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Sample records for chk1 haploinsufficiency results

  1. Nuclear Chk1 prevents premature mitotic entry.

    Science.gov (United States)

    Matsuyama, Makoto; Goto, Hidemasa; Kasahara, Kousuke; Kawakami, Yoshitaka; Nakanishi, Makoto; Kiyono, Tohru; Goshima, Naoki; Inagaki, Masaki

    2011-07-01

    Chk1 inhibits the premature activation of the cyclin-B1-Cdk1. However, it remains controversial whether Chk1 inhibits Cdk1 in the centrosome or in the nucleus before the G2-M transition. In this study, we examined the specificity of the mouse monoclonal anti-Chk1 antibody DCS-310, with which the centrosome was stained. Conditional Chk1 knockout in mouse embryonic fibroblasts reduced nuclear but not centrosomal staining with DCS-310. In Chk1(+/myc) human colon adenocarcinoma (DLD-1) cells, Chk1 was detected in the nucleus but not in the centrosome using an anti-Myc antibody. Through the combination of protein array and RNAi technologies, we identified Ccdc-151 as a protein that crossreacted with DCS-310 on the centrosome. Mitotic entry was delayed by expression of the Chk1 mutant that localized in the nucleus, although forced immobilization of Chk1 to the centrosome had little impact on the timing of mitotic entry. These results suggest that nuclear but not centrosomal Chk1 contributes to correct timing of mitotic entry.

  2. Chk1 suppressed cell death

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    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. Tumour growth environment modulates Chk1 signalling pathways and Chk1 inhibitor sensitivity

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    Massey, Andrew J.

    2016-01-01

    Clinical development of Chk1 inhibitors is currently focussed on evaluating activity as monotherapy and as potentiators of chemotherapy. To aid translation of pre-clinical studies, we sought to understand the effects of the tumour growth environment on Chk1 signalling and sensitivity to small molecule Chk1 inhibition. Spheroid culture altered Chk1 signalling to a more xenograft like state but decreased sensitivity to Chk1 inhibition. Growth in low serum did not alter DDR signalling but increased the sensitivity of A2058 and U2OS tumour cells to Chk1 inhibition. An analysis of the expression levels of replication associated proteins identified a correlation between Cdc6 and pChk1 (S296) as well as total Chk1 in xenograft derived samples and between Cdc6 and total Chk1 in anchorage-dependent growth derived protein samples. No apparent correlation between Chk1 or Cdc6 expression and sensitivity to Chk1 inhibition in vitro was observed. A database analysis revealed upregulation of CDC6 mRNA expression in tumour compared to normal tissue and a correlation between CDC6 and CHEK1 mRNA expression in human cancers. We suggest that Cdc6 overexpression in human tumours requires a concomitant increase in Chk1 to counterbalance the deleterious effects of origin hyperactivation-induced DNA damage. PMID:27775084

  4. CHK1 as a therapeutic target to bypass chemoresistance in AML.

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    David, Laure; Fernandez-Vidal, Anne; Bertoli, Sarah; Grgurevic, Srdana; Lepage, Benoît; Deshaies, Dominique; Prade, Naïs; Cartel, Maëlle; Larrue, Clément; Sarry, Jean-Emmanuel; Delabesse, Eric; Cazaux, Christophe; Didier, Christine; Récher, Christian; Manenti, Stéphane; Hoffmann, Jean-Sébastien

    2016-09-13

    The nucleoside analog cytarabine, an inhibitor of DNA replication fork progression that results in DNA damage, is currently used in the treatment of acute myeloid leukemia (AML). We explored the prognostic value of the expression of 72 genes involved in various aspects of DNA replication in a set of 198 AML patients treated by cytarabine-based chemotherapy. We unveiled that high expression of the DNA replication checkpoint gene CHEK1 is a prognostic marker associated with shorter overall, event-free, and relapse-free survivals and determined that the expression of CHEK1 can predict more frequent and earlier postremission relapse. CHEK1 encodes checkpoint kinase 1 (CHK1), which is activated by the kinase ATR when DNA replication is impaired by DNA damage. High abundance of CHK1 in AML patient cells correlated with higher clonogenic ability and more efficient DNA replication fork progression upon cytarabine treatment. Exposing the patient cells with the high abundance of CHK1 to SCH900776, an inhibitor of the kinase activity of CHK1, reduced clonogenic ability and progression of DNA replication in the presence of cytarabine. These results indicated that some AML cells rely on an efficient CHK1-mediated replication stress response for viability and that therapeutic strategies that inhibit CHK1 could extend current cytarabine-based treatments and overcome drug resistance. Furthermore, monitoring CHEK1 expression could be used both as a predictor of outcome and as a marker to select AML patients for CHK1 inhibitor treatments.

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

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    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.

  6. Chk1 prevents abnormal mitosis of S-phase HeLa cells containing DNA damage

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    LI XiaoFang; WARD Tarsha; YAO XueBiao; WU JiaRui

    2009-01-01

    To explore effects of DNA damage on cell-cycle progression in p53-deficient tumor cells,synchronized HeLa cells at G1,S and G2/M phases were treated with methyl methanesulfnate (MMS).The results showed that the MMS treatment resulted in the cell-cycle arrest or delay in all 3 phases,while the S-phase cells were the most sensitive to MMS.Further studies demonstrated that ATM-Chk2 and p38 MAPK signaling pathways were activated in all 3 phases when the cells were treated with MMS;whereas Chk1 was activated only in S phase under the drug treatment,indicating that Chk1 specifically participated in S-phase checkpoints.To analyze the role of Chk1 in S-phase checkpoints,we administered a specific Chk1 inhibitor,UCN-01,to the S-phase cells.The results showed that the S-phase cells treated with MMS+UCN-01 could enter aberrant mitosis without finishing DNA replication,indicating that Chk1 mainly functions in the DNA damage checkpoint rather than in the replication checkpoint.In addition,MMS treatment alone inhibited the accumulation of cyclin B1,a key component of M-phase CDK-cyclin complex,in the S-phase cells,whereas the inhibition of Chk1 activation resulted in the accumulation of cyclin B1 in the MMS-treated S-phase cells.This observation further supports the view that DNA-damaged S-phase cells enter abnormal mitosis when Chk1 activation is inhibited.Our results demonstrate that Chk1 is a specific kinase that plays an important role in the MMS-induced S-phase DNA damage checkpoint.As p53 is not involved in this process,Chk1 may be a potential target for p53-deficient tumor therapy.

  7. Phosphorylation-dependent interactions between Crb2 and Chk1 are essential for DNA damage checkpoint.

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    Meng Qu

    2012-07-01

    Full Text Available In response to DNA damage, the eukaryotic genome surveillance system activates a checkpoint kinase cascade. In the fission yeast Schizosaccharomyces pombe, checkpoint protein Crb2 is essential for DNA damage-induced activation of downstream effector kinase Chk1. The mechanism by which Crb2 mediates Chk1 activation is unknown. Here, we show that Crb2 recruits Chk1 to double-strand breaks (DSBs through a direct physical interaction. A pair of conserved SQ/TQ motifs in Crb2, which are consensus phosphorylation sites of upstream kinase Rad3, is required for Chk1 recruitment and activation. Mutating both of these motifs renders Crb2 defective in activating Chk1. Tethering Crb2 and Chk1 together can rescue the SQ/TQ mutations, suggesting that the main function of these phosphorylation sites is promoting interactions between Crb2 and Chk1. A 19-amino-acid peptide containing these SQ/TQ motifs is sufficient for Chk1 binding in vitro when one of the motifs is phosphorylated. Remarkably, the same peptide, when tethered to DSBs by fusing with either recombination protein Rad22/Rad52 or multi-functional scaffolding protein Rad4/Cut5, can rescue the checkpoint defect of crb2Δ. The Rad22 fusion can even bypass the need for Rad9-Rad1-Hus1 (9-1-1 complex in checkpoint activation. These results suggest that the main role of Crb2 and 9-1-1 in DNA damage checkpoint signaling is recruiting Chk1 to sites of DNA lesions.

  8. 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...... by a combined action of Chk1 and Chk2 kinases. Finally, phosphorylation of Chk1 by ATM was required to fully accelerate the IR-induced degradation of Cdc25A. Our results provide evidence that the mammalian S phase checkpoint functions via amplification of physiologically operating, Chk1-dependent mechanisms....

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

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    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.

  10. Checkpoint kinase1 (CHK1) is an important biomarker in breast cancer having a role in chemotherapy response

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    Al-kaabi, M M; Alshareeda, A T; Jerjees, D A; Muftah, A A; Green, A R; Alsubhi, N H; Nolan, C C; Chan, S; Cornford, E; Madhusudan, S; Ellis, I O; Rakha, E A

    2015-01-01

    Background: Checkpoint kinase1 (CHK1), which is a key component of DNA-damage-activated checkpoint signalling response, may have a role in breast cancer (BC) pathogenesis and influence response to chemotherapy. This study investigated the clinicopathological significance of phosphorylated CHK1 (pCHK1) protein in BC. Method: pCHK1 protein expression was assessed using immunohistochemistry in a large, well-characterized annotated series of early-stage primary operable invasive BC prepared as tissue microarray (n=1200). Result: pCHK1 showed nuclear and/or cytoplasmic expression. Tumours with nuclear expression showed positive associations with favourable prognostic features such as lower grade, lower mitotic activity, expression of hormone receptor and lack of expression of KI67 and PI3K (P<0.001). On the other hand, cytoplasmic expression was associated with features of poor prognosis such as higher grade, triple-negative phenotype and expression of KI67, p53, AKT and PI3K. pCHK1 expression showed an association with DNA damage response (ATM, RAD51, BRCA1, KU70/KU80, DNA-PKCα and BARD1) and sumoylation (UBC9 and PIASγ) biomarkers. Subcellular localisation of pCHK1 was associated with the expression of the nuclear transport protein KPNA2. Positive nuclear expression predicted better survival outcome in patients who did not receive chemotherapy in the whole series and in ER-positive tumours. In ER-negative and triple-negative subgroups, nuclear pCHK1 predicted shorter survival in patients who received cyclophosphamide, methotrexate and 5-florouracil chemotherapy. Conclusions: Our data suggest that pCHK1 may have prognostic and predictive significance in BC. Subcellular localisation of pCHK1 protein is related to its function. PMID:25688741

  11. Targeted Radiosensitization by the Chk1 Inhibitor SAR-020106

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    Borst, Gerben R., E-mail: g.borst@nki.nl [The Institute of Cancer Research, London (United Kingdom); Netherlands Cancer Institute-Antoni van Leeuwenhoek Hospital, Amsterdam (Netherlands); McLaughlin, Martin; Kyula, Joan N.; Neijenhuis, Sari; Khan, Aadil; Good, James; Zaidi, Shane [The Institute of Cancer Research, London (United Kingdom); Powell, Ned G. [HPV Research Group, School of Medicine, Cardiff University, Cardiff (United Kingdom); Meier, Pascal; Collins, Ian; Garrett, Michelle D. [The Institute of Cancer Research, London (United Kingdom); Verheij, Marcel [Netherlands Cancer Institute-Antoni van Leeuwenhoek Hospital, Amsterdam (Netherlands); Harrington, Kevin J. [The Institute of Cancer Research, London (United Kingdom)

    2013-03-15

    Purpose: To explore the activity of a potent Chk1 inhibitor (SAR-020106) in combination with radiation. Methods and Materials: Colony and mechanistic in vitro assays and a xenograft in vivo model. Results: SAR-020106 suppressed-radiation-induced G{sub 2}/M arrest and reduced clonogenic survival only in p53-deficient tumor cells. SAR-020106 promoted mitotic entry following irradiation in all cell lines, but p53-deficient cells were likely to undergo apoptosis or become aneuploid, while p53 wild-type cells underwent a postmitotic G{sub 1} arrest followed by subsequent normal cell cycle re-entry. Following combined treatment with SAR-020106 and radiation, homologous-recombination-mediated DNA damage repair was inhibited in all cell lines. A significant increase in the number of pan-γH2AX-staining apoptotic cells was observed only in p53-deficient cell lines. Efficacy was confirmed in vivo in a clinically relevant human head-and-neck cell carcinoma xenograft model. Conclusion: The Chk1 inhibitor SAR-020106 is a potent radiosensitizer in tumor cell lines defective in p53 signaling.

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

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    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.

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

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

    2005-01-01

    -nuclear phosphorylation of histone H2AX, p53, Smc1, replication protein A, and Chk1 itself in human S-phase cells. These phosphorylations were inhibited by ATR siRNA and caffeine, but they occurred independently of ATM. Chk1 inhibition also caused an increased initiation of DNA replication, which was accompanied...... 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...... that Chk1 is required during normal S phase to avoid aberrantly increased initiation of DNA replication, thereby protecting against DNA breakage. These results may help explain why Chk1 is an essential kinase and should be taken into account when drugs to inhibit this kinase are considered for use...

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

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    Tibelius, Alexandra; Marhold, Joachim; Zentgraf, Hanswalter

    2009-01-01

    in microcephalin (MCPH1), cells from patients with Seckel syndrome and MOPD II harbor mutations in ataxia telangiectasia and Rad3 related (ATR) or pericentrin (PCNT), leading to disturbed ATR signaling. In this study, we show that a lack of MCPH1 or PCNT results in a loss of Chk1 from centrosomes with subsequently...

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

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    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.

  16. A kinome screen identifies checkpoint kinase 1 (CHK1 as a sensitizer for RRM1-dependent gemcitabine efficacy.

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    Jun Zhou

    Full Text Available Gemcitabine is among the most efficacious and widely used antimetabolite agents. Its molecular targets are ribonucleotide reductase M1 (RRM1 and elongating DNA. Acquired and de novo resistance as a result of RRM1 overexpression are major obstacles to therapeutic efficacy. We deployed a synthetic lethality screen to investigate if knockdown of 87 selected protein kinases by siRNA could overcome RRM1-dependent gemcitabine resistance in high and low RRM1-expressing model systems. The models included genetically RRM1-modified lung and breast cancer cell lines, cell lines with gemcitabine-induced RRM1 overexpression, and a series of naturally gemcitabine-resistant cell lines. Lead molecular targets were validated by determination of differential gemcitabine activity using cell lines with and without target knock down, and by assessing synergistic activity between gemcitabine and an inhibitor of the lead target. CHK1 was identified has the kinase with the most significant and robust interaction, and it was validated using AZD7762, a small-molecule ATP-competitive inhibitor of CHK1 activation. Synergism between CHK1 inhibition and RRM1-dependent gemcitabine efficacy was observed in cells with high RRM1 levels, while antagonism was observed in cells with low RRM1 levels. In addition, four cell lines with natural gemcitabine resistance demonstrated improved gemcitabine efficacy after CHK1 inhibition. In tumor specimens from 187 patients with non-small-cell lung cancer, total CHK1 and RRM1 in situ protein levels were significantly (p = 0.003 and inversely correlated. We conclude that inhibition of CHK1 may have its greatest clinical utility in malignancies where gemcitabine resistance is a result of elevated RRM1 levels. We also conclude that CHK1 inhibition in tumors with low RRM1 levels may be detrimental to gemcitabine efficacy.

  17. Suppressed miR-424 expression via upregulation of target gene Chk1 contributes to the progression of cervical cancer.

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    Xu, J; Li, Y; Wang, F; Wang, X; Cheng, B; Ye, F; Xie, X; Zhou, C; Lu, W

    2013-02-21

    MicroRNAs (miRNAs) act as important gene regulators in human genomes and their aberrant expression links to many malignancies. We previously identified a different characteristic miRNA expression profile in cervical cancer from that in cervical normal tissues, including the downregulated miR-424. However, the role and mechanism of miR-424 in cervical cancer still remain unknown. Here, we focused on identifying the tumor-suppressive function and clinical significance of miR-424 and exploring the mechanistic relevance by characterizing its target. We showed a significantly decreased expression of miR-424 in 147 cervical cancer tissues versus 74 cervical normal tissues by performing quantitative RT-PCR. In 147 cervical cancer tissue samples, low-level expression of miR-424 was positively correlated with poor tumor differentiation, advanced clinical stage, lymph node metastasis and other poor prognostic clinicopathological parameters. Further in vitro observations showed that enforced expression of miR-424 inhibited cell growth by both enhancing apoptosis and blocking G1/S transition, and suppressed cell migration and invasion in two human cervical cancer cell lines, SiHa and CaSki, implying that miR-424 functions as a tumor suppressor in the progression of cervical cancer. Interestingly, overexpression of miR-424 inhibited the expression of protein checkpoint kinase 1 (Chk1) and phosphorylated Chk1 (p-Chk1) at residues Ser345 and decreased the activity of luciferase-reporter containing the 3'-untranslated region (UTR) of Chk1 with predicted miR-424-binding site. Moreover, miR-424 expression levels were inversely correlated with Chk1 and p-Chk1 protein levels in both cervical cancer and normal tissues. Furthermore, RNAi-mediated knockdown of Chk1 decreased matrix metalloproteinase 9 expression and phenocopied the tumor suppressive effects of miR-424 in cell models. Taken together, our results identify a crucial tumor suppressive role of miR-424 in the progression of

  18. Clonning and expression analysis of Chk1 gene in Daphnia pulex%蚤状溞(Daphnia pulex)Chk1基因的克隆与表达分析

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    方增冰; 戴新宇; 邹秀; 郭晓鸽; 徐善良; 王丹丽; 赵云龙

    2015-01-01

    The full-length cDNA of a Chk1 (DpChk1) was cloned from cladoceran Daphnia pulex using rapid amplification of comple-mentary DNA ends ( RACE) method.The DpChk1 cDNA is 1767 bp in length;and it has a 1497-bp open reading frame that encodes a 498-amino-acid polypeptide containing three conserved Ser-Gln (SQ), and Thr-Gln (TQ) sequence.In addition, DpChk1 shared homology of 51%-55% with gene in Rhipicephalus pulchellus, Megachile rotundata, Metaseiulus occidentalis, Acyrthosiphon pisum and Drosophila melanogaster.Phylogenetic analysis revealed that DpChk 1 protein has a close genetic relationship with Phylum arthropo-da such as Acyrthosiphon pisum, Megachile rotundata, Drosophila melanogaster, Rhipicephalus pulchellus, Metaseiulus occidenat lis and so on.qPCR results (real-time quantitative PCR) showed that the DpChk1 expression was significantly higher (P<0.05) in ephippial female than in parthenogenetic female and was the lowest in the resting egg .Therefore, Chk1 was closely related to the reproduction conversion of Daphnia pulex.%用RACE技术从蚤状溞( Daphnia pulex)中克隆到Chk1基因cDNA全长为1767 bp,开放阅读框为1497 bp,编码了498个氨基酸,其结构中存在3个保守的Ser-Gln ( SQ)和Thr-Gln ( TQ)序列。同源性比对结果显示,蚤状溞Chk1基因与丽色扇头蜱、切叶蜂、转基因捕食螨、豌豆长管蚜和黑腹果蝇等的同源性均为51%~55%。进化分析发现,蚤状溞Chk1基因与豌豆长管蚜、切叶蜂、黑腹果蝇、丽色扇头蜱和转基因捕食螨等节肢动物亲缘关系最近。Real Time PCR实验结果表明,Chk1 mRNA在两性溞的表达量显著高于孤雌溞( P<0.05),且在休眠卵中表达量最低。推测Chk1基因可能在蚤状溞的生殖转化调控中发挥重要作用。

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

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    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...

  20. DNA topoisomerase 2 mutant allele mildly delays the mitotic progression and activates the checkpoint protein kinase Chk1 in fission yeast Schizosaccharomyces pombe.

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    Yadav, Sudhanshu; Verma, Sumit Kumar; Ahmed, Shakil

    2011-08-01

    DNA topoisomerases are specialized nuclear enzymes that perform topological modifications on double-stranded DNA (dsDNA) and hence are essential for DNA metabolism such as replication, transcription, recombination, condensation and segregation. In a genetic screen, we identified a temperature-sensitive mutant allele of topoisomerase 2 that exhibits conditional synthetic lethality with a chk1 knockout strain. The mutant allele of topoisomerase 2 is defective in chromosome segregation at a non-permissive temperature and there was increase in chromosome segregation defects in the double mutant of top2-10 and chk1 delete at a non-permissive temperature. More importantly, topoisomearse 2 mutant cells mildly delay the mitotic progression at non-permissive temperature that is mediated by checkpoint protein kinase Chk1. Additionally, top2-10 mutant cells also activate the Chk1 at a non-permissive temperature and this activation of Chk1 takes place at the time of mitosis. Interestingly, top2-10 mutant cells retain their viability at a non-permissive temperature if the cells are not allowed to enter into mitosis. Taking together our results, we speculate that in the top2-10 mutant, the segregation of entangled chromatids during mitosis could result in delaying the mitotic progression through the activation of Chk1 kinase.

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

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    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.

  2. The radioresistance to killing of A1-5 cells derives from activation of the Chk1 pathway

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    Hu, B.; Zhou, X. Y.; Wang, X.; Zeng, Z. C.; Iliakis, G.; Wang, Y.

    2001-01-01

    Checkpoints respond to DNA damage by arresting the cell cycle to provide time for facilitating repair. In mammalian cells, the G(2) checkpoint prevents the Cdc25C phosphatase from removing inhibitory phosphate groups from the mitosis-promoting kinase Cdc2. Both Chk1 and Chk2, the checkpoint kinases, can phosphorylate Cdc25C and inactivate its in vitro phosphatase activity. Therefore, both Chk1 and Chk2 are thought to regulate the activation of the G(2) checkpoint. Here we report that A1-5, a transformed rat embryo fibroblast cell line, shows much more radioresistance associated with a much stronger G(2) arrest response when compared with its counterpart, B4, although A1-5 and B4 cells have a similar capacity for nonhomologous end-joining DNA repair. These phenotypes of A1-5 cells are accompanied by a higher Chk1 expression and a higher phosphorylation of Cdc2. On the other hand, Chk2 expression increases slightly following radiation; however, it has no difference between A1-5 and B4 cells. Caffeine or UCN-01 abolishes the extreme radioresistance with the strong G(2) arrest and at the same time reduces the phosphorylation of Cdc2 in A1-5 cells. In addition, Chk1 but not Chk2 antisense oligonucleotide sensitizes A1-5 cells to radiation-induced killing and reduces the G(2) arrest of the cells. Taken together these results suggest that the Chk1/Cdc25C/Cdc2 pathway is the major player for the radioresistance with G(2) arrest in A1-5 cells.

  3. The nucleolus stress response is coupled to an ATR-Chk1-mediated G2 arrest.

    Science.gov (United States)

    Ma, Hanhui; Pederson, Thoru

    2013-05-01

    We report experiments on the connection between nucleolar stress and cell cycle progression, using HeLa cells engineered with the fluorescent ubiquitinylation-based cell cycle indicator. Nucleolar stress elicited by brief exposure of cells to a low concentration of actinomycin D that selectively inhibits rRNA synthesis had no effect on traverse of G1 or S, but stalled cells in very late interphase. Additional experiments revealed that a switch occurs during a specific temporal window during nucleolar stress and that the subsequent cell cycle arrest is not triggered simply by the stress-induced decline in the synthesis of rRNA or by a ribosome starvation phenomenon. Further experiments revealed that this nucleolus stress-induced cell cycle arrest involves the action of a G2 checkpoint mediated by the ataxia telangiectasia and Rad3-related protein (ATR)-checkpoint kinase 1 (Chk1) pathway. Based on analysis of the cell cycle stages at which this nucleolar stress effect is put into action, to become manifest later, our results demonstrate a feedforward mechanism that leads to G2 arrest and identify ATR and Chk1 as molecular agents of the requisite checkpoint.

  4. The Transcription Factor E4F1 Coordinates CHK1-Dependent Checkpoint and Mitochondrial Functions

    Directory of Open Access Journals (Sweden)

    Geneviève Rodier

    2015-04-01

    Full Text Available Recent data support the notion that a group of key transcriptional regulators involved in tumorigenesis, including MYC, p53, E2F1, and BMI1, share an intriguing capacity to simultaneously regulate metabolism and cell cycle. Here, we show that another factor, the multifunctional protein E4F1, directly controls genes involved in mitochondria functions and cell-cycle checkpoints, including Chek1, a major component of the DNA damage response. Coordination of these cellular functions by E4F1 appears essential for the survival of p53-deficient transformed cells. Acute inactivation of E4F1 in these cells results in CHK1-dependent checkpoint deficiency and multiple mitochondrial dysfunctions that lead to increased ROS production, energy stress, and inhibition of de novo pyrimidine synthesis. This deadly cocktail leads to the accumulation of uncompensated oxidative damage to proteins and extensive DNA damage, ending in cell death. This supports the rationale of therapeutic strategies simultaneously targeting mitochondria and CHK1 for selective killing of p53-deficient cancer cells.

  5. The transcription factor E4F1 coordinates CHK1-dependent checkpoint and mitochondrial functions.

    Science.gov (United States)

    Rodier, Geneviève; Kirsh, Olivier; Baraibar, Martín; Houlès, Thibault; Lacroix, Matthieu; Delpech, Hélène; Hatchi, Elodie; Arnould, Stéphanie; Severac, Dany; Dubois, Emeric; Caramel, Julie; Julien, Eric; Friguet, Bertrand; Le Cam, Laurent; Sardet, Claude

    2015-04-14

    Recent data support the notion that a group of key transcriptional regulators involved in tumorigenesis, including MYC, p53, E2F1, and BMI1, share an intriguing capacity to simultaneously regulate metabolism and cell cycle. Here, we show that another factor, the multifunctional protein E4F1, directly controls genes involved in mitochondria functions and cell-cycle checkpoints, including Chek1, a major component of the DNA damage response. Coordination of these cellular functions by E4F1 appears essential for the survival of p53-deficient transformed cells. Acute inactivation of E4F1 in these cells results in CHK1-dependent checkpoint deficiency and multiple mitochondrial dysfunctions that lead to increased ROS production, energy stress, and inhibition of de novo pyrimidine synthesis. This deadly cocktail leads to the accumulation of uncompensated oxidative damage to proteins and extensive DNA damage, ending in cell death. This supports the rationale of therapeutic strategies simultaneously targeting mitochondria and CHK1 for selective killing of p53-deficient cancer cells.

  6. Targeting radioresistant breast cancer cells by single agent CHK1 inhibitor via enhancing replication stress

    Science.gov (United States)

    Du, Zhanwen; Gao, Jinnan; Yang, Shuming; Gorityala, Shashank; Xiong, Xiahui; Deng, Ou; Ma, Zhefu; Yan, Chunhong; Susana, Gonzalo; Xu, Yan; Zhang, Junran

    2016-01-01

    Radiotherapy (RT) remains a standard therapeutic modality for breast cancer patients. However, intrinsic or acquired resistance limits the efficacy of RT. Here, we demonstrate that CHK1 inhibitor AZD7762 alone significantly inhibited the growth of radioresistant breast cancer cells (RBCC). Given the critical role of ATR/CHK1 signaling in suppressing oncogene-induced replication stress (RS), we hypothesize that CHK1 inhibition leads to the specific killing for RBCC due to its abrogation in the suppression of RS induced by oncogenes. In agreement, the expression of oncogenes c-Myc/CDC25A/c-Src/H-ras/E2F1 and DNA damage response (DDR) proteins ATR/CHK1/BRCA1/CtIP were elevated in RBCC. AZD7762 exposure led to significantly higher levels of RS in RBCC, compared to the parental cells. The mechanisms by which CHK1 inhibition led to specific increase of RS in RBCC were related to the interruptions in the replication fork dynamics and the homologous recombination (HR). In summary, RBCC activate oncogenic pathways and thus depend upon mechanisms controlled by CHK1 signaling to maintain RS under control for survival. Our study provided the first example where upregulating RS by CHK1 inhibitor contributes to the specific killing of RBCC, and highlight the importance of the CHK1 as a potential target for treatment of radioresistant cancer cells. PMID:27167194

  7. 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.

  8. 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.

