This review reports preliminary results of time-dependent measurements of decays of $B^0$ mesons and $B^0_s$ mesons coming from the analysis of about 36 pb$^{-1}$ of data collected by the LHCb experiment during the 2010 run of the Large Hadron Collider at $\\sqrt{s}$ = 7 TeV.

  4. LHCb time-dependent results

    OpenAIRE

    Calvi, Marta; Collaboration, for the LHCb

    2011-01-01

    This review reports preliminary results of time-dependent measurements of decays of B^0 mesons and B^0_s mesons coming from the analysis of about 36 pb^-1 of data collected by the LHCb experiment during the 2010 run of the Large Hadron Collider at sqrt(s)=7 TeV.

  5. Report of scientific results 1977

    International Nuclear Information System (INIS)

    1977-01-01

    The scientific progress report of the HMI for 1977 gives a survey of the main results of HMI research in the fields of neutron scattering, radiation damage in solids, reactor chemistry, trace element research in biomedicine, geochemistry, reactor operation, and radionuclide production. After this, short summaries are given of HMI publications and papers in the above fields. (HK) [de

  6. STANFORD (SLAC): Precision electroweak result

    International Nuclear Information System (INIS)

    Anon.

    1994-01-01

    Precision testing of the electroweak sector of the Standard Model has intensified with the recent publication* of results from the SLD collaboration's 1993 run on the Stanford Linear Collider, SLC. Using a highly polarized electron beam colliding with an unpolarized positron beam, SLD physicists measured the left-right asymmetry at the Z boson resonance with dramatically improved accuracy over 1992

  7. HADES results in elementary reactions

    Directory of Open Access Journals (Sweden)

    Ramstein B.

    2014-01-01

    Full Text Available Recent results obtained with the HADES experimental set-up at GSI are presented with a focus on dielectron production and strangeness in pp and quasi-free np reactions. Perspectives related to the very recent experiment using the pion beam at GSI are also discussed.

  8. Latest results from B factories

    CERN Document Server

    Ben Haim, Eli

    2015-01-01

    I will briefly review recent results from Babar and Belle. For example, I will discuss probes for new physics in radiative penguin decays and the CP asymmetry in B0-B0bar mixing. I will also discuss direct searches for new physics, such as a light Higgs resonance or long lived particles.

  9. Electroweak results from hadron colliders

    International Nuclear Information System (INIS)

    Demarteau, Marcel

    1997-01-01

    A review of recent electroweak results from hadron colliders is given. Properties of the W ± and Z 0 gauge bosons using final states containing electrons and muons based on large integrated luminosities are presented. The emphasis is placed on the measurement of the mass of the W boson and the measurement of trilinear gauge boson couplings

  10. Juridical utilization of dosimetric results

    International Nuclear Information System (INIS)

    Hebert, J.

    1976-01-01

    The problems of the legal use of the results of dosimetry, for the solution of an action for instance, are considered first with respect to civil and occasionally administrative third part liability law making a distinction between common law and the special regime of civil liability for nuclear damage, secondly with respect to social security law [fr

  11. Recent results from DORIS II

    International Nuclear Information System (INIS)

    Bloom, E.D.

    1985-01-01

    This report contains a brief review of recent results from the ARGUS and Crystal Ball experiments at DORIS II, concentrating on UPSILON(1S) and UPSILON(2S) spectroscopy with a short foray into γγ physics. 18 refs., 10 figs

  12. CMS results on soft diffraction

    CERN Document Server

    INSPIRE-00086121

    2013-01-01

    We present measurements of soft single- and double-diffractive cross sections, as well as of forward rapidity gap cross sections at 7 TeV at the LHC, and compare the results to other measurements and to theoretical predictions implemented in various Monte Carlo simulations.

  13. Experimental results obtained at GANIL

    International Nuclear Information System (INIS)

    Borrel, V.

    1993-01-01

    A review of experimental results obtained at GANIL on the study of nuclear structure and nuclear reactions with secondary radioactive beams is presented. Mass measurements by means of the GANIL cyclotrons are described. The possibilities of GANIL/LISE3 for the production and separation of radioactive beams are illustrated through a large variety of experiments. (author). 19 refs., 8 figs

  14. Complexity Results in Epistemic Planning

    DEFF Research Database (Denmark)

    Bolander, Thomas; Jensen, Martin Holm; Schwarzentruber, Francois

    2015-01-01

    Epistemic planning is a very expressive framework that extends automated planning by the incorporation of dynamic epistemic logic (DEL). We provide complexity results on the plan existence problem for multi-agent planning tasks, focusing on purely epistemic actions with propositional preconditions...

  15. Stability of Global Geodetic Results

    Science.gov (United States)

    Herring, T.

    The precision of global geodetic techniques has reached unprecedented levels. Sys- tems capable of millimeter level horizontal and several millimeter vertical precisions are now deployed. The Global Positioning System (GPS) has the most deployed continuously-operating receivers with several hundred providing data through the in- ternet for analysis. However, the satellite system used with GPS evolves with time as new generations of GPS satellites are launched. During the 1990's, the constellation evolved from Block I to Block II and IIA with the most recent generation being Block IIR. There are considerable differences in the size and antenna configurations in the different generations of satellites. The antenna configuration specifically could cause systematic changes in the terrestrial reference system. Results from the ITRF2000 combinations suggest that there are significant time variations in the scale of GPS system possibly due to phase center variations in GPS transmission antennas. These variations could result in height changes of up to 3 mm/yr. We will investigate the stability of the GPS system through combination of GPS results with results from VLBI and SLR. All components of the transformation between the systems, rotation, translation and scale will be investigated.

  16. Recent results in strangeonium spectroscopy

    International Nuclear Information System (INIS)

    Aston, D.; Awaji, N.; Bienz, T.

    1988-10-01

    Data from exclusive s/bar s/ meson final states are shown. The data were obtained in a 4.1 ev/nb exposure of K - p interactions at 11 GeV/c in the LASS spectrometer at SLAC. The results from the analyses of these data is presented and the spectrum of strangeonium states is discussed. 8 refs., 8 figs

  17. New results from cosmic rays

    Energy Technology Data Exchange (ETDEWEB)

    Tonwar, S. C.

    1980-07-01

    Behavior of elementary particles at very high energies and new phenomena observed are discussed in the light of results obtained by cosmic ray studies. Methods of determining hadron-nucleus inelastic cross-sections are described. Proton energy spectra are studied at 2000-50,000 GeV and the hadron-proton total cross section is deduced. Measurement of the cross-section by measurement of the intensity of transition radiation is described. The instrumental effects and the corrections effected are mentioned. The results obtained by different groups of investigators are compared. Observations on the scaling violation at high energies are reported. New particles or phenomena observed include: (i) the long flying component (ii) centauro events, (iii) delayed particles (iv) high energy cascades in underground experiments and (v) charm hadron production in hadron collisions. New experiments being planned for further research are mentioned.

  18. First Physics Results from ALICE

    International Nuclear Information System (INIS)

    Peressounko, Dmitri; Castillo Castellanos, Javier; Belikov, Iouri

    2010-01-01

    ALICE is the LHC experiment dedicated to the study of heavy-ion collisions. The main purpose of ALICE is to investigate the properties of a state of deconfined nuclear matter, the Quark Gluon Plasma. Heavy flavour measurements will play a crucial role in this investigation. The physics programme of ALICE has started by studying proton-proton collisions at unprecedented high energies. We will present the first results on open heavy flavour and quarkonia in proton-proton collisions at √s = 7 TeV measured by the ALICE experiment at both mid- and forward-rapidities. We will conclude with the prospects for heavy flavour and quarkonium measurements in both proton-proton and nucleus-nucleus collisions. Also presented are first results of neutral meson reconstruction and its perspectives, as well as further physics studies. (author)

  19. Summary of CCTF test results

    International Nuclear Information System (INIS)

    Iguchi, T.; Murao, Y.; Sugimoto, J.; Akimoto, H.; Okubo, T.; Hojo, T.

    1987-01-01

    Conservatism of current safety analysis was assessed by comparing the predicted result with cylindrical core test facility (CCTF) test result performed at Japan Atomic Energy Research Institute. WREM code was selected for the assessment. The overall conservatism of the WREM code on the peak clad temperature prediction was confirmed against CCTF evaluation model (EM) test which simulated the typical initial and boundary conditions in the safety evaluation analysis. WREM code predicted the reasonable core boundary conditions and the conservatism of the code came mainly from core calculation. The conservatism of the WREM code against CCTF data could be attributed to the following three points: (1) no horizontal mixing assumption between subchannels at each elevation; (2) no modeling on heat transfer enhancement caused by the radial core power profile; and (3) conservative heat transfer correlations in the code

  20. Communicating Performance Assessments Results - 13609

    Energy Technology Data Exchange (ETDEWEB)

    Layton, Mark [Savannah River Remediation LLC, Building 705-1C, Aiken, SC 29808 (United States)

    2013-07-01

    The F-Area Tank Farms (FTF) and H-Area Tank Farm (HTF) are owned by the U.S. Department of Energy (DOE) and operated by Savannah River Remediation LLC (SRR), Liquid Waste Operations contractor at DOE's Savannah River Site (SRS). The FTF and HTF are active radioactive waste storage and treatment facilities consisting of 51 carbon steel waste tanks and ancillary equipment such as transfer lines, evaporators and pump tanks. Performance Assessments (PAs) for each Tank Farm have been prepared to support the eventual closure of the underground radioactive waste tanks and ancillary equipment. PAs provide the technical bases and results to be used in subsequent documents to demonstrate compliance with the pertinent requirements for final closure of the Tank Farms. The Tank Farms are subject to a number of regulatory requirements. The State regulates Tank Farm operations through an industrial waste water permit and through a Federal Facility Agreement approved by the State, DOE and the Environmental Protection Agency (EPA). Closure documentation will include State-approved Tank Farm Closure Plans and tank-specific closure modules utilizing information from the PAs. For this reason, the State of South Carolina and the EPA must be involved in the performance assessment review process. The residual material remaining after tank cleaning is also subject to reclassification prior to closure via a waste determination pursuant to Section 3116 of the Ronald W. Reagan National Defense Authorization Act of Fiscal Year 2005. PAs are performance-based, risk-informed analyses of the fate and transport of FTF and HTF residual wastes following final closure of the Tank Farms. Since the PAs serve as the primary risk assessment tools in evaluating readiness for closure, it is vital that PA conclusions be communicated effectively. In the course of developing the FTF and HTF PAs, several lessons learned have emerged regarding communicating PA results. When communicating PA results it is

  1. PREVAIL: latest electron optics results

    Science.gov (United States)

    Pfeiffer, Hans C.; Golladay, Steven D.; Gordon, Michael S.; Kendall, Rodney A.; Lieberman, Jon E.; Rockrohr, James D.; Stickel, Werner; Yamaguchi, Takeshi; Okamoto, Kazuya; Umemoto, Takaaki; Shimizu, Hiroyasu; Kojima, Shinichi; Hamashima, Muneki

    2002-07-01

    The PREVAIL electron optics subsystem developed by IBM has been installed at Nikon's facility in Kumagaya, Japan, for integration into the Nikon commercial EPL stepper. The cornerstone of the electron optics design is the Curvilinear Variable Axis Lens (CVAL) technique originally demonstrated with a proof of concept system. This paper presents the latest experimental results obtained with the electron optical subsystem at Nikon's facility. The results include micrographs illustrating proper CVAL operation through the spatial resolution achieved over the entire optical field of view. They also include data on the most critical issue of the EPL exposure approach: subfield stitching. The methodology of distortion correction will be described and both micrographs and metrology data of stitched subfields will be presented. This paper represents a progress report of the IBM/Nikon alliance activity on EPL.

  2. CMS results on multijet correlations

    CERN Document Server

    INSPIRE-00008500

    2015-04-10

    We present recent measurements of multijet correlations using forward and low-$p_{\\mathrm{T}}$ jets performed by the CMS collaboration at the LHC collider. In pp collisions at $\\sqrt{s} = 7$ TeV, azimuthal correlations in dijets separated in rapidity by up to 9.4 units were measured. The results are compared to BFKL- and DGLAP-based Monte Carlo generator and analytic predictions. In pp collisions at $\\sqrt{s} = 8$ TeV, cross sections for jets with $p_{\\mathrm{T}}$ > 21 GeV and |y| 1 GeV (minijets) are presented. The minijet results are sensitive to the bound imposed by the total inelastic cross section, and are compared to various models for taming the growth of the $2 \\rightarrow 2$ cross section at low $p_{\\mathrm{T}}$.

  3. Forget about data, deliver results

    Science.gov (United States)

    Walter, Roland

    2015-12-01

    High-energy astrophysics space missions have pioneered and demonstrated the power of legacy data sets for generating new discoveries, especially when analysed in ways original researchers could not have anticipated. The only way to ensure that the data of present observatories can be effectively used in the future is to allow users to perform on-the-fly data analysis to produce straightforwardly scientific results for any sky position, time and energy intervals without requiring mission specific software or detailed instrumental knowledge. Providing a straightforward interface to complex data and data analysis makes the data and the process of generating science results available to the public and higher education and promotes the visibility of the investment in science to the society. This is a fundamental step to transmit the values of science and to evolve towards a knowledge society.

  4. Analytical results for Abelian projection

    International Nuclear Information System (INIS)

    Ogilivie, Michael C.

    1999-01-01

    Analytic methods for Abelian projection are developed, and a number of results related to string tension measurements are obtained. It is proven that even without gauge fixing, Abelian projection yields string tensions of the underlying non-Abelian theory. Strong arguments are given for similar results in the case where gauge fixing is employed. The subgroup used for projection need only contain the center of the gauge group, and need not be Abelian. While gauge fixing is shown to be in principle unnecessary for the success of Abelian projection, it is computationally advantageous for the same reasons that improved operators, e.g., the use of fat links, are advantageous in Wilson loop measurements

  5. Marshland study brings fruitful results

    Energy Technology Data Exchange (ETDEWEB)

    1978-03-01

    There are approximately 110,000 square kilometers of marshland in China containing peat and other valuable resources. The results of a marshland study have been presented as a chapter in a book titled Physical Geography of China. In 1970, the Kirin Normal University established an experimental plant for the utilization of peat. Four kinds of peat fertilizers produced by this plant have been used with good results at 20 communes in Kirin Province. Four kinds of construction materials (peat board, peat tiles, peat insulation bricks and peat insulation tubes) were also successfully made. A certain type of peat can be used as fuel to heat malt in the process of whiskey making. New applications of peat have been found in medicine, water purification, and in the manufacturing of electrodes for condensers.

  6. Results on light quark spectroscopy

    International Nuclear Information System (INIS)

    Bienlein, J.K.; Harjes, J.; Kolanoski, H.

    1991-12-01

    This report contains a survey article of resonance production by the Crystal Ball Collaboration from J. K. Bienlein, an article on CELLO results for γγΠ*p* +- - from J. Harjes, a survey article on the production of scalar and tensor mesons in two-photon collisions, and an article on the study of the a 1 resonance by τ decays, the last two articles are both from H. Kolanoski. See hints under the relevant topics. (HSI)

  7. Interatom results for stage 2

    International Nuclear Information System (INIS)

    Coors, D.

    1990-01-01

    This report contains the Interatom results for Stage 2 of the ''IWGFR Programme on Intercomparison of LMFBR Core Mechanics Codes'' which was agreed upon on a Consultants Meeting in Vienna, 8-10 December, 1987. The calculations were performed with the 3D core mechanics code system DDT developed at Interatom and with the 2D core mechanics code FIAT. (author). 5 refs, 11 figs, 8 tabs

  8. Supersymmetry results at the Tevatron

    International Nuclear Information System (INIS)

    Badaud, Frederique

    2007-01-01

    The results for searches for Supersymmetry by the CDF and D0 collaborations in pp-bar collisions at √s=1.96 TeV are presented here. Searches for chargino/neutralino and the lightest stop, as well as scenarios with R-parity violation are focused here. The integrated luminosity analyzed ranges from 300 to 800 pb -1 depending on the search. Further informations can be found on the public web pages of the two experiments. (author)

  9. Recent results from Daya Bay

    Directory of Open Access Journals (Sweden)

    Chua Ming-chung

    2016-01-01

    Full Text Available Utilizing powerful nuclear reactors as antineutrino sources, high mountains to provide ample shielding from cosmic rays in the vicinity, and functionally identical detectors with large target volume for near-far relative measurement, the Daya Bay Reactor Neutrino Experiment has achieved unprecedented precision in measuring the neutrino mixing angle θ13 and the neutrino mass squared difference |Δm2ee|. I will report the latest Daya Bay results on neutrino oscillations and light sterile neutrino search.

  10. Recent DIII-D results

    International Nuclear Information System (INIS)

    Petersen, P.I.

    1994-07-01

    This paper summarizes the recent DIII-D experimental results and the development of the relevant hardware systems. The DIII-D program focuses on divertor solutions for next generation tokamaks such as International Thermo-nuclear Experimental Reactor (ITER) and Tokamak Physics Experiment (TPX), and on developing configurations with enhanced confinement and stability properties that will lead to a more compact and economical fusion reactor. The DIII-D program carries out this research in an integrated fashion

  11. Results from the FDIRC prototype

    Energy Technology Data Exchange (ETDEWEB)

    Roberts, D.A., E-mail: roberts@umd.edu [University of Maryland, College Park, MD 20742 (United States); Arnaud, N. [Laboratoire de l’Accélérateur Linéaire, Centre Scientifique d’Orsay, F-91898 Orsay Cedex (France); Dey, B. [University of California, Riverside, CA 92521 (United States); Borsato, M. [Laboratoire de l’Accélérateur Linéaire, Centre Scientifique d’Orsay, F-91898 Orsay Cedex (France); Leith, D.W.G.S.; Nishimura, K.; Ratcliff, B.N. [SLAC, Stanford University, Palo Alto, CA 94309 (United States); Varner, G. [University of Hawaii, Honolulu, HI 96822 (United States); Va’vra, J. [SLAC, Stanford University, Palo Alto, CA 94309 (United States)

    2014-12-01

    We present results from a novel Cherenkov imaging detector called the Focusing DIRC (FDIRC). This detector was designed as a prototype of the particle identification system for the SuperB experiment, and comprises 1/12 of the SuperB barrel azimuthal coverage with partial electronics implementation. The prototype was tested in the SLAC Cosmic Ray Telescope (CRT) which provides 3-D muon tracking with an angular resolution of ∼1.5 mrad, track position resolution of 5–6 mm, start time resolution of 70 ps, and a muon low-energy cutoff of ∼2 GeV provided by an iron range stack. The quartz focusing photon camera couples to a full-size BaBar DIRC bar box and is read out by 12 Hamamatsu H8500 MaPMTs providing 768 pixels. We used IRS2 waveform digitizing electronics to read out the MaPMTs. We present several results from our on-going development activities that demonstrate that the new optics design works very well, including: (a) single photon Cherenkov angle resolutions with and without chromatic corrections, (b) S/N ratio between the Cherenkov peak and background, which consists primarily of ambiguities in possible photon paths to a given pixel, (c) dTOP=TOP{sub measured}–TOP{sub expected} resolutions, and (d) performance of the detector in the presence of high-rate backgrounds. We also describe data analysis methods and point out limits of the present performance. - Highlights: • We present results from a novel Cherenkov imaging detector called the Focusing DIRC (FDIRC). • The prototype was tested in the SLAC Cosmic Ray Telescope (CRT) which provides 3-D muon tracking. • We present several results from our on-going development activities that demonstrate that new optics design works very well. • We describe data analysis methods and point out limits of the present performance.

  12. Results of recent LOFT experiments

    International Nuclear Information System (INIS)

    Leach, L.P.; Hanson, D.J.; Batt, D.L.

    1982-01-01

    Five experiments were performed in the Loss-of-Fluid Test (LOFT) facility during the past year. The experiments conducted spanned a wide range of potential accident scenarios, including large and small break loss-of-coolant accidents (LOCAs), control rod withdrawal accidents, uncontrolled boron dilution, and anticipated transients without scram (ATWS). This summary describes these experiments and presents results available from the experiments and experiment prediction calculations. A brief overview is given for the remaining experiment planned in the LOFT Program

  13. CMS results on hard diffraction

    CERN Document Server

    INSPIRE-00107098

    2013-01-01

    In these proceedings we present CMS results on hard diffraction. Diffractive dijet production in pp collisions at $\\sqrt{s}$=7 TeV is discussed. The cross section for dijet production is presented as a function of $\\tilde{\\xi}$, representing the fractional momentum loss of the scattered proton in single-diffractive events. The observation of W and Z boson production in events with a large pseudo-rapidity gap is also presented.