  9. STAT3 interrupts ATR-Chk1 signaling to allow oncovirus-mediated cell proliferation.

    Science.gov (United States)

    Koganti, Siva; Hui-Yuen, Joyce; McAllister, Shane; Gardner, Benjamin; Grasser, Friedrich; Palendira, Umaimainthan; Tangye, Stuart G; Freeman, Alexandra F; Bhaduri-McIntosh, Sumita

    2014-04-01

    DNA damage response (DDR) is a signaling network that senses DNA damage and activates response pathways to coordinate cell-cycle progression and DNA repair. Thus, DDR is critical for maintenance of genome stability, and presents a powerful defense against tumorigenesis. Therefore, to drive cell-proliferation and transformation, viral and cellular oncogenes need to circumvent DDR-induced cell-cycle checkpoints. Unlike in hereditary cancers, mechanisms that attenuate DDR and disrupt cell-cycle checkpoints in sporadic cancers are not well understood. Using Epstein-Barr virus (EBV) as a source of oncogenes, we have previously shown that EBV-driven cell proliferation requires the cellular transcription factor STAT3. EBV infection is rapidly followed by activation and increased expression of STAT3, which mediates relaxation of the intra-S phase cell-cycle checkpoint; this facilitates viral oncogene-driven cell proliferation. We now show that replication stress-associated DNA damage, which results from EBV infection, is detected by DDR. However, signaling downstream of ATR is impaired by STAT3, leading to relaxation of the intra-S phase checkpoint. We find that STAT3 interrupts ATR-to-Chk1 signaling by promoting loss of Claspin, a protein that assists ATR to phosphorylate Chk1. This loss of Claspin which ultimately facilitates cell proliferation is mediated by caspase 7, a protein that typically promotes cell death. Our findings demonstrate how STAT3, which is constitutively active in many human cancers, suppresses DDR, fundamental to tumorigenesis. This newly recognized role for STAT3 in attenuation of DDR, discovered in the context of EBV infection, is of broad interest as the biology of cell proliferation is central to both health and disease.

  10. Signaling from Mus81-Eme2-Dependent DNA Damage Elicited by Chk1 Deficiency Modulates Replication Fork Speed and Origin Usage

    Directory of Open Access Journals (Sweden)

    Hervé Técher

    2016-02-01

    Full Text Available Mammalian cells deficient in ATR or Chk1 display moderate replication fork slowing and increased initiation density, but the underlying mechanisms have remained unclear. We show that exogenous deoxyribonucleosides suppress both replication phenotypes in Chk1-deficient, but not ATR-deficient, cells. Thus, in the absence of exogenous stress, depletion of either protein impacts the replication dynamics through different mechanisms. In addition, Chk1 deficiency, but not ATR deficiency, triggers nuclease-dependent DNA damage. Avoiding damage formation through invalidation of Mus81-Eme2 and Mre11, or preventing damage signaling by turning off the ATM pathway, suppresses the replication phenotypes of Chk1-deficient cells. Damage and resulting DDR activation are therefore the cause, not the consequence, of replication dynamics modulation in these cells. Together, we identify moderate reduction of precursors available for replication as an additional outcome of DDR activation. We propose that resulting fork slowing, and subsequent firing of backup origins, helps replication to proceed along damaged templates.

  11. Induction of DNA damage and G2 cell cycle arrest by diepoxybutane through the activation of the Chk1-dependent pathway in mouse germ cells.

    Science.gov (United States)

    Dong, Jianyun; Wang, Zhi; Zou, Peng; Zhang, Guowei; Dong, Xiaomei; Ling, Xi; Zhang, Xi; Liu, Jinyi; Ye, Dongqing; Cao, Jia; Ao, Lin

    2015-03-16

    1,2:3,4-Diepoxybutane (DEB) is a major carcinogenic metabolite of 1,3-butadiene (BD), which has been shown to cause DNA strand breaks in cells through its potential genotoxicity. The adverse effect of DEB on male reproductive cells in response to DNA damage has not been thoroughly studied, and the related mechanism is yet to be elucidated. Using mouse spermatocyte-derived GC-2 cells, we demonstrated in the present study that DEB caused the proliferation inhibition and marked cell cycle arrest at the G2 phase but not apoptosis. DEB also induced DNA damage as evidenced by γ-H2AX expression, the comet assay, and the cytokinesis-block micronucleus assay. Meanwhile, DEB triggered the Chk1/Cdc25c/Cdc2 signal pathway, which could be abated in the presence of UCN-01 or Chk1 siRNA. GC-2 cells exposed to DEB experienced ROS generation and pretreatment of N-acetyl-l-cysteine, partly attenuated DEB-induced DNA damage, and G2 arrest. Furthermore, measurement of testicular cells showed an increased proportion of tetraploid cells in mice administrated with DEB, alongside the enhanced expression of p-Chk1. Also, the defective reproductive phenotypes, including reduced sperm motility, increased sperm malformation, and histological abnormality of testes, were observed. In conclusion, these results suggest DEB induces DNA damage and G2 cell cycle arrest by activating the Chk1-dependent pathway, while oxidative stress may be associated with eliciting toxicity in male reproductive cells.

  12. CHK1 Inhibition Radiosensitizes Head and Neck Cancers to Paclitaxel-Based Chemoradiotherapy.

    Science.gov (United States)

    Barker, Holly E; Patel, Radhika; McLaughlin, Martin; Schick, Ulrike; Zaidi, Shane; Nutting, Christopher M; Newbold, Katie L; Bhide, Shreerang; Harrington, Kevin J

    2016-09-01

    Head and neck squamous cell carcinoma (HNSCC) is a leading cause of cancer-related deaths, with increasingly more cases arising due to high-risk human papillomavirus (HPV) infection. Cisplatin-based chemoradiotherapy is a standard-of-care for locally advanced head and neck cancer but is frequently ineffective. Research into enhancing radiation responses as a means of improving treatment outcomes represents a high priority. Here, we evaluated a CHK1 inhibitor (CCT244747) as a radiosensitiser and investigated whether a mechanistically rational triple combination of radiation/paclitaxel/CHK1 inhibitor delivered according to an optimized schedule would provide added benefit. CCT244747 abrogated radiation-induced G2 arrest in the p53-deficient HNSCC cell lines, HN4 and HN5, causing cells to enter mitosis with unrepaired DNA damage. The addition of paclitaxel further increased cell kill and significantly reduced tumor growth in an HN5 xenograft model. Importantly, a lower dose of paclitaxel could be used when CCT244747 was included, therefore potentially limiting toxicity. Triple therapy reduced the expression of several markers of radioresistance. Moreover, the more radioresistant HN5 cell line exhibited greater radiation-mediated CHK1 activation and was more sensitive to triple therapy than HN4 cells. We analyzed CHK1 expression in a panel of head and neck tumors and observed that primary tumors from HPV(+) patients, who went on to recur postradiotherapy, exhibited significantly stronger expression of total, and activated CHK1. CHK1 may serve as a biomarker for identifying tumors likely to recur and, therefore, patients who may benefit from concomitant treatment with a CHK1 inhibitor and paclitaxel during radiotherapy. Clinical translation of this strategy is under development. Mol Cancer Ther; 15(9); 2042-54. ©2016 AACR.

  13. miR-107 activates ATR/Chk1 pathway and suppress cervical cancer invasion by targeting MCL1.

    Directory of Open Access Journals (Sweden)

    Chengyan Zhou

    Full Text Available MicroRNAs (miRNAs are a class of single-stranded, non-coding RNAs of about 22 nucleotides in length. Increasing evidence implicates miRNAs may function as oncogenes or tumor suppressors. Here we showed that miR-107 directly targeted MCL1 and activated ATR/Chk1 pathway to inhibit proliferation, migration and invasiveness of cervical cancer cells. Moreover, we found that MCL1 was frequently up-regulated in cervical cancer, and knockdown of MCL1 markedly inhibited cancer cell proliferation, migration and invasion, whereas ectopic expression of MCL1 significantly enhances these properties. The restoration of MCL1 expression can counteract the effect of miR-107 on the cancer cells. Together, miR-107 is a new regulator of MCL1, and both miR-107 and MCL1 play important roles in the pathogenesis of cervical cancer. We have therefore identified a mechanism for ATR/Chk1 pathway which involves an increase in miR-107 leading to a decrease in MCL1. Correspondingly, our results revealed that miR-107 affected ATR/Chk1 signalling and gene expression, and implicated miR-107 as a therapeutic target in human cervical cancer. We also demonstrated that taxol attenuated migration and invasion in cervical cancer cells by activating the miR-107, in which miR-107 play an important role in regulating the expression of MCL1. Elucidation of this discovered MCL1 was directly regulated by miR-107 will greatly enhance our understanding of the mechanisms responsible for cervical cancer and will provide an additional arm for the development of anticancer therapies.

  14. Suppression of allelic recombination and aneuploidy by cohesin is independent of Chk1 in Saccharomyces cerevisiae.

    Directory of Open Access Journals (Sweden)

    Shay Covo

    Full Text Available Sister chromatid cohesion (SCC, which is established during DNA replication, ensures genome stability. Establishment of SCC is inhibited in G2. However, this inhibition is relived and SCC is established as a response to DNA damage, a process known as Damage Induced Cohesion (DIC. In yeast, Chk1, which is a kinase that functions in DNA damage signal transduction, is considered an activator of SCC through DIC. Nonetheless, here we show that, unlike SCC mutations, loss of CHK1 did not increase spontaneous or damage-induced allelic recombination or aneuploidy. We suggest that Chk1 has a redundant role in the control of DIC or that DIC is redundant for maintaining genome stability.

  15. Suppression of Allelic Recombination and Aneuploidy by Cohesin Is Independent of Chk1 in Saccharomyces cerevisiae

    Science.gov (United States)

    Gordenin, Dmitry A.; Resnick, Michael A.

    2014-01-01

    Sister chromatid cohesion (SCC), which is established during DNA replication, ensures genome stability. Establishment of SCC is inhibited in G2. However, this inhibition is relived and SCC is established as a response to DNA damage, a process known as Damage Induced Cohesion (DIC). In yeast, Chk1, which is a kinase that functions in DNA damage signal transduction, is considered an activator of SCC through DIC. Nonetheless, here we show that, unlike SCC mutations, loss of CHK1 did not increase spontaneous or damage-induced allelic recombination or aneuploidy. We suggest that Chk1 has a redundant role in the control of DIC or that DIC is redundant for maintaining genome stability. PMID:25551702

  16. 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...

  17. 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.

  18. The stress-activated protein kinases p38α/β and JNK1/2 cooperate with Chk1 to inhibit mitotic entry upon DNA replication arrest.

    Science.gov (United States)

    Llopis, Alba; Salvador, Noelia; Ercilla, Amaia; Guaita-Esteruelas, Sandra; Barrantes, Ivan del Barco; Gupta, Jalaj; Gaestel, Matthias; Davis, Roger J; Nebreda, Angel R; Agell, Neus

    2012-10-01

    Accurate DNA replication is crucial for the maintenance of genome integrity. To this aim, cells have evolved complex surveillance mechanisms to prevent mitotic entry in the presence of partially replicated DNA. ATR and Chk1 are key elements in the signal transduction pathways of DNA replication checkpoint; however, other kinases also make significant contributions. We show here that the stress kinases p38 and JNK are activated when DNA replication is blocked, and that their activity allows S/M, but not G 2/M, checkpoint maintenance when Chk1 is inhibited. Activation of both kinases by DNA replication inhibition is not mediated by the caffeine-sensitive kinases ATR or ATM. Phosphorylation of MKK3/6 and MKK4, p38 and JNK upstream kinases was also observed upon DNA replication inhibition. Using a genetic approach, we dissected the p38 pathway and showed that both p38α and p38β isoforms collaborate to inhibit mitotic entry. We further defined MKK3/6 and MK2/3 as the key upstream and downstream elements in the p38 signaling cascade after replication arrest. Accordingly, we found that the stress signaling pathways collaborate with Chk1 to keep cyclin B1/Cdk1 complexes inactive when DNA replication is inhibited, thereby preventing cell cycle progression when DNA replication is stalled. Our results show a complex response to replication stress, where multiple pathways are activated and fulfill overlapping roles to prevent mitotic entry with unreplicated DNA.

  19. Microcephalin is a DNA damage response protein involved in regulation of CHK1 and BRCA1.

    Science.gov (United States)

    Xu, Xingzhi; Lee, Juhie; Stern, David F

    2004-08-13

    Microcephalin (MCPH1) is the first gene identified among at least six loci that contribute to the autosomal recessive disease, primary microcephaly. MCPH1, like NFBD1/MDC1, 53BP1, and BRCA1, encodes a protein with twin carboxyl-terminal BRCT domains (PTCB). Here, we report that Mcph1 forms ionizing radiation-induced foci. Down-regulation of Mcph1, like other PTCBs, by siRNA, impairs ionizing radiation-induced intra-S-phase and G(2)/M checkpoints. Inhibition of the expression of Mcph1 decreases both protein and transcript levels of endogenous Brca1 but not exogenous Brca1. Mcph1 inhibition also decreases both endogenous and heterologous Chk1 transcripts and protein. We conclude that Mcph1 is involved in DNA damage-induced cellular responses, and we propose that regulation of Brca1 and/or Chk1 by Mcph1 may contribute to these cellular responses.

  20. 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.

  1. ATR, Claspin and the Rad9-Rad1-Hus1 complex regulate Chk1 and Cdc25A in the absence of DNA damage

    DEFF Research Database (Denmark)

    Sørensen, Claus Storgaard; Syljuåsen, Randi G; Lukas, Jiri

    2004-01-01

    The ATR and Chk1 kinases are essential to maintain genomic integrity. ATR, with Claspin and the Rad9-Rad1-Hus1 complex, activates Chk1 after DNA damage. Chk1-mediated phosphorylation of the Cdc25A phosphatase is required for the mammalian S-phase checkpoint. Here, we show that during physiological...... S phase the regulation of the Chk1-Cdc25A pathway depends on ATR, Claspin, Rad9, and Hus1. Human cells with chemically or genetically ablated ATR showed inhibition of Chk1-dependent phosphorylation of Cdc25A, and they accumulated Cdc25A without external DNA damage. Furthermore, si......RNA-mediated depletion of Claspin, Rad9 and Hus1 also stabilized Cdc25A. ATR ablation also inhibited the activatory phosphorylation of Chk1 on serine 345. Thus, the ATR-Chk1-Cdc25A pathway represents an integral part of physiological S-phase progression, and interference with this mechanism undermines viability...

  2. Down-regulation of ubiquitin ligase Cbl induced by twist haploinsufficiency in Saethre-Chotzen syndrome results in increased PI3K/Akt signaling and osteoblast proliferation.

    Science.gov (United States)

    Guenou, Hind; Kaabeche, Karim; Dufour, Cécilie; Miraoui, Hichem; Marie, Pierre J

    2006-10-01

    Genetic mutations of Twist, a basic helix-loop-helix transcription factor, induce premature fusion of cranial sutures in Saethre-Chotzen syndrome (SCS). We report here a previously undescribed mechanism involved in the altered osteoblastogenesis in SCS. Cranial osteoblasts from an SCS patient with a Twist mutation causing basic helix-loop-helix deletion exhibited decreased expression of E3 ubiquitin ligase Cbl compared with wild-type osteoblasts. This was associated with decreased ubiquitin-mediated degradation of phosphatidyl inositol 3 kinase (PI3K) and increased PI3K expression and PI3K/Akt signaling. Increased PI3K immunoreactivity was also found in osteoblasts in histological sections of affected cranial sutures from SCS patients. Transfection with Twist or Cbl abolished the increased PI3K/Akt signaling in Twist mutant osteoblasts. Forced overexpression of Cbl did not correct the altered expression of osteoblast differentiation markers in Twist mutant cells. In contrast, pharmacological inhibition of PI3K/Akt, but not ERK signaling, corrected the increased cell growth in Twist mutant osteoblasts. The results show that Twist haploinsufficiency results in decreased Cbl-mediated PI3K degradation in osteoblasts, causing PI3K accumulation and activation of PI3K/Akt-dependent osteoblast growth. This provides genetic and biochemical evidence for a role for Cbl-mediated PI3K signaling in the altered osteoblast phenotype induced by Twist haploinsufficiency in SCS.

  3. Design of targeted libraries against the human Chk1 kinase using PGVL Hub.

    Science.gov (United States)

    Peng, Zhengwei; Hu, Qiyue

    2011-01-01

    PGVL Hub is a Pfizer internal desktop tool for chemical library and singleton design. In this chapter, we give a short introduction to PGVL Hub, the core workflow it supports, and the rich design capabilities it provides. By re-creating two legacy targeted libraries against the human checkpoint kinase 1 (Chk1) as a showcase, we illustrate how PGVL Hub could be used to help library designers carry out the steps in library design and realize design objectives such as SAR expansion and improvement in both kinase selectivity and compound aqueous solubility. Finally we share several tips about library design and usage of PGVL Hub.

  4. Smith-Magenis syndrome: haploinsufficiency of RAI1 results in altered gene regulation in neurological and metabolic pathways.

    Science.gov (United States)

    Elsea, Sarah H; Williams, Stephen R

    2011-04-19

    Smith-Magenis syndrome (SMS) is a complex neurobehavioural disorder characterised by intellectual disability, self-injurious behaviours, sleep disturbance, obesity, and craniofacial and skeletal anomalies. Diagnostic strategies are focused towards identification of a 17p11.2 microdeletion encompassing the gene RAI1 (retinoic acid induced 1) or a mutation of RAI1. Molecular evidence shows that most SMS features are due to RAI1 haploinsufficiency, whereas variability and severity are modified by other genes in the 17p11.2 region for 17p11.2 deletion cases. The functional role of RAI1 is not completely understood, but it is probably a transcription factor acting in several different biological pathways that are dysregulated in SMS. Functional studies based on the hypothesis that RAI1 acts through phenotype-specific pathways involving several downstream genes have shown that RAI1 gene dosage is crucial for normal regulation of circadian rhythm, lipid metabolism and neurotransmitter function. Here, we review the clinical and molecular features of SMS and explore more recent studies supporting possible therapeutic strategies for behavioural management.

  5. 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. PMID:24594907

  6. 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.

  7. 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.

  8. Chk1防止DNA损伤的S期肿瘤细胞进行异常的有丝分裂%Chk1 prevents abnormal mitosis of S-phase HeLa cells containing DNA damage

    Institute of Scientific and Technical Information of China (English)

    李小方; Tarsha Ward; 姚雪彪; 吴家睿

    2009-01-01

    为探讨在p53失活的肿瘤细胞中DNA甲基化试剂引发的DNA损伤对于细胞周期的影响,我们将同步化在G1,S和G2/M期的HeLa细胞分别进行甲磺酸甲酯(MMS)处理.MMS的处理结果表明,各个时相的细胞周期进程均发生延迟或阻滞,其中S期细胞对药物最为敏感.进一步的分子机理研究表明,3个时相中ATM-Chk2和p38 MAPK通路均被激活,但是Chk1仅在S期中被活化,提示Chk1特异地参与了S期的DNA损伤检查点(DNAdamage checkpoint)或者DNA复制检查点(DNA replication checkpoint)的作用.为了进一步确定Chk1在S期的检查点功能,用专一的小分子抑制剂抑制Chk1的磷酸化.发现被MMS处理的S期细胞能在未完成复制的情况下进行异常的有丝分裂,提示Chk1主要是在HeLa细胞S期的DNA损伤检查点而不是DNA复制检查点发挥其作用.另外,本研究还检查了参与G2/M期进程的cyclin B1的表达变化情况.在MMS处理的S期细胞中,cyclin B1表达量不能上调;而在加入Chk1抑制剂处理后,cyclin B1则有所增加.这一结果进一步支持DNA损伤S期细胞在Chk1失活时进入异常有丝分裂的推论.研究结果表明,Chk1是MMS诱发的HeLa细胞S期DNA损伤检查点的专一性的重要蛋白激酶;当MMS引发DNA损伤后,上游蛋白激酶对Chk1进行磷酸化,从而激活了S期的DNA损伤检查点.阻止细胞进入G2/M期.由于这一过程不依赖于p53的活性,因此Chk1有可能作为p53失活的肿瘤细胞的药物靶标.

  9. A balanced pyrimidine pool is required for optimal Chk1 activation to prevent ultrafine anaphase bridge formation.

    Science.gov (United States)

    Gemble, Simon; Buhagiar-Labarchède, Géraldine; Onclercq-Delic, Rosine; Biard, Denis; Lambert, Sarah; Amor-Guéret, Mounira

    2016-08-15

    Cytidine deaminase (CDA) deficiency induces an excess of cellular dCTP, which reduces basal PARP-1 activity, thereby compromising complete DNA replication, leading to ultrafine anaphase bridge (UFB) formation. CDA dysfunction has pathological implications, notably in cancer and in Bloom syndrome. It remains unknown how reduced levels of PARP-1 activity and pyrimidine pool imbalance lead to the accumulation of unreplicated DNA during mitosis. We report that a decrease in PARP-1 activity in CDA-deficient cells impairs DNA-damage-induced Chk1 activation, and, thus, the downstream checkpoints. Chemical inhibition of the ATR-Chk1 pathway leads to UFB accumulation, and we found that this pathway was compromised in CDA-deficient cells. Our data demonstrate that ATR-Chk1 acts downstream from PARP-1, preventing the accumulation of unreplicated DNA in mitosis, and, thus, UFB formation. Finally, delaying entry into mitosis is sufficient to prevent UFB formation in both CDA-deficient and CDA-proficient cells, suggesting that both physiological and pathological UFBs are derived from unreplicated DNA. Our findings demonstrate an unsuspected requirement for a balanced nucleotide pool for optimal Chk1 activation both in unchallenged cells and in response to genotoxic stress.

  10. 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.

  11. 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.

  12. Phosphorylation of pRB at Ser612 by Chk1/2 leads to a complex between pRB and E2F-1 after DNA damage.

    Science.gov (United States)

    Inoue, Yasumichi; Kitagawa, Masatoshi; Taya, Yoichi

    2007-04-18

    The retinoblastoma tumor suppressor protein (pRB) plays a critical role in the control of cell proliferation and in the DNA damage checkpoints. pRB inhibits cell cycle progression through interactions with the E2F family of transcription factors. Here, we report that DNA damage induced not only the dephosphorylation of pRB at Cdk phosphorylation sites and the binding of pRB to E2F-1, but also the phosphorylation of pRB at Ser612. Phosphorylation of pRB at Ser612 enhanced the formation of a complex between pRB and E2F-1. Substitution of Ser612 with Ala decreased pRB-E2F-1 binding and the transcriptional repression activity. Until now, Ser612 of pRB has been thought to be phosphorylated by Cdk2. However, the phosphorylation of pRB at Ser612 was conducted by Chk1/2 after DNA damage, and inhibition of ATM-Chk1/2 activity suppressed the phosphorylation of Ser612 and the binding of pRB to E2F-1. These results suggest that Ser612 is phosphorylated by Chk1/2 after DNA damage, leading to the formation of pRB-E2F-1. This is the first report that pRB is phosphorylated in vivo by a kinase other than Cdk.

  13. Staurosporine is chemoprotective by inducing G1 arrest in a Chk1- and pRb-dependent manner.

    Science.gov (United States)

    Murray, Mollianne McGahren; Bui, Tuyen; Smith, Michelle; Bagheri-Yarmand, Rozita; Wingate, Hannah; Hunt, Kelly K; Keyomarsi, Khandan

    2013-10-01

    Chemotherapeutic agents have been the mainstay of cancer therapy for years. However, their effectiveness has been limited by toxicities they impart on normal cells. Staurosporine (ST) has been shown to arrest normal, but not breast cancer, cells in G1. Therefore, ST may become a chemoprotective agent, arresting normal cells while allowing tumor cells to enter cell cycle phases where they are sensitive to chemotherapeutic agents. Understanding the mechanism of ST-mediated G1 arrest may allow for a beneficial chemoprotective treatment strategy for patients. We utilized 76NE6 (pRb+/p53-), 76NF2V (pRb+/p53+) and 76NE7 (pRb-/P53+) non-tumorigenic human mammary epithelial cell lines to understand the role of the Rb and p53 pathways in ST-directed G1 arrest. CDK4 was downregulated by ST in Rb+ cells, but its presence could not reverse the arrest, neither did its stable downregulation alter ST-mediated cellular response. ST-mediated G1 arrest required pRb, which in turn initiated a cascade of events leading to inhibition of CDK4. Further assessment of this pathway revealed that Chk1 expression and activity were required for the Rb-dependent arrest. For example, pRb+ cells with small interfering RNA to Chk1 had approximately 60% less cells in G1 phase compared with controls and pRb- cells do not arrest upon ST. Furthermore, Chk1 expression facilitates the release of the Rb+ cells from G1 arrest. Collectively, our data suggest that pRb cooperates with Chk1 to mediate a G1 arrest only in pRb+ cells. The elucidation of this pathway can help identify novel agents to protect cancer patients against the debilitating effects of chemotherapy.

  14. Munc18-1 haploinsufficiency results in enhanced anxiety-like behavior as determined by heart rate responses in mice.

    Science.gov (United States)

    Hager, Torben; Maroteaux, Grégoire; Pont, Paula du; Julsing, Joris; van Vliet, Rick; Stiedl, Oliver

    2014-03-01

    Heterozygous (HZ) missense mutations in the gene encoding syntaxin binding protein 1 (Stxbp1 or Munc18-1), a presynaptic protein essential for neurotransmitter release, causes early infantile epileptic encephalopathy, abnormal brain structure and mental retardation in humans. Here we investigated whether the mouse model mimics symptoms of the human phenotype. The effects of the deletion of munc18-1 were studied in HZ and wild-type (WT) mice based on heart rate (HR) and its variability (HRV) as independent measures to expand previous behavioral results of enhanced anxiety and impaired emotional learning suggesting mild cognitive impairments. HR responses were assessed during novelty exposure, during the expression and extinction of conditioned tone-dependent fear and during the diurnal phase. Novelty exposure yielded no differences in activity patterns between the two genotypes, while maximum HR differed significantly (WT: 770 bpm; HZ: 790 bpm). Retention tests after both auditory delay and trace fear conditioning showed a delayed extinction of the conditioned HR response in HZ mice compared to WT mice. Since the HR versus HRV correlation and HR dynamics assessed by nonlinear methods revealed similar function in HZ and WT mice, the higher HR responses of munc18-1 HZ mice to different emotional challenges cannot be attributed to differences in autonomic nervous system function. Thus, in contrast to the adverse consequences of deletion of a single allele of munc18-1 in humans, C57BL/6J mice show enhanced anxiety responses based on HR adjustments that extend previous results on the behavioral level without support of cognitive impairment, epileptic seizures and autonomic dysregulation.

  15. Rai1 haploinsufficiency causes reduced Bdnf expression resulting in hyperphagia, obesity and altered fat distribution in mice and humans with no evidence of metabolic syndrome.

    Science.gov (United States)

    Burns, Brooke; Schmidt, Kristie; Williams, Stephen R; Kim, Sun; Girirajan, Santhosh; Elsea, Sarah H

    2010-10-15

    Smith-Magenis syndrome (SMS) is a genetic disorder caused by haploinsufficiency of the retinoic acid induced 1 (RAI1) gene. In addition to intellectual disabilities, behavioral abnormalities and sleep disturbances, a majority of children with SMS also have significant early-onset obesity. To study the role of RAI1 in obesity, we investigated the growth and obesity phenotype in a mouse model haploinsufficient for Rai1. Data show that Rai1(+/-) mice are hyperphagic, have an impaired satiety response and have altered abdominal and subcutaneous fat distribution, with Rai1(+/-) female mice having a higher proportion of abdominal fat when compared with wild-type female mice. Expression analyses revealed that Bdnf (brain-derived neurotrophic factor), a gene previously associated with hyperphagia and obesity, is downregulated in the Rai1(+/-) mouse hypothalamus, and reporter studies show that RAI1 directly regulates the expression of BDNF. Even though the Rai1(+/-) mice are significantly obese, serum analyses do not reveal any evidence of metabolic syndrome. Supporting these findings, a caregiver survey revealed that even though a high incidence of abdominal obesity is observed in females with SMS, they did not exhibit a higher incidence of indicators of metabolic syndrome above the general population. We conclude that Rai1 haploinsufficiency represents a single-gene model of obesity with hyperphagia, abnormal fat distribution and altered hypothalamic gene expression associated with satiety, food intake, behavior and obesity. Linking RAI1 and BDNF provides a more thorough understanding of the role of Rai1 in growth and obesity and insight into the complex pathogenicity of obesity, behavior and sex-specific differences in adiposity.

  16. Mangiferin induces cell cycle arrest at G2/M phase through ATR-Chk1 pathway in HL-60 leukemia cells.

    Science.gov (United States)

    Peng, Z G; Yao, Y B; Yang, J; Tang, Y L; Huang, X

    2015-05-12

    This study aimed to determine the effect of mangiferin on the cell cycle in HL-60 leukemia cells and expression of the cell cycle-regulatory genes Wee1, Chk1 and CDC25C and to further investigate the molecular mechanisms of the antileukemic action of mangiferin. The inhibitory effect of mangiferin on HL-60 leukemia cell proliferation was determined by the MTT assay. The impact of mangiferin on the HL-60 cell cycle was evaluated by flow cytometry. After the cells were treated with different concentrations of mangiferin, the expression levels of Wee1, Chk1 and CDC25C mRNA were determined by RT-PCR, and Western blot was used to evaluate the expression levels of cdc25c, cyclin B1, and Akt proteins. The inhibition of HL-60 cell growth by mangiferin was dose- and time-dependent. After treatment for 24 h, cells in G2/M phase increased, and G2/M phase arrest appeared with increased mRNA expression of Wee1, Chk1 and CDC25C. Mangiferin inhibited Chk1 and cdc25c mRNA expression at high concentrations and induced Wee1 mRNA expression in a dose-dependent manner. It significantly inhibited ATR, Chk1, Wee1, Akt, and ERK1/2 phosphorylation but increased cdc2 and cyclin B1 phosphorylation. Furthermore, mangiferin reduced cdc25c, cyclin B1, and Akt protein levels while inducing Wee1 protein expression. It also antagonized the phosphorylation effect of vanadate on ATR, and the phosphorylation effect of EGF on Wee1. These findings indicated that mangiferin inhibits cell cycle progression through the ATR-Chk1 stress response DNA damage pathway, leading to cell cycle arrest at G2/M phase in leukemia cells.

  17. 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 mammals, the ATM (ataxia-telangiectasia-mutated) and ATR (ATM and Rad3-related) protein kinases function as critical regulators of the cellular DNA damage response. The checkpoint functions of ATR and ATM are mediated, in part, by a pair of checkpoint effector kinases termed Chk1 and Chk2...

  18. 口腔黏膜癌变过程中Chk1和Chk2的表达及意义%Expression of Chk1 and Chk2 proteins in precancerous lesions and squamous cell carcinomas of oral mucosa

    Institute of Scientific and Technical Information of China (English)

    金刚石; 蔡扬; 周瑛

    2014-01-01

    目的 探讨Chk1和Chk2在口腔黏膜癌变过程中的作用及意义.方法 采用免疫组化SABC法检测10例口腔正常黏膜组织、29例口腔黏膜癌前病变组织及40例口腔鳞状细胞癌(oral squamous cell carcinoma,OSCC)组织中Chk1和Chk2蛋白的表达,分析二者表达的相关性及二者在口腔黏膜癌变过程中的作用及意义.结果 (1) Chk1和Chk2在口腔黏膜癌前病变组织及OSCC组织中的阳性率明显低于口腔正常黏膜组织,差异均有统计学意义(P<0.05).(2)Ⅰ+Ⅱ期OSCC组织中Chk1的阳性率明显高于Ⅲ+Ⅳ期,差异有统计学意义(P <0.05);Chk2在伴有淋巴结转移的OSCC组织中的阳性率明显低于无淋巴结转移组,差异有统计学意义(P<0.05).(3)Chk1在Chk2阳性的OSCC组织中的阳性率为60% (6/10),在Chk2阴性的OSCC组织中阳性率为20% (6/30),Chk1和Chk2表达呈正相关(r=0.378,P<0.05).结论 细胞周期调控因子Chk1和Chk2表达下调是口腔黏膜癌变过程中的早期事件,可能是口腔黏膜上皮发生癌变的重要因素之一;Chk1和Chk2在OSCC 组织中的失表达有可能作为临床评估OSCC预后的参考指标之一.

  19. Epstein-Barr virus-encoded latent membrane protein 1 impairs G2 checkpoint in human nasopharyngeal epithelial cells through defective Chk1 activation.

    Directory of Open Access Journals (Sweden)

    Wen Deng

    Full Text Available Nasopharyngeal carcinoma (NPC is a common cancer in Southeast Asia, particularly in southern regions of China. EBV infection is closely associated with NPC and has long been postulated to play an etiological role in the development of NPC. However, the role of EBV in malignant transformation of nasopharyngeal epithelial cells remains enigmatic. The current hypothesis of NPC development is that premalignant nasopharyngeal epithelial cells harboring genetic alterations support EBV infection and expression of EBV genes induces further genomic instability to facilitate the development of NPC. The latent membrane protein 1 (LMP1 is a well-documented EBV-encoded oncogene. The involvement of LMP1 in human epithelial malignancies has been implicated, but the mechanisms of oncogenic actions of LMP1, particularly in nasopharyngeal cells, are unclear. Here we observed that LMP1 expression in nasopharyngeal epithelial cells impaired G2 checkpoint, leading to formation of unrepaired chromatid breaks in metaphases after γ-ray irradiation. We further found that defective Chk1 activation was involved in the induction of G2 checkpoint defect in LMP1-expressing nasopharyngeal epithelial cells. Impairment of G2 checkpoint could result in loss of the acentrically broken chromatids and propagation of broken centric chromatids in daughter cells exiting mitosis, which facilitates chromosome instability. Our findings suggest that LMP1 expression facilitates genomic instability in cells under genotoxic stress. Elucidation of the mechanisms involved in LMP1-induced genomic instability in nasopharyngeal epithelial cells will shed lights on the understanding of role of EBV infection in NPC development.

  20. 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

    Cdc7 kinase regulates DNA replication. However, its role in DNA repair and recombination is poorly understood. Here we describe a pathway that stabilizes the human Cdc7-ASK (activator of S-phase kinase; also called Dbf4), its regulation, and its function in cellular responses to compromised DNA...... 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......) with RAD18 disables foci formation by RAD18 and hinders chromatin loading of translesion DNA polymerase h. These findings define a novel mechanism that orchestrates replication checkpoint signaling and ubiquitin-proteasome machinery with the DNA damage bypass pathway to guard against replication collapse...

  1. 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.

  2. Phosphorylation of the regulatory beta-subunit of protein kinase CK2 by checkpoint kinase Chk1: identification of the in vitro CK2beta phosphorylation site

    DEFF Research Database (Denmark)

    Kristensen, Lars P; Larsen, Martin Røssel; Højrup, Peter;

    2004-01-01

    The regulatory beta-subunit of protein kinase CK2 mediates the formation of the CK2 tetrameric form and it has functions independent of CK2 catalytic subunit through interaction with several intracellular proteins. Recently, we have shown that CK2beta associates with the human checkpoint kinase Chk...... by the modification of Thr213 but it does require the presence of an active Chk1 kinase....

  3. Dcc haploinsufficiency regulates dopamine receptor expression across postnatal lifespan.

    Science.gov (United States)

    Pokinko, Matthew; Grant, Alanna; Shahabi, Florence; Dumont, Yvan; Manitt, Colleen; Flores, Cecilia

    2017-03-27

    Adolescence is a period during which the medial prefrontal cortex (mPFC) undergoes significant remodeling. The netrin-1 receptor, deleted in colorectal cancer (DCC), controls the extent and organization of mPFC dopamine connectivity during adolescence and in turn directs mPFC functional and structural maturation. Dcc haploinsufficiency leads to increased mPFC dopamine input, which causes improved cognitive processing and resilience to behavioral effects of stimulant drugs of abuse. Here we examine the effects of Dcc haploinsufficiency on the dynamic expression of dopamine receptors in forebrain targets of C57BL6 mice. We conducted quantitative receptor autoradiography experiments with [(3)H]SCH-23390 or [(3)H]raclopride to characterize D1 and D2 receptor expression in mPFC and striatal regions in male Dcc haploinsufficient and wild-type mice. We generated autoradiograms at early adolescence (PND21±1), mid-adolescence (PND35±2), and adulthood (PND75±15). C57BL6 mice exhibit overexpression and pruning of D1, but not D2, receptors in striatal regions, and a lack of dopamine receptor pruning in the mPFC. We observed age- and region-specific differences in D1 and D2 receptor density between Dcc haploinsufficient and wild-type mice. Notably, neither group shows the typical pattern of mPFC dopamine receptor pruning in adolescence, but adult haploinsufficient mice show increased D2 receptor density in the mPFC. These results show that DCC receptors contribute to the dynamic refinement of D1 and D2 receptor expression in striatal regions across adolescence. The age-dependent expression of dopamine receptor in C57BL6 mice shows marked differences from previous characterizations in rats.

  4. 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

    as a result of defective chromosome segregation when irradiated cells entered their first mitosis, either prematurely without S and G(2) checkpoint arrest in the presence of CEP-3891 or after a prolonged S and G(2) checkpoint arrest in the absence of CEP-3891. The nuclear fragmentation was clearly...

  5. SHOX Haploinsufficiency as a Cause of Syndromic and Nonsyndromic Short Stature.

    Science.gov (United States)

    Fukami, Maki; Seki, Atsuhito; Ogata, Tsutomu

    2016-04-01

    SHOX in the short arm pseudoautosomal region (PAR1) of sex chromosomes is one of the major growth genes in humans. SHOX haploinsufficiency results in idiopathic short stature and Léri-Weill dyschondrosteosis and is associated with the short stature of patients with Turner syndrome. The SHOX protein likely controls chondrocyte apoptosis by regulating multiple target genes including BNP,Fgfr3, Agc1, and Ctgf. SHOX haploinsufficiency frequently results from deletions and duplications in PAR1 involving SHOX exons and/or the cis-acting enhancers, while exonic point mutations account for a small percentage of cases. The clinical severity of SHOX haploinsufficiency reflects hormonal conditions rather than mutation types. Growth hormone treatment seems to be beneficial for cases with SHOX haploinsufficiency, although the long-term outcomes of this therapy require confirmation. Future challenges in SHOX research include elucidating its precise function in the developing limbs, identifying additional cis-acting enhancers, and determining optimal therapeutic strategies for patients.

  6. Targeting the DNA replication checkpoint by pharmacologic inhibition of Chk1 kinase: a strategy to sensitize APC mutant colon cancer cells to 5-fluorouracil chemotherapy.

    Science.gov (United States)

    Martino-Echarri, Estefania; Henderson, Beric R; Brocardo, Mariana G

    2014-10-30

    5-fluorouracil (5-FU) is the first line component used in colorectal cancer (CRC) therapy however even in combination with other chemotherapeutic drugs recurrence is common. Mutations of the adenomatous polyposis coli (APC) gene are considered as the initiating step of transformation in familial and sporadic CRCs. We have previously shown that APC regulates the cellular response to DNA replication stress and recently hypothesized that APC mutations might therefore influence 5-FU resistance. To test this, we compared CRC cell lines and show that those expressing truncated APC exhibit a limited response to 5-FU and arrest in G1/S-phase without undergoing lethal damage, unlike cells expressing wild-type APC. In SW480 APC-mutant CRC cells, 5-FU-dependent apoptosis was restored after transient expression of full length APC, indicating a direct link between APC and drug response. Furthermore, we could increase sensitivity of APC truncated cells to 5-FU by inactivating the Chk1 kinase using drug treatment or siRNA-mediated knockdown. Our findings identify mutant APC as a potential tumor biomarker of resistance to 5-FU, and importantly we show that APC-mutant CRC cells can be made more sensitive to 5-FU by use of Chk1 inhibitors.

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

    Science.gov (United States)

    Tenorio-Gómez, María; de Sena-Tomás, Carmen; Pérez-Martín, Jose

    2015-01-01

    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.

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

    Science.gov (United States)

    Ortega-Atienza, Sara; Green, Samantha E.; Zhitkovich, Anatoly

    2015-01-01

    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 (DPC) 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. PMID:25817892

  9. 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

  10. The Error-Prone DNA Polymerase κ Promotes Temozolomide Resistance in Glioblastoma through Rad17-Dependent Activation of ATR-Chk1 Signaling.

    Science.gov (United States)

    Peng, Chenghao; Chen, Zhengxin; Wang, Shuai; Wang, Hong-Wei; Qiu, Wenjin; Zhao, Lin; Xu, Ran; Luo, Hui; Chen, Yuanyuan; Chen, Dan; You, Yongping; Liu, Ning; Wang, Huibo

    2016-04-15

    The acquisition of drug resistance is a persistent clinical problem limiting the successful treatment of human cancers, including glioblastoma (GBM). However, the molecular mechanisms by which initially chemoresponsive tumors develop therapeutic resistance remain poorly understood. In this study, we report that Pol κ, an error-prone polymerase that participates in translesion DNA synthesis, was significantly upregulated in GBM cell lines and tumor tissues following temozolomide treatment. Overexpression of Pol κ in temozolomide-sensitive GBM cells conferred resistance to temozolomide, whereas its inhibition markedly sensitized resistant cells to temozolomide in vitro and in orthotopic xenograft mouse models. Mechanistically, depletion of Pol κ disrupted homologous recombination (HR)-mediated repair and restart of stalled replication forks, impaired the activation of ATR-Chk1 signaling, and delayed cell-cycle re-entry and progression. Further investigation of the relationship between Pol κ and temozolomide revealed that Pol κ inactivation facilitated temozolomide-induced Rad17 ubiquitination and proteasomal degradation, subsequently silencing ATR-Chk1 signaling and leading to defective HR repair and the reversal of temozolomide resistance. Moreover, overexpression of Rad17 in Pol κ-depleted GBM cells restored HR efficiency, promoted the clearance of temozolomide-induced DNA breaks, and desensitized cells to the cytotoxic effects of temozolomide observed in the absence of Pol κ. Finally, we found that Pol κ overexpression correlated with poor prognosis in GBM patients undergoing temozolomide therapy. Collectively, our findings identify a potential mechanism by which GBM cells develop resistance to temozolomide and suggest that targeting the DNA damage tolerance pathway may be beneficial for overcoming resistance. Cancer Res; 76(8); 2340-53. ©2016 AACR.

  11. 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.

  12. Haploinsufficiency of the STX1B gene is associated with myoclonic astatic epilepsy

    NARCIS (Netherlands)

    Vlaskamp, Danique R.M.; Rump, Patrick; Callenbach, Petra M.C.; Vos, Yvonne J.; Sikkema-Raddatz, Birgit; van Ravenswaaij-Arts, Conny M.A.; Brouwer, Oebele F.

    2016-01-01

    We describe an 18-year-old male patient with myoclonic astatic epilepsy (MAE), moderate to severe intellectual disability, behavioural problems, several dysmorphisms and a 1.2-Mb de novo deletion on chromosome 16p11.2. This deletion results in haploinsufficiency of STX1B and other genes. Recently, v

  13. SHOX Haploinsufficiency as a Cause of Syndromic and Nonsyndromic Short Stature

    Science.gov (United States)

    Fukami, Maki; Seki, Atsuhito; Ogata, Tsutomu

    2016-01-01

    SHOX in the short arm pseudoautosomal region (PAR1) of sex chromosomes is one of the major growth genes in humans. SHOX haploinsufficiency results in idiopathic short stature and Léri-Weill dyschondrosteosis and is associated with the short stature of patients with Turner syndrome. The SHOX protein likely controls chondrocyte apoptosis by regulating multiple target genes including BNP,Fgfr3, Agc1, and Ctgf. SHOX haploinsufficiency frequently results from deletions and duplications in PAR1 involving SHOX exons and/or the cis-acting enhancers, while exonic point mutations account for a small percentage of cases. The clinical severity of SHOX haploinsufficiency reflects hormonal conditions rather than mutation types. Growth hormone treatment seems to be beneficial for cases with SHOX haploinsufficiency, although the long-term outcomes of this therapy require confirmation. Future challenges in SHOX research include elucidating its precise function in the developing limbs, identifying additional cis-acting enhancers, and determining optimal therapeutic strategies for patients. PMID:27194967

  14. Nf1 Haploinsufficiency Alters Myeloid Lineage Commitment and Function, Leading to Deranged Skeletal Homeostasis.

    Science.gov (United States)

    Rhodes, Steven D; Yang, Hao; Dong, Ruizhi; Menon, Keshav; He, Yongzheng; Li, Zhaomin; Chen, Shi; Staser, Karl W; Jiang, Li; Wu, Xiaohua; Yang, Xianlin; Peng, Xianghong; Mohammad, Khalid S; Guise, Theresa A; Xu, Mingjiang; Yang, Feng-Chun

    2015-10-01

    Although nullizygous loss of NF1 leads to myeloid malignancies, haploinsufficient loss of NF1 (Nf1) has been shown to contribute to osteopenia and osteoporosis which occurs in approximately 50% of neurofibromatosis type 1 (NF1) patients. Bone marrow mononuclear cells of haploinsufficient NF1 patients and Nf1(+/-) mice exhibit increased osteoclastogenesis and accelerated bone turnover; however, the culprit hematopoietic lineages responsible for perpetuating these osteolytic manifestations have yet to be elucidated. Here we demonstrate that conditional inactivation of a single Nf1 allele within the myeloid progenitor cell population (Nf1-LysM) is necessary and sufficient to promote multiple osteoclast gains-in-function, resulting in enhanced osteoclastogenesis and accelerated osteoclast bone lytic activity in response to proresorptive challenge in vivo. Surprisingly, mice conditionally Nf1 heterozygous in mature, terminally differentiated osteoclasts (Nf1-Ctsk) do not exhibit any of these skeletal phenotypes, indicating a critical requirement for Nf1 haploinsufficiency at a more primitive/progenitor stage of myeloid development in perpetuating osteolytic activity. We further identified p21Ras-dependent hyperphosphorylation of Pu.1 within the nucleus of Nf1 haploinsufficient myelomonocytic osteoclast precursors, providing a novel therapeutic target for the potential treatment of NF1 associated osteolytic manifestations.

  15. Immunodeficiency and autoimmune enterocolopathy linked to NFAT5 haploinsufficiency.

    Science.gov (United States)

    Boland, Brigid S; Widjaja, Christella E; Banno, Asoka; Zhang, Bing; Kim, Stephanie H; Stoven, Samantha; Peterson, Michael R; Jones, Marilyn C; Su, H Irene; Crowe, Sheila E; Bui, Jack D; Ho, Samuel B; Okugawa, Yoshinaga; Goel, Ajay; Marietta, Eric V; Khosroheidari, Mahdieh; Jepsen, Kristen; Aramburu, Jose; López-Rodríguez, Cristina; Sandborn, William J; Murray, Joseph A; Harismendy, Olivier; Chang, John T

    2015-03-15

    The link between autoimmune diseases and primary immunodeficiency syndromes has been increasingly appreciated. Immunologic evaluation of a young man with autoimmune enterocolopathy and unexplained infections revealed evidence of immunodeficiency, including IgG subclass deficiency, impaired Ag-induced lymphocyte proliferation, reduced cytokine production by CD8(+) T lymphocytes, and decreased numbers of NK cells. Genetic evaluation identified haploinsufficiency of NFAT5, a transcription factor regulating immune cell function and cellular adaptation to hyperosmotic stress, as a possible cause of this syndrome. Inhibition or deletion of NFAT5 in normal human and murine cells recapitulated several of the immune deficits identified in the patient. These results provide evidence of a primary immunodeficiency disorder associated with organ-specific autoimmunity linked to NFAT5 deficiency.

  16. Complex Haploinsufficiency-Based Genetic Analysis of the NDR/Lats Kinase Cbk1 Provides Insight into Its Multiple Functions in Candida albicans.

    Science.gov (United States)

    Saputo, Sarah; Norman, Kaitlyn L; Murante, Thomas; Horton, Brooke N; Diaz, Jacinto De La Cruz; DiDone, Louis; Colquhoun, Jennifer; Schroeder, Jeremy W; Simmons, Lyle A; Kumar, Anuj; Krysan, Damian J

    2016-07-01

    Although the analysis of genetic interactions and networks is a powerful approach to understanding biology, it has not been applied widely to the pathogenic yeast Candida albicans Here, we describe the use of both screening and directed genetic interaction studies based on complex haploinsufficiency to probe the function of the R: egulation of A: ce2 and M: orphogenesis (RAM) pathway in C. albicans A library of 5200 Tn7-mutagenized derivatives of a parental strain heterozygous at CBK1, the key kinase in the RAM pathway, was screened for alterations in serum-induced filamentation. Following confirmation of phenotypes and identification of insertion sites by sequencing, a set of 36 unique double heterozygous strains showing complex haploinsufficiency was obtained. In addition to a large set of genes regulated by the RAM transcription factor Ace2, genes related to cell wall biosynthesis, cell cycle, polarity, oxidative stress, and nitrogen utilization were identified. Follow-up analysis led to the first demonstration that the RAM pathway is required for oxidative stress tolerance in a manner related to the two-component-regulated kinase Chk1 and revealed a potential direct connection between the RAM pathway and the essential Mps1 spindle pole-related kinase. In addition, genetic interactions with CDC42-related genes MSB1, a putative scaffold protein, and RGD3, a putative Rho GTPase-activating protein (GAP) were identified. We also provide evidence that Rgd3 is a GAP for Cdc42 and show that its localization and phosphorylation are dependent on Cbk1.

  17. Establishing Rps6 hemizygous mice as a model for studying how ribosomal protein haploinsufficiency impairs erythropoiesis

    OpenAIRE

    2011-01-01

    Diamond-Blackfan Anemia(DBA) is a congenital hypoproliferative macrocytic anemia; 5q-syndrome myelodysplastic syndrome(MDS) is an acquired hypoproliferative macrocytic anemia. Their common erythroid phenotype reflects a shared pathophysiology -- haploinsufficiency of one of many ribosomal proteins and somatic deletion of one allele of the ribosomal protein S14 gene, respectively. Although these abnormalities lead to defective ribosome biogenesis, why ribosomal protein hemizygosity results in ...

  18. 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.

    2015-01-01

    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 intelle

  19. BAG-1 haplo-insufficiency impairs lung tumorigenesis

    Directory of Open Access Journals (Sweden)

    Camarero Guadalupe

    2004-11-01

    Full Text Available Abstract Background BAG-1 is a multifunctional co-chaperone of heat shock proteins (Hsc70/Hsp70 that is expressed in most cells. It interacts with Bcl-2 and Raf indicating that it might connect protein folding with other signaling pathways. Evidence that BAG-1 expression is frequently altered in human cancers, in particular in breast cancer, relative to normal cells has been put forward but the notion that overexpression of BAG-1 contributes to poor prognosis in tumorigenesis remains controversial. Methods We have evaluated the effect of BAG-1 heterozygosity in mice in a model of non-small-cell lung tumorigenesis with histological and molecular methods. We have generated mice heterozygous for BAG-1, carrying a BAG-1 null allele, that in addition express oncogenic, constitutively active C-Raf kinase (SP-C C-Raf BxB in type II pneumocytes. SP-C C-Raf BxB mice develop multifocal adenomas early in adulthood. Results We show that BAG-1 heterozygosity in mice impairs C-Raf oncogene-induced lung adenoma growth. Lung tumor initiation was reduced by half in BAG-1 heterozygous SP-C C-Raf BxB mice compared to their littermates. Tumor area was reduced by 75% in 4 month lungs of BAG-1 haploinsufficient mice compared to mice with two BAG-1 copies. Whereas BAG-1 heterozygosity did not affect the rate of cell proliferation or signaling through the mitogenic cascade in adenoma cells, it increased the rate of apoptosis. Conclusion Reduced BAG-1 expression specifically targets tumor cells to apoptosis and impairs tumorigenesis. Our data implicate BAG-1 as a key player in oncogenic transformation by Raf and identify it as a potential molecular target for cancer treatment.

  20. Haploinsufficiency of MYBPC3 exacerbates the development of hypertrophic cardiomyopathy in heterozygous mice.

    Science.gov (United States)

    Barefield, David; Kumar, Mohit; Gorham, Joshua; Seidman, Jonathan G; Seidman, Christine E; de Tombe, Pieter P; Sadayappan, Sakthivel

    2015-02-01

    Mutations in MYBPC3, the gene encoding cardiac myosin binding protein-C (cMyBP-C), account for ~40% of hypertrophic cardiomyopathy (HCM) cases. Most pathological MYBPC3 mutations encode truncated protein products not found in tissue. Reduced protein levels occur in symptomatic heterozygous human HCM carriers, suggesting haploinsufficiency as an underlying mechanism of disease. However, we do not know if reduced cMyBP-C content results from, or initiates the development of HCM. In previous studies, heterozygous (HET) mice with a MYBPC3 C'-terminal truncation mutation and normal cMyBP-C levels show altered contractile function prior to any overt hypertrophy. Therefore, this study aimed to test whether haploinsufficiency occurs, with decreased cMyBP-C content, following cardiac stress and whether the functional impairment in HET MYBPC3 hearts leads to worsened disease progression. To address these questions, transverse aortic constriction (TAC) was performed on three-month-old wild-type (WT) and HET MYBPC3-truncation mutant mice and then characterized at 4 and 12weeks post-surgery. HET-TAC mice showed increased hypertrophy and reduced ejection fraction compared to WT-TAC mice. At 4weeks post-surgery, HET myofilaments showed significantly reduced cMyBP-C content. Functionally, HET-TAC cardiomyocytes showed impaired force generation, higher Ca(2+) sensitivity, and blunted length-dependent increase in force generation. RNA sequencing revealed several differentially regulated genes between HET and WT groups, including regulators of remodeling and hypertrophic response. Collectively, these results demonstrate that haploinsufficiency occurs in HET MYBPC3 mutant carriers following stress, causing, in turn, reduced cMyBP-C content and exacerbating the development of dysfunction at myofilament and whole-heart levels.

  1. NFIA haploinsufficiency is associated with a CNS malformation syndrome and urinary tract defects.

    Directory of Open Access Journals (Sweden)

    Weining Lu

    2007-05-01

    Full Text Available Complex central nervous system (CNS malformations frequently coexist with other developmental abnormalities, but whether the associated defects share a common genetic basis is often unclear. We describe five individuals who share phenotypically related CNS malformations and in some cases urinary tract defects, and also haploinsufficiency for the NFIA transcription factor gene due to chromosomal translocation or deletion. Two individuals have balanced translocations that disrupt NFIA. A third individual and two half-siblings in an unrelated family have interstitial microdeletions that include NFIA. All five individuals exhibit similar CNS malformations consisting of a thin, hypoplastic, or absent corpus callosum, and hydrocephalus or ventriculomegaly. The majority of these individuals also exhibit Chiari type I malformation, tethered spinal cord, and urinary tract defects that include vesicoureteral reflux. Other genes are also broken or deleted in all five individuals, and may contribute to the phenotype. However, the only common genetic defect is NFIA haploinsufficiency. In addition, previous analyses of Nfia(-/- knockout mice indicate that Nfia deficiency also results in hydrocephalus and agenesis of the corpus callosum. Further investigation of the mouse Nfia(+/- and Nfia(-/- phenotypes now reveals that, at reduced penetrance, Nfia is also required in a dosage-sensitive manner for ureteral and renal development. Nfia is expressed in the developing ureter and metanephric mesenchyme, and Nfia(+/- and Nfia(-/- mice exhibit abnormalities of the ureteropelvic and ureterovesical junctions, as well as bifid and megaureter. Collectively, the mouse Nfia mutant phenotype and the common features among these five human cases indicate that NFIA haploinsufficiency contributes to a novel human CNS malformation syndrome that can also include ureteral and renal defects.

  2. Myf5 haploinsufficiency reveals distinct cell fate potentials for adult skeletal muscle stem cells.

    Science.gov (United States)

    Gayraud-Morel, Barbara; Chrétien, Fabrice; Jory, Aurélie; Sambasivan, Ramkumar; Negroni, Elisa; Flamant, Patricia; Soubigou, Guillaume; Coppée, Jean-Yves; Di Santo, James; Cumano, Ana; Mouly, Vincent; Tajbakhsh, Shahragim

    2012-04-01

    Skeletal muscle stem cell fate in adult mice is regulated by crucial transcription factors, including the determination genes Myf5 and Myod. The precise role of Myf5 in regulating quiescent muscle stem cells has remained elusive. Here we show that most, but not all, quiescent satellite cells express Myf5 protein, but at varying levels, and that resident Myf5 heterozygous muscle stem cells are more primed for myogenic commitment compared with wild-type satellite cells. Paradoxically however, heterotypic transplantation of Myf5 heterozygous cells into regenerating muscles results in higher self-renewal capacity compared with wild-type stem cells, whereas myofibre regenerative capacity is not altered. By contrast, Pax7 haploinsufficiency does not show major modifications by transcriptome analysis. These observations provide a mechanism linking Myf5 levels to muscle stem cell heterogeneity and fate by exposing two distinct and opposing phenotypes associated with Myf5 haploinsufficiency. These findings have important implications for how stem cell fates can be modulated by crucial transcription factors while generating a pool of responsive heterogeneous cells.

  3. Haploinsufficiency networks identify targetable patterns of allelic deficiency in low mutation ovarian cancer

    Science.gov (United States)

    Delaney, Joe Ryan; Patel, Chandni B.; Willis, Katelyn McCabe; Haghighiabyaneh, Mina; Axelrod, Joshua; Tancioni, Isabelle; Lu, Dan; Bapat, Jaidev; Young, Shanique; Cadassou, Octavia; Bartakova, Alena; Sheth, Parthiv; Haft, Carley; Hui, Sandra; Saenz, Cheryl; Schlaepfer, David D.; Harismendy, Olivier; Stupack, Dwayne G.