  14. First half 2006 financial results

    International Nuclear Information System (INIS)

    2006-09-01

    Areva provides technological solutions for highly reliable nuclear power generation and electricity transmission and distribution. The group is the world leader in nuclear power and the only company to cover all industrial activities in this field. This Press release presents the first half 2006 financial results: the overall performance and the performance by division (front end, reactors and services, back end, transmission and distribution). (A.L.B.)

  15. LHC Results Highlights (CLASHEP 2013)

    CERN Document Server

    Gonzalez, O.

    2015-05-22

    The good performance of the LHC provided enough data at 7 TeV and 8 TeV to allow the experiments to perform very competitive measurements and to expand the knowledge about the fundamental interaction far beyond that from previous colliders. This report summarizes the highlights of the results obtained with these data samples by the four large experiments, covering all the topics of the physics program and focusing on those exploiting the possibilities of the LHC.

  16. Energy conservation. Ambitions and results

    International Nuclear Information System (INIS)

    2011-01-01

    From results of monitoring it is shown that energy conservation in the Netherlands is behind the ambitions of the Dutch government. The Dutch Court of Audit examined the reasons why energy conservation targets are not met and what the consequences are for the national and European energy and climate goals for 2020. Also the Dutch Court of Audit looked at the possibilities to make energy saving policies more effective. [nl

  17. Presentation of RTE results 2003

    International Nuclear Information System (INIS)

    2004-01-01

    For RTE, the financial year 2003 was marked by a number of achievements: our financial performances registered a clear improvement, above objectives, with turnover growing strongly; net income reached levels almost three times higher than those recorded in 2002; the economic rate of return rose to 7.1%; and debt was reduced by 470 Meuros. These results are explained by the substantial improvement in productivity, which has risen by 5% per year on average over the last three years

  18. SPQR - Spectroscopy: Prospects, Questions & Results

    Science.gov (United States)

    Pennington, M. R.

    2014-06-01

    Tremendous progress has been made in mapping out the spectrum of hadrons over the past decade with plans to make further advances in the decade ahead. Baryons and mesons, both expected and unexpected, have been found, the results of precision experiments often with polarized beams, polarized targets and sometimes polarization of the final states. All these hadrons generate poles in the complex energy plane that are consequences of the strong coupling regime of QCD. They reveal how this works.

  19. Audit result and its users

    Directory of Open Access Journals (Sweden)

    Shalimova Nataliya S.

    2014-01-01

    Full Text Available The article identifies essence of the “audit result” and “users of audit result” notions and characteristics of the key audit results user. It shows that in order to give a wide characteristic of users it is expedient to unite all objects, which could be used (audit report, fact of refusal to conduct audit and information that is submitted to managers in the process of audit with the term “audit result” and classify it depending on the terms of submission by final and intermediate result. The article offers to define audit results user as a person, persons or category of persons for whom the auditor prepares the audit report and, in cases, envisaged by international standards of the audit and domestic legislative and regulatory acts, provides other additional information concerning audit issues. In order to identify the key audit results user the article distributes all audit tasks into two groups depending on possibilities of identification of users. The article proves that the key user should be identified especially in cases of a mandatory audit and this process should go in interconnection with the mechanism of allocation of a key user of financial reports. It offers to consider external users with direct financial interests, who cannot request economic subjects directly to provide information and who should rely on general financial reports and audit report when receiving significant portion of information they need, as the key user. The article makes proposals on specification of the categorical mechanism in the sphere of audit, which are the basis for audit quality assessment, identification of possibilities and conditions of appearance of the necessary and sufficient trust to the auditor opinion.

  20. Analysis of Benchmark 2 results

    International Nuclear Information System (INIS)

    Bacha, F.; Lefievre, B.; Maillard, J.; Silva, J.

    1994-01-01

    The code GEANT315 has been compared to different codes in two benchmarks. We analyze its performances through our results, especially in the thick target case. In spite of gaps in nucleus-nucleus interaction theories at intermediate energies, benchmarks allow possible improvements of physical models used in our codes. Thereafter, a scheme of radioactive waste burning system is studied. (authors). 4 refs., 7 figs., 1 tab

  1. Physics results from polarized DIS

    International Nuclear Information System (INIS)

    Ramsey, G. P.

    1998-01-01

    We have extracted polarized nucleon distributions from recent data at CERN, SLAC and DESY. The flavor-dependent valence and sea quark spin distributions are determined for each experiment. We take into account possible differences in the up and down sea distributions, and assume that the strange sea contribution is suppressed by mass effects. Physics results determined from different experiments are compared, including higher order corrections

  2. Physics results from polarized DIS.

    Energy Technology Data Exchange (ETDEWEB)

    Ramsey, G. P.

    1998-03-23

    We have extracted polarized nucleon distributions from recent data at CERN, SLAC and DESY. The flavor-dependent valence and sea quark spin distributions are determined for each experiment. We take into account possible differences in the up and down sea distributions, and assume that the strange sea contribution is suppressed by mass effects. Physics results determined from different experiments are compared, including higher order corrections.

  3. Result-Based Public Governance

    DEFF Research Database (Denmark)

    Boll, Karen

    Within the public sector, many institutions are either steered by governance by targets or result-based governance. The former sets up quantitative internal production targets, while the latter advocates that production is planned according to outcomes which are defined as institution-produced ef......Within the public sector, many institutions are either steered by governance by targets or result-based governance. The former sets up quantitative internal production targets, while the latter advocates that production is planned according to outcomes which are defined as institution......-produced effects on individuals or businesses in society; effects which are often produced by ‘nudging’ the citizenry in a certain direction. With point of departure in these two governance-systems, the paper explores a case of controversial inspection of businesses’ negative VAT accounts and it describes...... explores how and why this state of affairs appears and problematizes the widespread use of result-based governance and nudging-techniques by public sector institutions....

  4. Presentation of the results 97

    International Nuclear Information System (INIS)

    1998-01-01

    Gaz de France (GDF) presents in a press kit the main results achieved in 1997. The European community has formulated a project of definition of rules concerning the natural gas market. Minima values for annual consumptions have been defined and the consumption and use of natural gas in EC countries is described. The financial results of GDF in 1997 are compared with previous years. Net sales grew by nearly 1 billion french francs to reach 55 billion. Overall sales were down by 4% but the share of natural gas in french energy consumption increased and sales to industrial users went up in particular due to new cogeneration plants installed in 1996. A comparison of gas prices in Europe is given for the years 1985 to 1998. The efforts of GDF to offer increased quality of services concerning in particular safety aspects as checking programs and installation of new safeguard appliances are described. The efforts of GDF to increase the energy market share of natural gas resulted in the development of new products like cogeneration, air conditioning and fuels for automotive needs. (C.B.)

  5. Presentation of RTE results 2003

    International Nuclear Information System (INIS)

    2003-01-01

    In 2003, RTE recorded a clear improvement in its financial results, and continued its debt reduction programme. The financial year 2003 was marked by a clear improvement in RTE's financial performance: results exceeded objectives, with turnover growing strongly, net income reached levels almost three times higher than those recorded in 2002, the economic rate of return rose to 7.1%, and debt was reduced by 470 Meuros. These results are explained by the substantial improvement in productivity, which has risen by 5% per year on average over the last three years. Net income has almost tripled due to RTE's improved productivity completed by a significant rise in its turnover and stabilizing operating costs RTE's finances therefore remain healthy, enabling the company to continue its debt reduction programme. Satisfactory economic and financial rates of return. Deadlines facing RTE in 2004: in application of the second European Directive, adopted on 26 June 2003, RTE faces two major deadlines in 2004: - the implementation of the 2. phase in the process of opening up the French electricity market, - its legal independence. On 1 July 2004, the market will be opened up to competition for all professional customers. At that date RTE, like all other electricity transmission system operators (TSOs) in the European Union, should be a legally independent body. The new central role of TSOs in Europe: how are electricity transmission system operators in other EU countries organised?

  6. Results Evaluation in Reduction Rhinoplasty

    Directory of Open Access Journals (Sweden)

    Arima, Lisandra Megumi

    2011-01-01

    Full Text Available Introduction: Final results evaluation after rhinoplasty is a not a topic widely studied from the patient's viewpoint. Objective:Evaluate the satisfaction of the patients submitted to reduction rhinoplasty, from the questionnaire Rhinoplasty Outcomes Evaluation (ROE. Method: Longitudinal study, retrospective cut type, of the preoperative and postoperative satisfaction. The sample was composed by 28 patients who were submitted to rhinoplasty and answered the ROE questionnaire. Three variables were obtained: satisfaction note that the patient had with his/her image before the surgery; note of satisfaction with the current appearance; the difference of the average satisfaction notes between postoperative and preoperative approaches. Results: The postoperative note was higher than the preoperative in all patients. We noticed a difference between the average of the postoperative and preoperative of 48.3 (p75 considered to be an excellent outcome (67.9%. Conclusions: The ROE questionnaire is a helpful tool to show the satisfaction of the patient submitted to reduction rhinoplasty. About 92% of the patients submitted to reduction rhinoplasty consider the postoperative result to be good or excellent.

  7. Planck 2015 results. I. Overview of products and scientific results

    CERN Document Server

    Adam, R.; Aghanim, N.; Akrami, Y.; Alves, M.I.R.; Arnaud, M.; Arroja, F.; Aumont, J.; Baccigalupi, C.; Ballardini, M.; Banday, A.J.; Barreiro, R.B.; Bartlett, J.G.; Bartolo, N.; Basak, S.; Battaglia, P.; Battaner, E.; Battye, R.; Benabed, K.; Benoit, A.; Benoit-Levy, A.; Bernard, J.P.; Bersanelli, M.; Bertincourt, B.; Bielewicz, P.; Bonaldi, A.; Bonavera, L.; Bond, J.R.; Borrill, J.; Bouchet, F.R.; Boulanger, F.; Bucher, M.; Burigana, C.; Butler, R.C.; Calabrese, E.; Cardoso, J.F.; Carvalho, P.; Casaponsa, B.; Castex, G.; Catalano, A.; Challinor, A.; Chamballu, A.; Chary, R.R.; Chiang, H.C.; Chluba, J.; Christensen, P.R.; Church, S.; Clemens, M.; Clements, D.L.; Colombi, S.; Colombo, L.P.L.; Combet, C.; Comis, B.; Contreras, D.; Couchot, F.; Coulais, A.; Crill, B.P.; Cruz, M.; Curto, A.; Cuttaia, F.; Danese, L.; Davies, R.D.; Davis, R.J.; de Bernardis, P.; de Rosa, A.; de Zotti, G.; Delabrouille, J.; Delouis, J.M.; Desert, F.X.; Di Valentino, E.; Dickinson, C.; Diego, J.M.; Dolag, K.; Dole, H.; Donzelli, S.; Dore, O.; Douspis, M.; Ducout, A.; Dunkley, J.; Dupac, X.; Efstathiou, G.; Eisenhardt, P.R.M.; Elsner, F.; Ensslin, T.A.; Eriksen, H.K.; Falgarone, E.; Fantaye, Y.; Farhang, M.; Feeney, S.; Fergusson, J.; Fernandez-Cobos, R.; Feroz, F.; Finelli, F.; Florido, E.; Forni, O.; Frailis, M.; Fraisse, A.A.; Franceschet, C.; Franceschi, E.; Frejsel, A.; Frolov, A.; Galeotta, S.; Galli, S.; Ganga, K.; Gauthier, C.; Genova-Santos, R.T.; Gerbino, M.; Ghosh, T.; Giard, M.; Giraud-Heraud, Y.; Giusarma, E.; Gjerlow, E.; Gonzalez-Nuevo, J.; Gorski, K.M.; Grainge, K.J.B.; Gratton, S.; Gregorio, A.; Gruppuso, A.; Gudmundsson, J.E.; Hamann, J.; Handley, W.; Hansen, F.K.; Hanson, D.; Harrison, D.L.; Heavens, A.; Helou, G.; Henrot-Versille, S.; Hernandez-Monteagudo, C.; Herranz, D.; Hildebrandt, S.R.; Hivon, E.; Hobson, M.; Holmes, W.A.; Hornstrup, A.; Hovest, W.; Huang, Z.; Huffenberger, K.M.; Hurier, G.; Ilic, S.; Jaffe, A.H.; Jaffe, T.R.; Jin, T.; Jones, W.C.; Juvela, M.; Karakci, A.; Keihanen, E.; Keskitalo, R.; Kiiveri, K.; Kim, J.; Kisner, T.S.; Kneissl, R.; Knoche, J.; Krachmalnicoff, N.; Kunz, M.; Kurki-Suonio, H.; Lacasa, F.; Lagache, G.; Lahteenmaki, A.; Lamarre, J.M.; Langer, M.; Lasenby, A.; Lattanzi, M.; Lawrence, C.R.; Le Jeune, M.; Leahy, J.P.; Lellouch, E.; Leonardi, R.; Leon-Tavares, J.; Lesgourgues, J.; Levrier, F.; Lewis, A.; Liguori, M.; Lilje, P.B.; Linden-Vornle, M.; Lindholm, V.; Liu, H.; Lopez-Caniego, M.; Lubin, P.M.; Ma, Y.Z.; Macias-Perez, J.F.; Maggio, G.; Mak, D.S.Y.; Mandolesi, N.; Mangilli, A.; Marchini, A.; Marcos-Caballero, A.; Marinucci, D.; Marshall, D.J.; Martin, P.G.; Martinelli, M.; Martinez-Gonzalez, E.; Masi, S.; Matarrese, S.; Mazzotta, P.; McEwen, J.D.; McGehee, P.; Mei, S.; Meinhold, P.R.; Melchiorri, A.; Melin, J.B.; Mendes, L.; Mennella, A.; Migliaccio, M.; Mikkelsen, K.; Mitra, S.; Miville-Deschenes, M.A.; Molinari, D.; Moneti, A.; Montier, L.; Moreno, R.; Morgante, G.; Mortlock, D.; Moss, A.; Mottet, S.; Muenchmeyer, M.; Munshi, D.; Murphy, J.A.; Narimani, A.; Naselsky, P.; Nastasi, A.; Nati, F.; Natoli, P.; Negrello, M.; Netterfield, C.B.; Norgaard-Nielsen, H.U.; Noviello, F.; Novikov, D.; Novikov, I.; Olamaie, M.; Oppermann, N.; Orlando, E.; Oxborrow, C.A.; Paci, F.; Pagano, L.; Pajot, F.; Paladini, R.; Pandolfi, S.; Paoletti, D.; Partridge, B.; Pasian, F.; Patanchon, G.; Pearson, T.J.; Peel, M.; Peiris, H.V.; Pelkonen, V.M.; Perdereau, O.; Perotto, L.; Perrott, Y.C.; Perrotta, F.; Pettorino, V.; Piacentini, F.; Piat, M.; Pierpaoli, E.; Pietrobon, D.; Plaszczynski, S.; Pogosyan, D.; Pointecouteau, E.; Polenta, G.; Popa, L.; Pratt, G.W.; Prezeau, G.; Prunet, S.; Puget, J.L.; Rachen, J.P.; Racine, B.; Reach, W.T.; Rebolo, R.; Reinecke, M.; Remazeilles, M.; Renault, C.; Renzi, A.; Ristorcelli, I.; Rocha, G.; Roman, M.; Romelli, E.; Rosset, C.; Rossetti, M.; Rotti, A.; Roudier, G.; d'Orfeuil, B.Rouille; Rowan-Robinson, M.; Rubino-Martin, J.A.; Ruiz-Granados, B.; Rumsey, C.; Rusholme, B.; Said, N.; Salvatelli, V.; Salvati, L.; Sandri, M.; Sanghera, H.S.; Santos, D.; Saunders, R.D.E.; Sauve, A.; Savelainen, M.; Savini, G.; Schaefer, B.M.; Schammel, M.P.; Scott, D.; Seiffert, M.D.; Serra, P.; Shellard, E.P.S.; Shimwell, T.W.; Shiraishi, M.; Smith, K.; Souradeep, T.; Spencer, L.D.; Spinelli, M.; Stanford, S.A.; Stern, D.; Stolyarov, V.; Stompor, R.; Strong, A.W.; Sudiwala, R.; Sunyaev, R.; Sutter, P.; Sutton, D.; Suur-Uski, A.S.; Sygnet, J.F.; Tauber, J.A.; Tavagnacco, D.; Terenzi, L.; Texier, D.; Toffolatti, L.; Tomasi, M.; Tornikoski, M.; Tristram, M.; Troja, A.; Trombetti, T.; Tucci, M.; Tuovinen, J.; Turler, M.; Umana, G.; Valenziano, L.; Valiviita, J.; Van Tent, B.; Vassallo, T.; Vidal, M.; Viel, M.; Vielva, P.; Villa, F.; Wade, L.A.; Walter, B.; Wandelt, B.D.; Watson, R.; Wehus, I.K.; Welikala, N.; Weller, J.; White, M.; White, S.D.M.; Wilkinson, A.; Yvon, D.; Zacchei, A.; Zibin, J.P.; Zonca, A.

    2016-01-01

    The European Space Agency's Planck satellite, dedicated to studying the early Universe and its subsequent evolution, was launched 14~May 2009 and scanned the microwave and submillimetre sky continuously between 12~August 2009 and 23~October 2013. In February~2015, ESA and the Planck Collaboration released the second set of cosmology products based on data from the entire Planck mission, including both temperature and polarization, along with a set of scientific and technical papers and a web-based explanatory supplement. This paper gives an overview of the main characteristics of the data and the data products in the release, as well as the associated cosmological and astrophysical science results and papers. The science products include maps of the cosmic microwave background (CMB), the thermal Sunyaev-Zeldovich effect, and diffuse foregrounds in temperature and polarization, catalogues of compact Galactic and extragalactic sources (including separate catalogues of Sunyaev-Zeldovich clusters and Galactic col...

  8. Overview of the FTU results

    International Nuclear Information System (INIS)

    Alladio, F.; Angelini, B.; Apicella, M.L.

    1999-01-01

    An overview of the Frascati Tokamak Upgrade results during the period 1996-1998 is presented. Most of the activity has been devoted to the investigation of the electron heat transport with flat/nonmonotonic safety factor profiles. Up to 14 keV of electron temperature have been obtained using electron cyclotron resonance heating (ECRH) on the current ramp. The transport analysis shows a very low electron heat transport in the region with flat/nonmonotonic safety factor profile. The electron thermal conductivity is strongly dependent on the MHD activity and it drops to values of the order 0.1 m 2 /s in the absence of MHD fluctuations. Upon varying the resonance position in steady state conditions the effect of the ECRH on the sawtooth stabilization has been also investigated. Lower hybrid current drive studies have been performed in order to investigate the dependence of the current drive efficiency with density. Previous results of the Alcator C tokamak pointed out that at high density rather low efficiency values were obtained. The investigation carried out on FTU shows that such a result can be explained as due to the electron temperature dependence of the current drive efficiency. No degradation of the current drive efficiency is indeed observed on FTU even at density values of the order 10 20 m -3 . Ion Bernstein wave (IBW) heating studies have been also carried out in order to check the behaviour of wave-plasma coupling which is found in agreement with linear theory. Finally, impurity transport studies have been carried out. It has been possible to have a direct measurement of the flux of Mo33 which turns out to be in agreement with the expectation of quasilinear theory. (author)

  9. Visible nulling coronagraph testbed results

    Science.gov (United States)

    Lyon, Richard G.; Clampin, Mark; Woodruff, Robert A.; Vasudevan, Gopal; Thompson, Patrick; Petrone, Peter; Madison, Timothy; Rizzo, Maxime; Melnick, Gary; Tolls, Volker

    2009-08-01

    We report on our recent laboratory results with the NASA/Goddard Space Flight Center (GSFC) Visible Nulling Coronagraph (VNC) testbed. We have experimentally achieved focal plane contrasts of 1 x 108 and approaching 109 at inner working angles of 2 * wavelength/D and 4 * wavelength/D respectively where D is the aperture diameter. The result was obtained using a broadband source with a narrowband spectral filter of width 10 nm centered on 630 nm. To date this is the deepest nulling result with a visible nulling coronagraph yet obtained. Developed also is a Null Control Breadboard (NCB) to assess and quantify MEMS based segmented deformable mirror technology and develop and assess closed-loop null sensing and control algorithm performance from both the pupil and focal planes. We have demonstrated closed-loop control at 27 Hz in the laboratory environment. Efforts are underway to first bring the contrast to > 109 necessary for the direct detection and characterization of jovian (Jupiter-like) and then to > 1010 necessary for terrestrial (Earth-like) exosolar planets. Short term advancements are expected to both broaden the spectral passband from 10 nm to 100 nm and to increase both the long-term stability to > 2 hours and the extent of the null out to a ~ 10 * wavelength / D via the use of MEMS based segmented deformable mirror technology, a coherent fiber bundle, achromatic phase shifters, all in a vacuum chamber at the GSFC VNC facility. Additionally an extreme stability textbook sized compact VNC is under development.