    2017-01-01

    Identification of specific oncogenic gene changes has enabled the modern generation of targeted cancer therapeutics. In high-grade serous ovarian cancer (OV), the bulk of genetic changes is not somatic point mutations, but rather somatic copy-number alterations (SCNAs). The impact of SCNAs on tumour biology remains poorly understood. Here we build haploinsufficiency network analyses to identify which SCNA patterns are most disruptive in OV. Of all KEGG pathways (N=187), autophagy is the most significantly disrupted by coincident gene deletions. Compared with 20 other cancer types, OV is most severely disrupted in autophagy and in compensatory proteostasis pathways. Network analysis prioritizes MAP1LC3B (LC3) and BECN1 as most impactful. Knockdown of LC3 and BECN1 expression confers sensitivity to cells undergoing autophagic stress independent of platinum resistance status. The results support the use of pathway network tools to evaluate how the copy-number landscape of a tumour may guide therapy. PMID:28198375

  4. Abrogation of Chk1-mediated S/G2 checkpoint by UCN-01 enhances ara-C-induced cytotoxicity in human colon cancer cells

    Institute of Scientific and Technical Information of China (English)

    Rong-guang SHAO; Chun-Xia CAO; Yves POMMIER

    2004-01-01

    AIM: To investigate whether 7-hydroxystaurosporine (UCN-01) affects cell cycle progression in arabinosylcytosine (ara-C) treated human colon carcinoma HT-29 cells. METHODS: Cytotoxicity, DNA synthesis, cell cycle distribution,protein level, and kinase activity were determined by clonogenic assay, flow cytometry, DNA synthesis assay,immunoblotting, and kinase assays, respectively. RESULTS: UCN-01 abrogated an S/G2-phase checkpoint in HT29 cells treated with ara-C. When UCN-01 was added after treatment with ara-C, the rate of recovery of DNA synthesis was enhanced and colony-forming ability diminished. Thus, premature recovery of DNA synthesis was associated with increased cytotoxicity. Measurements of cyclin A and B protein levels, Cdk2 and Cdc2 kinase activities, Cdc25C phosphorylation, and Chkl kinase activity were consistent with UCN-01-induced abrogation of the S/G2-phase checkpoint in ara-C treated cells. CONCLUSION: The abrogation of the S/G2 checkpoint may be due to inhibition of Chkl kinase by UCN-01. The enhanced cytotoxicity produced when UCN-01 was combined with ara-C suggested a rationale for the use of this drug combination for tumors that might be susceptible to cell cycle checkpoint abrogation.

  5. Haploinsufficiency of Cyfip1 produces fragile X-like phenotypes in mice.

    Directory of Open Access Journals (Sweden)

    Ozlem Bozdagi

    Full Text Available BACKGROUND: Copy number variation (CNV at the 15q11.2 region, which includes a gene that codes for CYFIP1 (cytoplasmic FMR1 interacting protein 1, has been implicated in autism, intellectual disability and additional neuropsychiatric phenotypes. In the current study we studied the function of Cyfip1 in synaptic physiology and behavior, using mice with a disruption of the Cyfip1 gene. METHODOLOGY/PRINCIPAL FINDINGS: We observed that in Cyfip1 heterozygous mice metabotropic glutamate receptor (mGluR-dependent long-term depression (LTD induced by paired-pulse low frequency stimulation (PP-LFS was significantly increased in comparison to wildtype mice. In addition, mGluR-LTD was not affected in the presence of protein synthesis inhibitor in the Cyfip1 heterozygous mice, while the same treatment inhibited LTD in wildtype littermate controls. mGluR-agonist (RS-3,5-dihydroxyphenylglycine (DHPG-induced LTD was also significantly increased in hippocampal slices from Cyfip1 heterozygous mice and again showed independence from protein synthesis only in the heterozygous animals. Furthermore, we observed that the mammalian Target of Rapamycin (mTOR inhibitor rapamycin was only effective at reducing mGluR-LTD in wildtype animals. Behaviorally, Cyfip1 heterozygous mice showed enhanced extinction of inhibitory avoidance. Application of both mGluR5 and mGluR1 antagonist to slices from Cyfip1 heterozygous mice reversed the increase in DHPG-induced LTD in these mice. CONCLUSIONS/SIGNIFICANCE: These results demonstrate that haploinsufficiency of Cyfip1 mimics key aspects of the phenotype of Fmr1 knockout mice and are consistent with the hypothesis that these effects are mediated by interaction of Cyfip1 and Fmrp in regulating activity-dependent translation. The data provide support for a model where CYFIP1 haploinsufficiency in patients results in intermediate phenotypes increasing risk for neuropsychiatric disorders.

  6. HOXA2 haploinsufficiency in dominant bilateral microtia and hearing loss.

    Science.gov (United States)

    Brown, Kerry K; Viana, Lucas M; Helwig, Cecilia C; Artunduaga, Maria A; Quintanilla-Dieck, Lourdes; Jarrin, Patricia; Osorno, Gabriel; McDonough, Barbara; DePalma, Steven R; Eavey, Roland D; Seidman, Jonathan G; Seidman, Christine E

    2013-10-01

    Microtia is a rare, congenital malformation of the external ear that in some cases has a genetic etiology. We ascertained a three-generation family with bilateral microtia and hearing loss segregating as an autosomal dominant trait. Exome sequencing of affected family members detected only seven shared, rare, heterozygous, nonsynonymous variants, including one protein truncating variant, a HOXA2 nonsense change (c.703C>T, p.Q235*). The HOXA2 variant was segregated with microtia and hearing loss in the family and was not seen in 6,500 individuals sequenced by the NHLBI Exome Sequencing Project or in 218 control individuals sequenced in this study. HOXA2 has been shown to be critical for outer and middle ear development through mouse models and has previously been associated with autosomal recessive bilateral microtia. Our data extend these conclusions and define HOXA2 haploinsufficiency as the first genetic cause for autosomal-dominant nonsyndromic microtia.

  7. Hyperactive RAS/PI3-K/MAPK Signaling Cascade in Migration and Adhesion of Nf1 Haploinsufficient Mesenchymal Stem/Progenitor Cells.

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    Zhou, Yuan; He, Yongzheng; Sharma, Richa; Xing, Wen; Estwick, Selina A; Wu, Xiaohua; Rhodes, Steven D; Xu, Mingjiang; Yang, Feng-Chun

    2015-06-01

    Neurofibromatosis type 1 (NF1) is an autosomal dominant disease caused by mutations in the NF1 tumor suppressor gene, which affect approximately 1 out of 3000 individuals. Patients with NF1 suffer from a range of malignant and nonmalignant manifestations such as plexiform neurofibromas and skeletal abnormalities. We previously demonstrated that Nf1 haploinsufficiency in mesenchymal stem/progenitor cells (MSPCs) results in impaired osteoblastic differentiation, which may be associated with the skeletal manifestations in NF1 patients. Here we sought to further ascertain the role of Nf1 in modulating the migration and adhesion of MSPCs of the Nf1 haploinsufficient (Nf1(+/-)) mice. Nf1(+/-) MSPCs demonstrated increased nuclear-cytoplasmic ratio, increased migration, and increased actin polymerization as compared to wild-type (WT) MSPCs. Additionally, Nf1(+/-) MSPCs were noted to have significantly enhanced cell adhesion to fibronectin with selective affinity for CH271 with an overexpression of its complimentary receptor, CD49e. Nf1(+/-) MSPCs also showed hyperactivation of phosphoinositide 3-kinase (PI3-K) and mitogen activated protein kinase (MAPK) signaling pathways when compared to WT MSPCs, which were both significantly reduced in the presence of their pharmacologic inhibitors, LY294002 and PD0325901, respectively. Collectively, our study suggests that both PI3-K and MAPK signaling pathways play a significant role in enhanced migration and adhesion of Nf1 haploinsufficient MSPCs.

  8. Hyperactive RAS/PI3-K/MAPK Signaling Cascade in Migration and Adhesion of Nf1 Haploinsufficient Mesenchymal Stem/Progenitor Cells

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    Yuan Zhou

    2015-06-01

    Full Text Available Neurofibromatosis type 1 (NF1 is an autosomal dominant disease caused by mutations in the NF1 tumor suppressor gene, which affect approximately 1 out of 3000 individuals. Patients with NF1 suffer from a range of malignant and nonmalignant manifestations such as plexiform neurofibromas and skeletal abnormalities. We previously demonstrated that Nf1 haploinsufficiency in mesenchymal stem/progenitor cells (MSPCs results in impaired osteoblastic differentiation, which may be associated with the skeletal manifestations in NF1 patients. Here we sought to further ascertain the role of Nf1 in modulating the migration and adhesion of MSPCs of the Nf1 haploinsufficient (Nf1+/− mice. Nf1+/− MSPCs demonstrated increased nuclear-cytoplasmic ratio, increased migration, and increased actin polymerization as compared to wild-type (WT MSPCs. Additionally, Nf1+/− MSPCs were noted to have significantly enhanced cell adhesion to fibronectin with selective affinity for CH271 with an overexpression of its complimentary receptor, CD49e. Nf1+/− MSPCs also showed hyperactivation of phosphoinositide 3-kinase (PI3-K and mitogen activated protein kinase (MAPK signaling pathways when compared to WT MSPCs, which were both significantly reduced in the presence of their pharmacologic inhibitors, LY294002 and PD0325901, respectively. Collectively, our study suggests that both PI3-K and MAPK signaling pathways play a significant role in enhanced migration and adhesion of Nf1 haploinsufficient MSPCs.

  9. Haploinsufficiency of the ESCRT Component HD-PTP Predisposes to Cancer

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    Sanaz Manteghi

    2016-05-01

    Full Text Available Endosomal sorting complexes required for transport (ESCRT drive cell surface receptor degradation resulting in attenuation of oncogenic signaling and pointing to a tumor suppressor function. Here, we show that loss of function of an ESCRT protein (HD-PTP encoded by the PTPN23 gene, located on the tumor suppressor gene cluster 3p21.3 drives tumorigenesis in vivo. Indeed, Ptpn23+/− loss predisposes mice to sporadic lung adenoma, B cell lymphoma, and promotes Myc-driven lymphoma onset, dissemination, and aggressiveness. Ptpn23+/−-derived tumors exhibit an unaltered remaining allele and maintain 50% of HD-PTP expression. Consistent with the role of HD-PTP in attenuation of integrin recycling, cell migration, and invasion, hemizygous Ptpn23+/− loss increases integrin β1-dependent B cell lymphoma survival and dissemination. Finally, we reveal frequent PTPN23 deletion and downregulation in human tumors that correlates with poor survival. Altogether, we establish HD-PTP/PTPN23 as a prominent haploinsufficient tumor suppressor gene preventing tumor progression through control of integrin trafficking.

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

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

    2015-11-06

    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 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.

  11. Adenylyl cyclase 3 haploinsufficiency confers susceptibility to diet-induced obesity and insulin resistance in mice

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    Tong, Tao; Shen, Ying; Lee, Han-Woong; Yu, Rina; Park, Taesun

    2016-01-01

    Adenylyl cyclase 3 (Adcy3), a member of the mammalian adenylyl cyclase family responsible for generating the second messenger cAMP, has long been known to play an essential role in olfactory signal transduction. Here, we demonstrated that Adcy3 heterozygous null mice displayed increased visceral adiposity in the absence of hyperphagia and developed abnormal metabolic features characterized by impaired insulin sensitivity, dyslipidemia, and increased plasma levels of proinflammatory cytokines on both chow and high-fat diet (HFD). Of note, HFD decreased the Adcy3 expression in white adipose tissue, liver, and muscle. We also report for the first time that Adcy3 haploinsufficiency resulted in reduced expression of genes involved in thermogenesis, fatty acid oxidation, and insulin signaling, with enhanced expression of genes related to adipogenesis in peripheral tissues of mice. In conclusion, these findings suggest that cAMP signals generated by Adcy3 in peripheral tissues may play a pivotal role in modulating obesity and insulin sensitivity. PMID:27678003

  12. Twist haploinsufficiency in Saethre-Chotzen syndrome induces calvarial osteoblast apoptosis due to increased TNFalpha expression and caspase-2 activation.

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    Yousfi, Malika; Lasmoles, Francoise; El Ghouzzi, Vincent; Marie, Pierre J

    2002-02-15

    Saethre-Chotzen syndrome (SCS) is a human autosomal dominant disorder characterized by premature fusion of cranial sutures caused by mutations of the Twist gene encoding a basic helix-loop-helix (bHLH) transcription factor. We previously showed that Twist haploinsufficiency caused by a Y103X nonsense mutation in SCS alters both proliferation and osteoblast gene expression in human calvarial osteoblasts, indicating that Twist is an important regulator of osteoblast differentiation. Here we show that Twist haploinsufficiency alters osteoblast apoptosis in SCS. Analysis of terminal deoxynucleotidyl transferase-mediated nick-end labelling (TUNEL) demonstrated increased osteoblast and osteocyte apoptosis in coronal sutures from two SCS patients with nonsense mutations (Y103X and Q109X) that result in the synthesis of bHLH-truncated proteins, and one patient with a missense mutation in the basic domain (R118C) that abolishes Twist DNA binding. To assess the mechanisms involved, we studied osteoblast apoptosis in mutant (M-Tw) calvarial cells bearing the Y103X mutation resulting in decreased Twist mRNA and protein levels. M-Tw cells cultured in low serum conditions showed enhanced DNA fragmentation compared to normal (Nl) age-matched calvarial cells. Biochemical analysis showed increased activity of initiator caspases-2 and -8 and downstream effector caspases-3, -6 and -7 in mutant osteoblasts. Caspase-2 was upstream of caspase-8 and effector caspases-3, -6 and -7 because their activities were suppressed by a specific caspase-2 inhibitor. M-Tw osteoblasts also showed increased cytochrome c release from the mitochondria. However, the activity of the downstream effector caspase-9 was not increased due to overexpression of the antagonist protein Hsp70. Detection of differentially expressed genes using cDNA expression array revealed increased Bax and TNFalpha mRNA levels in M-Tw compared to Nl cells, a finding confirmed by RT-PCR and western blot analyses. Neutralization of

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

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    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.

  14. Haploinsufficiency of HDAC4 causes brachydactyly mental retardation syndrome, with brachydactyly type E, developmental delays, and behavioral problems.

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    Williams, Stephen R; Aldred, Micheala A; Der Kaloustian, Vazken M; Halal, Fahed; Gowans, Gordon; McLeod, D Ross; Zondag, Sara; Toriello, Helga V; Magenis, R Ellen; Elsea, Sarah H

    2010-08-13

    Brachydactyly mental retardation syndrome (BDMR) is associated with a deletion involving chromosome 2q37. BDMR presents with a range of features, including intellectual disabilities, developmental delays, behavioral abnormalities, sleep disturbance, craniofacial and skeletal abnormalities (including brachydactyly type E), and autism spectrum disorder. To date, only large deletions of 2q37 have been reported, making delineation of a critical region and subsequent identification of candidate genes difficult. We present clinical and molecular analysis of six individuals with overlapping deletions involving 2q37.3 that refine the critical region, reducing the candidate genes from >20 to a single gene, histone deacetylase 4 (HDAC4). Driven by the distinct hand and foot anomalies and similar cognitive features, we identified other cases with clinical findings consistent with BDMR but without a 2q37 deletion, and sequencing of HDAC4 identified de novo mutations, including one intragenic deletion probably disrupting normal splicing and one intragenic insertion that results in a frameshift and premature stop codon. HDAC4 is a histone deacetylase that regulates genes important in bone, muscle, neurological, and cardiac development. Reportedly, Hdac4(-/-) mice have severe bone malformations resulting from premature ossification of developing bones. Data presented here show that deletion or mutation of HDAC4 results in reduced expression of RAI1, which causes Smith-Magenis syndrome when haploinsufficient, providing a link to the overlapping findings in these disorders. Considering the known molecular function of HDAC4 and the mouse knockout phenotype, taken together with deletion or mutation of HDAC4 in multiple subjects with BDMR, we conclude that haploinsufficiency of HDAC4 results in brachydactyly mental retardation syndrome.

  15. Identification of Significant Pathways Induced by PAX5 Haploinsufficiency Based on Protein-Protein Interaction Networks and Cluster Analysis in Raji Cell Line

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    Jia Gu

    2017-01-01

    Full Text Available PAX5 encodes a transcription factor essential for B-cell differentiation, and PAX5 haploinsufficiency is involved in tumorigenesis. There were few studies on how PAX5 haploinsufficiency regulated genes expression to promote tumorigenesis. In this study, we constructed the cell model of PAX5 haploinsufficiency using gene editing technology in Raji cells, detected differentially expressed genes in PAX5 haploinsufficiency Raji cells, and used protein-protein interaction networks and cluster analysis to comprehensively investigate the cellular pathways involved in PAX5 haploinsufficiency. The clusters of gene transcription, inflammatory and immune response, and cancer pathways were identified as three important pathways associated with PAX5 haploinsufficiency in Raji cells. These changes hinted that the mechanism of PAX5 haploinsufficiency promoting tumorigenesis may be related to genomic instability, immune tolerance, and tumor pathways.

  16. Identification of Significant Pathways Induced by PAX5 Haploinsufficiency Based on Protein-Protein Interaction Networks and Cluster Analysis in Raji Cell Line

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    Gu, Jia; Li, TongJuan; Zhao, Lei; Liang, Xue; Fu, Xing; Wang, Jue; Shang, Zhen; Zhou, Jianfeng

    2017-01-01

    PAX5 encodes a transcription factor essential for B-cell differentiation, and PAX5 haploinsufficiency is involved in tumorigenesis. There were few studies on how PAX5 haploinsufficiency regulated genes expression to promote tumorigenesis. In this study, we constructed the cell model of PAX5 haploinsufficiency using gene editing technology in Raji cells, detected differentially expressed genes in PAX5 haploinsufficiency Raji cells, and used protein-protein interaction networks and cluster analysis to comprehensively investigate the cellular pathways involved in PAX5 haploinsufficiency. The clusters of gene transcription, inflammatory and immune response, and cancer pathways were identified as three important pathways associated with PAX5 haploinsufficiency in Raji cells. These changes hinted that the mechanism of PAX5 haploinsufficiency promoting tumorigenesis may be related to genomic instability, immune tolerance, and tumor pathways. PMID:28316978

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

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    Janice B B Lam

    Full Text Available BACKGROUND: 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. METHODOLOGY/PRINCIPAL FINDINGS: 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. CONCLUSION: Adiponectin haploinsufficiency facilitated mammary tumorigenesis by down-regulation of PTEN activity and activation of PI3K

  18. LKB1 Haploinsufficiency Cooperates With Kras to Promote Pancreatic Cancer Through Suppression of p21-Dependent Growth Arrest

    Science.gov (United States)

    Morton, Jennifer P.; Jamieson, Nigel B.; Karim, Saadia A.; Athineos, Dimitris; Ridgway, Rachel A.; Nixon, Colin; McKay, Colin J.; Carter, Ross; Brunton, Valerie G.; Frame, Margaret C.; Ashworth, Alan; Oien, Karin A.; Evans, T.R. Jeffry; Sansom, Owen J.

    2010-01-01

    Background & Aims Patients carrying germline mutations of LKB1 have an increased risk of pancreatic cancer; however, it is unclear whether down-regulation of LKB1 is an important event in sporadic pancreatic cancer. In this study, we aimed to investigate the impact of LKB1 down-regulation for pancreatic cancer in mouse and human and to elucidate the mechanism by which Lkb1 deregulation contributes to this disease. Methods We first investigated the consequences of Lkb1 deficiency in a genetically modified mouse model of pancreatic cancer, both in terms of disease progression and at the molecular level. To test the relevance of our findings to human pancreatic cancer, we investigated levels of LKB1 and its potential targets in human pancreatic cancer. Results We definitively show that Lkb1 haploinsufficiency can cooperate with oncogenic KrasG12D to cause pancreatic ductal adenocarcinoma (PDAC) in the mouse. Mechanistically, this was associated with decreased p53/p21-dependent growth arrest. Haploinsufficiency for p21 (Cdkn1a) also synergizes with KrasG12D to drive PDAC in the mouse. We also found that levels of LKB1 expression were decreased in around 20% of human PDAC and significantly correlated with low levels of p21 and a poor prognosis. Remarkably, all tumors that had low levels of LKB1 had low levels of p21, and these tumors did not express mutant p53. Conclusions We have identified a novel LKB1-p21 axis that suppresses PDAC following Kras mutation in vivo. Down-regulation of LKB1 may therefore serve as an alternative to p53 mutation to drive pancreatic cancer in vivo. PMID:20452353

  19. SF3B1 haploinsufficiency leads to formation of ring sideroblasts in myelodysplastic syndromes.

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    Visconte, Valeria; Rogers, Heesun J; Singh, Jarnail; Barnard, John; Bupathi, Manoj; Traina, Fabiola; McMahon, James; Makishima, Hideki; Szpurka, Hadrian; Jankowska, Anna; Jerez, Andres; Sekeres, Mikkael A; Saunthararajah, Yogen; Advani, Anjali S; Copelan, Edward; Koseki, Haruhiko; Isono, Kyoichi; Padgett, Richard A; Osman, Sami; Koide, Kazunori; O'Keefe, Christine; Maciejewski, Jaroslaw P; Tiu, Ramon V

    2012-10-18

    Whole exome/genome sequencing has been fundamental in the identification of somatic mutations in the spliceosome machinery in myelodysplastic syndromes (MDSs) and other hematologic disorders. SF3B1, splicing factor 3b subunit 1 is mutated in 60%-80% of refractory anemia with ring sideroblasts (RARS) and RARS associated with thrombocytosis (RARS-T), 2 distinct subtypes of MDS and MDS/myeloproliferative neoplasms (MDSs/MPNs). An idiosyncratic feature of RARS/RARS-T is the presence of abnormal sideroblasts characterized by iron overload in the mitochondria, called RS. Based on the high frequency of mutations of SF3B1 in RARS/RARS-T, we investigated the consequences of SF3B1 alterations. Ultrastructurally, SF3B1 mutants showed altered iron distribution characterized by coarse iron deposits compared with wild-type RARS patients by transmission electron microscopy. SF3B1 knockdown experiments in K562 cells resulted in down-regulation of U2-type intron-splicing by RT-PCR. RNA-sequencing analysis of SF3B1 mutants showed differentially used genes relevant in MDS pathogenesis, such as ASXL1, CBL, EZH, and RUNX families. A SF3B pharmacologic inhibitor, meayamycin, induced the formation of RS in healthy BM cells. Further, BM aspirates of Sf3b1 heterozygous knockout mice showed RS by Prussian blue. In conclusion, we report the first experimental evidence of the association between SF3B1 and RS phenotype. Our data suggest that SF3B1 haploinsufficiency leads to RS formation.

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

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    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.

  1. Effect of brain-derived neurotrophic factor haploinsufficiency on stress-induced remodeling of hippocampal neurons.

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    Magariños, A M; Li, C J; Gal Toth, J; Bath, K G; Jing, D; Lee, F S; McEwen, B S

    2011-03-01

    Chronic restraint stress (CRS) induces the remodeling (i.e., retraction and simplification) of the apical dendrites of hippocampal CA3 pyramidal neurons in rats, suggesting that intrahippocampal connectivity can be affected by a prolonged stressful challenge. Since the structural maintenance of neuronal dendritic arborizations and synaptic connectivity requires neurotrophic support, we investigated the potential role of brain derived neurotrophic factor (BDNF), a neurotrophin enriched in the hippocampus and released from neurons in an activity-dependent manner, as a mediator of the stress-induced dendritic remodeling. The analysis of Golgi-impregnated hippocampal sections revealed that wild type (WT) C57BL/6 male mice showed a similar CA3 apical dendritic remodeling in response to three weeks of CRS to that previously described for rats. Haploinsufficient BDNF mice (BDNF(±) ) did not show such remodeling, but, even without CRS, they presented shorter and simplified CA3 apical dendritic arbors, like those observed in stressed WT mice. Furthermore, unstressed BDNF(±) mice showed a significant decrease in total hippocampal volume. The dendritic arborization of CA1 pyramidal neurons was not affected by CRS or genotype. However, only in WT mice, CRS induced changes in the density of dendritic spine shape subtypes in both CA1 and CA3 apical dendrites. These results suggest a complex role of BDNF in maintaining the dendritic and spine morphology of hippocampal neurons and the associated volume of the hippocampal formation. The inability of CRS to modify the dendritic structure of CA3 pyramidal neurons in BDNF(±) mice suggests an indirect, perhaps permissive, role of BDNF in mediating hippocampal dendritic remodeling.

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

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    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.

  3. A role for fibroblast growth factor receptor-2 in the altered osteoblast phenotype induced by Twist haploinsufficiency in the Saethre-Chotzen syndrome.

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    Guenou, Hind; Kaabeche, Karim; Mée, Sandrine Le; Marie, Pierre J

    2005-06-01

    Genetic mutations of Twist, a bHLH transcription factor, induce premature fusion of cranial sutures (craniosynostosis) in the Saethre-Chotzen syndrome (SCS). The mechanisms by which Twist haploinsufficiency may alter osteoblast differentiation are poorly understood. In this study, we investigated the role of fibroblast growth factor receptor-2 (Fgfr2) in the abnormal osteoblast differentiation in SCS. Cranial osteoblasts from an SCS patient with a Y103X mutation inducing deletion of the Twist bHLH domain showed decreased Fgfr2 mRNA levels associated with decreased expression of Runx2, bone sialoprotein (BSP) and osteocalcin (OC), markers of differentiated osteoblasts, compared with wild-type osteoblasts. Transfection with Twist or Runx2 expression vectors, but not with Runx2 mutant which impairs DNA binding, restored Fgfr2, Runx2, BSP and OC expression in Twist mutant osteoblasts. EMSA analysis of mutant osteoblast nuclear extracts showed reduced Runx2 binding to a target OSE2 site in the Fgfr2 promoter. ChIP analyses showed that both Twist and Runx2 in mutant osteoblast nuclear extracts bind to a specific region in the Fgfr2 promoter. Significantly, forced expression of Fgfr2 restored Runx2 and osteoblast marker genes, whereas a dominant-negative Fgfr2 further decreased Runx2 and downstream genes in Twist mutant osteoblasts, indicating that alteration of Fgfr2 results in downregulation of osteoblast genes in Twist mutant osteoblasts. We conclude that Twist haploinsufficiency downregulates Fgfr2 mRNA expression, which in turn reduces Runx2 and downstream osteoblast-specific genes in human calvarial osteoblasts. This provides genetic and biochemical evidence for a role of Fgfr2 in the altered osteoblast phenotype induced by Twist haploinsufficiency in the SCS.

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

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    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.

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

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    Li-Ying Sung

    2014-12-01

    Full Text Available 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.

  6. Haploinsufficiency of activation-induced deaminase for antibody diversification and chromosome translocations both in vitro and in vivo.

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    Isora V Sernández

    Full Text Available The humoral immune response critically relies on the secondary diversification of antibodies. This diversification takes places through somatic remodelling of the antibody genes by two molecular mechanisms, Class Switch Recombination (CSR and Somatic Hypermutation (SHM. The enzyme Activation Induced Cytidine Deaminase (AID initiates both SHM and CSR by deaminating cytosine residues on the DNA of immunoglobulin genes. While crucial for immunity, AID-catalysed deamination is also the triggering event for the generation of lymphomagenic chromosome translocations. To address whether restricting the levels of AID expression in vivo contributes to the regulation of its function, we analysed mice harbouring a single copy of the AID gene (AID(+/-. AID(+/- mice express roughly 50% of normal AID levels, and display a mild hyperplasia, reminiscent of AID deficient mice and humans. Moreover, we found that AID(+/- cells have an impaired competence for CSR and SHM, which indicates that AID gene dose is limiting for its physiologic function. We next evaluated the impact of AID reduction in AID(+/- mice on the generation of chromosome translocations. Our results show that the frequency of AID-promoted c-myc/IgH translocations is reduced in AID(+/- mice, both in vivo and in vitro. Therefore, AID is haploinsufficient for antibody diversification and chromosome translocations. These findings suggest that limiting the physiologic levels of AID expression can be a regulatory mechanism that ensures an optimal balance between immune proficiency and genome integrity.

  7. PGRN haploinsufficiency increased Wnt5a signaling in peripheral cells from frontotemporal lobar degeneration-progranulin mutation carriers.

    Science.gov (United States)

    Alquézar, Carolina; Esteras, Noemí; de la Encarnación, Ana; Alzualde, Ainhoa; Moreno, Fermín; López de Munain, Adolfo; Martín-Requero, Angeles

    2014-04-01

    Loss-of-function progranulin (PGRN) mutations have been identified as the major cause of frontotemporal lobar degeneration with TDP-43 protein inclusions (FTLD-TDP). Previously, we reported cell cycle-related alterations in lymphoblasts from FTLD-TDP patients, carrying the c.709-1G>A null PGRN mutation, suggesting aberrant cell cycle activation in affected neurons. Here we report that PGRN haploinsufficiency activates the extracellular signal-regulated protein kinases 1 and 2 pathway in a Ca(2+), protein kinase C-dependent, and pertussis toxin-sensitive manner. Addition of exogenous PGRN or conditioned medium from control cells normalized the response of PGRN-deficient lymphoblasts to serum activation. Our data indicated that noncanonical Wnt5a signaling might be overactivated by PGRN deficiency. We detected increased cellular and secreted levels of Wnt5a in PGRN-deficient lymphoblasts associated with enhanced phosphorylated calmodulin kinase II. Moreover, treatment of control cells with exogenous Wingless-type 5a (Wnt5a)-activated Ca(2+)/calmodulin kinase II (CaMKII), increased extracellular signal-regulated protein kinases 1 and 2 activity and cell proliferation up to the levels found in c.709-1G>A carrier cells. PGRN knockdown SH-SY5Y neuroblastoma cells also show enhanced Wnt5a content and signaling. Taken together, our results revealed an important role of Wnt signaling in FTLD-TDP pathology and suggest a novel target for therapeutic intervention.

  8. Unique haploinsufficient role of the microRNA-processing molecule Dicer1 in a murine colitis-associated tumorigenesis model.

    Directory of Open Access Journals (Sweden)

    Takeshi Yoshikawa

    Full Text Available A widespread downregulated expression of microRNAs (miRNAs is commonly observed in human cancers. Similarly, deregulated expression of miRNA-processing pathway components, which results in the reduction of global miRNA expression, may also be associated with tumorigenesis. Here, we show that specific ablation of Dicer1 in intestinal epithelial cells accelerates intestinal inflammation-associated tumorigenesis. This effect was apparent only when a single copy of Dicer1 was deleted, but not with complete Dicer1 ablation. DICER expression and subsequent mature miRNA levels were inversely correlated with the number of intact Dicer1 alleles. Because the expression levels of DICER were retained in tumors and its surrounding tissues even after induction of colitis-associated tumors, the effects of Dicer1 deletion were cell-autonomous. Although the expression levels of representative oncogenes and tumor suppressor genes were in most cases inversely correlated with the expression levels of DICER, some genes were not affected by Dicer1 deletion. Thus, deregulating the delicate balance between the expression levels of tumor-promoting and -suppressive genes may be crucial for tumorigenesis in this unique haploinsufficient case.

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

    Science.gov (United States)

    Prasad, Vikram; Lorenz, John N; Lasko, Valerie M; Nieman, Michelle L; Huang, Wei; Wang, Yigang; Wieczorek, David W; Shull, Gary E

    2015-01-01

    Null mutations in one copy of ATP2A2, the gene encoding sarco/endoplasmic reticulum Ca(2+)-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 Ca(2+)-sensitivity, SERCA2 deficiency caused no enhancement of the disease state. However, when combined with a transgenic model of increased myofibrillar Ca(2+)-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 Ca(2+)-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.

  10. MLL3 is a haploinsufficient 7q tumor suppressor in acute myeloid leukemia.

    Science.gov (United States)

    Chen, Chong; Liu, Yu; Rappaport, Amy R; Kitzing, Thomas; Schultz, Nikolaus; Zhao, Zhen; Shroff, Aditya S; Dickins, Ross A; Vakoc, Christopher R; Bradner, James E; Stock, Wendy; LeBeau, Michelle M; Shannon, Kevin M; Kogan, Scott; Zuber, Johannes; Lowe, Scott W

    2014-05-12

    Recurring deletions of chromosome 7 and 7q [-7/del(7q)] occur in myelodysplastic syndromes and acute myeloid leukemia (AML) and are associated with poor prognosis. However, the identity of functionally relevant tumor suppressors on 7q remains unclear. Using RNAi and CRISPR/Cas9 approaches, we show that an ∼50% reduction in gene dosage of the mixed lineage leukemia 3 (MLL3) gene, located on 7q36.1, cooperates with other events occurring in -7/del(7q) AMLs to promote leukemogenesis. Mll3 suppression impairs the differentiation of HSPC. Interestingly, Mll3-suppressed leukemias, like human -7/del(7q) AMLs, are refractory to conventional chemotherapy but sensitive to the BET inhibitor JQ1. Thus, our mouse model functionally validates MLL3 as a haploinsufficient 7q tumor suppressor and suggests a therapeutic option for this aggressive disease.

  11. A case of pancreatic agenesis and congenital heart defects with a novel GATA6 nonsense mutation: evidence of haploinsufficiency due to nonsense-mediated mRNA decay.

    Science.gov (United States)

    Suzuki, Shigeru; Nakao, Atsushi; Sarhat, Ashoor R; Furuya, Akiko; Matsuo, Kumihiro; Tanahashi, Yusuke; Kajino, Hiroki; Azuma, Hiroshi

    2014-02-01

    Recently, GATA6 heterozygous loss-of-function mutations were reported to cause pancreatic agenesis and congenital heart defects (PACHD [OMIM:600001]). However, the molecular mechanisms resulting from premature termination codons have not been examined in this disorder. The objective of this study was to perform a genetic analysis of a patient with PACHD. A female patient presented with ventricular septal defect, patent ductus arteriosus, and congenital diaphragmatic hernia at birth. Permanent neonatal diabetes mellitus and pancreatic exocrine deficiency due to pancreatic agenesis was diagnosed at 1 month of age. PCR-direct sequencing of GATA6 revealed that the patient is heterozygous for a novel de novo nonsense mutation of c.1477C>T, p. Arg493X in exon 5. RT-PCR direct sequencing of the RT-PCR products of total RNA from peripheral blood of the patient for the region encompassing exons 4-6 revealed only the wild-type allele. This finding provides the evidence for the occurrence of nonsense-mediated mRNA decay (NMD) in the p.Arg493X mutation. Quantitative RT-PCR analysis revealed that the expression of GATA6 transcript in the patient was less than half compared with normal control samples. This is the first evidence that GATA6 haploinsufficiency is caused by NMD in vivo, and we conclude that GATA6 haploinsufficiency causes not only PACHD but may affect other organs derived from the endoderm. Further screenings of GATA6 mutations in patients with various forms of diabetes and/or congenital heart disease with other visceral malformation may reveal the impact of GATA6 mutations on diabetes and congenital malformation.

  12. MBD5 haploinsufficiency is associated with sleep disturbance and disrupts circadian pathways common to Smith-Magenis and fragile X syndromes.

    Science.gov (United States)

    Mullegama, Sureni V; Pugliesi, Loren; Burns, Brooke; Shah, Zalak; Tahir, Raiha; Gu, Yanghong; Nelson, David L; Elsea, Sarah H

    2015-06-01

    Individuals with autism spectrum disorders (ASD) who have an identifiable single-gene neurodevelopmental disorder (NDD), such as fragile X syndrome (FXS, FMR1), Smith-Magenis syndrome (SMS, RAI1), or 2q23.1 deletion syndrome (del 2q23.1, MBD5) share phenotypic features, including a high prevalence of sleep disturbance. We describe the circadian deficits in del 2q23.1 through caregiver surveys in which we identify several frequent sleep anomalies, including night/early awakenings, coughing/snoring loudly, and difficulty falling asleep. We couple these findings with studies on the molecular analysis of the circadian deficits associated with haploinsufficiency of MBD5 in which circadian gene mRNA levels of NR1D2, PER1, PER2, and PER3 were altered in del 2q23.1 lymphoblastoid cell lines (LCLs), signifying that haploinsufficiency of MBD5 can result in dysregulation of circadian rhythm gene expression. These findings were further supported by expression microarrays of MBD5 siRNA knockdown cells that showed significantly altered expression of additional circadian rhythm signaling pathway genes. Based on the common sleep phenotypes observed in del 2q23.1, SMS, and FXS patients, we explored the possibility that MBD5, RAI1, and FMR1 function in overlapping circadian rhythm pathways. Bioinformatic analysis identified conserved putative E boxes in MBD5 and RAI1, and expression levels of NR1D2 and CRY2 were significantly reduced in patient LCLs. Circadian and mTOR signaling pathways, both associated with sleep disturbance, were altered in both MBD5 and RAI1 knockdown microarray data, overlapping with findings associated with FMR1. These data support phenotypic and molecular overlaps across these syndromes that may be exploited to provide therapeutic intervention for multiple disorders.

  13. 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

    ) on the response to high fat diet feeding in mice. Rb(+/-) mice had body weight and adiposity indistinguishable from that of wild-type (Rb(+/+)) littermates when maintained on a standard diet, yet they gained less body weight and body fat after long-term high fat diet feeding, coupled to reduced feed efficiency...... and increased rectal temperature. Rb haploinsufficiency ameliorated insulin resistance and hepatosteatosis after high fat diet in male mice, in which these disturbances were more marked than in females. Compared to wild-type littermates Rb(+/-) mice fed a high fat diet displayed higher expression of peroxisome......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...

  14. 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

    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......Corpus callosum abnormalities, intellectual disability, speech impairment, and autism in patients with haploinsufficiency of ARID1B. Corpus callosum abnormalities are common brain malformations with a wide clinical spectrum ranging from severe intellectual disability to normal cognitive function...... with various sized deletions encompassing ARID1B confirms that haploinsufficiency of ARID1B is associated with CC abnormalities, intellectual disability, severe speech impairment, and autism. Our findings emphasize that ARID1B is important in human brain development and function in general...

  15. Analysis of haploinsufficiency in women carrying germline mutations in the BRCA1 gene: Different mutations, different phenotypes ?

    OpenAIRE

    Vaclová, Tereza

    2015-01-01

    Tesis doctoral inédita leída en la Universidad Autónoma de Madrid, Facultad de Medicina, Departamento de Bioquímica. Fecha de lectura: 30-01-2015 BRCA1 germline mutations are associated with significantly increased lifetime risk of developing breast and ovarian cancers. However, taking into account considerable differences in disease manifestation among mutation carriers, it is probable that various BRCA1 mutations lead to formation of distinct phenotypes and haploinsufficiency ef...

  16. Murine Glut-1 transporter haploinsufficiency: postnatal deceleration of brain weight and reactive astrocytosis.

    Science.gov (United States)

    Ullner, Paivi M; Di Nardo, Alessia; Goldman, James E; Schobel, Scott; Yang, Hong; Engelstad, Kristin; Wang, Dong; Sahin, Mustafa; De Vivo, Darryl C

    2009-10-01

    Glucose transporter type 1 (Glut-1) facilitates glucose flux across the blood-brain-barrier. In humans, Glut-1 deficiency causes acquired microcephaly, seizures and ataxia, which are recapitulated in our Glut-1 haploinsufficient mouse model. Postnatal brain weight deceleration and development of reactive astrogliosis were significant by P21 in Glut-1(+/-) mice. The brain weight differences remained constant after P21 whereas the reactive astrocytosis continued to increase and peaked at P90. Brain immunoblots showed increased phospho-mTOR and decreased phospho-GSK3-beta by P14. After fasting, the mature Glut-1(+/-) females showed a trend towards elevated phospho-GSK3-beta, a possible neuroprotective response. Lithium chloride treatment of human skin fibroblasts from control and Glut-1 DS patients produced a 45% increase in glucose uptake. Brain imaging of mature Glut-1(+/-) mice revealed a significantly decreased hippocampal volume. These subtle immunochemical changes reflect chronic nutrient deficiency during brain development and represent the experimental correlates to the human neurological phenotype associated with Glut-1 DS.

  17. Haploinsufficiency of TBK1 causes familial ALS and fronto-temporal dementia.

    Science.gov (United States)

    Freischmidt, Axel; Wieland, Thomas; Richter, Benjamin; Ruf, Wolfgang; Schaeffer, Veronique; Müller, Kathrin; Marroquin, Nicolai; Nordin, Frida; Hübers, Annemarie; Weydt, Patrick; Pinto, Susana; Press, Rayomond; Millecamps, Stéphanie; Molko, Nicolas; Bernard, Emilien; Desnuelle, Claude; Soriani, Marie-Hélène; Dorst, Johannes; Graf, Elisabeth; Nordström, Ulrika; Feiler, Marisa S; Putz, Stefan; Boeckers, Tobias M; Meyer, Thomas; Winkler, Andrea S; Winkelman, Juliane; de Carvalho, Mamede; Thal, Dietmar R; Otto, Markus; Brännström, Thomas; Volk, Alexander E; Kursula, Petri; Danzer, Karin M; Lichtner, Peter; Dikic, Ivan; Meitinger, Thomas; Ludolph, Albert C; Strom, Tim M; Andersen, Peter M; Weishaupt, Jochen H

    2015-05-01

    Amyotrophic lateral sclerosis (ALS) is a genetically heterogeneous neurodegenerative syndrome hallmarked by adult-onset loss of motor neurons. We performed exome sequencing of 252 familial ALS (fALS) and 827 control individuals. Gene-based rare variant analysis identified an exome-wide significant enrichment of eight loss-of-function (LoF) mutations in TBK1 (encoding TANK-binding kinase 1) in 13 fALS pedigrees. No enrichment of LoF mutations was observed in a targeted mutation screen of 1,010 sporadic ALS and 650 additional control individuals. Linkage analysis in four families gave an aggregate LOD score of 4.6. In vitro experiments confirmed the loss of expression of TBK1 LoF mutant alleles, or loss of interaction of the C-terminal TBK1 coiled-coil domain (CCD2) mutants with the TBK1 adaptor protein optineurin, which has been shown to be involved in ALS pathogenesis. We conclude that haploinsufficiency of TBK1 causes ALS and fronto-temporal dementia.

  18. Dnmt3b is a haploinsufficient tumor suppressor gene in Myc-induced lymphomagenesis.

    Science.gov (United States)

    Vasanthakumar, Aparna; Lepore, Janet B; Zegarek, Matthew H; Kocherginsky, Masha; Singh, Mahi; Davis, Elizabeth M; Link, Petra A; Anastasi, John; Le Beau, Michelle M; Karpf, Adam R; Godley, Lucy A

    2013-03-14

    The drivers of abnormal DNA methylation in human cancers include widespread aberrant splicing of the DNMT3B gene, producing abnormal transcripts that encode truncated proteins that may act as dominant negative isoforms. To test whether reduced Dnmt3b dosage can alter tumorigenesis, we bred Dnmt3b(+/-) mice to Eµ-Myc mice, a mouse model susceptible to B-cell lymphomas. Eµ-Myc/Dnmt3b(+/-) mice showed a dramatic acceleration of lymphomagenesis, greater even than that observed in Eµ-Myc mice that express a truncated DNMT3B isoform found in human tumors, DNMT3B7. This finding indicates that Dnmt3b can act as a haploinsufficient tumor suppressor gene. Although reduction in both Dnmt3b dosage and expression of DNMT3B7 within the Eµ-Myc system had similar effects on tumorigenesis and DNA hypermethylation, different molecular mechanisms appear to underlie these changes. This study offers insight into how de novo DNA methyltransferases function as tumor suppressors and the sensitivity of Myc-induced lymphomas to DNA methylation.

  19. Genome-Wide Screen for Haploinsufficient Cell Size Genes in the Opportunistic Yeast Candida albicans

    Directory of Open Access Journals (Sweden)

    Julien Chaillot

    2017-02-01

    Full Text Available One of the most critical but still poorly understood aspects of eukaryotic cell proliferation is the basis for commitment to cell division in late G1 phase, called Start in yeast and the Restriction Point in metazoans. In all species, a critical cell size threshold coordinates cell growth with cell division and thereby establishes a homeostatic cell size. While a comprehensive survey of cell size genetic determinism has been performed in the saprophytic yeasts Saccharomyces cerevisiae and Schizosaccharomyces pombe, very little is known in pathogenic fungi. As a number of critical Start regulators are haploinsufficient for cell size, we applied a quantitative analysis of the size phenome, using elutriation-barcode sequencing methodology, to 5639 barcoded heterozygous deletion strains of the opportunistic yeast Candida albicans. Our screen identified conserved known regulators and biological processes required to maintain size homeostasis in the opportunistic yeast C. albicans. We also identified novel C. albicans-specific size genes and provided a conceptual framework for future mechanistic studies. Interestingly, some of the size genes identified were required for fungal pathogenicity suggesting that cell size homeostasis may be elemental to C. albicans fitness or virulence inside the host.

  20. Genome-Wide Screen for Haploinsufficient Cell Size Genes in the Opportunistic Yeast Candida albicans

    Science.gov (United States)

    Chaillot, Julien; Cook, Michael A.; Corbeil, Jacques; Sellam, Adnane

    2016-01-01

    One of the most critical but still poorly understood aspects of eukaryotic cell proliferation is the basis for commitment to cell division in late G1 phase, called Start in yeast and the Restriction Point in metazoans. In all species, a critical cell size threshold coordinates cell growth with cell division and thereby establishes a homeostatic cell size. While a comprehensive survey of cell size genetic determinism has been performed in the saprophytic yeasts Saccharomyces cerevisiae and Schizosaccharomyces pombe, very little is known in pathogenic fungi. As a number of critical Start regulators are haploinsufficient for cell size, we applied a quantitative analysis of the size phenome, using elutriation-barcode sequencing methodology, to 5639 barcoded heterozygous deletion strains of the opportunistic yeast Candida albicans. Our screen identified conserved known regulators and biological processes required to maintain size homeostasis in the opportunistic yeast C. albicans. We also identified novel C. albicans-specific size genes and provided a conceptual framework for future mechanistic studies. Interestingly, some of the size genes identified were required for fungal pathogenicity suggesting that cell size homeostasis may be elemental to C. albicans fitness or virulence inside the host. PMID:28040776

  1. 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.

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

    Science.gov (United States)

    Intini, Giuseppe; Nyman, Jeffry S

    2015-06-01

    Bone fractures remain a serious health burden and prevention and enhanced healing of fractures have 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 (Bmp2(c/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 Bmp2(c/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.

  3. Haploinsufficiency of cytosolic serine hydroxymethyltransferase in the Smith-Magenis syndrome

    Energy Technology Data Exchange (ETDEWEB)

    Elsea, S.H.; Juyal, R.C.; Jiralerspong, S. [Baylor College of Medicine, Houston, TX (United States)] [and others

    1995-12-01

    Folate-dependent one-carbon metabolism is critical for the synthesis of numerous cellular constituents required for cell growth, and serine hydroxymethyltransferase (SHMT) is central to this process. Our studies reveal that the gene for cytosolic SHMT (cSHMT) maps to the critical interval for Smith-Magenis syndrome (SMS) on chromosome 17p11.2. The basic organization of the cSHMT locus on chromosome 17 was determined and was found to span{approximately}40 kb. The gene for cSHMT was found to be deleted in all 26 SMS patients examined by PCR, FISH, and/or Southern analysis. Furthermore, with respect to haploinsufficiency, cSHMT enzyme activity in patient lymphoblasts was determined to be {approximately}50% that of unaffected parent lymphoblasts. Serine, glycine, and folate levels were also assessed in three SMS patients and were found to be within normal ranges. The possible effects of cSHMT hemizygosity on the SMS phenotype are discussed. 40 refs., 3 figs., 21 tabs.

  4. BRCA1 haploinsufficiency leads to altered expression of genes involved in cellular proliferation and development.

    Directory of Open Access Journals (Sweden)

    Harriet E Feilotter

    Full Text Available The assessment of BRCA1 and BRCA2 coding sequences to identify pathogenic mutations associated with inherited breast/ovarian cancer syndrome has provided a method to identify high-risk individuals, allowing them to seek preventative treatments and strategies. However, the current test is expensive, and cannot differentiate between pathogenic variants and those that may be benign. Focusing only on one of the two BRCA partners, we have developed a biological assay for haploinsufficiency of BRCA1. Using a series of EBV-transformed cell lines, we explored gene expression patterns in cells that were BRCA1 wildtype compared to those that carried (heterozygous BRCA1 pathogenic mutations. We identified a subset of 43 genes whose combined expression pattern is a sensitive predictor of BRCA1 status. The gene set was disproportionately made up of genes involved in cellular differentiation, lending credence to the hypothesis that single copy loss of BRCA1 function may impact differentiation, rendering cells more susceptible to undergoing malignant processes.

  5. 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.

  6. Haploinsufficiency of Def activates p53-dependent TGFβ signalling and causes scar formation after partial hepatectomy.

    Directory of Open Access Journals (Sweden)

    Zhihui Zhu

    Full Text Available The metazoan liver exhibits a remarkable capacity to regenerate lost liver mass without leaving a scar following partial hepatectomy (PH. Whilst previous studies have identified components of several different signaling pathways that are essential for activation of hepatocyte proliferation during liver regeneration, the mechanisms that enable such regeneration to occur without accompanying scar formation remain poorly understood. Here we use the adult zebrafish liver, which can regenerate within two weeks following PH, as a new genetic model to address this important question. We focus on the role of Digestive-organ-expansion-factor (Def, a nucleolar protein which has recently been shown to complex with calpain3 (Capn3 to mediate p53 degradation specifically in the nucleolus, in liver regeneration. Firstly, we show that Def expression is up-regulated in the wild-type liver following amputation, and that the defhi429/+ heteroozygous mutant (def+/- suffers from haploinsufficiency of Def in the liver. We then show that the expression of pro-inflammatory cytokines is up-regulated in the def+/- liver, which leads to distortion of the migration and the clearance of leukocytes after PH. Transforming growth factor β (TGFβ signalling is thus activated in the wound epidermis in def+/- due to a prolonged inflammatory response, which leads to fibrosis at the amputation site. Fibrotic scar formation in def+/- is blocked by the over-expression of Def, by the loss-of-function of p53, and by treatment with anti-inflammation drug dexamethasone or TGFβ-signalling inhibitor SB431542. We finally show that the Def- p53 pathway suppresses fibrotic scar formation, at least in part, through the regulation of the expression of the pro-inflammatory factor, high-mobility group box 1. We conclude that the novel Def- p53 nucleolar pathway functions specifically to prevent a scar formation at the amputation site in a normal amputated liver.

  7. 1p13.2 deletion displays clinical features overlapping Noonan syndrome, likely related to NRAS gene haploinsufficiency.

    Science.gov (United States)

    Linhares, Natália Duarte; Freire, Maíra Cristina Menezes; Cardenas, Raony Guimarães Corrêa do Carmo Lisboa; Pena, Heloisa Barbosa; Lachlan, Katherine; Dallapiccola, Bruno; Bacino, Carlos; Delobel, Bruno; James, Paul; Thuresson, Ann-Charlotte; Annerén, Göran; Pena, Sérgio D J

    2016-01-01

    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.

  8. The haploinsufficient hematopoietic microenvironment is critical to the pathological fracture repair in murine models of neurofibromatosis type 1.

    Directory of Open Access Journals (Sweden)

    Xiaohua Wu

    Full Text Available Germline mutations in the NF1 tumor suppressor gene cause neurofibromatosis type 1 (NF1, a complex genetic disorder with a high predisposition of numerous skeletal dysplasias including short stature, osteoporosis, kyphoscoliosis, and fracture non-union (pseudoarthrosis. We have developed murine models that phenocopy many of the skeletal dysplasias observed in NF1 patients, including reduced bone mass and fracture non-union. We also show that the development of these skeletal manifestations requires an Nf1 haploinsufficient background in addition to nullizygous loss of Nf1 in mesenchymal stem/progenitor cells (MSCs and/or their progenies. This is replicated in two animal models of NF1, PeriCre(+;Nf1(flox/- and Col2.3Cre(+;Nf1(flox/- mice. Adoptive transfer experiments demonstrate a critical role of the Nf1+/- marrow microenvironment in the impaired fracture healing in both models and adoptive transfer of WT bone marrow cells improves fracture healing in these mice. To our knowledge, this is the first demonstration of a non-cell autonomous mechanism in non-malignant NF1 manifestations. Collectively, these data provide evidence of a combinatory effect between nullizygous loss of Nf1 in osteoblast progenitors and haploinsufficiency in hematopoietic cells in the development of non-malignant NF1 manifestations.

  9. Haploinsufficiency of RPS14 in 5q− syndrome is associated with deregulation of ribosomal- and translation-related genes

    Science.gov (United States)

    Pellagatti, Andrea; Hellström-Lindberg, Eva; Giagounidis, Aristoteles; Perry, Janet; Malcovati, Luca; Della Porta, Matteo G; Jädersten, Martin; Killick, Sally; Fidler, Carrie; Cazzola, Mario; Wainscoat, James S; Boultwood, Jacqueline

    2008-01-01

    We have previously demonstrated haploinsufficiency of the ribosomal gene RPS14, which is required for the maturation of 40S ribosomal subunits and maps to the commonly deleted region, in the 5q− syndrome. Patients with Diamond-Blackfan anaemia (DBA) show haploinsufficiency of the closely related ribosomal protein RPS19, and show a consequent downregulation of multiple ribosomal- and translation-related genes. By analogy with DBA, we have investigated the expression profiles of a large group of ribosomal- and translation-related genes in the CD34+ cells of 15 myelodysplastic syndrome (MDS) patients with 5q− syndrome, 18 MDS patients with refractory anaemia (RA) and a normal karyotype, and 17 healthy controls. In this three-way comparison, 55 of 579 ribosomal- and translation-related probe sets were found to be significantly differentially expressed, with approximately 90% of these showing lower expression levels in the 5q− syndrome patient group. Using hierarchical clustering, patients with the 5q− syndrome could be separated both from other patients with RA and healthy controls solely on the basis of the deregulated expression of ribosomal- and translation-related genes. Patients with the 5q− syndrome have a defect in the expression of genes involved in ribosome biogenesis and in the control of translation, suggesting that the 5q− syndrome represents a disorder of aberrant ribosome biogenesis. PMID:18477045

  10. Engineered zinc-finger proteins can compensate genetic haploinsufficiency by transcriptional activation of the wild-type allele: application to Willams-Beuren syndrome and supravalvular aortic stenosis.

    Science.gov (United States)

    Zhang, Pei; Huang, Angela; Morales-Ruiz, Manuel; Starcher, Barry C; Huang, Yan; Sessa, William C; Niklason, Laura E; Giordano, Frank J

    2012-11-01

    Williams-Beuren syndrome (WBS) and supravalvular aortic stenosis (SVAS) are genetic syndromes marked by the propensity to develop severe vascular stenoses. Vascular lesions in both syndromes are caused by haploinsufficiency of the elastin gene. We used these distinct genetic syndromes as models to evaluate the feasibility of using engineered zinc-finger protein transcription factors (ZFPs) to achieve compensatory expression of haploinsufficient genes by inducing augmented expression from the remaining wild-type allele. For complex genes with multiple splice variants, this approach could have distinct advantages over cDNA-based gene replacement strategies. Targeting the elastin gene, we show that transcriptional activation by engineered ZFPs can induce compensatory expression from the wild-type allele in the setting of classic WBS and SVAS genetic mutations, increase elastin expression in wild-type cells, induce expression of the major elastin splice variants, and recapitulate their natural stoichiometry. Further, we establish that transcriptional activation of the mutant allele in SVAS does not overcome nonsense-mediated decay, and thus ZFP-mediated transcriptional activation is not likely to induce production of a mutant protein, a crucial consideration. Finally, we show in bioengineered blood vessels that ZFP-mediated induction of elastin expression is capable of stimulating functional elastogenesis. Haploinsufficiency is a common mechanism of genetic disease. These findings have significant implications for WBS and SVAS, and establish that haploinsufficiency can be overcome by targeted transcriptional activation without inducing protein expression from the mutant allele.