  10. Overview of recent ALICE results

    Energy Technology Data Exchange (ETDEWEB)

    Gunji, Taku

    2016-12-15

    The ALICE experiment explores the properties of strongly interacting QCD matter at extremely high temperatures created in Pb-Pb collisions at LHC and provides further insight into small-system physics in (high-multiplicity) pp and p-Pb collisions. The ALICE collaboration presented 27 parallel talks, 50 posters, and 1 flash talk at Quark Matter 2015 and covered various topics including collective dynamics, correlations and fluctuations, heavy flavors, quarkonia, jets and high p{sub T} hadrons, electromagnetic probes, small system physics, and the upgrade program. This paper highlights some of the selected results.

  11. Recent QCD results from ATLAS

    CERN Document Server

    Meyer, C; The ATLAS collaboration

    2014-01-01

    The ATLAS collaboration has performed studies of a wide range of QCD phenomena, from soft particle to hard photon and jet production. Recent soft-QCD measurements include studies of underlying event and vector meson production. Differential measurements of inclusive and dijet production provide stringent tests of high-order QCD predictions and provide input for determination of parton density functions. Measurements of isolated inclusive and di-photons cross sections for high transverse momentum photons test theoretical predictions of perturbative QCD and constrain parton density functions. An overview of these results is given.

  12. The OPERA Experiment. Latest results

    Energy Technology Data Exchange (ETDEWEB)

    Hollnagel, Annika [Universitaet Hamburg, Institut fuer Experimentalphysik (Germany); Collaboration: OPERA-Hamburg-Collaboration

    2015-07-01

    The long-baseline neutrino oscillation experiment OPERA has been designed for the direct observation of ν{sub τ} appearance in the CNGS ν{sub μ} beam. The OPERA detector is located at the LNGS underground laboratory, with a distance of 730 km from the neutrino source at CERN. It is a hybrid detector, combining the micrometric precision of emulsion cloud chambers with electronic detector elements for online readout. While CNGS beam data taking lasted from 2008 to 2012, the neutrino oscillation analysis is still ongoing. Updated results with increased statistics are presented, including the recent observation of ν{sub τ} appearance.

  13. RSG Deployment Case Testing Results

    Energy Technology Data Exchange (ETDEWEB)

    Owsley, Stanley L.; Dodson, Michael G.; Hatchell, Brian K.; Seim, Thomas A.; Alexander, David L.; Hawthorne, Woodrow T.

    2005-09-01

    The RSG deployment case design is centered on taking the RSG system and producing a transport case that houses the RSG in a safe and controlled manner for transport. The transport case was driven by two conflicting constraints, first that the case be as light as possible, and second that it meet a stringent list of Military Specified requirements. The design team worked to extract every bit of weight from the design while striving to meet the rigorous Mil-Spec constraints. In the end compromises were made primarily on the specification side to control the overall weight of the transport case. This report outlines the case testing results.

  14. Overview of recent ALICE results

    CERN Document Server

    Gunji, Taku

    2016-01-01

    The ALICE experiment explores the properties of strongly interacting QCD matter at extremely high temperatures created in Pb-Pb collisions at LHC and provides further insight into small-system physics in (high-multiplicity) pp and p-Pb collisions. The ALICE collaboration presented 27 parallel talks, 50 posters, and 1 flash talk at Quark Matter 2015 and covered various topics including collective dynamics, correlations and fluctuations, heavy flavors, quarkonia, jets and high $p_{\\rm T}$ hadrons, electromagnetic probes, small system physics, and the upgrade program. This paper highlights some of the selected results.

  15. Data bases for LDEF results

    Science.gov (United States)

    Bohnhoff-Hlavacek, Gail

    1993-01-01

    The Long Duration Exposure Facility (LDEF) carried 57 experiments and 10,000 specimens for some 200 LDEF experiment investigators. The external surface of LDEF had a large variety of materials exposed to the space environment which were tested preflight, during flight, and post flight. Thermal blankets, optical materials, thermal control paints, aluminum, and composites are among the materials flown. The investigations have produced an abundance of analysis results. One of the responsibilities of the Boeing Support Contract, Materials and Systems Special Investigation Group, is to collate and compile that information into an organized fashion. The databases developed at Boeing to accomplish this task is described.

  16. Results of nuclear fusion development

    International Nuclear Information System (INIS)

    Yamamoto, Kenzo

    1975-01-01

    Compared with the nuclear fission research which followed that in advanced countries, Japan has treaded on its own track in nuclear fusion development; in the former, she had been far behind other leading countries. Characteristic of the efforts in Japan is the collaboration with educational institutions. Works are now carried out mainly in Tokamak plasma confinement, though other means being studied simultaneously. The nation's fusion research program is the realization of a fusion reactor at the turn of the present century, based on the world-level results attained with Tokamak. Past developments in the nuclear fusion research, the current status, and aspects for the future are discribed. (Mori, K.)

  17. Engineering model cryocooler test results

    International Nuclear Information System (INIS)

    Skimko, M.A.; Stacy, W.D.; McCormick, J.A.

    1992-01-01

    This paper reports that recent testing of diaphragm-defined, Stirling-cycle machines and components has demonstrated cooling performance potential, validated the design code, and confirmed several critical operating characteristics. A breadboard cryocooler was rebuilt and tested from cryogenic to near-ambient cold end temperatures. There was a significant increase in capacity at cryogenic temperatures and the performance results compared will with code predictions at all temperatures. Further testing on a breadboard diaphragm compressor validated the calculated requirement for a minimum axial clearance between diaphragms and mating heads

  18. Recent results for Mark III

    International Nuclear Information System (INIS)

    Brient, J.C.

    1987-12-01

    This paper presents recent results from the Mark III detector at SPEAR, in the open charm sector. The first topic discussed is the reanalysis of the direct measurement of the D hadronic branching fractions, where a detailed study has been made of the Cabibbo suppressed and multi-π 0 's D decays backgrounds in the double tag sample. Next, the Dalitz plot analysis of the D decays to Kππ is presented, leading to the relative fractions of three-body versus pseudoscalarvector decays. 7 refs., 5 figs

  19. Results from Nikko-Maru

    International Nuclear Information System (INIS)

    Kinoshita, K.

    1990-01-01

    At the Nikko area of the TRISTAN storage ring the Search for Highly Ionizing Particles (SHIP) Nikko-Maru employs etchable solid state track detectors to search for heavily ionizing particles produced in the e + e - annihilations. New results are reported from exposures to 13.9 pb -1 integrated luminosity at √s=57-60.8 GeV. New upper limits are established on the production of Dirac monopoles with mass up to 28.8 GeV/c 2 . (author)

  20. Free-electron laser results

    International Nuclear Information System (INIS)

    Stein, W.E.; Brau, C.A.; Newnam, B.E.; Warren, R.W.; Winston, J.; Young, L.M.

    1981-01-01

    The Los Alamos free-electron laser (FEL) amplifier experiment was designed to demonstrate high efficiency for transfer of energy from an electron beam to a light beam in the magnetic field of a tapered wiggler. Initial results indicate an energy transfer consistent with theory. Distinct groups of decelerated electrons as well as accelerated electrons are clearly present in the energy spectrum of electrons emerging from the wiggler when the laser light is present. The observed energy decrease for the electrons captured in the decelerating bucket is approx. 6% and the average decrease of the entire energy distribution is approx. 2% for the conditions of these initial measurements

  1. Recent photon results from ATLAS

    CERN Document Server

    Glasman, Claudia; The ATLAS collaboration

    2017-01-01

    The production of prompt isolated photons at hadron colliders provides a stringent test of perturbative QCD and can be used to probe the gluon density function of the proton. The ATLAS collaboration has performed precise measurements of the inclusive production o f isolated prompt photons at a center-of-mass energy of 13 TeV, differential in both rap idity and the photon transverse momentum. In addition, the integrated and differential c ross sections for isolated photon pair production 8 TeV have been measured. The results are compared with state-of-the-art theory predictions at NLO in QCD and with predictions of several MC generators.

  2. Reporting of Diagnostic Cytogenetic Results.

    Science.gov (United States)

    Giersch, Anne B S; Bieber, Frederick R; Dubuc, Adrian M; Fletcher, Jonathan A; Ligon, Azra H; Mason-Suares, Heather; Morton, Cynthia C; Weremowicz, Stanislawa; Xiao, Sheng; Dal Cin, Paola

    2016-04-01

    This appendix, developed by the staff at the Center for Advanced Molecular Diagnostics in the Department of Pathology at the Brigham and Women's Hospital, includes a comprehensive list of current "macros" or standardized statements used to facilitate reporting of cytogenetic results. These are provided as a useful reference for other laboratories. The statements are organized under the general categories of constitutional or acquired abnormalities and subdivided into analysis type (GTG-banding, FISH, or chromosomal microarray). Multi-specimen usage macros are included that can be applied to two or more specimen types. Copyright © 2016 John Wiley & Sons, Inc.

  3. Optical Array Processor: Laboratory Results

    Science.gov (United States)

    Casasent, David; Jackson, James; Vaerewyck, Gerard

    1987-01-01

    A Space Integrating (SI) Optical Linear Algebra Processor (OLAP) is described and laboratory results on its performance in several practical engineering problems are presented. The applications include its use in the solution of a nonlinear matrix equation for optimal control and a parabolic Partial Differential Equation (PDE), the transient diffusion equation with two spatial variables. Frequency-multiplexed, analog and high accuracy non-base-two data encoding are used and discussed. A multi-processor OLAP architecture is described and partitioning and data flow issues are addressed.

  4. CELLO results on multiparticle production

    International Nuclear Information System (INIS)

    Podobrin, O.

    1991-10-01

    In this talk result from CELLO on multiparticle production in e + e - annihilation are presented. The three-dimensional distribution of charged particles, and its one- and two-dimensional projections, are extensively studied through the bin-size dependence of their factorial moments. The data are found to have an excellent description by standard Monte Carlo models. This implies an explanation of the observed intermittency behaviour in terms of known physics. The study is extended by an analysis of two-particle rapidity correlations. (orig.)

  5. First half 2005 financial results

    International Nuclear Information System (INIS)

    2005-01-01

    With manufacturing facilities in over 40 countries and a sales network in over 100, AREVA offers customers technological solutions for nuclear power generation and electricity transmission and distribution. The group also provides interconnect systems to the telecommunications, computer and automotive markets. This document presents the first half 2005 financial results of the group: 1 - overall performance: sales revenue, operating income, consolidated net income, operating cash flow, balance sheet; 2 - outlook; 3 - performance by business division: front-end division, reactors and services division, back end division, transmission and distribution division, connectors division

  6. Results of Austin Moore replacement.

    Directory of Open Access Journals (Sweden)

    Jadhav A

    1996-04-01

    Full Text Available Forty cases of Austin Moore Replacement done for transcervical fractures of the femur in patients were reviewed after a period of 12 to 48 months postoperatively (mean 26 mth. 30 cases (75% had mild to severe pain of non-infective origin, starting as early as 6 months postoperatively. This was irrespective of the make, size or position (varus/valgus of the prosthesis. Though the Aufranc and Sweet clinical scoring was satisfactory in 65% cases, radiological evidence of complications like sinking, protrusion, etc. were seen in majority of the cases. Calcar resorption was seen in 34 cases (85% as early as 4 months postoperatively. Results of THR and bipolar replacement done for transcervical fractures in recent literature show 85% pain-free cases at 5 years. We feel that Austin Moore Replacement should be reserved for patients more than 65 years of age and those who are less active or debilitated because of other factors, because of increased acetabular wear with time in the younger individual. This is corroborated by unsatisfactory results in patients less than 65 years of age (p < 0.05.

  7. Results from the NOMAD experiment

    CERN Document Server

    Popov, B A

    2000-01-01

    The NOMAD experiment has sought nu /sub mu / implies/implied by nu /sub tau / oscillations by looking for the emergence of tau /sup -/ in events from the CERN SPS neutrino beam. With some improvements in the techniques of analysis in relation to the results published previously and with the inclusion of data from the 1998 run, no evidence for the oscillations has been found, which results in an updated limit on the oscillation probability [P( nu /sub mu / to nu /sub tau /)<0.5* 10/sup -3/ at a 90% C.L.]. The corresponding limit on the oscillation mixing angle is given by sin/sup 2/2 theta /sub mu tau /<1.0*10/sup -3/ for large Delta m/sup 2/. By using a 1% contamination of nu /sub e/ in the neutrino beam, we can also rule out nu /sub e/ implies/implied by nu /sub tau / oscillations and constrain the probability of the relevant transition as P( nu /sub 3/ to nu /sub tau /)<3*10/sup -2/ at a 90% C.L. (sin/sup 2/2Q/sub e tau /<6*10/sup -2/ at large Delta m/sup 2/). (10 refs).

  8. Unfavourable results following reduction mammoplasty

    Directory of Open Access Journals (Sweden)

    Lakshmi Saleem

    2013-01-01

    Full Text Available Breast reduction is a common cosmetic surgical procedure. It aims not only at bringing down the size of the breast proportionate to the build of the individual, but also to overcome the discomfort caused by massive, ill-shaped and hanging breasts. The operative procedure has evolved from mere reduction of breast mass to enhanced aesthetic appeal with a minimum of scar load. The selection of technique needs to be individualised. Bilateral breast reduction is done most often. Haematoma, seroma, fat necrosis, skin loss, nipple loss and unsightly, painful scars can be the complications of any procedure on the breast. These may result from errors in judgement, wrong surgical plan and imprecise execution of the plan. Though a surfeit of studies are available on breast reduction, very few dwell upon its complications. The following article is a distillation of three decades of experience of the senior author (L.S. in reduction mammoplasty. An effort is made to understand the reasons for unfavourable results. To conclude, most complications can be overcome with proper selection of procedure for the given patient and with gentle tissue handling.

  9. First results of spherical GEMs

    CERN Document Server

    Pinto, Serge Duarte; Brock, Ian; Croci, Gabriele; David, Eric; de Oliveira, Rui; Ropelewski, Leszek; van Stenis, Miranda; Taureg, Hans; Villa, Marco

    2010-01-01

    We developed a method to make GEM foils with a spherical geometry. Tests of this procedure and with the resulting spherical GEMs are presented. Together with a spherical drift electrode, a spherical conversion gap can be formed. This eliminates the parallax error for detection of x-rays, neutrons or UV photons when a gaseous converter is used. This parallax error limits the spatial resolution at wide scattering angles. Besides spherical GEMs, we have developed curved spacers to maintain accurate spacing, and a conical field cage to prevent edge distortion of the radial drift field up to the limit of the angular acceptance of the detector. With these components first tests are done in a setup with a spherical entrance window but a planar readout structure; results will be presented and discussed. A flat readout structure poses difficulties, however. Therefore we will show advanced plans to make a prototype of an entirely spherical double-GEM detector, including a spherical 2D readout structure. This detector w...

  10. Drug overdose resulting in quadriplegia.

    Science.gov (United States)

    Wang, Teresa S; Grunch, Betsy H; Moreno, Jessica R; Bagley, Carlos A; Gottfried, Oren N

    2012-06-01

    To describe a case of cervical flexion myelopathy resulting from a drug overdose. A 56-year-old male presented to the emergency department unable to move his extremities following drug overdose. Neurological examination revealed him to be at C6 ASIA A spinal cord injury. The CT of his cervical spine revealed no fracture; however, an MRI revealed cord edema extending from C3 to C6 as well as posterior paraspinal signal abnormalities suggestive of ligamentous injury. The patient underwent a posterior cervical laminectomy and fusion from C3 to C7. Neurologically he regained 3/5 bilateral tricep function and 2/5 grip; otherwise, he remained at ASIA A spinal cord injury at 6 months. Our patient suffered a spinal cord injury likely due to existing cervical stenosis, and in addition to an overdose of sedating medications, he likely sat in flexed neck position for prolonged period of time with the inability to modify his position. This likely resulted in cervical spine vascular and/or neurological compromise producing an irreversible spinal cord injury. Spinal cord injury is a rare finding in patients presenting with drug overdose. The lack of physical exam findings suggestive of trauma may delay prompt diagnosis and treatment, and thus clinicians must have a high index of suspicion when evaluating patients in this setting.

  11. New Results on Cepheid Masses

    Science.gov (United States)

    Evans, N. R.; Bohm-Vitense, E.; Carpenter, K.; Robinson, R.; Beck-Winchatz, B.

    1996-12-01

    Masses for Cepheid variable stars can be measured by combining the orbital velocity amplitude for the Cepheid (from a ground-based orbit) with the orbital velocity amplitude of a hot main sequence companion (observed in the ultraviolet from satellites such as IUE and HST) and the mass of the companion (inferred from from the ultraviolet energy distribution). Observations of 5 binary systems are now completed or in progress with the Goddard High Resolution Spectrograph on the Hubble Space Telescope. Recently completed observations of U Aql lead to a mass of 5.1 +/- 1.1 Msun . We will discuss the results for S Mus, V350 Sgr, U Aql, and Y Car, and the constraints they place on stellar evolution calculations. As would be expected, some of the B companions have high rotational velocities, decreasing the accuracy with which their orbital velocities can be measured. The preliminary conclusion from the 4 HST targets and SU Cyg (mass from IUE observations) is that a weighted mean indicates no convective overshoot but the mode (which reflects the HST results better) agrees with the modest overshoot used in the Geneva evolutionary calculations. Financial Support was provided by a NASA grant GO-4541-01 to EB--V and GO-4541.02 to KGC, a grant from the Natural Sciences and Engineering Council, Canada to NRE, from the AXAF Science Center NASA Contract NAS8-39073.

  12. TMX-U experimental results

    International Nuclear Information System (INIS)

    Simonen, T.C.; Allen, S.L.; Casper, T.A.

    1983-01-01

    This paper describes results from the Tandem Mirror Experiment-Upgrade (TMX-U). Mirror-confined electrons with 30 to 70 keV mean energy densities of 0.5 to 2.0 x 10 12 cm -3 and average betas of 3 to 5% are produced using electron-cyclotron resonant heating (ECRH). These results are consistent with an electron Fokker-Planck code. Improved ion-cyclotron microstability is observed using neutral beam injection at 47 0 to the magnetic axis, rather than at 90 0 as in the previous experiment, TMX. Strong end plugging has been produced using a combination of ECRH gyrotrons with sloshing-ion beam injection. In these low-density central cell experiments (3 x 10 11 cm -3 ) the axial losses (tau/sub parallel/ = 20 to 80 ms) are smaller than the nonambipolar radial losses (tau/sub perpendicular/ = 4 to 8 ms). Plugging has been achieved with a central cell density double that of the end plugs. Although no direct measurements are yet available to determine if a thermal barrier potential dip is generated, these experiments support many theoretical features of the thermal barrier concept

  13. Results of the dosimetry intercomparison

    International Nuclear Information System (INIS)

    Dure, Elsa S.

    2000-07-01

    The appropriate way to verify the accuracy of the results of dose reported by the laboratories that offer lend personal dosimetry service is in the periodic participation of round of intercomparison dosimetry, undertaken by laboratories whose standards are trace (Secondary Laboratory). The Laboratory of External Personal Dosimetry of the CNEA-PY has participated in three rounds of intercomparison. The first two were organized in the framework of the Model Project RLA/9/030 RADIOLOGICAL WASTE SECURITY, and the irradiations were carried out in the Laboratory of Regional Calibration of the Center of Nuclear Technology Development, Belo Horizonte-Brazil (1998) and in the National Laboratory of Metrology of the ionizing radiations of the Institute of Radioprotection and Dosimetry, Rio de Janeiro-Brazil (1999). The third was organized by the IAEA and the irradiations were made in the Physikalisch-Technische Bundesanstalt PTB, Braunschweig - Federal Republic of Germany (1999-2000) [es

  14. Framatome announces its 1997 results

    International Nuclear Information System (INIS)

    1998-01-01

    This press dossier presents the 1997 financial year of Framatome group: turnover and key-numbers, results, sectoral analysis (nuclear engineering (nuclear realizations, fuels, services and equipments); connectors engineering (automotive, electrical, electronic, interconnection and microelectronic industries), industrial equipments). Then, the 1998 objectives are presented with the strategy of the group (Chinese, central and eastern Europe nuclear programs, French-German joint EPR project, services and nuclear fuels, connectors engineering, industrial equipments, manpower, research and development programs). This part is followed by a presentation of some 1997 events and by the text of the press conference from May 18, 1998 which presented the activities of the group, its competences and know-how in the nuclear domain. (J.S.)