  11. Haploinsufficiency for NR3C1, the gene encoding the glucocorticoid receptor, in blastic plasmacytoid dendritic cell neoplasms

    Science.gov (United States)

    Emadali, Anouk; Hoghoughi, Neda; Duley, Samuel; Hajmirza, Azadeh; Verhoeyen, Els; Cosset, Francois-Loic; Bertrand, Philippe; Roumier, Christophe; Roggy, Anne; Suchaud-Martin, Céline; Chauvet, Martine; Bertrand, Sarah; Hamaidia, Sieme; Rousseaux, Sophie; Josserand, Véronique; Charles, Julie; Templier, Isabelle; Maeda, Takahiro; Bruder-Costa, Juliana; Chaperot, Laurence; Plumas, Joel; Jacob, Marie-Christine; Bonnefoix, Thierry; Park, Sophie; Gressin, Remy; Tensen, Cornelis P.; Mecucci, Cristina; Macintyre, Elizabeth; Leroux, Dominique; Brambilla, Elisabeth; Nguyen-Khac, Florence; Luquet, Isabelle; Penther, Dominique; Bastard, Christian; Jardin, Fabrice; Lefebvre, Christine; Garnache, Francine

    2016-01-01

    Blastic plasmacytoid dendritic cell neoplasm (BPDCN) is a rare and highly aggressive leukemia for which knowledge on disease mechanisms and effective therapies are currently lacking. Only a handful of recurring genetic mutations have been identified and none is specific to BPDCN. In this study, through molecular cloning in an index case that presented a balanced t(3;5)(q21;q31) and molecular cytogenetic analyses in a further 46 cases, we identify monoallelic deletion of NR3C1 (5q31), encoding the glucocorticoid receptor (GCR), in 13 of 47 (28%) BPDCN patients. Targeted deep sequencing in 36 BPDCN cases, including 10 with NR3C1 deletion, did not reveal NR3C1 point mutations or indels. Haploinsufficiency for NR3C1 defined a subset of BPDCN with lowered GCR expression and extremely poor overall survival (P = .0006). Consistent with a role for GCR in tumor suppression, functional analyses coupled with gene expression profiling identified corticoresistance and loss-of-EZH2 function as major downstream consequences of NR3C1 deletion in BPDCN. Subsequently, more detailed analyses of the t(3;5)(q21;q31) revealed fusion of NR3C1 to a long noncoding RNA (lncRNA) gene (lincRNA-3q) that encodes a novel, nuclear, noncoding RNA involved in the regulation of leukemia stem cell programs and G1/S transition, via E2F. Overexpression of lincRNA-3q was a consistent feature of malignant cells and could be abrogated by bromodomain and extraterminal domain (BET) protein inhibition. Taken together, this work points to NR3C1 as a haploinsufficient tumor suppressor in a subset of BPDCN and identifies BET inhibition, acting at least partially via lncRNA blockade, as a novel treatment option in BPDCN. PMID:27060168

  12. Analyses of loss-of-function mutations of the MITF gene suggest that haploinsufficiency is a cause of Waardenburg syndrome type 2A

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    Nobukuni, Yoshitaka; Watanabe, A.; Takeda, Kazushisa; Skarka, Hana; Tachibana, Masayoshi [National Inst. of Health, Bethesda, MD (United States)

    1996-07-01

    Waardenburg syndrome type 2 (WS2) is a dominantly inherited disorder characterized by a pigmentation anomaly and hearing impairment due to lack of melanocyte. Previous work has linked a subset of families with WS2 (WS2A) to the MITF gene that encodes a transcription factor with a basic-helix-loop-helix-leucine zipper (bHLH-Zip) motif and that is involved in melanocyte differentiation. Several splice-site and missense mutations have been reported in individuals affected with WS2A. In this report, we have identified two novel point mutations in the MITF gene in affected individuals from two different families with WS2A. The two mutations (C760{r_arrow}T and C895{r_arrow}T) create stop codons in exons 7 and 8, respectively. Corresponding mutant alleles predict the truncated proteins lacking HLH-Zip or Zip structure. To understand how these mutations cause WS2 in heterozygotes, we generated mutant MITF cDNAs and used them for DNA-binding and luciferase reporter assays. The mutated MITF proteins lose the DNA-binding activity and fail to transactivate the promoter of tyrosinase, a melanocyte-specific enzyme. However, these mutated proteins do not appear to interfere with the activity of wild-type MITF protein in these assays, indicating that they do not show a dominant-negative effect. These findings suggest that the phenotypes of the two families with WS2A in the present study are caused by loss-of-function mutations in one of the two alleles of the MITF gene, resulting in haploinsufficiency of the MITF protein, the protein necessary for normal development of melanocytes. 37 refs., 4 figs.

  13. A large-scale complex haploinsufficiency-based genetic interaction screen in Candida albicans: analysis of the RAM network during morphogenesis.

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    Nike Bharucha

    2011-04-01

    Full Text Available The morphogenetic transition between yeast and filamentous forms of the human fungal pathogen Candida albicans is regulated by a variety of signaling pathways. How these pathways interact to orchestrate morphogenesis, however, has not been as well characterized. To address this question and to identify genes that interact with the Regulation of Ace2 and Morphogenesis (RAM pathway during filamentation, we report the first large-scale genetic interaction screen in C. albicans.Our strategy for this screen was based on the concept of complex haploinsufficiency (CHI. A heterozygous mutant of CBK1(cbk1Δ/CBK1, a key RAM pathway protein kinase, was subjected to transposon-mediated, insertional mutagenesis. The resulting double heterozygous mutants (6,528 independent strains were screened for decreased filamentation on SpiderMedium (SM. From the 441 mutants showing altered filamentation, 139 transposon insertion sites were sequenced,yielding 41 unique CBK1-interacting genes. This gene set was enriched in transcriptional targets of Ace2 and, strikingly, the cAMP-dependent protein kinase A (PKA pathway, suggesting an interaction between these two pathways. Further analysis indicates that the RAM and PKA pathways co-regulate a common set of genes during morphogenesis and that hyperactivation of the PKA pathway may compensate for loss of RAM pathway function. Our data also indicate that the PKA–regulated transcription factor Efg1 primarily localizes to yeast phase cells while the RAM–pathway regulated transcription factor Ace2 localizes to daughter nuclei of filamentous cells, suggesting that Efg1 and Ace2 regulate a common set of genes at separate stages of morphogenesis. Taken together, our observations indicate that CHI–based screening is a useful approach to genetic interaction analysis in C. albicans and support a model in which these two pathways regulate a common set of genes at different stages of filamentation.

  14. Effects of BACE1 haploinsufficiency on APP processing and Aβ concentrations in male and female 5XFAD Alzheimer mice at different disease stages.

    Science.gov (United States)

    Devi, L; Ohno, M

    2015-10-29

    β-Site APP-cleaving enzyme 1 (BACE1) initiates the generation of amyloid-β (Aβ), thus representing a prime therapeutic target for Alzheimer's disease (AD). Previous work including ours has used BACE1 haploinsufficiency (BACE1(+/-); i.e., 50% reduction) as a therapeutic relevant model to evaluate the efficacy of partial β-secretase inhibition. However, it is unclear whether the extent of Aβ reductions in amyloid precursor protein (APP) transgenic mice with BACE1(+/-) gene ablation may vary with sex or disease progression. Here, we compared the impacts of BACE1 haploinsufficiency on Aβ concentrations and APP processing in 5XFAD Alzheimer mice (1) between males and females and (2) between different stages with moderate and robust Aβ accumulation. First, male and female 5XFAD mice at 6-7 months of age showed equivalent levels of Aβ, BACE1, full-length APP and its metabolites. BACE1 haploinsufficiency significantly lowered soluble Aβ oligomers, total Aβ42 levels and plaque burden in 5XFAD mouse brains irrespective of sex. Furthermore, there was no sex difference in reductions of β-cleavage products of APP (C99 and sAPPβ) found in BACE1(+/-)·5XFAD mice relative to BACE1(+/+)·5XFAD controls. Meanwhile, APP and sAPPα levels in BACE1(+/-)·5XFAD mice were higher than those of 5XFAD controls regardless of sex. Based on these observations, we next combined male and female data to examine the effects of BACE1 haploinsufficiency in 5XFAD mice at 12-14 months of age, as compared with those in 6-7-month-old 5XFAD mice. Oligomeric Aβ and C99 levels were dramatically elevated in older 5XFAD mice. Although the β-metabolites of APP were significantly reduced by BACE1 haploinsufficiency in both age groups, high levels of these toxic amyloidogenic fragments remained in 12-14-month-old BACE1(+/-)·5XFAD mice. The present findings are consistent with our previous behavioral data showing that BACE1 haploinsufficiency rescues memory deficits in 5XFAD mice irrespective of

  15. p27 kip1 haplo-insufficiency improves cardiac function in early-stages of myocardial infarction by protecting myocardium and increasing angiogenesis by promoting IKK activation.

    Science.gov (United States)

    Zhou, Ningtian; Fu, Yuxuan; Wang, Yunle; Chen, Pengsheng; Meng, Haoyu; Guo, Shouyu; Zhang, Min; Yang, Zhijian; Ge, Yingbin

    2014-08-07

    p27(kip1) (p27) is widely known as a potent cell cycle inhibitor in several organs, especially in the heart. However, its role has not been fully defined during the early phase of myocardial infarction (MI). In this study, we investigated the relationships between p27, vascular endothelial growth factor/hepatocyte growth factor (VEGF/HGF) and NF-κB in post-MI cardiac function repair both in vivo and in the hypoxia/ischemia-induced rat myocardiocyte model. In vivo, haplo-insufficiency of p27 improved cardiac function, diminished the infarct zone, protected myocardiocytes and increased angiogenesis by enhancing the production of VEGF/HGF. In vitro, the presence of conditioned medium from hypoxia/ischemia-induced p27 knockdown myocardiocytes reduced the injury caused by hypoxia/ischemia in myocardiocytes, and this effect was reversed by VEGF/HGF neutralizing antibodies, consistent with the cardioprotection being due to VEGF/HGF secretion. We also observed that p27 bound to IKK and that p27 haplo-insufficiency promoted IKK/p65 activation both in vivo and in vitro, thereby inducing the NF-κB downstream regulator, VEGF/HGF. Furthermore, IKKi and IKK inhibitor negated the effect of VEGF/HGF. Therefore, we conclude that p27 haplo-insufficiency protects against heart injury by VEGF/HGF mediated cardioprotection and increased angiogenesis through promoting IKK activation.

  16. Loss-of-function mutations in TNFAIP3 leading to A20 haploinsufficiency cause an early-onset autoinflammatory disease.

    Science.gov (United States)

    Zhou, Qing; Wang, Hongying; Schwartz, Daniella M; Stoffels, Monique; Park, Yong Hwan; Zhang, Yuan; Yang, Dan; Demirkaya, Erkan; Takeuchi, Masaki; Tsai, Wanxia Li; Lyons, Jonathan J; Yu, Xiaomin; Ouyang, Claudia; Chen, Celeste; Chin, David T; Zaal, Kristien; Chandrasekharappa, Settara C; P Hanson, Eric; Yu, Zhen; Mullikin, James C; Hasni, Sarfaraz A; Wertz, Ingrid E; Ombrello, Amanda K; Stone, Deborah L; Hoffmann, Patrycja; Jones, Anne; Barham, Beverly K; Leavis, Helen L; van Royen-Kerkof, Annet; Sibley, Cailin; Batu, Ezgi D; Gül, Ahmet; Siegel, Richard M; Boehm, Manfred; Milner, Joshua D; Ozen, Seza; Gadina, Massimo; Chae, JaeJin; Laxer, Ronald M; Kastner, Daniel L; Aksentijevich, Ivona

    2016-01-01

    Systemic autoinflammatory diseases are driven by abnormal activation of innate immunity. Herein we describe a new disease caused by high-penetrance heterozygous germline mutations in TNFAIP3, which encodes the NF-κB regulatory protein A20, in six unrelated families with early-onset systemic inflammation. The disorder resembles Behçet's disease, which is typically considered a polygenic disorder with onset in early adulthood. A20 is a potent inhibitor of the NF-κB signaling pathway. Mutant, truncated A20 proteins are likely to act through haploinsufficiency because they do not exert a dominant-negative effect in overexpression experiments. Patient-derived cells show increased degradation of IκBα and nuclear translocation of the NF-κB p65 subunit together with increased expression of NF-κB-mediated proinflammatory cytokines. A20 restricts NF-κB signals via its deubiquitinase activity. In cells expressing mutant A20 protein, there is defective removal of Lys63-linked ubiquitin from TRAF6, NEMO and RIP1 after stimulation with tumor necrosis factor (TNF). NF-κB-dependent proinflammatory cytokines are potential therapeutic targets for the patients with this disease.

  17. Loss-of-function mutations in TNFAIP3 leading to A20 haploinsufficiency cause an early onset autoinflammatory syndrome

    Science.gov (United States)

    Zhou, Qing; Wang, Hongying; Schwartz, Daniella M.; Stoffels, Monique; Park, Yong Hwan; Zhang, Yuan; Yang, Dan; Demirkaya, Erkan; Takeuchi, Masaki; Tsai, Wanxia Li; Lyons, Jonathan J.; Yu, Xiaomin; Ouyang, Claudia; Chen, Celeste; Chin, David T.; Zaal, Kristien; Chandrasekharappa, Settara C.; Hanson, Eric P.; Yu, Zhen; Mullikin, James C.; Hasni, Sarfaraz A.; Wertz, Ingrid; Ombrello, Amanda K.; Stone, Deborah L.; Hoffmann, Patrycja; Jones, Anne; Barham, Beverly K.; Leavis, Helen L.; van Royen-Kerkof, Annet; Sibley, Cailin; Batu, Ezgi D.; Gül, Ahmet; Siegel, Richard M.; Boehm, Manfred; Milner, Joshua D.; Ozen, Seza; Gadina, Massimo; Chae, JaeJin; Laxer, Ronald M.; Kastner, Daniel L.; Aksentijevich, Ivona

    2016-01-01

    Systemic autoinflammatory diseases are driven by abnormal activation of innate immunity1. Herein we describe a new syndrome caused by high penetrance heterozygous germline mutations in the NFκB regulatory protein TNFAIP3 (A20) in six unrelated families with early onset systemic inflammation. The syndrome resembles Behçet’s disease (BD), which is typically considered a polygenic disorder with onset in early adulthood2. A20 is a potent inhibitor of the NFκB signaling pathway3. TNFAIP3 mutant truncated proteins are likely to act by haploinsufficiency since they do not exert a dominant-negative effect in overexpression experiments. Patients’ cells show increased degradation of IκBα and nuclear translocation of NFκB p65, and increased expression of NFκB-mediated proinflammatory cytokines. A20 restricts NFκB signals via deubiquitinating (DUB) activity. In cells expressing the mutant A20 protein, there is defective removal of K63-linked ubiquitin from TRAF6, NEMO, and RIP1 after TNF stimulation. NFκB-dependent pro-inflammatory cytokines are potential therapeutic targets for these patients. PMID:26642243

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

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    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.

  19. Haploinsufficiency of SF-1 Causes Female to Male Sex Reversal in Nile Tilapia, Oreochromis niloticus.

    Science.gov (United States)

    Xie, Qing-Ping; He, Xue; Sui, Yi-Ning; Chen, Li-Li; Sun, Li-Na; Wang, De-Shou

    2016-06-01

    Steroidogenic factor-1 (Sf-1) (officially designated nuclear receptor subfamily 5 group A member 1 [NR5A1]) is a master regulator of steroidogenesis and reproduction in mammals. However, its function remains unclear in nonmammalian vertebrates. In the present study, we used immunohistochemistry to detect expression of Sf-1 in the steroidogenic cells, the interstitial, granulosa, and theca cells of the ovary, and the Leydig cells of the testis, in Nile tilapia. Clustered regularly interspaced short palindromic repeats/CRISPR associated protein 9 (Cas9) cleavage of sf-1 resulted in a high mutation rate in the F0 generation and a phenotype of gonadal dysgenesis and reduced steroidogenic cells in XX and XY fish. Sf-1 deficiency also resulted in decreased cytochrome P450, family 19, subfamily A, polypeptide 1a, forkhead box L2 expression, and serum estradiol-17β in XX fish. In XY fish, Sf-1 deficiency increased cytochrome P450, family 19, subfamily A, polypeptide 1a and forkhead box L2 expression but decreased cytochrome P450, family 11, subfamily B, polypeptide 2 expression and serum 11-ketotestosterone levels. 17α-methyltestosterone treatment successfully rescued the gonadal phenotype of Sf-1-deficient XY fish, as demonstrated by normal spermatogenesis and production of F1 mutants. In contrast, estradiol-17β treatment only partially rescued the gonadal phenotype of Sf-1-deficient XX fish, as demonstrated by the appearance of phase II oocytes. Furthermore, both sf-1(+/-) F1 XX and XY mutants developed as fertile males, although spermatogenesis was delayed and efferent duct formation was disordered. Our data suggest that Sf-1 is a major regulator of steroidogenesis and reproduction in fish, as it is in mammals. Sf-1 deficiency resulted in gonadal dysgenesis and feminization of XY gonads. However, unlike in mammals, Sf-1 deficiency also resulted in female to male sex reversal in 8.1% of F0 and 92.1% of sf-1(+/-) F1 in XX fish.

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

    Science.gov (United States)

    2015-07-01

    based assay to be most reliable. 1c. Synthesize , purify and characterize a library of 2OG analogs using the scheme reported in the application...acetonitrile containing 0.1% acetic acid). Initially, we used phosphate buffer in solvents, which resulted in the desired separation of nucleosides. However...the residual phosphate ions suppressed the ionization of nucleosides during both the later LCMS and MALDI-TOF experiments. To overcome this

  1. Dietary regimens modify early onset of obesity in mice haploinsufficient for Rai1.

    Directory of Open Access Journals (Sweden)

    Joseph T Alaimo

    Full Text Available Smith-Magenis syndrome is a complex genomic disorder in which a majority of individuals are obese by adolescence. While an interstitial deletion of chromosome 17p11.2 is the leading cause, mutation or deletion of the RAI1 gene alone results in most features of the disorder. Previous studies have shown that heterozygous knockout of Rai1 results in an obese phenotype in mice and that Smith-Magenis syndrome mouse models have a significantly reduced fecundity and an altered transmission pattern of the mutant Rai1 allele, complicating large, extended studies in these models. In this study, we show that breeding C57Bl/6J Rai1+/- mice with FVB/NJ to create F1 Rai1+/- offspring in a mixed genetic background ameliorates both fecundity and Rai1 allele transmission phenotypes. These findings suggest that the mixed background provides a more robust platform for breeding and larger phenotypic studies. We also characterized the effect of dietary intake on Rai1+/- mouse growth during adolescent and early adulthood developmental stages. Animals fed a high carbohydrate or a high fat diet gained weight at a significantly faster rate than their wild type littermates. Both high fat and high carbohydrate fed Rai1+/- mice also had an increase in body fat and altered fat distribution patterns. Interestingly, Rai1+/- mice fed different diets did not display altered fasting blood glucose levels. These results suggest that dietary regimens are extremely important for individuals with Smith-Magenis syndrome and that food high in fat and carbohydrates may exacerbate obesity outcomes.

  2. Haploinsufficiency of ARID1B, a Member of the SWI/SNF-A Chromatin-Remodeling Complex, Is a Frequent Cause of Intellectual Disability

    Science.gov (United States)

    Hoyer, Juliane; Ekici, Arif B.; Endele, Sabine; Popp, Bernt; Zweier, Christiane; Wiesener, Antje; Wohlleber, Eva; Dufke, Andreas; Rossier, Eva; Petsch, Corinna; Zweier, Markus; Göhring, Ina; Zink, Alexander M.; Rappold, Gudrun; Schröck, Evelin; Wieczorek, Dagmar; Riess, Olaf; Engels, Hartmut; Rauch, Anita; Reis, André

    2012-01-01

    Intellectual disability (ID) is a clinically and genetically heterogeneous common condition that remains etiologically unresolved in the majority of cases. Although several hundred diseased genes have been identified in X-linked, autosomal-recessive, or syndromic types of ID, the establishment of an etiological basis remains a difficult task in unspecific, sporadic cases. Just recently, de novo mutations in SYNGAP1, STXBP1, MEF2C, and GRIN2B were reported as relatively common causes of ID in such individuals. On the basis of a patient with severe ID and a 2.5 Mb microdeletion including ARID1B in chromosomal region 6q25, we performed mutational analysis in 887 unselected patients with unexplained ID. In this cohort, we found eight (0.9%) additional de novo nonsense or frameshift mutations predicted to cause haploinsufficiency. Our findings indicate that haploinsufficiency of ARID1B, a member of the SWI/SNF-A chromatin-remodeling complex, is a common cause of ID, and they add to the growing evidence that chromatin-remodeling defects are an important contributor to neurodevelopmental disorders. PMID:22405089

  3. 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, Prakash; Yu, Jing; Eddins, Donnie; Mellado-Lagarde, Marcia M.; Earls, Laurie R.; Westmoreland, Joby J.; Quarato, Giovanni; Green, Douglas R.; Zakharenko, Stanislav S.

    2016-01-01

    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 (STP) 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 STP. 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. PMID:27184122

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

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    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.

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

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    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

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

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    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.

  7. Haploinsufficiency of MEIS2 is associated with orofacial clefting and learning disability.

    Science.gov (United States)

    Johansson, Stefan; Berland, Siren; Gradek, Gyri Aasland; Bongers, Ernie; de Leeuw, Nicole; Pfundt, Rolph; Fannemel, Madeleine; Rødningen, Olaug; Brendehaug, Atle; Haukanes, Bjørn Ivar; Hovland, Randi; Helland, Gunnar; Houge, Gunnar

    2014-07-01

    MEIS2 is a homeodomain-containing transcription factor of the TALE superfamily that has been proven important for development. We confirm and extend a recent single clinical report stating that deletions in MEIS2 can cause cleft palate [Crowley et al. (2010); Am J Med Genet 152A:1326-1327]. Here we report on five additional patients with 15q14 deletions of sizes 0.6, 0.6, 1.0, 1.9, and 4.8 Mb, respectively, all involving MEIS2. In addition, we present a family with four affected individuals and an intragenic 58 kb direct duplication disrupting MEIS2. In total, 7/9 cases had clefting, from mild (submucous cleft palate) to severe (cleft lip and palate), and 3/9 cases had ventricular septal defects. All cases had delayed motor development and most had learning disability, at worst in the mild intellectual disability range. The cases had overlapping facial features (broad forehead, finely arched eyebrows, mildly shortened philtrum, and tented upper lip) but individually they were not considered to be dysmorphic. Our results show that MEIS2 is a gene needed for palate closure. In syndromic cases of cleft palate, MEIS2 should be considered among the candidate genes, for example, in cases without 22q11.2 deletions.

  8. Down syndrome as a model of DNA polymerase beta haploinsufficiency and accelerated aging.

    Science.gov (United States)

    Patterson, David; Cabelof, Diane C

    2012-04-01

    Down syndrome is a condition of intellectual disability characterized by accelerated aging. As with other aging syndromes, evidence accumulated over the past several decades points to a DNA repair defect inherent in Down syndrome. This evidence has led us to suggest that Down syndrome results in reduced DNA base excision repair (BER) capacity, and that this contributes to the genomic instability and the aging phenotype of Down syndrome. We propose important roles for microRNA and/or folate metabolism and oxidative stress in the dysregulation of BER in Down syndrome. Further, we suggest these pathways are involved in the leukemogenesis of Down syndrome. We have reviewed the role of BER in the processing of oxidative stress, and the impact of folate depletion on BER capacity. Further, we have reviewed the role that loss of BER, specifically DNA polymerase beta, plays in accelerating the rate of aging. Like that seen in the DNA polymerase beta heterozygous mouse, the aging phenotype of Down syndrome is subtle, unlike the aging phenotypes seen in the classical progeroid syndromes and mouse models of aging. As such, Down syndrome may provide a model for elucidating some of the basic mechanisms of aging.

  9. Haploinsufficiency of EHMT1 improves pattern separation and increases hippocampal cell proliferation

    Science.gov (United States)

    Benevento, Marco; Oomen, Charlotte A.; Horner, Alexa E.; Amiri, Houshang; Jacobs, Tessa; Pauwels, Charlotte; Frega, Monica; Kleefstra, Tjitske; Kopanitsa, Maksym V.; Grant, Seth G. N.; Bussey, Timothy J.; Saksida, Lisa M.; Van der Zee, Catharina E.E.M.; van Bokhoven, Hans; Glennon, Jeffrey C.; Kasri, Nael Nadif

    2017-01-01

    Heterozygous mutations or deletions of the human Euchromatin Histone Methyltransferase 1 (EHMT1) gene are the main causes of Kleefstra syndrome, a neurodevelopmental disorder that is characterized by impaired memory, autistic features and mostly severe intellectual disability. Previously, Ehmt1+/− heterozygous knockout mice were found to exhibit cranial abnormalities and decreased sociability, phenotypes similar to those observed in Kleefstra syndrome patients. In addition, Ehmt1+/− knockout mice were impaired at fear extinction and novel- and spatial object recognition. In this study, Ehmt1+/− and wild-type mice were tested on several cognitive tests in a touchscreen-equipped operant chamber to further investigate the nature of learning and memory changes. Performance of Ehmt1+/− mice in the Visual Discrimination & Reversal learning, object-location Paired-Associates learning- and Extinction learning tasks was found to be unimpaired. Remarkably, Ehmt1+/− mice showed enhanced performance on the Location Discrimination test of pattern separation. In line with improved Location Discrimination ability, an increase in BrdU-labelled cells in the subgranular zone of the dentate gyrus was observed. In conclusion, reduced levels of EHMT1 protein in Ehmt1+/− mice does not result in general learning deficits in a touchscreen-based battery, but leads to increased adult cell proliferation in the hippocampus and enhanced pattern separation ability. PMID:28071689

  10. Prenatal Diagnosis of Cystic Hygroma related to a Deletion of 16q24.1 with Haploinsufficiency of FOXF1 and FOXC2 Genes

    Directory of Open Access Journals (Sweden)

    Matthew J. Garabedian

    2012-01-01

    Full Text Available We report the prenatal diagnosis of cystic hygroma that was subsequently identified to have haploinsufficiency of the FOXF1 and FOXC2 genes via array comparative genomic hybridization (aCGH. Deletion o f these genes has previously neither been associated with cystic hygroma nor prenatally diagnosed. The FOX gene cluster is involved in cardiopulmonary development. This case expands the phenotypic spectrum o f abnormalities of the FOXF1 and FOXC2 genes, as it seems within the spectrum of function that disruption of the FOX gene cluster would lead to include abnormalities of prenatal onset. Identification of this association would not be possible with conventional karyotype or targeted aCGH. This case highlights the power of whole genomic aCGH to further delineate the etiology of birth defects.

  11. Prenatal Diagnosis of Cystic Hygroma related to a Deletion of 16q24.1 with Haploinsufficiency of FOXF1 and FOXC2 Genes.

    Science.gov (United States)

    Garabedian, Matthew J; Wallerstein, Donna; Medina, Nubia; Byrne, James; Wallerstein, Robert J

    2012-01-01

    We report the prenatal diagnosis of cystic hygroma that was subsequently identified to have haploinsufficiency of the FOXF1 and FOXC2 genes via array comparative genomic hybridization (aCGH). Deletion o f these genes has previously neither been associated with cystic hygroma nor prenatally diagnosed. The FOX gene cluster is involved in cardiopulmonary development. This case expands the phenotypic spectrum o f abnormalities of the FOXF1 and FOXC2 genes, as it seems within the spectrum of function that disruption of the FOX gene cluster would lead to include abnormalities of prenatal onset. Identification of this association would not be possible with conventional karyotype or targeted aCGH. This case highlights the power of whole genomic aCGH to further delineate the etiology of birth defects.

  12. 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

  13. 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.

  14. Haploinsufficiency of SOX5, a member of the SOX (SRY-related HMG-box) family of transcription factors is a cause of intellectual disability.

    Science.gov (United States)

    Schanze, Ina; Schanze, Denny; Bacino, Carlos A; Douzgou, Sofia; Kerr, Bronwyn; Zenker, Martin

    2013-02-01

    Intellectual disability (ID) is a clinically and genetically heterogeneous condition; the cause is unknown in most non-specific and sporadic cases. To establish an etiological basis in those patients represents a difficult challenge. Over the last years it has become apparent that chromosomal rearrangements below the detection level of conventional karyotyping contribute significantly to the cause of ID. We present three patients with non-specific intellectual disability who all have overlapping microdeletions in the chromosomal region 12p12.1. De novo occurrence of the deletion could be proven in the two cases from which parental samples were available. All three identified deletions have different breakpoints and range in size from 120 kb to 4.9 Mb. The smallest deletion helps to narrow down the critical region to a genomic segment (chr12:23,924,800-24,041,698, build 37/hg19) encompassing only one gene, SOX5. SOX5 is a member of the SOX (SRY-related HMG-box) family of transcription factors shown to play roles in chondroblast function, oligodendrocyte differentiation and migration, as well as ensuring proper development of specific neuronal cell types. Because of these biological functions, mutations in SOX5 are predicted to cause complex disease syndromes, as it is the case for other SOX genes, but such mutations have not yet been identified. Our findings indicate that haploinsufficiency of SOX5 is a cause of intellectual disability without any striking physical anomalies.

  15. Benzo[a]pyrene (BP) DNA adduct formation in DNA repair-deficient p53 haploinsufficient [Xpa(-/-)p53(+/-)] and wild-type mice fed BP and BP plus chlorophyllin for 28 days.

    Science.gov (United States)

    John, Kaarthik; Pratt, M Margaret; Beland, Frederick A; Churchwell, Mona I; McMullen, Gail; Olivero, Ofelia A; Pogribny, Igor P; Poirier, Miriam C

    2012-11-01

    We have evaluated DNA damage (DNA adduct formation) after feeding benzo[a]pyrene (BP) to wild-type (WT) and cancer-susceptible Xpa(-/-)p53(+/-) mice deficient in nucleotide excision repair and haploinsufficient for the tumor suppressor p53. DNA damage was evaluated by high-performance liquid chromatography/electrospray ionization tandem mass spectrometry (HPLC/ES-MS/MS), which measures r7,t8,t9-trihydroxy-c-10-(N (2)-deoxyguanosyl)-7,8,9,10-tetrahydrobenzo[a]pyrene (BPdG), and a chemiluminescence immunoassay (CIA), using anti-r7,t8-dihydroxy-t-9,10-epoxy-7,8,9,10-tetrahydrobenzo[a]pyrene (BPDE)-DNA antiserum, which measures both BPdG and the other stable BP-DNA adducts. When mice were fed 100 ppm BP for 28 days, BP-induced DNA damage measured in esophagus, liver and lung was typically higher in Xpa(-/-)p53(+/-) mice, compared with WT mice. This result is consistent with the previously observed tumor susceptibility of Xpa(-/-)p53(+/-) mice. BPdG, the major DNA adduct associated with tumorigenicity, was the primary DNA adduct formed in esophagus (a target tissue in the mouse), whereas total BP-DNA adducts predominated in higher levels in the liver (a non-target tissue in the mouse). In an attempt to lower BP-induced DNA damage, we fed the WT and Xpa(-/-)p53(+/-) mice 0.3% chlorophyllin (CHL) in the BP-containing diet for 28 days. The addition of CHL resulted in an increase of BP-DNA adducts in esophagus, liver and lung of WT mice, a lowering of BPdG in esophagi of WT mice and livers of Xpa(-/-)p53(+/-) mice and an increase of BPdG in livers of WT mice. Therefore, the addition of CHL to a BP-containing diet showed a lack of consistent chemoprotective effect, indicating that oral CHL administration may not reduce PAH-DNA adduct levels consistently in human organs.

  16. Mice heterozygous for the oxytocin receptor gene (Oxtr(+/-)) show impaired social behaviour but not increased aggression or cognitive inflexibility: evidence of a selective haploinsufficiency gene effect.

    Science.gov (United States)

    Sala, M; Braida, D; Donzelli, A; Martucci, R; Busnelli, M; Bulgheroni, E; Rubino, T; Parolaro, D; Nishimori, K; Chini, B

    2013-02-01

    We characterised the behavioural phenotype of mice heterozygous (Oxtr(+/-)) for the oxytocin receptor gene (Oxtr) and compared it with that of Oxtr null mice (Oxtr(-/-)), which display autistic-like behaviours, including impaired sociability and preference for social novelty, impaired cognitive flexibility, and increased aggression. Similar to Oxtr(-/-) mice, the Oxtr(+/-) showed impaired sociability and preference for social novelty but, unlike the null genotype, their cognitive flexibility and aggression were normal. By autoradiography, Oxtr(+/-) mice were found to have approximately 50% fewer oxytocin receptors (OXTRs) in all of the examined brain regions. Thus, because a partial reduction in Oxtr gene expression is sufficient to compromise social behaviour, the Oxtr acts as a haploinsufficient gene. Furthermore, the inactivation of the Oxtr gene affects specific behaviours in a dose-dependent manner: social behaviour is sensitive to even a partial reduction in Oxtr gene expression, whereas defects in aggression and cognitive flexibility require the complete inactivation of the Oxtr gene to emerge. We then investigated the rescue of the Oxtr(+/-) social deficits by oxytocin (OT) and Thr(4)Gly(7)OT (TGOT) administered i.c.v. at different doses. TGOT was more potent than OT in rescuing sociability and social novelty in both genotypes. Furthermore, the TGOT doses that reverted impaired sociability and preference for social novelty in Oxtr(+/-) were lower than those required in Oxtr(-/-), thus suggesting that the rescue effect is mediated by OXTR in Oxtr(+/-) and by other receptors (presumably vasopressin V1a receptors) in Oxtr(-/-). In line with this, a low dose of the selective oxytocin antagonist desGlyDTyrOVT blocks the rescue effect of TGOT only in the Oxtr(+/-) genotype, whereas the less selective antagonist SR49059 blocks rescue in both genotypes. In conclusion, the Oxtr(+/-) mouse is a unique animal model for investigating how partial loss of the Oxtr gene

  17. 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.

  18. 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.

  19. 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.

  20. Truncating plakophilin-2 mutations in arrhythmogenic cardiomyopathy are associated with protein haploinsufficiency in both myocardium and epidermis

    DEFF Research Database (Denmark)

    Rasmussen, Torsten B; 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...... individuals. It was evident that PKP2 mutations introducing a premature termination codon in the reading frame were associated with PKP2 transcript and protein levels reduced to ≈50%, whereas a missense variant did not seem to affect the amount of PKP2 protein. CONCLUSIONS: The results of this study showed...

  1. Endoglin haplo-insufficiency modifies the inflammatory response in irradiated mouse hearts without affecting structural and mircovascular changes.

    Directory of Open Access Journals (Sweden)

    Ingar Seemann

    Full Text Available BACKGROUND: It is now widely recognized that radiotherapy of thoracic and chest wall tumors increases the long-term risk of cardiovascular damage although the underlying mechanisms are not fully elucidated. There is increasing evidence that microvascular damage is involved. Endoglin, an accessory receptor for TGF-β1, is highly expressed in damaged endothelial cells and may play a crucial role in cell proliferation and revascularization of damaged heart tissue. We have therefore specifically examined the role of endoglin in microvascular damage and repair in the irradiated heart. MATERIALS & METHODS: A single dose of 16 Gy was delivered to the heart of adult Eng(+/+ or Eng(+/- mice and damage was evaluated at 4, 20 and 40 weeks, relative to age-matched controls. Gated single photon emission computed tomography (gSPECT was used to measure cardiac geometry and function, and related to histo-morphology, microvascular damage (detected using immuno- and enzyme-histochemistry and gene expression (detected by microarray and real time PCR. RESULTS: Genes categorized according to known inflammatory and immunological related disease were less prominently regulated in irradiated Eng(+/- mice compared to Eng(+/+ littermates. Fibrosis related genes, TGF-β1, ALK 5 and PDGF, were only upregulated in Eng(+/+ mice during the early phase of radiation-induced cardiac damage (4 weeks. In addition, only the Eng(+/+ mice showed significant upregulation of collagen deposition in the early fibrotic phase (20 weeks after irradiation. Despite these differences in gene expression, there was no reduction in inflammatory invasion (CD45+cells of irradiated Eng(+/- hearts. Microvascular damage (microvascular density, alkaline phosphatase and von-Willebrand-Factor expression was also similar in both strains. CONCLUSION: Eng(+/- mice displayed impaired early inflammatory and fibrotic responses to high dose irradiation compared to Eng(+/+ littermates. This did not result in

  2. Haploinsufficiencies of FOXF1 and FOXC2 genes associated with lethal alveolar capillary dysplasia and congenital heart disease.

    Science.gov (United States)

    Yu, Shihui; Shao, Lei; Kilbride, Howard; Zwick, David L

    2010-05-01

    Neonatal deaths account for about 67% of all deaths during the first year of life in the USA. Genetic defects are important factors contributing to neonatal deaths and congenital anomalies. Here we report on the identification of a 1.37 Mb de novo deletion of chromosome 16q24.1-q24.2 by microarray-based comparative genomic hybridization (aCGH) technique in a newborn boy with lethal severe alveolar capillary dysplasia and multiple congenital anomalies who died of irreversible pulmonary hypertension, respiratory failure and cor pulmonale at three days of age. The phenotypic findings and causal genes (FOXF1 and FOXC2) involved in producing this unusual syndrome are detailed. Our findings independently confirm the results in a previous publication describing multiple patients with similar clinical and genetic observations, and highlight the importance of scanning human genomes at high resolution for identifications of micro-imbalances as pathogenic causes in neonates with unexplained congenital anomalies. (c) 2010 Wiley-Liss, Inc.

  3. 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.

  4. Haploinsufficiency for BRCA1 is associated with normal levels of DNA nucleotide excision repair in breast tissue and blood lymphocytes

    Directory of Open Access Journals (Sweden)

    Johnson Jennifer M

    2005-06-01

    proliferation or deficient differentiation potential in breast epithelial cells from this patient which might have contributed to her cancer susceptibility. Although NER deficiency has been demonstrated repeatedly in blood samples from sporadic breast cancer patients, analysis of blood cultured lymphocytes and breast epithelial cells for this patient proves definitively that heterozygosity for inactivation of BRCA1 does not intrinsically confer this type of genetic instability. These data suggest that the mechanism of genomic instability driving the carcinogenic process may be fundamentally different in hereditary and sporadic breast cancer, resulting in different genotoxic susceptibilities, oncogene mutations, and a different molecular pathogenesis.

  5. The HSP90 Inhibitor NVP-AUY922 Radiosensitizes by Abrogation of Homologous Recombination Resulting in Mitotic Entry with Unresolved DNA Damage

    Science.gov (United States)

    Bhide, Shreerang A.; Eccles, Suzanne A.; Workman, Paul; Nutting, Christopher M.; Huddart, Robert A.; Harrington, Kevin J.

    2012-01-01

    Background 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. Principal Findings 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. Conclusions 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 G2/M arrest, but that the contribution of cell cycle perturbation to

  6. Is activation of the intra-S checkpoint in human fibroblasts an important factor in protection against UV-induced mutagenesis?

    Science.gov (United States)

    Sproul, Christopher D; Rao, Shangbang; Ibrahim, Joseph G; Kaufmann, William K; Cordeiro-Stone, Marila

    2013-11-15

    The ATR/CHK1-dependent intra-S checkpoint inhibits replicon initiation and replication fork progression in response to DNA damage caused by UV (UV) radiation. It has been proposed that this signaling cascade protects against UV-induced mutations by reducing the probability that damaged DNA will be replicated before it can be repaired. Normal human fibroblasts (NHF) were depleted of ATR or CHK1, or treated with the CHK1 kinase inhibitor TCS2312, and the UV-induced mutation frequency at the HPRT locus was measured. Despite clear evidence of S-phase checkpoint abrogation, neither ATR/CHK1 depletion nor CHK1 inhibition caused an increase in the UV-induced HPRT mutation frequency. These results question the premise that the UV-induced intra-S checkpoint plays a prominent role in protecting against UV-induced mutagenesis.

  7. Mouse Prkar1a haploinsufficiency leads to an increase in tumors in the Trp53+/− or Rb1+/− backgrounds and chemically induced skin papillomas by dysregulation of the cell cycle and Wnt signaling

    Science.gov (United States)

    Almeida, Madson Q.; Muchow, Michael; Boikos, Sosipatros; Bauer, Andrew J.; Griffin, Kurt J.; Tsang, Kit Man; Cheadle, Chris; Watkins, Tonya; Wen, Feng; Starost, Matthew F.; Bossis, Ioannis; Nesterova, Maria; Stratakis, Constantine A.

    2010-01-01

    PRKAR1A inactivation leads to dysregulated cAMP signaling and Carney complex (CNC) in humans, a syndrome associated with skin, endocrine and other tumors. The CNC phenotype is not easily explained by the ubiquitous cAMP signaling defect; furthermore, Prkar1a+/− mice did not develop skin and other CNC tumors. To identify whether a Prkar1a defect is truly a generic but weak tumorigenic signal that depends on tissue-specific or other factors, we investigated Prkar1a+/− mice when bred within the Rb1+/− or Trp53+/− backgrounds, or treated with a two-step skin carcinogenesis protocol. Prkar1a+/− Trp53+/− mice developed more sarcomas than Trp53+/− mice (P < 0.05) and Prkar1a+/− Rb1+/− mice grew more (and larger) pituitary and thyroid tumors than Rb1+/− mice. All mice with double heterozygosity had significantly reduced life-spans compared with their single-heterozygous counterparts. Prkar1a+/− mice also developed more papillomas than wild-type animals. A whole-genome transcriptome profiling of tumors produced by all three models identified Wnt signaling as the main pathway activated by abnormal cAMP signaling, along with cell cycle abnormalities; all changes were confirmed by qRT–PCR array and immunohistochemistry. siRNA down-regulation of Ctnnb1, E2f1 or Cdk4 inhibited proliferation of human adrenal cells bearing a PRKAR1A-inactivating mutation and Prkar1a+/− mouse embryonic fibroblasts and arrested both cell lines at the G0/G1 phase of the cell cycle. In conclusion, Prkar1a haploinsufficiency is a relatively weak tumorigenic signal that can act synergistically with other tumor suppressor gene defects or chemicals to induce tumors, mostly through Wnt-signaling activation and cell cycle dysregulation, consistent with studies in human neoplasms carrying PRKAR1A defects. PMID:20080939

  8. 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.

  9. 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.

  10. 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.

  11. 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.

  12. 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

  13. 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

  14. Haploinsufficiency of Dmxl2, Encoding a Synaptic Protein, Causes Infertility Associated with a Loss of GnRH Neurons in Mouse

    Science.gov (United States)

    Jacquier, Sandrine; Csaba, Zsolt; Genin, Emmanuelle; Meyer, Vincent; Leka, Sofia; Dupont, Joelle; Charles, Perrine; Chevenne, Didier; Carel, Jean-Claude; Léger, Juliane; de Roux, Nicolas

    2014-01-01

    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 complex neurological

  15. Enceladus Results

    Data.gov (United States)

    National Aeronautics and Space Administration — Here are some results from the Spectra Decomposition Algorithm on infrared spectral images of Saturn's moon Enceladus. Figure 1 is the spatial contribution of the...

  16. Smith-Magenis syndrome results in disruption of CLOCK gene transcription and reveals an integral role for RAI1 in the maintenance of circadian rhythmicity.

    Science.gov (United States)

    Williams, Stephen R; Zies, Deborah; Mullegama, Sureni V; Grotewiel, Michael S; Elsea, Sarah H

    2012-06-08

    Haploinsufficiency of RAI1 results in Smith-Magenis syndrome (SMS), a disorder characterized by intellectual disability, multiple congenital anomalies, obesity, neurobehavioral abnormalities, and a disrupted circadian sleep-wake pattern. An inverted melatonin rhythm (i.e., melatonin peaks during the day instead of at night) and associated sleep-phase disturbances in individuals with SMS, as well as a short-period circadian rhythm in mice with a chromosomal deletion of Rai1, support SMS as a circadian-rhythm-dysfunction disorder. However, the molecular cause of the circadian defect in SMS has not been described. The circadian oscillator temporally orchestrates metabolism, physiology, and behavior largely through transcriptional modulation. Data support RAI1 as a transcriptional regulator, but the genes it might regulate are largely unknown. Investigation into the role that RAI1 plays in the regulation of gene transcription and circadian maintenance revealed that RAI1 regulates the transcription of circadian locomotor output cycles kaput (CLOCK), a key component of the mammalian circadian oscillator that transcriptionally regulates many critical circadian genes. Data further show that haploinsufficiency of RAI1 and Rai1 in SMS fibroblasts and the mouse hypothalamus, respectively, results in the transcriptional dysregulation of the circadian clock and causes altered expression and regulation of multiple circadian genes, including PER2, PER3, CRY1, BMAL1, and others. These data suggest that heterozygous mutation of RAI1 and Rai1 leads to a disrupted circadian rhythm and thus results in an abnormal sleep-wake cycle, which can contribute to an abnormal feeding pattern and dependent cognitive performance. Finally, we conclude that RAI1 is a positive transcriptional regulator of CLOCK, pinpointing a novel and important role for this gene in the circadian oscillator.

  17. The oxidative stress responsive transcription factor Pap1 confers DNA damage resistance on checkpoint-deficient fission yeast cells.

    Directory of Open Access Journals (Sweden)

    Carrie Belfield

    Full Text Available Eukaryotic cells invoke mechanisms to promote survival when confronted with cellular stress or damage to the genome. The protein kinase Chk1 is an integral and conserved component of the DNA damage response pathway. Mutation or inhibition of Chk1 results in mitotic death when cells are exposed to DNA damage. Oxidative stress activates a pathway that results in nuclear accumulation of the bZIP transcription factor Pap1. We report the novel finding that fission yeast Pap1 confers resistance to drug- and non-drug-induced DNA damage even when the DNA damage checkpoint is compromised. Multi-copy expression of Pap1 restores growth to chk1-deficient cells exposed to camptothecin or hydroxyurea. Unexpectedly, increased Pap1 expression also promotes survival of chk1-deficient cells with mutations in genes encoding DNA ligase (cdc17 or DNA polymerase δ (cdc6, but not DNA replication initiation mutants. The ability of Pap1 to confer resistance to DNA damage was not specific to chk1 mutants, as it also improved survival of rad1- and rad9-deficient cells in the presence of CPT. To confer resistance to DNA damage Pap1 must localize to the nucleus and be transcriptionally active.

  18. Structure-based design, discovery and development of checkpoint kinase inhibitors as potential anti-cancer therapies

    Science.gov (United States)

    Matthews, Thomas P; Jones, Alan M; Collins, Ian

    2014-01-01

    Introduction Checkpoint kinase inhibitors offer the promise of enhancing the effectiveness of widely prescribed cancer chemotherapies and radiotherapy by inhibiting the DNA damage response, as well as the potential for single agent efficacy. Areas covered This article surveys structural insights into the checkpoint kinases CHK1 and CHK2 that have been exploited to enhance the selectivity and potency of small molecule inhibitors. The use of mechanistic cellular assays to guide the optimisation of inhibitors is reviewed. The status of the current clinical candidates and emerging new clinical contexts for CHK1 and CHK2 inhibitors are discussed, including the prospects for single agent efficacy. Expert opinion Protein bound water molecules play key roles in structural features that can be targeted to gain high selectivity for either enzyme. The results of early phase clinical trials of checkpoint inhibitors have been mixed, but significant progress has been made in testing the combination of CHK1 inhibitors with genotoxic chemotherapy. Second generation CHK1 inhibitors are likely to benefit from increased selectivity and oral bioavailability. While the optimum therapeutic context for CHK2 inhibition remains unclear, the emergence of single agent preclinical efficacy for CHK1 inhibitors in specific tumour types exhibiting constitutive replication stress represents exciting progress in exploring the therapeutic potential of these agents. PMID:23594139

  19. 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.

  20. Haploinsufficiency of TAB2 causes congenital heart defects in humans

    DEFF Research Database (Denmark)

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

    2010-01-01

    Congenital heart defects (CHDs) are the most common major developmental anomalies and the most frequent cause for perinatal mortality, but their etiology remains often obscure. We identified a locus for CHDs on 6q24-q25. Genotype-phenotype correlations in 12 patients carrying a chromosomal deletion...... in cardiac development was further supported by its conserved expression in the developing human and zebrafish heart. Moreover, a critical, dosage-sensitive role during development was demonstrated by the cardiac defects observed upon titrated knockdown of tab2 expression in zebrafish embryos...

  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.

    Science.gov (United States)

    Gao, Xiaodong; Han, Liping; Ren, Yujie

    2016-05-05

    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. 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.

  3. 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.

  4. Cholesterol testing and results

    Science.gov (United States)

    Cholesterol test results; LDL test results; VLDL test results; HDL test results; Coronary risk profile results; Hyperlipidemia- ... Some cholesterol is considered good and some is considered bad. Different blood tests can be done to measure each ...

  5. Role of swi7H4 mutant allele of DNA polymerase α in the DNA damage checkpoint response.

    Science.gov (United States)

    Khan, Saman; Ahmed, Shakil

    2015-01-01

    Besides being a mediator of initiation of DNA replication, DNA polymerase α plays a key role in chromosome maintenance. Swi7H4, a novel temperature sensitive mutant of DNA polymerase α was shown to be defective in transcriptional silencing at the mating type centromere and telomere loci. It is also required for the establishment of chromatin state that can recruit the components of the heterochromatin machinery at these regions. Recently the role of DNA polymerase α in the S-phase alkylation damage response in S. pombe has also been studied. Here we investigate whether defects generated by swi7H4, a mutant allele of DNA polymerase α can activate a checkpoint response. We show that swi7H4 exhibit conditional synthetic lethality with chk1 null mutant and the double mutant of swi7H4 with chk1 deletion aggravate the chromosome segregation defects. More importantly swi7H4 mutant cells delay the mitotic progression at non permissive temperature that is mediated by checkpoint protein kinase Chk1. In addition we show that, in the swi7H4 mutant background, cells accumulate DNA damage at non permissive temperature activating the checkpoint kinase protein Chk1. Further, we observed synthetic lethality between swi7H4 and a number of genes involved in DNA repair pathway at semi permissive temperature. We summarize that defects in swi7H4 mutant results in DNA damage that delay mitosis in a Chk1 dependent manner that also require the damage repair pathway for proper recovery.

  6. Role of swi7H4 mutant allele of DNA polymerase α in the DNA damage checkpoint response.

    Directory of Open Access Journals (Sweden)

    Saman Khan

    Full Text Available Besides being a mediator of initiation of DNA replication, DNA polymerase α plays a key role in chromosome maintenance. Swi7H4, a novel temperature sensitive mutant of DNA polymerase α was shown to be defective in transcriptional silencing at the mating type centromere and telomere loci. It is also required for the establishment of chromatin state that can recruit the components of the heterochromatin machinery at these regions. Recently the role of DNA polymerase α in the S-phase alkylation damage response in S. pombe has also been studied. Here we investigate whether defects generated by swi7H4, a mutant allele of DNA polymerase α can activate a checkpoint response. We show that swi7H4 exhibit conditional synthetic lethality with chk1 null mutant and the double mutant of swi7H4 with chk1 deletion aggravate the chromosome segregation defects. More importantly swi7H4 mutant cells delay the mitotic progression at non permissive temperature that is mediated by checkpoint protein kinase Chk1. In addition we show that, in the swi7H4 mutant background, cells accumulate DNA damage at non permissive temperature activating the checkpoint kinase protein Chk1. Further, we observed synthetic lethality between swi7H4 and a number of genes involved in DNA repair pathway at semi permissive temperature. We summarize that defects in swi7H4 mutant results in DNA damage that delay mitosis in a Chk1 dependent manner that also require the damage repair pathway for proper recovery.

  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. RESULTS RESULTING FROM AUTOFRETTAGE OF CYLINDER

    Institute of Scientific and Technical Information of China (English)

    ZHU Ruilin

    2008-01-01

    Autofrettage is used to introduce advantageous residual stresses into wall of a cylinder and to even distributions of total stresses. Basic theory on autofrettage has been functioning for several decades. It is necessary to reveal profound relations between parameters in the theory. Therefore, based on the 3rd strength theory, δei/δy, δei/δy, δei′/δy, δei′/δy and their relations, as well as p/δy, are studied under ideal conditions, where δei/δy is equivalent stress of total stresses at elastoplastic juncture/yield strength, δei/δy is equivalent stress of total stresses at inside surface/yield strength, δei′/δy is equivalent stress of residual stresses at elastoplastic juncture/yield strength, δei′/δy is equivalent stress of residual stresses at inside surface/yield strength, p/δy is load-bearing capacity of an autofrettaged cylinder/yield strength. Theoretical study on the parameters results in noticeable results and laws. The main idea is: to satisfy |δei′|=δy, the relation between kj and k is , where k is outside/inside radius ratio of a cylinder, kj is ratio of elastoplastic juncture radius to inside radius of a cylinder; when the plastic region covers the whole wall of a cylinder, for compressive yield not to occur after removing autofrettage pressure, the ultimate k is k=2.218 46, with k=2.218 46, a cylinder's ultimate load-bearing capacity equals its entire yield pressure, or =lnk; when kj≤=1.648 72, no matter how great k is, compressive yield never occurs after removing pa; the maximum and optimum load-bearing capacity of an autofrettaged cylinder is just two times the loading which an unautofrettaged cylinder can bear elastically, or , thus the limit of the load-bearing capacity of an autofrettaged cylinder is also just 2 times that of an unautofrettaged cylinder.

  9. Resultative Predicates in Japanese

    Directory of Open Access Journals (Sweden)

    Kaori Takamine

    2007-12-01

    Full Text Available Washio (1997; 1999 observes that resultative predicates are divided into two different groups, strong and weak resultatives, depending on ‘patienthood’ of the object. This typology of resultatives seems to capture a point of crosslinguistic variation in resultatives; Japanese has weak but not strong resultatives, while English has both. Washio also observes that there is another group of examples that bears a superficial resemblance to resultatives but constitutes a different phenomenon, hence spurious resultatives. The difference between weak and strong resultatives is made in terms of the ‘affectedness’ of the verb. Thus the typology of resultatives proposed by Washio is semantically grounded. In this paper, I propose: (i a fine-grained distinction for Washio’s weak resultatives: (ii a syntactic analysis of the different resultative types. On the basis of syntactic evidence, I argue that there are two types of weak resultatives, an adjunct of VP and a complement of VP within the vP projection. I also argue that spurious resultatives are structurally higher than weak resultatives in Japanese.

  10. 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.)

  11. Overview of ALICE results

    CERN Document Server

    Ortiz, Antonio

    2015-01-01

    The ALICE detector was designed to study the physics of matter under extreme conditions of high energy density. Different results were reported by the experiment using data from the successful run I of the LHC. The goal of the present work is to present an overview of recent ALICE results. This comprises selected results from several analyses of pp, p-pb and Pb-Pb data at the LHC energies.

  12. The Arising of Results

    DEFF Research Database (Denmark)

    Sobisch, Jan-Ulrich

    2013-01-01

    Some Buddhist scholars have periodized the expected lifetime of the Buddha's teachings. According to them, these periods of 500 years each have different characteristics. The first is called 'the period of the results'. Therefore some scholars have claimed that only in the first 500 years after...... the Buddha results can arise. Kyobpa Jigten Sumgön has argued that results arise through practise as long as Dharma and Sangha exist....

  13. Unfavorable results in replantation

    OpenAIRE

    Abraham G Thomas

    2013-01-01

    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 younge...

  14. New results from COMPASS

    CERN Document Server

    Kabuß, Eva-Maria

    2015-01-01

    An overview on recent COMPASS results is given, including the extraction of the longitudinal spin structure functions interpreted with a NLO QCD fit, new results on the gluon polarisation and a measurement of pion and kaon multiplicities with a LO extraction of quark-to-hadron fragmentation functions

  15. Duration and Results (PECODR

    Directory of Open Access Journals (Sweden)

    Martin Dawes

    2007-01-01

    Conclusions Results suggest a PECODR-related structure exists in medical abstracts and that there might be lexical patterns specific to these elements. More sophisticated computer-assisted lexical-semantic analysis might refine these results, and pave the way to automating PECODR indexing, and improve information retrieval in primary care.

  16. 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.

  17. Ibis DDT test results

    Data.gov (United States)

    US Fish and Wildlife Service, Department of the Interior — This document contains test results from a study done to determine the organochlorine levels in the livers of white-faced ibis from Stillwater Wildlife Management...

  18. 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).

  19. Microenterprise Results Reporting

    Data.gov (United States)

    US Agency for International Development — Microenterprise Results Reporting (MRR) is an annual report to the U.S. Congress providing funding and program data on USAID's microenterprise activities. The MRR...

  20. 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...

  1. Higgs results from ATLAS

    Directory of Open Access Journals (Sweden)

    Chen Xin

    2016-01-01

    Full Text Available 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, bb̄, 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.

  2. ATLAS physics results

    CERN Document Server

    AUTHOR|(CDS)2074312

    2015-01-01

    The ATLAS experiment at the Large Hadron Collider at CERN has been successfully taking data since the end of 2009 in proton-proton collisions at centre-of-mass energies of 7 and 8 TeV, and in heavy ion collisions. In these lectures, some of the most recent ATLAS results will be given on Standard Model measurements, the discovery of the Higgs boson, searches for supersymmetry and exotics and on heavy-ion results.

  3. 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.

  4. Unfavorable results in replantation.

    Science.gov (United States)

    Thomas, Abraham G

    2013-05-01

    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.

  5. 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).

  6. Results of CPLEAR

    Energy Technology Data Exchange (ETDEWEB)

    Rickenbach, R. [Basel Univ. (Switzerland); Adler, R. [Basel Univ. (Switzerland); 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.; CPLEAR Collaboration

    1997-06-01

    The CPLEAR experiment uses tagged K{sup 0} and K{sup 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.).

  7. Recent results from INDRA

    Directory of Open Access Journals (Sweden)

    Chbihi A.

    2015-01-01

    Full Text Available Recent results of the INDRA collaboration are presented in this contribution. They concern the evolution of reaction dynamics from the first stage of the collision to the production of fragments. Different probes are used to evidence the stopping/transparency, collective flow and the symmetry energy term of the nuclear equation of state.

  8. Results from ARGUS

    Science.gov (United States)

    Darden, C.