  15. Recent results on Tore Supra

    International Nuclear Information System (INIS)

    Moreau, D.

    1995-01-01

    Recent results regarding heating, confinement, current drive and profile modifications, heat and particle exhaust are reported. Improved core confinement is obtained after pellet injection (PEP) or Lower Hybrid current drive (LHEP) and may be linked with small - or reversed - central magnetic shear. Conversely, by increasing the magnetic shear in the gradient region, both LHCD and fast wave electron heating (FWEH) have produced improved global confinement was carried by the bootstrap current. Fast wave current drive has been observed at the level of 80 kA in a 0.4 MA discharge. In the ergodic divertor configuration, stable radiative layers were obtained with neon injection. At least 80% of a total of 7 MW injected power were radiated without confinement degradation or impurity accumulation. Finally, the heat exhaust capability of the various actively cooled plasma facing components is briefly described. (author) 14 refs.; 13 figs

  16. First results on fast baking

    Energy Technology Data Exchange (ETDEWEB)

    Visentin, B. [CEA-Saclay, DSM/DAPNIA/SACM - 91191 Gif/Yvette Cedex (France)]. E-mail: bvisentin@cea.fr; Gasser, Y. [CEA-Saclay, DSM/DAPNIA/SACM - 91191 Gif/Yvette Cedex (France); Charrier, J.P. [CEA-Saclay, DSM/DAPNIA/SACM - 91191 Gif/Yvette Cedex (France)

    2006-07-15

    High gradient performances of bulk niobium cavities go through a low-temperature baking during one or two days, the temperature parameter is adjusted in a narrow tuning range around 110 or 120deg, C. With such treatment, the intrinsic quality factor Q{sub 0} is improved at high fields. Assuming the oxygen diffusion is involved in this phenomenon, we have developed the 'fast baking' (145deg, C/3h) as an alternative method. Similar results have been achieved with this method compared to standard baking. Consequently, for the first time, a link between oxygen diffusion and high field Q-slope has been demonstrated. Furthermore, this method open the way to a simpler and better baking procedure for the large-scale cavity production due to:*time reduction and *possibility to combine baking and drying during cavity preparation.

  17. Cassini at Saturn Huygens results

    CERN Document Server

    Harland, David M

    2007-01-01

    "Cassini At Saturn - Huygens Results" will bring the story of the Cassini-Huygens mission and their joint exploration of the Saturnian system right up to date. Cassini is due to enter orbit around Saturn on the 1 July 2004 and the author will have 8 months of scientific data available for review, including the most spectacular images of Saturn, its rings and satellites ever obtained by a space mission. As the Cassini spacecraft approached its destination in spring 2004, the quality of the images already being returned by the spacecraft clearly demonstrate the spectacular nature of the close-range views that will be obtained. The book will contain a 16-page colour section, comprising a carefully chosen selection of the most stunning images to be released during the spacecraft's initial period of operation. The Huygens craft will be released by Cassini in December 2004 and is due to parachute through the clouds of Saturn's largest moon, Titan, in January 2005.

  18. First results on fast baking

    International Nuclear Information System (INIS)

    Visentin, B.; Gasser, Y.; Charrier, J.P.

    2006-01-01

    High gradient performances of bulk niobium cavities go through a low-temperature baking during one or two days, the temperature parameter is adjusted in a narrow tuning range around 110 or 120deg, C. With such treatment, the intrinsic quality factor Q 0 is improved at high fields. Assuming the oxygen diffusion is involved in this phenomenon, we have developed the 'fast baking' (145deg, C/3h) as an alternative method. Similar results have been achieved with this method compared to standard baking. Consequently, for the first time, a link between oxygen diffusion and high field Q-slope has been demonstrated. Furthermore, this method open the way to a simpler and better baking procedure for the large-scale cavity production due to:*time reduction and *possibility to combine baking and drying during cavity preparation

  19. Treatment Results of Ovarian Dysqerminoma

    International Nuclear Information System (INIS)

    Chung, Eun Ji; Suh, Chang Ok; Seong, Jin Sil; Keum, Ki Chang; Kim, Gwi Eon

    1996-01-01

    Purpose : We tried to evaluate the clinical characteristics, the treatment methods, the results of treatments, and the patterns of failure in ovarian dysgerminoma retrospectively. According to the results we would like to suggest the proper management guideline of stage la ovarian dysgerminoma patients who want to maintain fertility. Methods and Materials : Between 1975 and 1990, 34 patients with ovarian dysgerminoma were treated at the Yonsei University Hospital. The case records of these patients have been reviewed for presenting symptoms, treatment methods, local control, and survival following treatment. Excluded from analysis were five patients with mixed ovarian germ cell tumors and gonadoblastomas (46,XY). Treatment results of the twenty nine patients were analysed by each treatment modality. Twenty one patients were treated with surgery and postoperative adjuvant radiotherapy(group 1). The other eight patients were treated with operation alone (group 2). The median age of twenty-nine patients was 23 years with a range of 8 to 39 years. Presenting symptoms were abdominal mass(20), pelvic discomfort or pain(5) et al. Radiotherapy was performed by 10MV LINAC or Co-60 teletherapy unit. The total radiation dose of the whole abdomen was 20-25 Gy/3 weeks, 1-1.5 Gy/fraction with a boost to the whole pelvis 10-15 Gy / 1-2 weeks1.8-2.0 Gy/fraction. Advanced stage disease (stage II or stage III) patients received prophylactic mediastinal and supraclavicular irradiation to a dose of 16-26 Gy. Median duration of follow-up of living patients was 80 months (range : 13-201 months). Results : All of the twenty one patients of group 1 were alive without disease (100%). Among the eight patients who were not treated with radiotherapy (group 2), six patients developed local recurrence. Four patients referred with recurrent disease were treated with salvage radiotherapy. Three of four patients were salvaged and one patient who had recurrent intra-abdominal disease died of

  20. Latest results from KLOE-2

    Directory of Open Access Journals (Sweden)

    Bloise Caterina

    2014-01-01

    Full Text Available The KLOE experiment at the Frascati φ–factory recently obtained results on i CPT and Lorentz invariance tests from the study of quantum interference of the neutral kaon pairs; ii precision measurement of the branching fraction, BR(K+ → π+π−π+(γ = 0.05565 ± 0.00031stat ± 0.00025syst, and iii on dark photon searches with the analysis of the e+e− → µµγ final state. We have also studied the transition form factors of the φ meson to the pseudoscalars, π0 and η, that is presented in a separate contribution to this volume.

  1. The Bigfoot Drive; Experimental Results

    Science.gov (United States)

    Baker, Kevin; Thomas, Cliff; Khan, Shahab; Casey, Daniel; Spears, Brian; Nora, Ryan; Munro, Davis; Eder, David; Milovich, Jose; Berger, Dick; Strozzi, David; Goyon, Clement; Turnbull, David; Ma, Tammy; Izumi, Nobuhiko; Benedetti, Robin; Millot, Marius; Celliers, Peter; Yeamans, Charles; Hatarik, Robert; Landen, Nino; Hurricane, Omar; Callahan, Debbie

    2016-10-01

    The Bigfoot platform was developed on the National Ignition Facility to investigate low convergence, high adiabat, high rhoR hotspot implosions. This platform was designed to be less susceptible to wall motion, LPI and CBET and to be more robust against capsule hydrodynamic instabilities. To date experimental studies have been carried out at two hohlraum scales, a 5.75 and 5.4 mm diameter hohlraum. We will present experimental results from these tuning campaigns including the shape vs. cone fraction, surrogacy comparisons of self-emission from the capsules vs. radiography of the imploding capsule and doped vs. undoped capsules. Prepared by LLNL under Contract DE-AC52-07NA27344.

  2. Some results on inverse scattering

    International Nuclear Information System (INIS)

    Ramm, A.G.

    2008-01-01

    A review of some of the author's results in the area of inverse scattering is given. The following topics are discussed: (1) Property C and applications, (2) Stable inversion of fixed-energy 3D scattering data and its error estimate, (3) Inverse scattering with 'incomplete' data, (4) Inverse scattering for inhomogeneous Schroedinger equation, (5) Krein's inverse scattering method, (6) Invertibility of the steps in Gel'fand-Levitan, Marchenko, and Krein inversion methods, (7) The Newton-Sabatier and Cox-Thompson procedures are not inversion methods, (8) Resonances: existence, location, perturbation theory, (9) Born inversion as an ill-posed problem, (10) Inverse obstacle scattering with fixed-frequency data, (11) Inverse scattering with data at a fixed energy and a fixed incident direction, (12) Creating materials with a desired refraction coefficient and wave-focusing properties. (author)

  3. Selected recent results from AMANDA

    CERN Document Server

    Andrés, E; Bai, X; Barouch, G; Barwick, S W; Bay, R C; Becker, K H; Bergström, L; Bertrand, D; Bierenbaum, D; Biron, A; Booth, J; Botner, O; Bouchta, A; Boyce, M M; Carius, S; Chen, A; Chirkin, D; Conrad, J; Cooley, J; Costa, C G S; Cowen, D F; Dailing, J; Dalberg, E; De Young, T R; Desiati, P; Dewulf, J P; Doksus, P; Edsjö, J; Ekstrom, P; Erlandsson, B; Feser, T; Gaug, M; Goldschmidt, A; Goobar, A; Gray, L; Haase, H; Hallgren, A; Halzen, F; Hanson, K; Hardtke, R; He, Y D; Hellwig, M; Heukenkamp, H; Hill, G C; Hulth, P O; Hundertmark, S; Jacobsen, J; Kandhadai, V; Karle, A; Kim, J; Koci, B; Köpke, L; Kowalski, M; Leich, H; Leuthold, M; Lindahl, P; Liubarsky, I; Loaiza, P; Lowder, D M; Ludvig, J; Madsen, J; Marciniewski, P; Matis, H S; Mihályi, A; Mikolajski, T; Miller, T C; Minaeva, Y; Miocinovic, P; Mock, P C; Morse, R; Neunhoffer, T; Newcomer, F M; Niessen, P; Nygren, D R; Ogelman, H; Heros, C P D L; Porrata, R; Price, P B; Rawlins, K; Reed, C; Rhode, W; Richards, A; Richter, S; Martino, J R; Romenesko, P; Ross, D; Rubinstein, H; Sander, H G; Scheider, T; Schmidt, T; Schneider, D; Schneider, E; Schwarzl, R; Silvestri, A; Solarz, M; Spiczak, G M; Spiering, C; Starinsky, N; Steele, D; Steffen, P; Stokstad, R G; Streicher, O; Sun, A; Taboada, I; Thollander, L; Thon, T; Tilav, S; Usechak, N; Donckt, M V; Walck, C; Weinheimer, C; Wiebusch, C; Wischnewski, R; Wissing, H; Woschnagg, K; Wu, W; Yodh, G; Young, S

    2001-01-01

    We present a selection of results based on data taken in 1997 with the 302-PMT Antarctic Muon and Neutrino Detector Array-B10 ("AMANDA-B10") array. Atmospheric neutrinos created in the northern hemisphere are observed indirectly through their charged current interactions which produce relativistic, Cherenkov-light-emitting upgoing muons in the South Pole ice cap. The reconstructed angular distribution of these events is in good agreement with expectation and demonstrates the viability of this ice-based device as a neutrino telescope. Studies of nearly vertical upgoing muons limit the available parameter space for WIMP dark matter under the assumption that WIMPS are trapped in the earth's gravitational potential well and annihilate with one another near the earth's center.

  4. Cerebral infarcts resulting from trauma

    International Nuclear Information System (INIS)

    Busch, G.

    1985-01-01

    Vascular occlusions due to cerebral trauma have always been regarded as great rarities. However, we have found hypo-dense foci of vascular distribution in 3.5% of 3500 CT examinations for trauma during the late phase. Lesions in the vascular territory of the posterior cerebral artery are usually the result of supratentorial pressure rise from epidural and subdural haematomas, leading to compression of the vessels against the edge of the tentorium. Typical infacts in the territory of the medial and anterior cerebral arteries were found only rarely by CT after cerebral trauma. Infarcts at the watersheds between the three vascular territories were found with surprising frequency and small infarcts were found in the basal ganglia. It is assumed that these were due to ischaemic or hypoxic events due to cardiac or pulmonary complications during the initial phase. (orig.) [de

  5. Results from the AMANDA detector

    CERN Document Server

    Ackermann, M; Albrecht, H; Bai, X; Bartelt, M; Barwick, S W; Bay, R; Becka, T; Becker, J K; Becker, K H; Bernardini, E; Bertrand, D; Boersma, D J; Boser, S; Botner, O; Bouchta, A; Bouhali, O; Braun, J; Burgess, C; Burgess, T; Castermans, T; Chirkin, D; Collin, B; Conrad, J; Cooley, J; Cowen, D F; Davour, A; De Clercq, C; Pérez de los Heros, C; De Young, T R; Desiati, P; Ekstrom, P; Feser, T; Gaisser, T K; Ganugapati, R; Geenen, H; Gerhardt, L; Goldschmidt, A; Gross, A; Hallgren, A; Halzen, F; Hanson, K; Hardtke, R; Harenberg, T; Hauschildt, T; Helbing, K; Hellwig, M; Herquet, P; Hill, G C; Hodges, J; Hubert, D; Hughey, B; Hulth, P O; Hultqvist, K; Hundertmark, S; Jacobsen, J; Kampert, K H; Karle, A; Kelley, J; Kestel, M; Köpke, L; Kowalski, M; Krasberg, M; Kühn, K; Leich, H; Leuthold, M; Liubarsky, I; Madsen, J; Mandli, K; Marciniewski, P; Martino, J R; Matis, H S; McParland, C P; Messarius, T; Minaeva, Y; Miocinovic, P; Morse, R; Munich, K; Nahnhauer, R; Nam, J W; Neunhoffer, T; Niessen, P; Nygren, D R; Ogelman, H; Olbrechts, P; Pohl, A C; Porrata, R; Price, P B; Przybylski, G T; Rawlins, K; Resconi, E; Rhode, W; Ribordy, M; Richter, S; Sander, H G; Schinarakis, K; Schlenstedt, S; Schneider, D; Schwarz, R; Silvestri, A; Solarz, M; Spiczak, G M; Spiering, C; Stamatikos, M; Steele, D; Steffen, P; Stokstad, R G; Sulanke, K H; Taboada, I; Thollander, L; Tilav, S; Wagner, W; Walck, C; Walter, M; Wang, Y R; Wiebusch, C; Wischnewski, R; Wissing, H; Woschnagg, K; Yodh, G

    2004-01-01

    The Antarctic Muon And Neutrino Detector Array (AMANDA) is a high- energy neutrino telescope based at the geographic south pole. It is a lattice of photomultiplier tubes buried deep in the polar ice, which is used as interaction and detection medium. The primary goal of this detector is the observation of astronomical sources of high-energy neutrinos. This paper shows the latest results of the search for a diffuse flux of extraterrestrial nu /sub mu /s with energies between 10/sup 11/ eV and 10/sup 18/ eV, nu /sub mu /s emitted from point sources and nu /sub mu /s from dark matter annihilation in the Earth and the Sun.

  6. MITG test procedure and results

    International Nuclear Information System (INIS)

    Eck, M.E.; Mukunda, M.

    1983-01-01

    Elements and modules for Radioisotope Thermoelectric Generator have been performance tested since the inception of the RTG program. These test articles seldom resembled flight hardware and often lacked adequate diagnostic instrumentation. Because of this, performance problems were not identified in the early stage of program development. The lack of test data in an unexpected area often hampered the development of a problem solution. A procedure for conducting the MITG Test was developed in an effort to obtain data in a systematic, unambiguous manner. This procedure required the development of extensive data acquisition software and test automation. The development of a facility to implement the test procedure, the facility hardware and software requirements, and the results of the MITG testing are the subject of this paper

  7. CREAM: Results, Implications and Outlook

    CERN Document Server

    Seo, Eun-Suk

    The Cosmic Ray Energetics And Mass (CREAM) balloon-borne experiment has accumulated ∼161 days of exposure during six successful flights over Antarctica. Energy measurements are made with a transition radiation detector and an ionization calorimeter. Charge measurements are made with timing scintillators, pixelated Si, and Cherenkov detectors to minimize the effect of backscattered particles. High energy cosmicray data were collected over a wide energy range from ∼ 1010 to ∼ 1015 eV at an average altitude of ∼ 38.5 km, with ∼ 3.9 g/cm2 atmospheric overburden. All cosmic-ray elements from protons (Z = 1) to iron nuclei (Z = 26) are separated with excellent charge resolution. Recent results from the ongoing analysis including the discrepant hardening of elemental spectra at ∼ 200 GeV/n are presented and their implications on cosmic-ray origin, acceleration and propagation are discussed. The project status and plans are also presented.

  8. Benchmark results in radiative transfer

    International Nuclear Information System (INIS)

    Garcia, R.D.M.; Siewert, C.E.

    1986-02-01

    Several aspects of the F N method are reported, and the method is used to solve accurately some benchmark problems in radiative transfer in the field of atmospheric physics. The method was modified to solve cases of pure scattering and an improved process was developed for computing the radiation intensity. An algorithms for computing several quantities used in the F N method was done. An improved scheme to evaluate certain integrals relevant to the method is done, and a two-term recursion relation that has proved useful for the numerical evaluation of matrix elements, basic for the method, is given. The methods used to solve the encountered linear algebric equations are discussed, and the numerical results are evaluated. (M.C.K.) [pt

  9. Results from T2K

    International Nuclear Information System (INIS)

    Di Luise, S.

    2014-01-01

    T2K is an off-axis long baseline neutrino oscillation experiment designed to measure the θ 13 mixing parameter through the observation of ν e appearance in a ν μ beam. Concurrent measurement of ν μ disappearance allows refined measurements of the atmospheric Δm 23 2 and of the θ 23 mixing parameters. Analysis of data taken from January 2010 to March 2011 led to the first indication to ν μ → ν e appearance, it means θ 13 ≠ 0 (2.5σ significance), opening the way to CP violation searches in the leptonic sector. Measurement for ν μ disappearance were performed as well. Data taking restarted in March 2012 at higher intensities. Results, data taking status and future plans will be discussed. (author)

  10. Recent charmonium results at BESIII

    International Nuclear Information System (INIS)

    Guo, Y.

    2014-01-01

    Recent results on the charmonium decays based on 1.06*10 8 ψ' events taken with the BESIII (Beijing Spectrometer) detector operating at the BEPCII e + e - collider are presented in this talk. The properties and line-shape of η c , the production rate and properties of h c , and the first observation of the M1 transition φ' → γη' c are reported. In addition, the new decay modes of η' c are searched for in ρρ, K* 0 K-bar* 0 , and φφ final states, and the measurement of the multipole amplitude in ψ' → γχ c2 is presented. (author)

  11. HEAO A-2 extragalactic results

    Science.gov (United States)

    Boldt, E. A.

    1979-01-01

    The all-sky surveys made with the A-2 instrument aboard HEAO-1 involved spectroscopy over a broad enough band width, with sufficient resolution, to obtain the basic spectral characteristics for two extreme aspects of the extragalactic X-ray sky. The overall spectrum (above 3 KeV) is remarkably well decribed by a thermal model. At the other extreme, the detailed broad-band observations of individual sources are restricted to objects within the present epoch. The objects include several individual active galaxies studied in detail for the first time as well as clusters of galaxies. Relating these results to the vast spatially unresolved hard X-ray flux measured with this instruments as well as the softer X-rays (at less than 3 keV) spatially resolved to high redshifts with the Einstein Observatory remains a challenge.

  12. Recent ATLAS Heavy Ion results

    CERN Multimedia

    CERN. Geneva

    2012-01-01

    Lead nucleus collisions in the LHC recreate the state of matter which existed when the universe was a few microseconds old. This super-hot matter, composed of quark and gluons, emits thousands of particles as it expands, cools and converts back into hadrons. The ATLAS detector provides an excellent opportunity to perform detailed studies of this novel state of matter, measuring its bulk properties and its response to penetrating probes. Recent studies of particle correlations and fluctuations shed light on the initial geometry and its evolution into the final state. Studies of jet suppression and fragmentation show how the energetic partons interact with the medium. High precision measurements of boson production and first results on boson-jet correlations are important steps towards quantitative understanding of the parton energy loss mechanism.

  13. Results from ISTC frame work

    Energy Technology Data Exchange (ETDEWEB)

    Fukahori, Tokio [Japan Atomic Energy Research Inst., Tokai, Ibaraki (Japan). Tokai Research Establishment

    1998-03-01

    Under International Science Research Center (ISTC) projects, JAERI Nuclear Data Center has been taking a role of collaborator and monitor for following items; (1) Measurement of the Fission Neutron Spectra of the Minor Actinides and Spontaneous Fission of Curium Isotopes (ISTC no. 183: V.I. Khlopin Radium Institute, KRI, St. Petersburg, Russia), (2) Measurement and Analysis of the Basic Nuclear Data for Minor Actinides (ISTC no. 304: Institute of Physics and Power Engineering, IPPE, Obninsk, Russia), and Evaluation of Actinide Nuclear Data (ISTC no. CIS-3: Radiation Physics and Chemistry Problems Institute, RPCPI, Minsk, Belarus). These are related to the Japanese OMEGA Project and expected to supply minor actinide (MA) nuclear data, since Russia has good quality MA samples, experimental technique and nuclear data evaluation experiences. In this report, out-line and some results of above three projects are reviewed. (author)

  14. Recent SUSY results in ATLAS

    CERN Document Server

    Mamuzic, Judita; The ATLAS collaboration

    2018-01-01

    Supersymmetry (SUSY) is considered one of the best motivated extensions of the Standard Model. It postulates a fundamental symmetry between fermions and bosons, and introduces a set of new supersymmetric particles at the electroweak scale. It addresses the hierarchy and natu- ralness problem, gives a solution to the gauge couplings unification, and offers a cold dark matter candidate. Different aspects of SUSY searches, using strong, electroweak, third generation production, R-parity violation models, and long lived particles are being studied at the LHC. An overview of most recent results in SUSY searches using Run 2 ATLAS data, at 13 TeV with 36.1 fb−1 of integrated luminosity, was presented.

  15. Results from KASCADE–Grande

    International Nuclear Information System (INIS)

    Bertaina, M.; Apel, W.D.; Arteaga-Velázquez, J.C.; Bekk, K.; Blümer, J.; Bozdog, H.; Brancus, I.M.; Buchholz, P.; Cantoni, E.; Chiavassa, A.; Cossavella, F.

    2012-01-01

    The KASCADE–Grande experiment, located at Karlsruhe Institute of Technology (Germany) is a multi-component extensive air-shower experiment devoted to the study of cosmic rays and their interactions at primary energies 10 14 –10 18 eV. Main goals of the experiment are the measurement of the all-particle energy spectrum and mass composition in the 10 16 –10 18 eV range by sampling charged (N ch ) and muon (N μ ) components of the air shower. The method to derive the energy spectrum and its uncertainties, as well as the implications of the obtained result, is discussed. An overview of the analyses performed by KASCADE–Grande to derive the mass composition of the measured high-energy comic rays is presented as well.

  16. Results from KASCADE-Grande

    Energy Technology Data Exchange (ETDEWEB)

    Bertaina, M., E-mail: bertaina@to.infn.it [Dipartimento di Fisica Generale dell' Universita, Torino (Italy); Apel, W.D. [Institut fuer Kernphysik, KIT - Karlsruher Institut fuer Technologie (Germany); Arteaga-Velazquez, J.C. [Universidad Michoacana, Instituto de Fisica y Matematicas, Morelia (Mexico); Bekk, K. [Institut fuer Kernphysik, KIT - Karlsruher Institut fuer Technologie (Germany); Bluemer, J. [Institut fuer Kernphysik, KIT - Karlsruher Institut fuer Technologie (Germany); Institut fuer Experimentelle Kernphysik, KIT - Karlsruher Institut fuer Technologie (Germany); Bozdog, H. [Institut fuer Kernphysik, KIT - Karlsruher Institut fuer Technologie (Germany); Brancus, I.M. [National Institute of Physics and Nuclear Engineering, Bucharest (Romania); Buchholz, P. [Fachbereich Physik, Universitaet Siegen (Germany); Cantoni, E. [Dipartimento di Fisica Generale dell' Universita, Torino (Italy); Istituto di Fisica dello Spazio Interplanetario, INAF Torino (Italy); Chiavassa, A. [Dipartimento di Fisica Generale dell' Universita, Torino (Italy); Cossavella, F. [Institut fuer Experimentelle Kernphysik, KIT - Karlsruher Institut fuer Technologie (Germany); and others

    2012-11-11

    The KASCADE-Grande experiment, located at Karlsruhe Institute of Technology (Germany) is a multi-component extensive air-shower experiment devoted to the study of cosmic rays and their interactions at primary energies 10{sup 14}-10{sup 18} eV. Main goals of the experiment are the measurement of the all-particle energy spectrum and mass composition in the 10{sup 16}-10{sup 18} eV range by sampling charged (N{sub ch}) and muon (N{sub {mu}}) components of the air shower. The method to derive the energy spectrum and its uncertainties, as well as the implications of the obtained result, is discussed. An overview of the analyses performed by KASCADE-Grande to derive the mass composition of the measured high-energy comic rays is presented as well.

  17. Energy 21. Preconditions and results

    Energy Technology Data Exchange (ETDEWEB)

    NONE

    1998-03-01

    In 1988 the Danish government adopted an action plan for the environment and sustainable development. In 1990, the energy aspects of this plan were embodied in Energy 2000 and, in 1993, in Energy 2000 follow-up. The objective is a 20% reduction of CO{sub 2} emissions by the year 2005, compared with the level in 1988. Various measures are therefore being taken as time passes to help achieve this objective. As part of the monitoring of developments in the energy sector, it is necessary to take stock from time to time and to assess the direction in which the sector is moving. The government has therefore drawn up a new energy action plan, Energy 21, both to ensure that the overall objectives in the current plan are actively followed up on and to look ahead at the possibilities for action after the year 2005. The Danish Energy Agency has previously carried out a number of analyses of the technological and behavioural possibilities for reducing energy consumption in the short and the long term, for improving the efficiency of energy supply installations, and for using new and sustainable energy technologies. The results of this work are described in the report Denmark`s Energy Futures. The calculations in the report itself and its appendices. The more detailed assumptions and a description of the methods of analysis etc. are given in Basis for Analysis of Denmark`s Energy Futures. This report contains the assumptions, a description of methods and some of the results of the work on Energy 21. (au)

  18. Recent QCD Results from SLD

    International Nuclear Information System (INIS)

    Muller, David

    1999-01-01

    We present selected results on strong interaction physics from the SLD experiment at the SLAC Linear Collider. We report on several new studies of 3- and 4-jet hadronic Z 0 decays, in which jets are identified as quark, antiquark or gluon. The 3-jet Z 0 --> b anti-bg rate is sensitive to the b-quark mass; prospects for measuring m b are discussed. The gluon energy spectrum is measured over the full kinematic range, providing an improved test of QCD and limits on anomalous b anti-bg couplings. The parity violation in Z 0 --> b anti-bg decays is consistent with electroweak theory plus QCD. New tests of T- and CP-conservation at the bbg vertex are performed. A new measurement of the rate of gluon splitting into b anti-b pairs yields g b anti-b = 0.0031 ± 0.0007 (stat.)± 0.0006 (syst.) (Preliminary). We also present a number of new results on jet fragmentation into identified hadrons. The B hadron energy spectrum is measured over the full kinematic range using a new, inclusive technique, allowing stringent tests of predictions for its shape and a precise measurement of (xB) = 0.714 ± 0.005(stat.) ± 0.007(syst.) (Preliminary). A detailed study of correlations in rapidity y between pairs of identified pi ± , K ± and p/anti-p confirms that strangeness and baryon number are conserved locally, and shows local charge conservation between meson-baryon and strange-nonstrange pairs. Flavor-dependent long-range correlations are observed for all combinations of these hadron species, yielding new information on leading particle production. The first study of correlations using rapidities signed such that y > 0 corresponds to the quark direction provides additional new insights into fragmentation, including the first direct observation of baryon number ordering along the q anti-q axis

  19. RESULTS OF SUPPLEMENTAL MST STUDIES

    International Nuclear Information System (INIS)

    Peters, T; David Hobbs, D; Samuel Fink, S

    2006-01-01

    The current design of the Salt Waste Processing Facility (SWPF) includes an auxiliary facility, the Actinide Finishing Facility, which provides a second contact of monosodium titanate (MST) to remove soluble actinides and strontium from waste if needed. This treatment will occur after cesium removal by Caustic-Side Solvent Extraction (CSSX). Although the process changes and safety basis implications have not yet been analyzed, provisions also exist to recover the MST from this operation and return to the initial actinide removal step in the SWPF for an additional (third) contact with fresh waste. A U.S. Department of Energy (DOE) request identified the need to study the following issues involving this application of MST: Determine the effect of organics from the solvent extraction (CSSX) process on radionuclide sorption by MST; Determine the efficiency of re-using MST for multiple contacts; and Examine fissile loading on MST under conditions using a waste containing significantly elevated concentrations of plutonium, uranium, neptunium, and strontium. This report describes the results of three experimental studies conducted to address these needs: (1) Addition of high concentrations of entrained CSSX solvent had no noticeable effect, over a two week period, on the sorption of the actinides and strontium by MST in a direct comparison experiment. (2) Test results show that MST still retains appreciable capacity after being used once. For instance, reused MST--in the presence of entrained solvent--continued to sorb actinides and strontium. (3) A single batch of MST was used to sequentially contact five volumes of a simulant solution containing elevated concentrations of the radionuclides of interest. After the five contacts, we measured the following solution actinide loadings on the MST: plutonium: 0.884 ± 0.00539 wt % or (1.02 ± 0.0112) E+04 (micro)g/g MST, uranium: 12.1 ± 0.786 wt % or (1.40 ± 0.104) E+05 (micro)g/g MST, and neptunium: 0.426 ± 0.00406 wt % or

  20. TFTR D-T results

    International Nuclear Information System (INIS)

    Meade, D.M.

    1994-01-01

    Temperatures, densities and confinement of deuterium plasmas confined in tokamaks have been achieved within the last decade that are approaching those required for a D-T reactor. As a result, the unique phenomena present in a D-T reactor plasma (D-T plasma confinement, alpha confinement, alpha heating and possible alpha driven instabilities) can now be studied in the laboratory. Recent experiments on the Tokamak Fusion Test Reactor (TFTR) have been the first magnetic fusion experiments to study plasmas with reactor fuel concentrations of tritium. The injection of ∼ 20 MW of tritium and 14 MW of deuterium neutral beams into the TFTR produced a plasma with a T/D density ratio of ∼1 and yielded a maximum fusion power of ∼ 9.2 MW. The fusion power density in the core of the plasma was ∼ 1.8 MW m -3 approximating that expected in a D-T fusion reactor. A TFTR plasma with T/D density ratio of ∼ 1 was found to have ∼ 20% higher energy confinement time than a comparable D plasma, indicating a confinement scaling with average ion mass, A, of τ E ∼ A 0.6 . The core ion temperature increased from 30 keV to 37 keV due to a 35% improvement of ion thermal conductivity. Using the electron thermal conductivity from a comparable deuterium plasma, about 50% of the electron temperature increase from 9 keV to 10.6 keV can be attributed to electron heating by the alpha particles. The ∼ 5% loss of alpha particles, as observed on detectors near the bottom edge of the plasma, was consistent with classical first orbit loss without anomalous effects. Initial measurements have been made of the confined energetic alphas and the resultant alpha ash density. At fusion power levels of 7.5 MW, fluctuations at the Toroidal Alfven Eigenmode frequency were observed by the fluctuation diagnostics. However, no additional alpha loss due to the fluctuations was observed

  1. Evaluating the RELM Test Results

    Directory of Open Access Journals (Sweden)

    Michael K. Sachs

    2012-01-01

    Full Text Available We consider implications of the Regional Earthquake Likelihood Models (RELM test results with regard to earthquake forecasting. Prospective forecasts were solicited for M≥4.95 earthquakes in California during the period 2006–2010. During this period 31 earthquakes occurred in the test region with M≥4.95. We consider five forecasts that were submitted for the test. We compare the forecasts utilizing forecast verification methodology developed in the atmospheric sciences, specifically for tornadoes. We utilize a “skill score” based on the forecast scores λfi of occurrence of the test earthquakes. A perfect forecast would have λfi=1, and a random (no skill forecast would have λfi=2.86×10-3. The best forecasts (largest value of λfi for the 31 earthquakes had values of λfi=1.24×10-1 to λfi=5.49×10-3. The best mean forecast for all earthquakes was λ̅f=2.84×10-2. The best forecasts are about an order of magnitude better than random forecasts. We discuss the earthquakes, the forecasts, and alternative methods of evaluation of the performance of RELM forecasts. We also discuss the relative merits of alarm-based versus probability-based forecasts.

  2. Salt decontamination demonstration test results

    International Nuclear Information System (INIS)

    Snell, E.B.; Heng, C.J.

    1983-06-01

    The Salt Decontamination Demonstration confirmed that the precipitation process could be used for large-scale decontamination of radioactive waste sale solution. Although a number of refinements are necessary to safely process the long-term requirement of 5 million gallons of waste salt solution per year, there were no observations to suggest that any fundamentals of the process require re-evaluation. Major accomplishments were: (1) 518,000 gallons of decontaminated filtrate were produced from 427,000 gallons of waste salt solution from tank 24H. The demonstration goal was to produce a minimum of 200,000 gallons of decontaminated salt solution; (2) cesium activity in the filtrate was reduced by a factor of 43,000 below the cesium activity in the tank 24 solution. This decontamination factor (DF) exceeded the demonstration goal of a DF greater than 10,000; (3) average strontium-90 activity in the filtrate was reduced by a factor of 26 to less than 10 3 d/m/ml versus a goal of less than 10 4 d/m/ml; and (4) the concentrated precipitate was washed to a final sodium ion concentration of 0.15 M, well below the 0.225 M upper limit for DWPF feed. These accomplishments were achieved on schedule and without incident. Total radiation exposure to personnel was less than 350 mrem and resulted primarily from sampling precipitate slurry inside tank 48. 3 references, 6 figures, 2 tables

  3. Latest results from Daya Bay

    Science.gov (United States)

    Vorobel, Vit; Daya Bay Collaboration

    2017-07-01

    The Daya Bay Reactor Neutrino Experiment was designed to measure θ 13, the smallest mixing angle in the three-neutrino mixing framework, with unprecedented precision. The experiment consists of eight functionally identical detectors placed underground at different baselines from three pairs of nuclear reactors in South China. Since Dec. 2011, the experiment has been running stably for more than 4 years, and has collected the largest reactor anti-neutrino sample to date. Daya Bay is able to greatly improve the precision on θ 13 and to make an independent measurement of the effective mass splitting in the electron antineutrino disappearance channel. Daya Bay can also perform a number of other precise measurements, such as a high-statistics determination of the absolute reactor antineutrino flux and spectrum, as well as a search for sterile neutrino mixing, among others. The most recent results from Daya Bay are discussed in this paper, as well as the current status and future prospects of the experiment.

  4. EFTF cobalt test assembly results

    International Nuclear Information System (INIS)

    Rawlins, J.A.; Wootan, D.W.; Carter, L.L.; Brager, H.R.; Schenter, R.E.

    1988-01-01

    A cobalt test assembly containing yttrium hydride pins for neutron moderation was irradiated in the Fast Flux Test Facility during Cycle 9A for 137.7 equivalent full power days at a power level fo 291 MW. The 36 test pins consisted of a batch of 32 pins containing cobalt metal to produce Co-60, and a set of 4 pins with europium oxide to produce Gd-153, a radioisotope used in detection of the bone disease Osteoporosis. Post-irradiation examination of the cobalt pins determined the Co-60 produced with an accuracy of about 5 %. The measured Co-60 spatially distributed concentrations were within 20 % of the calculated concentrations. The assembly average Co-60 measured activity was 4 % less than the calculated value. The europium oxide pins were gamma scanned for the europium isotopes Eu-152 and Eu-154 to an absolute accuracy of about 10 %. The measured europium radioisotpe anc Gd-153 concentrations were within 20 % of calculated values. In conclusion, the hydride assembly performed well and is an excellent vehicle for many Fast Flux Test Facility isotope production applications. The results also demonstrate that the calculational methods developed by the Westinghouse Hanford Company are very accurate. (author)

  5. Integration process and logistics results

    International Nuclear Information System (INIS)

    2004-01-01

    The Procurement and Logistics functions have gone through a process of integration since the beginning of integrated management of Asco and Vandellos II up to the present. These are functions that are likely to be designed for delivering a single product to the rest of the organization, defined from a high level of expectations, and that admit simplifications and materialization of synergy's as they are approached from an integrated perspective. The analyzed functions are as follows: Service and Material Purchasing, Warehouse and Material Management, and Documentation and General Services Management. In all case, to accomplish the integration, objectives, procedures and information systems were unified. As for the organization, a decision was made in each case on whether or not to out source. The decisive corporate strategy to integrate, resulting in actions such as moving corporate headquarters to Vandellos II, corporate consolidation, regulation of employment and implementation of the ENDESA Group Economic Information System (SIE) , has shaped this process, which at present can be considered as practically complete. (Author)

  6. PTAC driving safety survey results

    Energy Technology Data Exchange (ETDEWEB)

    Lloyd, E. [Petroleum Technology Alliance Canada, Calgary, AB (Canada)

    2005-07-01

    The results of a survey conducted by the Petroleum Technology Alliance Canada were presented. The survey identified ways in which companies in the oil and gas industry can reduce the potential for vehicle incidents, as well as improve fleet management techniques. Respondents provided a list of over 60 relevant technologies with high potential for application. Top driving safety challenges included adverse weather and road conditions, as well as driver attitude and awareness. Driver speed and fatigue were also seen as significant challenges, as well as encounters with wildlife and road conditions. Poor site conditions were also identified as a challenge, along with poor hazard recognition training, and lack of experience. A total of 157 representatives responded, whose fleets collectively drive approximately 136,500,000 km per year. The fleets totalled 15,800 vehicles. Respondents' affiliations with the oil and gas industry were included, as well as ownership classifications and company fleet sizes. Total annual fleet kilometers were presented, as well as the number of incidents per company per year, along with the number of respondents' animal strikes per year. tabs, figs.

  7. LSND results and their implications

    International Nuclear Information System (INIS)

    Caldwell, D.O.

    1996-01-01

    The combined 1993, 1994, and 1995 data from the LSND experiment shows a statistically compelling excess of events of the type expected for ν μ →ν e neutrino oscillations. An electron between 36 and 60 MeV is identified by Cherenkov and scintillation light from ν e p→e + n, and if a γ is tightly constrained to be correlated with it from np→dγ (2.2 MeV), then 22 such events are observed, but only 4.6±0.6 are expected from background. The probability that this is a fluctuation is -7 . If subsequent analysis shows a similar effect from the independent channel ν μ →ν e , then this would imply a neutrino mass difference which would contribute significantly to the dark matter of the universe. Explaining also the solar and atmospheric neutrino deficits results in a neutrino mass pattern which gives a cold + hot dark matter which fits the structure of the universe on all scales and requires a critical density universe and an universe age compatible with that of the oldest stars. This mass pattern involves a sterile neutrino, evidence for which may come from the need for it in producing heavy elements by supernovae and for blowing off the supernova mantle. (author) 3 figs., 18 refs

  8. Results of the 2009 elections

    CERN Multimedia

    Association du personnel

    The elections to renew the Staff Council for the 2010-2011 period are now behind us and we are very pleased to have had at least as many candidates as posts in five of the six electoral colleges. Furthermore, the average rate of participation of 56.8% in these elections is a very good result compared to previous years. We thank the candidates who have committed themselves to actively defending the interests of the staff, and all our members have shown, by voting, their full support of the candidates in their college and Department. This newly-elected Staff Council (see its composition on the following page) will therefore be truly representative of all the sectors and professions of the Organization, which will be a major asset when the Staff Association representatives begin discussions with the Management and Member States in 2010 on the key issues of the five-yearly review and the measures to be taken to absorb the deficit of our Pension Fund. Armed with this vote of confidence, we know that we can count o...

  9. Experimental results on evaporation waves

    Science.gov (United States)

    Grana Otero, Jose; Parra Fabian, Ignacio

    2010-11-01

    A liquid contained in a vertical glass tube is suddenly depressurized from a high initial pressure down to one for which the stable state is vapour, so vaporization sets off at the free surface. For large enough evaporation rates, the planar vapour-liquid interface is Darrieus-Landau unstable [1], leading to the interface surface rippling close to the instability threshold. Further increasing the initial to final pressure ratio brings about evaporation waves [2,3], in which a highly corrugated front propagates downwards into the liquid. A new experimental method is presented as well as some experimental results obtained by tracking the evolution of the front with a high speed camera. In addition, a number of new phenomena related to the dynamics of bubbles growth at the walls has been uncovered. In particular, a new mode of propagation of the evaporation front is found. In this mode the front originates from below the interface, so the propagation is upwards against gravity with a curved but smooth front.[4pt] [1] F. J. Higuera, Phys. Fluids, V. 30, 679 (1987).[0pt] [2] J.E.Shepherd and B.Sturtevant, J.Fluid Mech., V.121,379 (1982).[0pt] [3] P.Reinke and G.Yadigaroglu, Int.J.Multiph. Flow, V.27,1487 (2001).

  10. Uncertainty of dustfall monitoring results

    Directory of Open Access Journals (Sweden)

    Martin A. van Nierop

    2017-06-01

    Full Text Available Fugitive dust has the ability to cause a nuisance and pollute the ambient environment, particularly from human activities including construction and industrial sites and mining operations. As such, dustfall monitoring has occurred for many decades in South Africa; little has been published on the repeatability, uncertainty, accuracy and precision of dustfall monitoring. Repeatability assesses the consistency associated with the results of a particular measurement under the same conditions; the consistency of the laboratory is assessed to determine the uncertainty associated with dustfall monitoring conducted by the laboratory. The aim of this study was to improve the understanding of the uncertainty in dustfall monitoring; thereby improving the confidence in dustfall monitoring. Uncertainty of dustfall monitoring was assessed through a 12-month study of 12 sites that were located on the boundary of the study area. Each site contained a directional dustfall sampler, which was modified by removing the rotating lid, with four buckets (A, B, C and D installed. Having four buckets on one stand allows for each bucket to be exposed to the same conditions, for the same period of time; therefore, should have equal amounts of dust deposited in these buckets. The difference in the weight (mg of the dust recorded from each bucket at each respective site was determined using the American Society for Testing and Materials method D1739 (ASTM D1739. The variability of the dust would provide the confidence level of dustfall monitoring when reporting to clients.

  11. Stapedectomy in tympanosclerosis, hearing results

    International Nuclear Information System (INIS)

    Al-Qahtani, M.; Hagr, A.

    2008-01-01

    The aim of present study was to evaluate the results of using stapedectomy to treat tympanosclerosis fixation of footplate. It is a retrospective review of tympanosclerosis of the oval window with stapes fixation, after undergoing surgery. Eight patients underwent stapedectomy for tympanosclerotic stapes. Postoperative post-op air-bone gap ABG closure to within 10 dB was achieved in 25% of the cases. An ABG of less than 20 db was obtained in 87.5% of the cases. The mean preoperative pre-op ABGs were 31.09 dB. Significant post-op improvement of air conduction thresholds more than, or equal to 20dB was found in 62.5% of cases. No significant sensorineural hearing loss was seen in this series with a mean pre-op bone-conduction threshold BC of 23.43 dB and a mean post-op BC threshold of 16.25 dB. The mean follow-up period was 6.5 months. (author)

  12. Cyclonic valve test: preliminary results

    Energy Technology Data Exchange (ETDEWEB)

    Monteiro, Andre Sampaio; Moraes, Carlos Alberto C.; Marins, Luiz Philipe M.; Soares, Fabricio; Oliveira, Dennis; Lima, Fabio Soares de; Airao, Vinicius [Petroleo Brasileiro S.A. (PETROBRAS), Rio de Janeiro, RJ (Brazil); Ton, Tijmen [Twister BV, Rijswijk (Netherlands)

    2012-07-01

    For many years, the petroleum industry has been developing a valve that input less shear to the flow for a given required pressure drop and this can be done using the cyclonic concept. This paper presents a comparison between the performances of a cyclonic valve (low shear) and a conventional globe valve. The aim of this work is to show the advantages of using a cyclonic low shear valve instead of the commonly used in the primary separation process by PETROBRAS. Tests were performed at PETROBRAS Experimental Center (NUEX) in Aracaju/SE varying some parameters: water cut; pressure loss (from 4 kgf/cm2 to 10 kgf/cm2); flow rates (30 m3/h and 45 m3/h). Results indicates a better performance of the cyclonic valve, if compared with a conventional one, and also that the difference of the performance, is a function of several parameters (emulsion stability, water content free, and oil properties). The cyclonic valve tested can be applied as a choke valve, as a valve between separation stages (for pressure drop), or for controlling the level of vessels. We must emphasize the importance to avoid the high shear imposed by conventional valves, because once the emulsion is created, it becomes more difficult to break it. New tests are being planned to occur in 2012, but PETROBRAS is also analyzing real cases where the applications could increase the primary process efficiency. In the same way, the future installations are also being designed considering the cyclonic valve usage. (author)

  13. Majorana Thermosyphon Prototype Experimental Results

    International Nuclear Information System (INIS)

    Fast, James E.; Reid, Douglas J.; Aguayo Navarrete, Estanislao

    2010-01-01

    The Majorana demonstrator will operate at liquid Nitrogen temperatures to ensure optimal spectrometric performance of its High Purity Germanium (HPGe) detector modules. In order to transfer the heat load of the detector module, the Majorana demonstrator requires a cooling system that will maintain a stable liquid nitrogen temperature. This cooling system is required to transport the heat from the detector chamber outside the shield. One approach is to use the two phase liquid-gas equilibrium to ensure constant temperature. This cooling technique is used in a thermosyphon. The thermosyphon can be designed so the vaporization/condensing process transfers heat through the shield while maintaining a stable operating temperature. A prototype of such system has been built at PNNL. This document presents the experimental results of the prototype and evaluates the heat transfer performance of the system. The cool down time, temperature gradient in the thermosyphon, and heat transfer analysis are studied in this document with different heat load applied to the prototype.

  14. Double Chooz: Results and Perspectives

    Energy Technology Data Exchange (ETDEWEB)

    Franke, A.J., E-mail: ajfranke@nevis.columbia.edu [Columbia University, New York, New York 10027 (United States)

    2013-04-15

    The Double Chooz experiment has been observing ν{sup ¯}{sub e} from two reactor cores at the Chooz nuclear power station in Ardennes, France, with a single 10.3 m{sup 3} fiducial volume Gd-doped liquid scintillator detector at a flux-weighted average baseline of ∼1050 m. This article reviews results achieved with a detector live time of 227.93 days and exposure of 33.71 GW-ton-years. A total of 8,249 candidate ν{sup ¯}{sub e} events have been observed, compared to an expected 8,937 events in the null-oscillation case: this deficit is interpreted as evidence for ν{sup ¯}{sub e} disappearance. A fit to the observed neutrino rate and spectral shape gives a best-fit value of sin{sup 2}(2θ{sub 13})=0.109±0.030(stat.)±0.025(syst.) at a mass-squared splitting of Δm{sub 31}{sup 2}=2.32×10{sup −3} eV{sup 2}. The null-oscillation hypothesis is excluded by the data at 99.8% CL (2.9σ). The Double Chooz Near Detector is under construction, and analysis efforts to measure neutrino directionality, test Lorentz violation, and measure backgrounds in situ are underway.

  15. Double Chooz: Results and Perspectives

    Science.gov (United States)

    Franke, A. J.

    2013-04-01

    The Double Chooz experiment has been observing ν from two reactor cores at the Chooz nuclear power station in Ardennes, France, with a single 10.3 m fiducial volume Gd-doped liquid scintillator detector at a flux-weighted average baseline of ˜1050 m. This article reviews results achieved with a detector live time of 227.93 days and exposure of 33.71 GW-ton-years. A total of 8,249 candidate ν events have been observed, compared to an expected 8,937 events in the null-oscillation case: this deficit is interpreted as evidence for ν disappearance. A fit to the observed neutrino rate and spectral shape gives a best-fit value of sin2(2θ13)=0.109±0.030 (stat.)±0.025 (syst.) at a mass-squared splitting of Δm312=2.32×10-3 eV. The null-oscillation hypothesis is excluded by the data at 99.8% CL (2.9σ). The Double Chooz Near Detector is under construction, and analysis efforts to measure neutrino directionality, test Lorentz violation, and measure backgrounds in situ are underway.

  16. Comparison of airtightness retesting results

    Energy Technology Data Exchange (ETDEWEB)

    1989-01-01

    Polyethylene vapour barrier and airtight drywall are two methods used by the building industry to reduce air leakage in residential homes. Concern has been expressed that polyethylene air/vapour barriers degrade over time. This concern has led various agencies to test and retest homes for air leakage. This report is the compilation of the data collected as a result of that testing. Raw data were collected on 145 homes from various sources. Data were screened and the tests of homes were omitted from the analysis if the fan tests were done on the same house by different firms, if the construction of the house was not sufficiently complete, or if the initial air change rate per hour (ACH) was greater than 3. With these omissions from the database, 90 homes remained to be analyzed. The 90 homes were separated into two groups, those with an initial ACH less than 1.5 and those with an initial ACH between 1.5 and 3.0. The data were recorded in two tables which included the ACH, the time in months, the percentage change, and the difference in change between the first test and each subsequent test. These data indicate a relatively minor average change in airtightness. Keeping in mind the quantity of data collected the time period examined, there is no indication that significant problems exist that would necessitate a change to the current building practice. 2 figs., 5 tabs.

  17. Excellent results for CERN runners

    CERN Multimedia

    Hervé Cornet, CERN Running club

    2015-01-01

    As in previous years, thirty or so runners from CERN took part in the Tour du Canton de Genève (more information here, in French only).   The men’s team that won the corporate challenge prize in the Tour du Canton de Genève: (standing, left to right) Patrick Villeton, Phil Hebda, Mika Vesterinen, Steffen Doebert; (sitting, left to right) Guillaume Michet and Camille Ruiz-Llamas. The Laboratory was represented in the corporate challenge by five teams, one of which came first in the men’s category. CERN’s other teams also put in good performances, with one finishing fourth in the men's category and another seventh in the mixed category. Runners from CERN did well in the individual classifications too. All the results can be found here. The Maxi Race team: (left to right) Sebastien Ponce, Alain Cauphy, Klaus Hanke and Christophe Biot. Elsewhere, four CERN runners competed in the finals of the Annecy Maxi Race (site in French only...

  18. LSND results and their implications

    Energy Technology Data Exchange (ETDEWEB)

    Caldwell, D O [California Univ., Santa Barbara, CA (United States). Dept. of Physics

    1996-11-01

    The combined 1993, 1994, and 1995 data from the LSND experiment shows a statistically compelling excess of events of the type expected for {nu}{sub {mu}} {yields}{nu}{sub e} neutrino oscillations. An electron between 36 and 60 MeV is identified by Cherenkov and scintillation light from {nu}{sub e}p{yields}e{sup +}n, and if a {gamma} is tightly constrained to be correlated with it from np{yields}d{gamma} (2.2 MeV), then 22 such events are observed, but only 4.6{+-}0.6 are expected from background. The probability that this is a fluctuation is <10{sup -7}. If subsequent analysis shows a similar effect from the independent channel {nu}{sub {mu}}{yields}{nu}{sub e}, then this would imply a neutrino mass difference which would contribute significantly to the dark matter of the universe. Explaining also the solar and atmospheric neutrino deficits results in a neutrino mass pattern which gives a cold + hot dark matter which fits the structure of the universe on all scales and requires a critical density universe and an universe age compatible with that of the oldest stars. This mass pattern involves a sterile neutrino, evidence for which may come from the need for it in producing heavy elements by supernovae and for blowing off the supernova mantle. (author) 3 figs., 18 refs.

  19. CMS results in Electroweak Physics

    CERN Multimedia

    CERN. Geneva

    2011-01-01

    We present the results of electroweak studies performed using data collected in 2010 at a center-of-mass energy of 7 TeV by the CMS experiment at the LHC. Besides their intrinsic interest as unique samples to calibrate and understand the CMS detector response to leptons, jets and missing energy, events containing W and Z bosons appear as dominant components in many Higgs seaches and in most of the searches beyond the Standard Model, either as signal or as background. In addition, the excellent level of theoretical and experimental understanding of these processes allows electroweak tests at the LHC at an unprecendented level of precision. CMS uses a wide range of final states to measure cross sections, asymmetries, polarizations and differential distributions in general. The current integrated luminosity is already sufficient to perform not just inclusive measurements using W and Z decays into muons and electrons, but also precise studies of associated jet production and final states containing taus, as well...

  20. Our Results in Penile Fractures

    Directory of Open Access Journals (Sweden)

    Tufan Süelözgen

    2016-06-01

    Full Text Available Introduction Penile fracture is a urological emergency caused by direct trauma to an erected penis, tearing the tunica albuginea in the corpus cavernosum. The preferred treatment method is draining the hematoma and surgical repair of tunica albuginea tear as soon as possible following diagnosis. Materials and Methods Forty-nine patients who were diagnosed with penile fracture between January 2009 and December 2014 were reviewed. Physical examination was performed to see the extent of penile hematoma, the side of the penile curvature and the presence of blood in the external meatus. Two patients who were diagnosed with urethrorrhagia underwent retrograde urethrogram for urethral injury. In all patients, penile skin was peeled using a circular subcoronal degloving incision and tunica tear was repaired using absorbable suture materials. The patients were then followed for painful erections, penile deformities and erection angles. Results The average age of the 49 patients, who were included in the study, was 36.5 years (21-65. In their etiological questioning, most patients reported the fracture occurring during sexual intercourse. Retrograde urethrography was indicated in 2 patients with blood in the external meatus and were diagnosed with urethral injury. The patients were taken to emergency surgery. Tunica defects varied between 1 and 2 cm. Incomplete urethral injuries were primarily repaired around 18 French Foley catheter. None of the patients reported penile deformity or painful erections. Their erection angles were found to be within the normal range. Conclusion Even though it is a relatively rare condition, penile fractures are so important that might cause serious complications when not treated surgically. A thorough anamnesis and physical examination suffice for diagnosis.

  1. Public Administration reforms and results

    Directory of Open Access Journals (Sweden)

    Gunnar Helgi Kristinsson

    2014-12-01

    Full Text Available Research on administrative reforms during the past thirty years indicates that reform efforts of countries differ. The Anglo Saxon states were at the forefront of the New Public Management movement while countries on mainland Europe were more hesitant and moved further towards the Neo-Weberian state. Academics have tried to explain different reform efforts within countries by looking at political, historical and cultural issues, values and economic factors to name just a few. Three hypotheses are put forward to explain reform efforts in different states. This research involves analysing the implementation of two different reform trends, New Public Management and the Neo-Weberian tradition. The analysis indicates that countries vary in their commitment to reform rather than in the emphasis on either New Public Management or the Neo-Weberian State. Decentralization, clear objectives and consultation with communities and experts are closely related to national reform efforts. However, Iceland does distinguish itself from Europe and the Nordic countries. The analysis reveals that although decentralization is high in the Icelandic system, autonomy of agencies does not have a strong relation to a varied use of administrative instruments. The second part of the article focuses on the results and achievements of reform programmes. The achievement of reform programmes are examined in relation to theories of bounded rationality, street level bureaucracy (bottom up and consensus decision making. Three hypotheses are presented and tested to explain what causes reforms programmes to be successful in some countries and not in others. The analysis reveals that countries are more likely to succeed if bounded rationality is applied with careful preparation and when stakeholders are consulted.

  2. 'Orion-2': first scientific results

    International Nuclear Information System (INIS)

    Gurzadyan, G.A.

    1975-01-01

    The first results of proceeding some data collected by the 'Orion-2' observatory set up in the 'Soyuz-13' are presented. The goal of the experiment is to get the photographs of ultraviolet (UV) spectra of weak stars in the range of 2000-5000 A. Spectrograms are obtained for stars with brightness of 9-9.5 stellar magnitude at 1.5 min exposure. It has been possible to take spectrograms of many stars weaker than the 12-th magnitude at the 18 min exposure and at the short-wave boundary of a spectrum of 2500 A. A group of stars of an unknown type has been observed not far from Capella. The group contains approximately twenty stars weaker than the 10-th photographic magnitude. The average position of the group is α=0.5sup(m)10sup(m), delta=+44deg30'. Spectrograms of more than twenty hot stars in the Sails constellation in the South Sky are obtained. According to the 'Orion-2' data the light absorption in the interstellar space in the range of 2000-3000 A is caused by graphite particles of an almost spheric shape, that is in accordance with present assumptions. In spectra of over 100 stars the doublet of ionized magnesium, 2800 Mg 2, has been distinguished and measured. Spectral photographs made by the 'Orion-2' allow one to reveal chromosphere of cool stars. A strange star is discovered (12sup(m),6 brigthness in photographic rays) not far from Capella, its spectrum displaying many emission lines. A unique spectrogram of the NGC 2 2149 planetary nebula and its nucleus has been obtained. The question is whether it is possible to classify stars not only by their lines but also by the continuous UV spectrum up to 2000 A. This method may turn out to be very effective for weak stars. The 'Orion-2' has demonstrated ample possibilities of carrying out astrophysical researches outside the atmosphere

  3. Mobile evaporator corrosion test results

    International Nuclear Information System (INIS)

    Rozeveld, A.; Chamberlain, D.B.

    1997-05-01

    Laboratory corrosion tests were conducted on eight candidates to select a durable and cost-effective alloy for use in mobile evaporators to process radioactive waste solutions. Based on an extensive literature survey of corrosion data, three stainless steel alloys (304L, 316L, AL-6XN), four nickel-based alloys (825, 625, 690, G-30), and titanium were selected for testing. The corrosion tests included vapor phase, liquid junction (interface), liquid immersion, and crevice corrosion tests on plain and welded samples of candidate materials. Tests were conducted at 80 degrees C for 45 days in two different test solutions: a nitric acid solution. to simulate evaporator conditions during the processing of the cesium ion-exchange eluant and a highly alkaline sodium hydroxide solution to simulate the composition of Tank 241-AW-101 during evaporation. All of the alloys exhibited excellent corrosion resistance in the alkaline test solution. Corrosion rates were very low and localized corrosion was not observed. Results from the nitric acid tests showed that only 316L stainless steel did not meet our performance criteria. The 316L welded interface and crevice specimens had rates of 22.2 mpy and 21.8 mpy, respectively, which exceeds the maximum corrosion rate of 20 mpy. The other welded samples had about the same corrosion resistance as the plain samples. None of the welded samples showed preferential weld or heat-affected zone (HAZ) attack. Vapor corrosion was negligible for all alloys. All of the alloys except 316L exhibited either open-quotes satisfactoryclose quotes (2-20 mpy) or open-quotes excellentclose quotes (<2 mpy) corrosion resistance as defined by National Association of Corrosion Engineers. However, many of the alloys experienced intergranular corrosion in the nitric acid test solution, which could indicate a susceptibility to stress corrosion cracking (SCC) in this environment

  4. Recent results in visual servoing

    Science.gov (United States)

    Chaumette, François

    2008-06-01

    Visual servoing techniques consist in using the data provided by a vision sensor in order to control the motions of a dynamic system. Such systems are usually robot arms, mobile robots, aerial robots,… but can also be virtual robots for applications in computer animation, or even a virtual camera for applications in computer vision and augmented reality. A large variety of positioning tasks, or mobile target tracking, can be implemented by controlling from one to all the degrees of freedom of the system. Whatever the sensor configuration, which can vary from one on-board camera on the robot end-effector to several free-standing cameras, a set of visual features has to be selected at best from the image measurements available, allowing to control the degrees of freedom desired. A control law has also to be designed so that these visual features reach a desired value, defining a correct realization of the task. With a vision sensor providing 2D measurements, potential visual features are numerous, since as well 2D data (coordinates of feature points in the image, moments, …) as 3D data provided by a localization algorithm exploiting the extracted 2D measurements can be considered. It is also possible to combine 2D and 3D visual features to take the advantages of each approach while avoiding their respective drawbacks. From the selected visual features, the behavior of the system will have particular properties as for stability, robustness with respect to noise or to calibration errors, robot 3D trajectory, etc. The talk will present the main basic aspects of visual servoing, as well as technical advances obtained recently in the field inside the Lagadic group at INRIA/INRISA Rennes. Several application results will be also described.

  5. Corral Monitoring System assessment results

    International Nuclear Information System (INIS)

    Filby, E.E.; Haskel, K.J.

    1998-03-01

    This report describes the results of a functional and operational assessment of the Corral Monitoring Systems (CMS), which was designed to detect and document accountable items entering or leaving a monitored site. Its development was motivated by the possibility that multiple sites in the nuclear weapons states of the former Soviet Union might be opened to such monitoring under the provisions of the Strategic Arms Reduction Treaty. The assessment was performed at three levels. One level evaluated how well the planned approach addressed the target application, and which involved tracking sensitive items moving into and around a site being monitored as part of an international treaty or other agreement. The second level examined the overall design and development approach, while the third focused on individual subsystems within the total package. Unfortunately, the system was delivered as disassembled parts and pieces, with very poor documentation. Thus, the assessment was based on fragmentary operating data coupled with an analysis of what documents were provided with the system. The system design seemed to be a reasonable match to the requirements of the target application; however, important questions about site manning and top level administrative control were left unanswered. Four weaknesses in the overall design and development approach were detected: (1) poor configuration control and management, (2) inadequate adherence to a well defined architectural standard, (3) no apparent provision for improving top level error tolerance, and (4) weaknesses in the object oriented programming approach. The individual subsystems were found to offer few features or capabilities that were new or unique, even at the conceptual level. The CMS might possibly have offered a unique combination of features, but this level of integration was never realized, and it had no unique capabilities that could be readily extracted for use in another system

  6. Corral Monitoring System assessment results

    Energy Technology Data Exchange (ETDEWEB)

    Filby, E.E.; Haskel, K.J.

    1998-03-01

    This report describes the results of a functional and operational assessment of the Corral Monitoring Systems (CMS), which was designed to detect and document accountable items entering or leaving a monitored site. Its development was motivated by the possibility that multiple sites in the nuclear weapons states of the former Soviet Union might be opened to such monitoring under the provisions of the Strategic Arms Reduction Treaty. The assessment was performed at three levels. One level evaluated how well the planned approach addressed the target application, and which involved tracking sensitive items moving into and around a site being monitored as part of an international treaty or other agreement. The second level examined the overall design and development approach, while the third focused on individual subsystems within the total package. Unfortunately, the system was delivered as disassembled parts and pieces, with very poor documentation. Thus, the assessment was based on fragmentary operating data coupled with an analysis of what documents were provided with the system. The system design seemed to be a reasonable match to the requirements of the target application; however, important questions about site manning and top level administrative control were left unanswered. Four weaknesses in the overall design and development approach were detected: (1) poor configuration control and management, (2) inadequate adherence to a well defined architectural standard, (3) no apparent provision for improving top level error tolerance, and (4) weaknesses in the object oriented programming approach. The individual subsystems were found to offer few features or capabilities that were new or unique, even at the conceptual level. The CMS might possibly have offered a unique combination of features, but this level of integration was never realized, and it had no unique capabilities that could be readily extracted for use in another system.

  7. FIRST RESULTS FROM OEDOTENSIOMETRIC TESTS

    Directory of Open Access Journals (Sweden)

    Luigi Cavazza

    2008-09-01

    Full Text Available An oedotensiometer was used to examine to examine the behaviour of sieved sample of a swelling soil (a vertisol as well as of the same soils treated with solution of Na+ + Ca2+ to simulate the soil changes from excessive irrigation with brackish water. The oedometer test consisted in an infiltration of water from below through a ceramic porous plate at a feeding pressure of +10 cm water and successive drainage under a depression mostly of -112 cm of water. The rate of water entry as well as the swelling rate of the sample were monitored. Preliminary considerations regards the domains in which the shrinkage curve of a swelling soil is subdivided and make hypothesis on the swelling process expected when the infiltration from below of the sample is applied. The results support the hypothesis that when the water pressure is applied some water enters rather rapidly in the larger structural pores and is followed later by the swelling in the smaller pores, responsible for the basic domain. This first conclusion demonstrates that the assumption of a simultaneous movement of solid and liquid components in the sample, which is the base of most theoretical developments for swelling soils, cannot be accepted for the tested samples. Some cases with water clogging on the sample surface confirm a late final swelling of the soil and permitted to evaluate the hydraulic conductivity of the swollen soil. These manifestations are more evident in sodicated soils. The loading of the sample reduces the swelling of the sample and seems to reduce its permeability. The reduction of the feeding water pressure further reduces the sample swelling. The draining process from saturated soil sample shows that most of the process occurs in the large pores of the structural domain. This gives the possibility to evaluate the water diffusivity coefficient for the structural domain of the sample. In draining the soil with the highest sodication there was a variation of soil volume

  8. ARTIST: introduction and first results

    International Nuclear Information System (INIS)

    Guentay, S.; Suckow, D.; Dehbi, A.; Kapulla, R.

    2004-01-01

    Aerosol Trapping In a Steam Generator (ARTIST) is a seven-phase international project (2003-2007) which investigates aerosol and droplet retention in a model steam generator under dry, wet and accident management conditions, respectively. The test section is comprised of a scaled steam generator tube bundle consisting of 270 tubes and three stages, one 1:1 separator unit, and one 1:1 dryer unit. As a prelude to the ARTIST project, four tests are conducted in the ARTIST bundle within the 5th EU FWP SGTR. These first tests address aerosol deposition phenomena on two different scales: near the tube break, where the gas velocities are sonic, and far away from the break, where the flow velocities are three orders of magnitude lower. With a dry bundle and the full flow representing the break stage conditions, there is strong evidence that the TiO 2 aerosols used (AMMD 2-4 μm, 32 nm primary particles) disintegrate into much smaller particles because of the sonic conditions at the break, hence promoting particle escape from the secondary and lowering the overall DF, which is found to be between 2.5 and 3. With a dry bundle and a small flow reproducing the far-field velocities, the overall bundle DF is of the order of 5, implying a DF of about 1.9 per stage. Extrapolating the results of the dry tests, it turns out that for steam generators with nine or more stages, it is expected that substantial DF's could be achieved when the break is located near the tube sheet region. In addition, better decontamination is expected using more representative proxies of severe accident aerosols (sticky, multi-component particles), a topic which is yet to be investigated. When the bundle is flooded, the DF is between 45 and 5740, depending on the mass flow rate, the steam content, and the water submergence. The presence of steam in the carrier gas and subsequent condensation inside the broken tube causes aerosol deposition and blockages near the break, leading to an increase in the

  9. ARTIST: introduction and first results

    International Nuclear Information System (INIS)

    Guntay, S.; Suckow, D.; Dehbi, A.; Kapulla, R.

    2004-01-01

    ARTIST (Aerosol Trapping In a Steam Generator) is an international project which investigates aerosol and droplet retention in a model steam generator under dry, wet and accident management conditions, respectively. The test section comprises a scaled steam generator tube bundle consisting of 270 tubes and 3 stages, one 1:1 separator unit, and one 1:1 dryer unit. As a prelude to the ARTIST project, four tests are conducted in the ARTIST bundle. These first tests address aerosol deposition phenomena on two different scales: near the tube break, where the gas velocities are sonic, and far away from the break, where the flow velocities are 3 orders of magnitude lower. With a dry bundle and the full flow representing the break stage conditions, there is strong evidence that the TiO 2 aerosols used (AMMD 2-4 μm, 32 nm primary particles) disintegrate into much smaller particles because of the sonic conditions at the break, hence promoting particle escape from the secondary and lowering the overall decontamination factor (DF), which is found to be between 2.5 and 3. With a dry bundle and a small flow reproducing the far-field velocities, the overall bundle DF is of the order of 5, implying a DF of about 1.9 per stage. Extrapolating the results of the dry tests, it turns out that for steam generators with 9 or more stages, it is expected that substantial DFs could be achieved when the break is located near the tube sheet region. In addition, better decontamination is expected using more representative proxies of severe accident aerosols (sticky, multicomponent particles), a topic which is yet to be investigated. When the bundle is flooded, the DF is between 45 and 5740, depending on the mass flow rate, the steam content, and the water submergence. The presence of steam in the carrier gas and subsequent condensation inside the broken tube causes aerosol deposition and blockages near the break, leading to an increase in the primary pressure. This has implications for real

  10. First half 2010 financial results

    International Nuclear Information System (INIS)

    2010-01-01

    The Supervisory Board of the AREVA group presents in this document the financial statements submitted by the Executive Board for the semester ended June 30, 2010. Areva backlog continued to rise in the first half of the year. Areva's revenue is up by more than 6% for the first six months to more than 4 billion euros. The performance of Areva's recurring business continues to improve, reflecting optimization plans deployed in all of the group's business units. However, Areva booked in the first half a non cash reversible accounting adjustment on the value of certain mining assets, following the publication in the second quarter of new prospective data on uranium prices, as well as an additional provision on the EPR project in Finland. Cumulated provisions on OL3 rose to 2.6 billion euros. Capitalizing on lessons learned from this project, Areva has reduced strongly the engineering hours needed for the completion of the nuclear steam supply system for the Taishan 1 and 2 EPR reactors. Net income attributable to owners of the parent rose to 843 million euros, including the 1.3 billion euro gain on the disposal of the Transmission and Distribution business, or 23.82 euros per share. For the full year of 2010, the group anticipates a substantial revenue and backlog growth, an increase in operating income excluding particular items, a negative operating income, and a strong increase in net income attributable to owners of the parent, which includes the capital gain on disposal of the Transmission and Distribution business. First half 2010 financial results in brief: - Backlog of euro 44.1 bn: +euro 1.2 bn compared with June 30, 2009; - Revenue of euro 4.158 bn: +6.4% compared with first half 2009; - Operating income excl. particular items: euro 213 m, for a 5.1% margin; - Operating income: -euro 485 m; - Net income group share: euro 843 m including the euro 1.27 bn gain on the sale of the T and D business; - Earnings per share: euro 23.82; - Net debt of euro 5.152 bn

  11. 1999 Annual report -- Generating results

    International Nuclear Information System (INIS)

    2000-01-01

    results and a consolidated financial statement, with the usual supporting information attached

  12. Carnosine attenuates cyclophosphamide-induced bone marrow suppression by reducing oxidative DNA damage

    Directory of Open Access Journals (Sweden)

    Jie Deng

    2018-04-01

    Full Text Available Oxidative DNA damage in bone marrow cells is the main side effect of chemotherapy drugs including cyclophosphamide (CTX. However, not all antioxidants are effective in inhibiting oxidative DNA damage. In this study, we report the beneficial effect of carnosine (β-alanyl-l-histidine, a special antioxidant with acrolein-sequestering ability, on CTX-induced bone marrow cell suppression. Our results show that carnosine treatment (100 and 200 mg/kg, i.p. significantly inhibited the generation of reactive oxygen species (ROS and 8-hydroxy-2′-deoxyguanosine (8-oxo-dG, and decreased chromosomal abnormalities in the bone marrow cells of mice treated with CTX (20 mg/kg, i.v., 24 h. Furthermore, carnosine evidently mitigated CTX-induced G2/M arrest in murine bone marrow cells, accompanied by reduced ratios of p-Chk1/Chk1 and p-p53/p53 as well as decreased p21 expression. In addition, cell apoptosis caused by CTX was also suppressed by carnosine treatment, as assessed by decreased TUNEL-positive cell counts, down-regulated expressions of Bax and Cyt c, and reduced ratios of cleaved Caspase-3/Caspase-3. These results together suggest that carnosine can protect murine bone marrow cells from CTX-induced DNA damage via its antioxidant activity. Keywords: Carnosine, Cyclophosphamide, Oxidative DNA damage, Sister chromatid exchange, Apoptosis, Cell cycle arrest

  13. Dual inhibition of ATR and ATM potentiates the activity of trabectedin and lurbinectedin by perturbing the DNA damage response and homologous recombination repair.

    Science.gov (United States)

    Lima, Michelle; Bouzid, Hana; Soares, Daniele G; Selle, Frédéric; Morel, Claire; Galmarini, Carlos M; Henriques, João A P; Larsen, Annette K; Escargueil, Alexandre E

    2016-05-03

    Trabectedin (Yondelis®, ecteinascidin-743, ET-743) is a marine-derived natural product approved for treatment of advanced soft tissue sarcoma and relapsed platinum-sensitive ovarian cancer. Lurbinectedin is a novel anticancer agent structurally related to trabectedin. Both ecteinascidins generate DNA double-strand breaks that are processed through homologous recombination repair (HRR), thereby rendering HRR-deficient cells particularly sensitive. We here characterize the DNA damage response (DDR) to trabectedin and lurbinectedin in HeLa cells. Our results show that both compounds activate the ATM/Chk2 (ataxia-telangiectasia mutated/checkpoint kinase 2) and ATR/Chk1 (ATM and RAD3-related/checkpoint kinase 1) pathways. Interestingly, pharmacological inhibition of Chk1/2, ATR or ATM is not accompanied by any significant improvement of the cytotoxic activity of the ecteinascidins while dual inhibition of ATM and ATR strongly potentiates it. Accordingly, concomitant inhibition of both ATR and ATM is an absolute requirement to efficiently block the formation of γ-H2AX, MDC1, BRCA1 and Rad51 foci following exposure to the ecteinascidins. These results are not restricted to HeLa cells, but are shared by cisplatin-sensitive and -resistant ovarian carcinoma cells. Together, our data identify ATR and ATM as central coordinators of the DDR to ecteinascidins and provide a mechanistic rationale for combining these compounds with ATR and ATM inhibitors.

  14. Optimising measles virus-guided radiovirotherapy with external beam radiotherapy and specific checkpoint kinase 1 inhibition

    International Nuclear Information System (INIS)

    Touchefeu, Yann; Khan, Aadil A.; Borst, Gerben; Zaidi, Shane H.; McLaughlin, Martin; Roulstone, Victoria; Mansfield, David; Kyula, Joan; Pencavel, Tim; Karapanagiotou, Eleni M.; Clayton, Jamie; Federspiel, Mark J.; Russell, Steve J.; Garrett, Michelle; Collins, Ian; Harrington, Kevin J.

    2013-01-01

    Background and purpose: We previously reported a therapeutic strategy comprising replication-defective NIS-expressing adenovirus combined with radioiodide, external beam radiotherapy (EBRT) and DNA repair inhibition. We have now evaluated NIS-expressing oncolytic measles virus (MV-NIS) combined with NIS-guided radioiodide, EBRT and specific checkpoint kinase 1 (Chk1) inhibition in head and neck and colorectal models. Materials and methods: Anti-proliferative/cytotoxic effects of individual agents and their combinations were measured by MTS, clonogenic and Western analysis. Viral gene expression was measured by radioisotope uptake and replication by one-step growth curves. Potential synergistic interactions were tested in vitro by Bliss independence analysis and in in vivo therapeutic studies. Results: EBRT and MV-NIS were synergistic in vitro. Furthermore, EBRT increased NIS expression in infected cells. SAR-020106 was synergistic with EBRT, but also with MV-NIS in HN5 cells. MV-NIS mediated 131 I-induced cytotoxicity in HN5 and HCT116 cells and, in the latter, this was enhanced by SAR-020106. In vivo studies confirmed that MV-NIS, EBRT and Chk1 inhibition were effective in HCT116 xenografts. The quadruplet regimen of MV-NIS, virally-directed 131 I, EBRT and SAR-020106 had significant anti-tumour activity in HCT116 xenografts. Conclusion: This study strongly supports translational and clinical research on MV-NIS combined with radiation therapy and radiosensitising agents

  15. Small-molecule inhibitors of Ataxia Telangiectasia and Rad3 related kinase (ATR) sensitize lymphoma cells to UVA radiation

    DEFF Research Database (Denmark)

    Biskup, Edyta; Naym, David Gram; Gniadecki, Robert

    2016-01-01

    inhibited by small molecule antagonists VE-821, VE-822 or Chir-124, or by small interfering RNAs (siRNAs). Cell cycle and viability were assessed by flow cytometry. RESULTS: Small molecule inhibitors of ATR and Chk1 potently sensitized all cell lines to PUVA and, importantly, also to UVA, which by itself...... did not cause apoptotic response. VE-821/2 blocked ATR pathway activation and released the cells from the G2/M block caused by UVA and PUVA, but did not affect apoptosis caused by other chemotherapeutics (etoposide, gemcitabine, doxorubicine) or by hydrogen peroxide. Knockdown of ATR and Chk1 with si......RNA also blocked the ATR pathway and released the cells from G2/M block but did not sensitize the cells to UVA as observed with the small molecule inhibitors. The latter suggested that the synergism between VE-821/2 or Chir-124 and UVA was not solely caused by specific blocking of ATR kinase but also ATR...

  16. Cortical Development Requires Mesodermal Expression of Tbx1, a Gene Haploinsufficient in 22q11.2 Deletion Syndrome.

    Science.gov (United States)

    Flore, Gemma; Cioffi, Sara; Bilio, Marchesa; Illingworth, Elizabeth

    2017-03-01

    In mammals, proper temporal control of neurogenesis and neural migration during embryonic development ensures correct formation of the cerebral cortex. Changes in the distribution of cortical projection neurons and interneurons are associated with behavioral disorders and psychiatric diseases, including schizophrenia and autism, suggesting that disrupted cortical connectivity contributes to the brain pathology. TBX1 is the major candidate gene for 22q11.2 deletion syndrome (22q11.2DS), a chromosomal deletion disorder characterized by a greatly increased risk for schizophrenia. We have previously shown that Tbx1 heterozygous mice have reduced prepulse inhibition, a behavioral abnormality that is associated with 22q11.2DS and nonsyndromic schizophrenia. Here, we show that loss of Tbx1 disrupts corticogenesis in mice by promoting premature neuronal differentiation in the medio-lateral embryonic cortex, which gives rise to the somatosensory cortex (S1). In addition, we found altered polarity in both radially migrating excitatory neurons and tangentially migrating inhibitory interneurons. Together, these abnormalities lead to altered lamination in the S1 at the terminal stages of corticogenesis in Tbx1 null mice and similar anomalies in Tbx1 heterozygous adult mice. Finally, we show that mesoderm-specific inactivation of Tbx1 is sufficient to recapitulate the brain phenotype indicating that Tbx1 exerts a cell nonautonomous role in cortical development from the mesoderm. © The Author 2016. Published by Oxford University Press. All rights reserved. For Permissions, please e-mail: journals.permissions@oup.com.

  17. Haploinsufficiency in the PPARα and LDL receptor genes leads to gender- and age-specific obesity and hyperinsulinemia

    International Nuclear Information System (INIS)

    Sugiyama, Eiko; Tanaka, Naoki; Nakajima, Tamie; Kamijo, Yuji; Yokoyama, Shin; Li Yufeng; Gonzalez, Frank J.; Aoyama, Toshifumi

    2006-01-01

    When preparing peroxisome proliferator-activated receptor (PPAR)α:low-density lipoprotein receptor (LDLR) (-/-) double knockout mice, we unexpectedly found a unique gender- and age-specific obesity in the F1 generation, PPARα (+/-):LDLR (+/-), even in mice fed standard chow. Body weights of the male heterozygous mice increased up to about 60 g at 75 weeks of age, then decreased by about 30 g at 100 weeks of age. More than 95% of the heterozygous mice between 35- and 75-week-olds were overweight. Of interest, the obese heterozygous mice also exhibited hyperinsulinemia correlating with moderate insulin resistance. Hepatic gene expression of LDLR was lower than expected in the heterozygous mice, particularly at 50 and 75 weeks of age. In contrast, the hepatic expression of PPARα was higher than expected in obese heterozygous mice, but decreased in non-obese older heterozygous mice. Modulated expression of these genes may be partially associated with the onset of the hyperinsulinemia

  18. Height outcome of the recombinant human growth hormone treatment in patients with SHOX gene haploinsufficiency: a meta-analysis.

    Science.gov (United States)

    Massart, Francesco; Bizzi, Martina; Baggiani, Angelo; Miccoli, Mario

    2013-04-01

    Patients with mutations or deletions of the SHOX gene present variable growth impairment, with or without mesomelic skeletal dysplasia. If untreated, short patients with SHOX haplodeficiency (SHOXD) remain short into adulthood. Although recombinant human growth hormone (rhGH) treatment improves short-term linear growth, there are episodic data on the final height of treated SHOXD subjects. After a thorough search of the published literature for pertinent studies, we undertook a meta-analysis evaluation of the efficacy and safety of rhGH treatment in SHOXD patients. In SHOXD patients, administration of rhGH progressively improved the height deficit from baseline to 24 months, although the major catch-up growth was detected after 12 months. The rhGH-induced growth appeared constant until final height. Our meta-analysis suggested rhGH therapy improves height outcome of SHOXD patients, though future studies using carefully titrated rhGH protocols are needed. Original submitted 29 October 2012; Revision submitted 22 February 2013.

  19. Corpus callosum abnormalities, intellectual disability, speech impairment, and autism in patients with haploinsufficiency of ARID1B

    DEFF Research Database (Denmark)

    Hansen, Christina Halgren; Kjaergaard, S; Bak, M

    2011-01-01

    . The etiology is expected to be genetic in as much as 30-50% of the cases, but the underlying genetic cause remains unknown in the majority of cases. By next-generation mate-pair sequencing we mapped the chromosomal breakpoints of a patient with a de novo balanced translocation, t(1;6)(p31;q25), agenesis...... of corpus callosum (CC), intellectual disability, severe speech impairment, and autism. The chromosome 6 breakpoint truncated ARID1B which was also truncated in a recently published translocation patient with a similar phenotype. Quantitative polymerase chain reaction (Q-PCR) data showed that a primer set...... proximal to the translocation showed increased expression of ARID1B, whereas primer sets spanning or distal to the translocation showed decreased expression in the patient relative to a non-related control set. Phenotype-genotype comparison of the translocation patient to seven unpublished patients...

  20. Mutations in SYNGAP1 Cause Intellectual Disability, Autism, and a Specific Form of Epilepsy by Inducing Haploinsufficiency

    DEFF Research Database (Denmark)

    Berryer, Martin H; Hamdan, Fadi F; Klitten, Laura L

    2013-01-01

    De novo mutations in SYNGAP1, which codes for a RAS/RAP GTP-activating protein, cause nonsyndromic intellectual disability (NSID). All disease-causing point mutations identified until now in SYNGAP1 are truncating, raising the possibility of an association between this type of mutations and NSID...... also showed ataxia, autism, and a specific form of generalized epilepsy that can be refractory to treatment. All of these mutations occurred de novo, except c.283dupC, which was inherited from a father who is a mosaic. Biolistic transfection of wild-type SYNGAP1 in pyramidal cells from cortical...

  1. Recql4 haploinsufficiency in mice leads to defects in osteoblast progenitors: Implications for low bone mass phenotype

    International Nuclear Information System (INIS)

    Yang Jieping; Murthy, Sreemala; Winata, Therry; Werner, Sean; Abe, Masumi; Prahalad, Agasanur K.; Hock, Janet M.

    2006-01-01

    The cellular and molecular mechanisms that underlie skeletal abnormalities in defective Recql4-related syndromes are poorly understood. Our objective in this study was to explore the function of Recql4 in osteoblast biology both in vitro and in vivo. Immunohistochemistry on adult mouse bone showed Recql4 protein localization in active osteoblasts around growth plate, but not in fully differentiated osteocytes. Consistent with this finding, Recql4 gene expression was high in proliferating mouse osteoblastic MC3T3.E1 cells and decreased as cells progressively lost their proliferation activity during differentiation. Recql4 overexpression in osteoblastic cells exhibited higher proliferation activity, while its depletion impeded cell growth. In addition, bone marrow stromal cells from male Recql4+/- mice had fewer progenitor cells, including osteoprogenitors, indicated by reduced total fibroblast colony forming units (CFU-f) and alkaline phosphatase-positive CFU-f colonies concomitant with reduced bone mass. These findings provide evidence that Recql4 functions as a regulatory protein during osteoprogenitor proliferation, a critical cellular event during skeleton development

  2. Haploinsufficiency of the Chromatin Remodeler BPTF Causes Syndromic Developmental and Speech Delay, Postnatal Microcephaly, and Dysmorphic Features

    NARCIS (Netherlands)

    Stankiewicz, P.; Khan, T.N.; Szafranski, P.; Slattery, L.; Streff, H.; Vetrini, F.; Bernstein, J.A.; Brown, C.W.; Rosenfeld, J.A.; Rednam, S.; Scollon, S.; Bergstrom, K.L.; Parsons, D.W.; Plon, S.E.; Vieira, M.W.; Quaio, C.; Baratela, W.A.R.; Guio, J.C.A.; Armstrong, R.; Mehta, S.G.; Rump, P.; Pfundt, R.P.; Lewandowski, R.; Fernandes, E.M.; Shinde, D.N.; Tang, S.; Hoyer, J.; Zweier, C.; Reis, A.; Bacino, C.A.; Xiao, R.; Breman, A.M.; Smith, J.L.; Katsanis, N.; Bostwick, B.; Popp, B.; Davis, E.E.; Yang, Y

    2017-01-01

    Bromodomain PHD finger transcription factor (BPTF) is the largest subunit of nucleosome remodeling factor (NURF), a member of the ISWI chromatin-remodeling complex. However, the clinical consequences of disruption of this complex remain largely uncharacterized. BPTF is required for

  3. Grp/DChk1 is required for G(2)-M checkpoint activation in Drosophila S2 cells, whereas Dmnk/DChk2 is dispensable

    NARCIS (Netherlands)

    de Vries, HI; Uyetake, L; Lemstra, W; Brunsting, JF; Su, TT; Kampinga, HH; Sibon, OCM

    2005-01-01

    Cell-cycle checkpoints are signal-transduction pathways required to maintain genomic stability in dividing cells. Previously, it was reported that two kinases essential for checkpoint signalling, Chk1 and Chk2 are structurally conserved. In contrast to yeast, Xenopus and mammals, the Chk1- and

  4. Aven-mediated checkpoint kinase control regulates proliferation and resistance to chemotherapy in conventional osteosarcoma.

    Science.gov (United States)

    Baranski, Zuzanna; Booij, Tijmen H; Cleton-Jansen, Anne-Marie; Price, Leo S; van de Water, Bob; Bovée, Judith V M G; Hogendoorn, Pancras C W; Danen, Erik H J

    2015-07-01

    Conventional high-grade osteosarcoma is the most common primary bone sarcoma, with relatively high incidence in young people. In this study we found that expression of Aven correlates inversely with metastasis-free survival in osteosarcoma patients and is increased in metastases compared to primary tumours. Aven is an adaptor protein that has been implicated in anti-apoptotic signalling and serves as an oncoprotein in acute lymphoblastic leukaemia. In osteosarcoma cells, silencing Aven triggered G2 cell-cycle arrest; Chk1 protein levels were attenuated and ATR-Chk1 DNA damage response signalling in response to chemotherapy was abolished in Aven-depleted osteosarcoma cells, while ATM, Chk2 and p53 activation remained intact. Osteosarcoma is notoriously difficult to treat with standard chemotherapy, and we examined whether pharmacological inhibition of the Aven-controlled ATR-Chk1 response could sensitize osteosarcoma cells to genotoxic compounds. Indeed, pharmacological inhibitors targeting Chk1/Chk2 or those selective for Chk1 synergized with standard chemotherapy in 2D cultures. Likewise, in 3D extracellular matrix-embedded cultures, Chk1 inhibition led to effective sensitization to chemotherapy. Together, these findings implicate Aven in ATR-Chk1 signalling and point towards Chk1 inhibition as a strategy to sensitize human osteosarcomas to chemotherapy. Copyright © 2015 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.

  5. Search Results | Page 88 | IDRC - International Development ...

    International Development Research Centre (IDRC) Digital Library (Canada)

    2010-01-01

    Results 871 - 880 of 8518 ... Research results : analyzing the impact of introducing an automated management information system within microfinance institutions. Published date. January 1, 2010. Studies.

  6. Search Results | Page 72 | IDRC - International Development ...

    International Development Research Centre (IDRC) Digital Library (Canada)

    2010-01-01

    Results 711 - 720 of 8491 ... Research results : analyzing the impact of introducing an automated management information system within microfinance institutions. Published date. January 1, 2010. Studies.

  7. Search Results | Page 5 | IDRC - International Development ...

    International Development Research Centre (IDRC) Digital Library (Canada)

    Results 41 - 50 of 163 ... Water Resource Management and the Changing Climate in ... Cambodia's Tonle Sap Lake is the largest freshwater lake in ... These events are resulting in higher economic, social, environmental, and human costs.

  8. Search Results | Page 842 | IDRC - International Development ...

    International Development Research Centre (IDRC) Digital Library (Canada)

    Results 8411 - 8420 of 8496 ... Land Tenure, Gender, and Globalization: Research and Analysis from ... Globalization, Labor Markets and Inequality in India ... the results of an international initiative to document the effects of how health systems ...

  9. Search Results | Page 779 | IDRC - International Development ...

    International Development Research Centre (IDRC) Digital Library (Canada)

    Results 7781 - 7790 of 9602 ... Land Tenure, Gender, and Globalization: Research and Analysis from ... Globalization, Labor Markets and Inequality in India ... the results of an international initiative to document the effects of how health systems ...

  10. Search Results | Page 842 | IDRC - International Development ...

    International Development Research Centre (IDRC) Digital Library (Canada)

    Results 8411 - 8420 of 8491 ... Globalization, Labor Markets and Inequality in India ... results of an international initiative to document the effects of how health systems in ... Natural Resource Management: The Impact of Gender and Social Issues.

  11. First results from Mark III at SPEAR

    International Nuclear Information System (INIS)

    Einsweiler, K.F.

    The paper presents data on meson decays obtained using the MARK III detector operating at SPEAR. Results on hadronic decays; decays of the etasub(e); and results on radiative decays; are all described. (U.K.)

  12. Search Results | Page 710 | IDRC - International Development ...

    International Development Research Centre (IDRC) Digital Library (Canada)

    Results 7091 - 7100 of 9601 ... ... and Practice in South Asia : Building a Community of Experts ... Social Psychology in Post Conflict Colombia. Psychosocial trauma resulting from the Colombian armed conflict constitutes a pressing social and ...

  13. Search Results | Page 538 | IDRC - International Development ...

    International Development Research Centre (IDRC) Digital Library (Canada)

    Search Results. Showing 5371 - 5380 of 9604 results. Reports ... Business training for microfinance clients : how it matters and for whom? ... building a regional platform for political engagement and strategic action; final technical report.

  14. Search Results | Page 51 | IDRC - International Development ...

    International Development Research Centre (IDRC) Digital Library (Canada)

    Results 501 - 510 of 1133 ... ... starch industry has resulted in increased disease prevalence, soil erosion, ... Food processing in developing countries is an important component of ... to improve child nutrition and food security in northern Malawi.

  15. Search Results | Page 43 | IDRC - International Development ...

    International Development Research Centre (IDRC) Digital Library (Canada)

    Results 421 - 430 of 1804 ... An investigation into the determinants of business performance in ... where it is associated with economic activity, transportation, and the use of ... many other Asian countries, rapid and unplanned growth has resulted ...

  16. Search Results | Page 8 | IDRC - International Development ...

    International Development Research Centre (IDRC) Digital Library (Canada)

    2009-01-01

    Results 71 - 80 of 132 ... Empowering regulators to protect consumer rights in the ICT sector, Introductory Workshop, Lusaka, 13 August 2009. Published date. January 1, 2009. Reports. EAST AFRICA RESEARCH RESULTS POLICY MAKING ...

  17. Search Results | Page 809 | IDRC - International Development ...

    International Development Research Centre (IDRC) Digital Library (Canada)

    Results 8081 - 8090 of 9602 ... Evaluating IDRC's role at major conferences, events. Over the ... Participatory GIS for resource management in Africa: Taking stock. This ICT4D article series features results from innovative research on participatory ...

  18. Search Results | Page 69 | IDRC - International Development ...

    International Development Research Centre (IDRC) Digital Library (Canada)

    Results 681 - 690 of 8531 ... Role of the sea kayak tour guide : mixed methods exploration into the ... from this study did not completely support the survey results, highl ... and institutional foundations within traditional rural communities that can ...

  19. Search Results | Page 94 | IDRC - International Development ...

    International Development Research Centre (IDRC) Digital Library (Canada)

    Results 931 - 940 of 8491 ... ... and institutional foundations within traditional rural communities that can ... Role of the sea kayak tour guide : mixed methods exploration into the ... from this study did not completely support the survey results, highl.

  20. Recent Results from the ATLAS Experiment

    CERN Document Server

    Djama, Fares; The ATLAS collaboration

    2015-01-01

    A selection of recent Run 1 ATLAS results and first preliminary results from Run 2 are shown. Overview plots on Higgs properties, top measurements and SUSY searches are presented as well as recent QCD and electroweak measurements.

  1. Search Results | Page 5 | IDRC - International Development ...

    International Development Research Centre (IDRC) Digital Library (Canada)

    Results 41 - 50 of 80 ... Applying ICT for Disaster Mitigation in the Central American ... Central America is subject to frequent climate variability resulting in floods and droughts. ... Accumulated environmental, economic, and social damages to date ...

  2. Search Results | Page 797 | IDRC - International Development ...

    International Development Research Centre (IDRC) Digital Library (Canada)

    Search Results. Showing 7961 - 7970 of 8491 results. Story. Health Natural Resources Mining ECOHEALTH ... CASE STUDY: Latin America — An engine for rural development in Latin America. Research in Action. Biodiversity Gender Crops ...

  3. Search Results | Page 33 | IDRC - International Development ...

    International Development Research Centre (IDRC) Digital Library (Canada)

    Results 321 - 330 of 420 ... Rapid economic growth in South Asia has not resulted in increased ... the national innovation system and its impact on the economy. ... through simple resource-based activities: oil, minerals, tourism and labour migrati.

  4. Search Results | Page 35 | IDRC - International Development ...

    International Development Research Centre (IDRC) Digital Library (Canada)

    Results 341 - 350 of 439 ... Rapid economic growth in South Asia has not resulted in increased ... the national innovation system and its impact on the economy. ... through simple resource-based activities: oil, minerals, tourism and labour migrati.

  5. Search Results | Page 88 | IDRC - International Development ...

    International Development Research Centre (IDRC) Digital Library (Canada)

    Search Results. Showing 871 - 880 of 8491 results. Studies ... Strengthening Nurses' Capacity in HIV Policy Development in Sub-Saharan Africa and the Caribbean ... Novel Epidemiological Method: Using Newspapers To Provide Insight Into ...

  6. Search Results | Page 916 | IDRC - International Development ...

    International Development Research Centre (IDRC) Digital Library (Canada)

    Results 9151 - 9160 of 9580 ... The publication "Practical Guide for producers and farmers: Collective ... assesses the intervention of AGROECO in the field of alternative organic ... The research resulted in documentation of over 100 plants and ...

  7. Search Results | Page 815 | IDRC - International Development ...

    International Development Research Centre (IDRC) Digital Library (Canada)

    Results 8141 - 8150 of 8491 ... ... routinely to illustrate the profound role of information in modern societies. ... worlds, the vital role of higher education in society is accepted. ... This crisis is the result of the breakdown of traditional farming systems.

  8. Search Results | Page 845 | IDRC - International Development ...

    International Development Research Centre (IDRC) Digital Library (Canada)

    Results 8441 - 8450 of 8494 ... Our chance to share the results of our work with Canadians and to ... structure, robust management processes, effective systems, and internal controls. ... as required under Canada's Financial Administration Act.

  9. Search Results | Page 642 | IDRC - International Development ...

    International Development Research Centre (IDRC) Digital Library (Canada)

    Search Results. Showing 6411 - 6420 of 9601 results. Project ... STI for Development in Asia : a Platform for Information Sharing and Learning. This project is based on the premise that science, technology and innovation (STI) are critical ...

  10. Search Results | Page 33 | IDRC - International Development ...

    International Development Research Centre (IDRC) Digital Library (Canada)

    Results 321 - 330 of 439 ... ... result in severe, long-term social and mental health problems for exposed children and adolescents. ... national-level networks in various parts of the word including the ... Women's Participation and Decentralization.

  11. Search Results | Page 763 | IDRC - International Development ...

    International Development Research Centre (IDRC) Digital Library (Canada)

    Search Results. Showing 7621 - 7630 of 8490 results. Books ... and practice in natural resource management are often depicted as a cyclical and rational process. ... to provide quality education, improve health care, allow open government, ...

  12. Search Results | Page 2 | IDRC - International Development ...

    International Development Research Centre (IDRC) Digital Library (Canada)

    Results 11 - 16 of 16 ... Under universal systems, health care is paid for in advance, via prepayment ... Research results have no value unless they are made available for due ... Community Based Adaptation to Climate Change in Africa.

  13. Search Results | Page 7 | IDRC - International Development ...

    International Development Research Centre (IDRC) Digital Library (Canada)

    Results 61 - 70 of 94 ... Under universal systems, health care is paid for in advance, via prepayment ... Research results have no value unless they are made available for due ... Community Based Adaptation to Climate Change in Africa.

  14. Search Results | Page 719 | IDRC - International Development ...

    International Development Research Centre (IDRC) Digital Library (Canada)

    Results 7181 - 7190 of 9601 ... Research on Business Process Outsourcing ... Rapid economic growth in South Asia has not resulted in increased ... The nature and scale of the problem are not captured by aggregate unemployment statistics.

  15. Search Results | Page 5 | IDRC - International Development ...

    International Development Research Centre (IDRC) Digital Library (Canada)

    Results 41 - 50 of 1643 ... Global water governance and the rise of the constitutional regulatory state in Colombia. This article interprets the regulatory state in the south as the result of a dialectic process between global governance institutions, ...

  16. Search Results | Page 912 | IDRC - International Development ...

    International Development Research Centre (IDRC) Digital Library (Canada)

    Results 9111 - 9120 of 9602 ... Trade facilitation and poverty reduction : China-ASEAN region case study. Results show that a 1 per cent increase in port efficiency results in a 1.051 ... is near the world average, but among ASEAN countries there is a big gap. ... The focus of the study is the Economic Corridors and Cross Border ...

  17. Search Results | Page 6 | IDRC - International Development ...

    International Development Research Centre (IDRC) Digital Library (Canada)

    2013-10-01

    Results 51 - 60 of 60 ... Results show that a 1 per cent increase in port efficiency results in a 1.051 per cent decrease in the poverty index. The level of Chinese trade facilitation is near the world average, but among ASEAN countries there is a big gap. Published date. October 1, 2013. Reports. EXPORT ORIENTED ...

  18. Current advances on polynomial resultant formulations

    Science.gov (United States)

    Sulaiman, Surajo; Aris, Nor'aini; Ahmad, Shamsatun Nahar

    2017-08-01

    Availability of computer algebra systems (CAS) lead to the resurrection of the resultant method for eliminating one or more variables from the polynomials system. The resultant matrix method has advantages over the Groebner basis and Ritt-Wu method due to their high complexity and storage requirement. This paper focuses on the current resultant matrix formulations and investigates their ability or otherwise towards producing optimal resultant matrices. A determinantal formula that gives exact resultant or a formulation that can minimize the presence of extraneous factors in the resultant formulation is often sought for when certain conditions that it exists can be determined. We present some applications of elimination theory via resultant formulations and examples are given to explain each of the presented settings.

  19. Monthly results of measurements, May 1989

    International Nuclear Information System (INIS)

    1989-01-01

    This report of the SCPRI exposes an interpretation of the principal results concerning the routine monitoring of environmental radioactivity in France: atmospheric dusts, rainwater, surface water, underground water, sewage water, drinking water, food chain (milk, vegetables, fishes), sea water around nuclear plant sites and other sites. The activities of various radioisotopes are presented in tables. This report exposes also the results of special radiation measurements resulting from the Chernobyl accident [fr

  20. Monthly results of measurements, october 1987

    International Nuclear Information System (INIS)

    1987-10-01

    This report of the SCPRI exposes an interpretation of the principal results concerning the routine monitoring of environmental radioactivity in France: atmospheric dusts, rainwater, surface waters, underground water, drinking water, sewage water, food chain (milk, vegetables, fishes), seawater around nuclear plant sites and other sites, sediments. The activities of various radioisotopes are presented in tables. This report exposes also the results of special radiation measurements resulting from the Chernobyl accident [fr