    1984-10-01

    The ARGUS collaboration reports results bearing on the fragmentation function for D*± mesons, the mass of the F± meson, the decays F±→φπ± and F±→φπ+π-π±, the decay γ'→π+π-γ and the radiative decay γ'→γΥ(3Pj).

  9. Recent CMS Results

    Directory of Open Access Journals (Sweden)

    Dorigo Tommaso

    2014-04-01

    Full Text Available The CMS experiment obtained a large number of groundbreaking results from the analysis of 7- and 8-TeV proton-proton collisions produced so far by the Large Hadron Collider at CERN. In this brief summary only a few of those results will be discussed. The new scalar discovered in 2012 has been studied in detail and all its characteristics have been found in agreement with standard model predictions for a Brout-Englert-Higgs boson. The large sample of top quark events collected in 2011 and 2012 have allowed world-class measurements of its mass; the combination of those results is Mt = 173.49 ± 0.36 ± 0.91 GeV. The rare decay Bs0 → μμ has been observed and found in agreement with standard model predictions; the search for the rare decay B0 → μμ has allowed to set a 95% CL limit on the branching fraction at 1.1 × 10−9. These two results strongly constrain new physics models.

  10. NIH Research to Results

    Science.gov (United States)

    ... on. The National Institute of Neurological Disorders and Stroke (NINDS) is researching treatments that can be given in the first hours after a TBI to prevent or reverse much of the brain damage resulting from the injury. A recently completed NINDS– ...

  11. 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....

  12. Top Quark Results

    CERN Document Server

    ATLAS collaboration; LHCb collaboration

    2016-01-01

    Measurements of top quarks from Run-I and Run-II of the LHC are presented. Results on differential and inclusive top quark production cross sections, measured by the ATLAS, CMS and LHCb experiments, and measurements of top quark properties and mass are reported.

  13. CPT Results from Ktev

    Science.gov (United States)

    Nguyen, Hogan

    2002-02-01

    We present several preliminary measurements from KTeVREFID="9789812778123_0014FN001"> of the fundamental neutral K parameters, and their implications for CPT violation. A new limit is given on the sidereal time dependence of φ+-. The results are based on data collected in 1996-97.

  14. Recent results from MAC

    Energy Technology Data Exchange (ETDEWEB)

    MAC Collaboration

    1982-05-01

    Some preliminary results from the MAC detector at PEP are presented. These include measurements of the angular distribution of ..gamma gamma.., ..mu mu.. and tau tau final states, a determination of the tau lifetime, a measurement of R, and a presentation of the inclusive muon p/sub perpendicular/ distribution for hadronic events.

  15. Recent CDF results

    Energy Technology Data Exchange (ETDEWEB)

    Gomez, Gervasio; /Cantabria Inst. of Phys.

    2007-11-01

    As of November of 2007, the CDF detector has recorded approximately 2.7 fb{sup -1} of data. This contribution describes some of the most recent and most relevant results from the CDF collaboration in all areas of its wide physics program, as well as some insights into the Tevatron reach for Higgs searches within the next few years.

  16. Final results from the $\

    CERN Document Server

    Vidal-Sitjes, G

    2001-01-01

    An updated analysis of the full NOMAD data corresponding to approx 1.35 x 10 sup 6 charged current interactions has been performed to search for neutrino oscillations through nu subtau appearance. This document updates the recently published results on the nu submu -> nu subtau and nu submu -> nu sub e oscillations search in NOMAD with a unified analysis of the hadronic channels.

  17. 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 minut

  18. New Results from RENO

    CERN Document Server

    ,

    2013-01-01

    RENO (Reactor Experiment for Neutrino Oscillation) is an experiment dedicated to measure the smallest neutrino mixing angle {\\theta}_13 using reactor neutrinos in Korea. Our first result measured in 2012 using about 220 live days of data showed non-zero {\\theta}_13 value with 4.9 {\\sigma} significance. In March 2013 we updated our first result with improvements in both statistical and systematic errors using 403 live days of data. The measured value using rate-only analysis is sin^2(2{\\theta}_13) = 0.100 +/- 0.010 (stat) +/- 0.015 (sys.) corresponding to 6.3 {\\sigma} significance. RENO has been taking data almost continuously since August 2011 and we have reached more than 800 live days of data that is currently being analyzed.

  19. Early results from ISO

    Science.gov (United States)

    1996-01-01

    First findings by Europe's new space telescope ISO (Infrared Space Observatory) will be announced at a press conference to be held at ESA's satellite tracking station in Villafranca, Apartado 50727 - 28080-Madrid, on Wednesday 14 February 1996 Astronomers responsible for ISO's instruments will show results ranging from materials in the planet Saturn, through the birth and death of stars, to the behaviour of colliding galaxies. All instruments are working well and even their preliminary results confirm that ISO is a unique observatory making an unprecedented exploration of the universe by infrared rays. Parallel press conferences will be held at ESA Headquarters in Paris, ESTEC Noordwijk (the Netherlands) and ESOC Darmstadt (Germany) where a live television link will be established with Villafranca and from where the media can participate in the discussion.

  20. Final NOMAD results on $\

    CERN Document Server

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

  1. CLEO Results B Decays

    CERN Document Server

    Cassel, David G

    2001-01-01

    Measurements of many Standard Model constants are clouded by uncertainties in nonperturbative QCD parameters that relate measurable quantities to the underlying parton-level processes. Generally these QCD parameters have been obtained from model calculations with large uncertainties that are difficult to quantify. The CLEO Collaboration has taken a major step towards reducing these uncertainties in determining the CKM matrix elements Vcb and Vub using new measurements of the branching fraction and photon energy spectrum of B -> s gamma decays. This report includes: the new CLEO measurements of B -> s gamma decays, Vcb, and Vub; the first results from CLEO III data -- studies of B -> K pi, pi pi, and K Kbar decays; mention of some other recent CLEO B decay results; and plans for operating CESR and CLEO in the charm threshold region.

  2. RESULTS OF SLICE MEASUREMENTS

    CERN Document Server

    Rudolph, J

    2011-01-01

    The linear accelerator ELBE delivers high-brightness electron bunches to multiple user stations, including two IR-FEL oscillators [1], [2]. In the framework of an upgrade program the current thermionic injector is being replaced by a SRF-photoinjector [3], [4]. The SRF injector promises higher beam quality, especially required for future experiments with high power laser radiation. During the commissioning phase, the SRF-injector was running in parallel to the thermionic gun. After installation of a injection beamline (dogleg), beam from the SRF-injector can now be injected into the ELBE linac. Detailed characterization of the electron beam quality delivered by the new electron injector includes vertical slice emittance measurements in addition to measurements of projected emittance values. This report gives an overview of the status of the project and summarizes first measurement results as well as results of simulations performed with measurement settings.

  3. Recent results from LEP

    Indian Academy of Sciences (India)

    A Gurtu

    2000-04-01

    Recent results from the LEP collider at CERN are presented: on the identification of +- → +- and the determination of the mass and width and limits on its anomalous couplings; the search for the Standard Model and non-minimal Higgs; search for SUSY and other new particles. Fits to all electroweak data leading to predictions of the Higgs mass within the Standard Model are presented.

  4. Recent BABAR Results

    CERN Document Server

    Eigen, Gerald

    2015-01-01

    We present herein the most recent BABAR results on direct CP asymmetry measurements in B -> Xs gamma, on partial branching fraction and CP asymmetry measurements in B -> Xs l+l-, on a search for B -> pi/eta l+l- decays, on a search for lepton number violation in B -> X-l+l'+ modes and a study of B-> omega omega and B-> omega phi decays.

  5. Recent QCD Results

    CERN Document Server

    Lincoln, Don

    2009-01-01

    The study of the inelastic scattering of hadrons has progressed in the last decade. With the availability of high-statistics data sets from HERA and the Tevatron, our understanding of high energy and high jet multiplicity events has become rather precise. In this Proceedings, I present an overview of recent jet-only results, as well as measurements of events which combine both jets and a W or Z boson.

  6. Overview of ATLAS results

    CERN Document Server

    Grabowska-Bold, Iwona; The ATLAS collaboration

    2016-01-01

    The ATLAS experiment at the Large Hadron Collider has undertaken a broad physics program to probe and characterize the hot nuclear matter created in relativistic lead-lead collisions. This talk presents recent results based on Run 2 data on production of jet, electroweak bosons and quarkonium, electromagnetic processes in ultra-peripheral collisions, and bulk particle collectivity from PbPb, pPb and pp collisions.

  7. Explaining embodied cognition results.

    Science.gov (United States)

    Lakoff, George

    2012-10-01

    From the late 1950s until 1975, cognition was understood mainly as disembodied symbol manipulation in cognitive psychology, linguistics, artificial intelligence, and the nascent field of Cognitive Science. The idea of embodied cognition entered the field of Cognitive Linguistics at its beginning in 1975. Since then, cognitive linguists, working with neuroscientists, computer scientists, and experimental psychologists, have been developing a neural theory of thought and language (NTTL). Central to NTTL are the following ideas: (a) we think with our brains, that is, thought is physical and is carried out by functional neural circuitry; (b) what makes thought meaningful are the ways those neural circuits are connected to the body and characterize embodied experience; (c) so-called abstract ideas are embodied in this way as well, as is language. Experimental results in embodied cognition are seen not only as confirming NTTL but also explained via NTTL, mostly via the neural theory of conceptual metaphor. Left behind more than three decades ago is the old idea that cognition uses the abstract manipulation of disembodied symbols that are meaningless in themselves but that somehow constitute internal "representations of external reality" without serious mediation by the body and brain. This article uniquely explains the connections between embodied cognition results since that time and results from cognitive linguistics, experimental psychology, computational modeling, and neuroscience.

  8. GIRAFFE test results summary

    Energy Technology Data Exchange (ETDEWEB)

    Yokobori, S.; Arai, K.; Oikawa, H. [Toshiba Corporation, Kawasaki (Japan)

    1996-03-01

    A passive system can provide engineered safety features enhancing safety system reliability and plant simplicity. Toshiba has conducted the test Program to demonstrate the feasibility of the SBWR passive safety system using a full-height, integral system test facility GIRAFFE. The test facility GIRAFFE models the SBWR in full height to correctly present the gravity driving head forces with a 1/400 volume scale. The GIRAFFE test Program includes the certification tests of the passive containment cooling system (PCCS) to remove the post-accident decay heat and the gravity driven cooling system (GDCS) to replenish the reactor coolant inventory during a LOCA. The test results have confirmed the PCCS and GDCS design and in addition, have demonstrated the operation of the pCCS with the presence of a lighter-than-steam noncondensable as well as with the presence of a heavier-than-steam, noncondensable. The GIRAFFE test Program has also provided the database to qualify a best estimate thermal-hydraulic computer code TRAC. The post test analysis results have shown that TRAC can accurately predict the PCCS heat removal Performance and the containment pressure response to a LOCA. This paper summarizes the GIRAFFE test results to investigate post-LOCA PCCS heat removal performance and post-test analysis using TRAC.

  9. 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.

  10. Recent Results from SELEX

    CERN Document Server

    Russ, J

    2001-01-01

    The SELEX experiment (E781) is 3-stage magnetic spectrometer for the study of charm hadroproduction at large xF using 600 Gev Sigma-, pi- and p beams. New precise measurements of the Lambda_c, D0, and Ds lifetimes are presented. We also report results on Lambda_c and Ds production by Sigma-, pi- and p beams at xF>0.2. The data agree with expectations from color-drag models to explain charm particle/antiparticle production asymmetries.

  11. First LHC Results

    CERN Document Server

    Horn, Claus; The ATLAS collaboration

    2010-01-01

    Since four month the Large Hadron Collider (LHC) is producing proton-proton collisions with a center of mass energy of 7 TeV offering the potential of directly producing dark matter particles in an energy range never reached before in accelerator-based particle physics. First the performance and first Standard Model measurements of the general purpose experiments CMS and ATLAS is presented. This talk then focuses on their potential to detect dark matter candidates. Results from ongoing physics analyzes are presented and expectations for possible future discoveries are discussed.

  12. New results from CLEO

    CERN Document Server

    Dubrovin, M S; Huang, G S; Lee, J; Miller, D H; Pavlunin, V; Rangarajan, R; Sanghi, B; Shibata, E I; Shipsey, I P J; Cronin-Hennessy, D; Park, C S; Park, W; Thayer, J B; Thorndike, E H; Coan, T E; Gao, Y S; Liu, F; Stroynowski, R; Artuso, M; Boulahouache, C; Blusk, S; Dambasuren, E; Dorjkhaidav, O; Mountain, R; Muramatsu, H; Nandakumar, R; Skwarnicki, T; Stone, S; Wang, J C; Csorna, S E; Danko, I; Bonvicini, G; Cinabro, D; Dubrovin, M; McGee, S; Bornheim, A; Lipeles, E; Pappas, S P; Shapiro, A; Sun, W M; Weinstein, A J; Briere, R A; Chen, G P; Ferguson, T; Tatishvili, G T; Vogel, H; Watkins, M E; Adam, N E; Alexander, J P; Berkelman, K; Boisvert, V; Cassel, D G; Duboscq, J E; Ecklund, K M; Ehrlich, R; Galik, R S; Gibbons, L; Gittelman, B; Gray, S W; Hartill, D L; Heltsley, B K; Hsu, L; Jones, C D; Kandaswamy, J; Kreinick, D L; Magerkurth, A; Mahlke-Krüger, H; Meyer, T O; Mistry, N B; Patterson, J R; Peterson, D; Pivarski, J; Richichi, S J; Riley, D; Sadoff, A J; Schwarthoff, H; Shepherd, M R; Thayer, J G; Urner, D; Wilksen, T; Warburton, A; Weinberger, M; Athar, S B; Avery, P; Breva-Newell, L; Potlia, V; Stöck, H; Yelton, J; Benslama, K; Cawlfield, C; Eisenstein, B I; Gollin, G D; Karliner, I; Lowrey, N; Plager, C; Sedlack, C; Selen, M; Thaler, J J; Williams, J; Edwards, K W; Besson, D; Anderson, S; Frolov, V V; Gong, D T; Kubota, Y; Li, S Z; Poling, R A; Smith, A; Stepaniak, C J; Urheim, J; Metreveli, Z V; Seth, K K; Tomaradze, A G; Zweber, P; Ahmed, S; Alam, M S; Ernst, J; Jian, L; Saleem, M; Wappler, F; Arms, K; Eckhart, E; Gan, K K; Gwon, C; Honscheid, K; Kagan, H; Kass, R; Pedlar, T K; Von Törne, E; Severini, H; Skubic, P L; Dytman, S A; Müller, J A; Nam, S; Savinov, V

    2005-01-01

    We present recent results from the CLEO Collaboration. The data used were collected from 1995 untill now at the Cornell Electron-positron Storage Ring (CESR). Measurements of the leptonic branching fractions for $\\psi(2S) \\to e^+ e^-, \\mu^+ \\mu^-$ and $\\Upsilon(1,2,3S) \\to \\mu^+ \\mu^-$, search for $D^0-\\bar{D^0}$ mixing using time dependent Dalitz plot analyses of the decay $D^0 \\to K^0_S\\pi^+\\pi^-$, and search for the process $e^+e^- \\to \\Lambda_b \\bar{\\Lambda_b}$ near threshold are discussed.

  13. Recent CDF results

    Energy Technology Data Exchange (ETDEWEB)

    Conway, J.S. [Rutgers--the State Univ., Piscataway, NJ (United States). Dept. of Physics and Astronomy; CDF Collaboration

    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{sup - 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 {ital e}{sup +}{ital e}{sup -} 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. Overview of ATLAS results

    CERN Document Server

    Grabowska-Bold, Iwona; The ATLAS collaboration

    2016-01-01

    The heavy-ion programme in the ATLAS experiment at the Large Hadron Collider aims to probe and characterise hot and dense matter created in relativistic lead-lead collisions. Moreover, smaller collision systems involving nuclei and hadrons are of interest to disentangle initial- from final-state effects. This report presents new results based on lead-lead and proton-proton data collected at √sNN = 5.02 TeV in 2015, including measurements of bulk collectivity, charged-particle production, electroweak bosons, photon-jet correlations, and quarkonium suppression. First attempts to measure electromagnetic processes in ultra-peripheral collisions are also discussed.

  15. Latest LHCb results

    Directory of Open Access Journals (Sweden)

    Martinelli Maurizio

    2014-01-01

    Full Text Available The LHCb experiment is one of the major research projects at the Large Hadron Collider. Its acceptance and instrumentation is optimised to perform high-precision studies of flavour physics and particle production in a unique kinematic range at unprecedented collision energies. Using large data samples accumulated in the years 2010-2012, the LHCb collaboration has conducted a series of measurements providing a sensitive test of the Standard Model and strengthening our knowledge of flavour physics, QCD and electroweak processes. The status of the experiment and some of its recent results are presented here.

  16. 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.

  17. Results of railgun experiments

    Energy Technology Data Exchange (ETDEWEB)

    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.

  18. Recent results from CMS

    CERN Document Server

    Dordevic, Milos

    2016-01-01

    The highlights of the most recent CMS results with 13 TeV data will be presented in this overview. The Standard Model precision measurements, including the top quark production, will be shown first. This will be followed by the presentation of Higgs boson studies with the early 13 TeV data. Then the focus will shift to searches for physics beyond the Standard Model, including the searches for several Supersymmetric scenarios, using different analysis techniques. The talk will conclude with searches for the exotic resonances, with an emphasis on studies of the high-mass diphoton production.

  19. 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).

  20. Unfavourable results in pollicisation

    Directory of Open Access Journals (Sweden)

    Mukund R Thatte

    2013-01-01

    Full Text Available Pollicisation of the index finger is perhaps one of the most complex and most rewarding operations in hand and plastic surgery. It however has a steep learning curve and demands very high skill levels and experience. There are multiple pitfalls and each can result in an unfavourable result. In essence we need to: Shorten the Index, recreate the carpo metacarpal joint from the metacarpo phalangeal (MP joint, rotate the digit by about 120° for pulp to pulp pinch, palmarly abduct by 40-50° to get a new first web gap, Shorten and readjust the tension of the extensors, re attach the intrinsics to form a thenar eminence capable of positioning the new thumb in various functional positions and finally close the flaps forming a new skin envelope. The author has performed over 75 pollicisations personally and has personal experience of some of the issues raised there. The steps mentioned therefore are an algorithm for helping the uninitiated into these choppy waters.

  1. Maquet Osteotomy, Results

    Science.gov (United States)

    Díaz, Jorge Luis; Vega, Marcelo; Matesevach, Ivan

    2017-01-01

    Objectives: The objectives are to assess the results and to discuss the indications for Maquet osteotomy in patients with patellofemoral osteoarthritis. Methods: Retrospective study of a series of 32 patients (4 bilateral, that is to say, 36 knees) operated between March 1999 and October 2013 in " Arthroscopy Private Center ", 12 male and 20 female, average age 59 years with an average postoperative surgery outcomes of 53 months. The technique consists of an arthroscopic procedure to treat joint lesions and a tibial tuberosity osteotomy of 5 cm long, by embedding a 1cm subsequent graft taken from the same metaphysis and fixed with 2 screws. Results: All patients had significant improvement, evaluated with Kujala’s score (54 points preop to 86 points postop) and Guillamon Ferguson’s criteria (27.2 very good and 60.7 good). The complication rate was acceptable. Conclusion: The available technics are surgeries on proximal soft structures, osteotomies of tibial tuberosity and patellofemoral arthroplasty. Maquet osteotomy is an excellent procedure when the patient’s selection is right. Obtaining the graft from the same metaphysis simplified the procedure.

  2. Double Chooz: Latest results

    CERN Document Server

    Crespo-Anadón, J I

    2014-01-01

    The latest results from the Double Chooz experiment on the neutrino mixing angle $\\theta_{13}$ are presented. A detector located at an average distance of 1050 m from the two reactor cores of the Chooz nuclear power plant has accumulated a live time of 467.90 days, corresponding to an exposure of 66.5 GW-ton-year (reactor power $\\times$ detector mass $\\times$ live time). A revised analysis has boosted the signal efficiency and reduced the backgrounds and systematic uncertainties compared to previous publications, paving the way for the two detector phase. The measured $\\sin^2 2\\theta_{13} = 0.090^{+0.032}_{-0.029}$ is extracted from a fit to the energy spectrum. A deviation from the prediction above a visible energy of 4 MeV is found, being consistent with an unaccounted reactor flux effect, which does not affect the $\\theta_{13}$ result. A consistent value of $\\theta_{13}$ is measured in a rate-only fit to the number of observed candidates as a function of the reactor power, confirming the robustness of the ...

  3. Organic Separation Test Results

    Energy Technology Data Exchange (ETDEWEB)

    Russell, Renee L.; Rinehart, Donald E.; Peterson, Reid A.

    2014-09-22

    Separable organics have been defined as “those organic compounds of very limited solubility in the bulk waste and that can form a separate liquid phase or layer” (Smalley and Nguyen 2013), and result from three main solvent extraction processes: U Plant Uranium Recovery Process, B Plant Waste Fractionation Process, and Plutonium Uranium Extraction (PUREX) Process. The primary organic solvents associated with tank solids are TBP, D2EHPA, and NPH. There is concern that, while this organic material is bound to the sludge particles as it is stored in the tanks, waste feed delivery activities, specifically transfer pump and mixer pump operations, could cause the organics to form a separated layer in the tank farms feed tank. Therefore, Washington River Protection Solutions (WRPS) is experimentally evaluating the potential of organic solvents separating from the tank solids (sludge) during waste feed delivery activities, specifically the waste mixing and transfer processes. Given the Hanford Tank Waste Treatment and Immobilization Plant (WTP) waste acceptance criteria per the Waste Feed Acceptance Criteria document (24590-WTP-RPT-MGT-11-014) that there is to be “no visible layer” of separable organics in the waste feed, this would result in the batch being unacceptable to transfer to WTP. This study is of particular importance to WRPS because of these WTP requirements.

  4. Recent Results from ARGUS

    Science.gov (United States)

    Schröder, Henning

    Using the ARGUS detector at the e+e- storage ring DORIS II at DESY new results on beauty and τ physics have been obtained. In particular, new measurements on fundamental constants in the Yukawa sector of the Standard Model are presented. These comprise measurements of CKM matrix elements from the study of B decays as well as determinations of properties of the τ lepton and its neutrino vτ. From semileptonic B decays ARGUS finds |Vcb|=0.050±0.008±0.007 and from B0 bar B0 mixing |Vtd|= 0.007±0.002. An analysis of the decay type τ-→π-π-π+ντ yields a τ mass of mτ=(1776.3±2.4±1.4) MeV/c2. This result also leads to an improvement of the upper limit on the m{ν r } < 31 {{{MeV}} {/ {{{MeV}} {{c}{2} }}} ; } {{c}{2} }} at the 95% confidence level.

  5. Emittance exchange results

    Energy Technology Data Exchange (ETDEWEB)

    Fliller, R.P., III; /Brookhaven; Koeth, T.; /Rutgers U., Piscataway

    2009-09-01

    The promise of next-generation light sources depends on the availability of ultra-low emittance electron sources. One method of producing low transverse emittance beams is to generate a low longitudinal emittance beam and exchange it with a large transverse emittance. Experiments are underway at Fermilab's A0 Photoinjector and ANL's Argonne Wakefield Accelerator using the exchange scheme of Kim and Sessler. The experiment at the A0 Photoinjector exchanges a large longitudinal emittance with a small transverse emittance. AWA expects to exchange a large transverse emittance with a small longitudinal emittance. In this paper we discuss recent results at A0 and AWA and future plans for these experiments.

  6. Emittance Exchange Results

    Energy Technology Data Exchange (ETDEWEB)

    Fliller III,R.; Koeth, T.

    2009-05-04

    The promise of next-generation light sources depends on the availability of ultra-low emittance electron sources. One method of producing low transverse emittance beams is to generate a low longitudinal emittance beam and exchange it with a large transverse emittance. Experiments are underway at Fermilab's A0 Photoinjector and ANL's Argonne Wakefield Accelerator using the exchange scheme of Kim and Sessler. The experiment at the A0 Photoinjector exchanges a large longitudinal emittance with a small transverse emittance. AWA expects to exchange a large transverse emittance with a small longitudinal emittance. In this paper we discuss recent results at A0 and AWA and future plans for these experiments.

  7. Iron Mountain Electromagnetic Results

    Energy Technology Data Exchange (ETDEWEB)

    Gail Heath

    2012-07-01

    Iron Mountain Mine is located seventeen miles northwest of Redding, CA. After the completion of mining in early 1960s, the mine workings have been exposed to environmental elements which have resulted in degradation in water quality in the surrounding water sheds. In 1985, the EPA plugged ore stoops in many of the accessible mine drifts in an attempt to restrict water flow through the mine workings. During this process little data was gathered on the orientation of the stoops and construction of the plugs. During the last 25 years, plugs have begun to deteriorate and allow acidic waters from the upper workings to flow out of the mine. A team from Idaho National Laboratory (INL) performed geophysical surveys on a single mine drift and 3 concrete plugs. The project goal was to evaluate several geophysical methods to determine competence of the concrete plugs and orientation of the stopes.

  8. 2012 election results

    Science.gov (United States)

    Robinson, Robert; Tetzlaff, Doerthe

    2012-10-01

    On 4 October 2012, AGU members completed voting for the 2013-2014 leadership term. Union officers, Board members, section and focus group officers, and student and early career representatives to the Council were elected. All members who joined or renewed their membership by 1 July 2012 were eligible to vote in this year's leadership election. The vote was held electronically, and access to voting was provided to all eligible voters for a period of 31 days. The voting was conducted by Survey and Ballot Systems, Inc. (SBS). SBS, which offers election planning and management services, provided unique login credentials and other support services for eligible voters throughout the election. Voting results were certified by SBS on 8 October and by the AGU Tellers Committee on 9 October. The overall participation rate was 21.9%, an increase over previous AGU elections.

  9. 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.

  10. 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.

  11. 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.

  12. Recent results from CMS

    CERN Document Server

    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.

  13. Recent results from ANTARES

    Directory of Open Access Journals (Sweden)

    Trovato Agata

    2015-01-01

    Full Text Available Operating 40 km off the coast of France since 2007, the ANTARES detector is the largest deep-sea neutrino telescope in the Northern Hemisphere with an instrumented volume of more than 0.01 cubic kilometers. It consists of an array of 885 photomultipliers detecting the Cherenkov light induced by charged leptons produced by neutrino interactions in and around the detector. The primary goal of ANTARES is to search for astrophysical neutrinos in the TeV–PeV range. This comprises generic searches for any diffuse cosmic neutrino flux as well as more specific searches for astrophysical galactic and extragalactic sources. The search program also includes multi-messenger analyses based on time and/or space coincidences with other cosmic probes. The ANTARES observatory is sensitive to a wide-range of other phenomena, from atmospheric neutrino oscillations to dark matter annihilation. In this contribution, recent results from the ANTARES neutrino telescope will be presented.

  14. 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

  15. SAA drift: Experimental results

    Science.gov (United States)

    Grigoryan, O. R.; Romashova, V. V.; Petrov, A. N.

    According to the paleomagnetic analysis there are variations of Earth’s magnetic field connected with magnetic moment changing. These variations affect on the South Atlantic Anomaly (SAA) location. Indeed different observations approved the existence of the SAA westward drift rate (0.1 1.0 deg/year) and northward drift rate (approximately 0.1 deg/year). In this work, we present the analysis of experimental results obtained in Scobeltsyn Institute of Nuclear Physics, Moscow State University (SINP MSU) onboard different Earth’s artificial satellites (1972 2003). The fluxes of protons with energy >50 MeV, gamma quanta with energy >500 keV and neutrons with energy 0.1 1.0 MeV in the SAA region have been analyzed. The mentioned above experimental data were obtained onboard the orbital stations Salut-6 (1979), MIR (1991, 1998) and ISS (2003) by the similar experimental equipment. The comparison of the data obtained during these two decades of investigations confirms the fact that the SAA drifts westward. Moreover the analysis of fluxes of electrons with energy about hundreds keV (Cosmos-484 (1972) and Active (Interkosmos-24, 1991) satellites) verified not only the SAA westward drift but northward drift also.

  16. LEARNING RESULTS TIME

    Directory of Open Access Journals (Sweden)

    Ignacio Polo Martínez

    2016-12-01

    Full Text Available In spite of the changes to education norms in our country in the last ten years, where we have tried to integrate the different curriculum components in teaching and learning design, it is still typical to detect (1 curriculum plans that encourage rote learning and (2 teachers that continue teaching in the same style in which they were taught as students, and/or simply copying the textbook, even though sometimes it doesn´t provide the appropriate teaching and reliable assessment which meets the needs of our society. The insufficient academic training of (1 teachers, superintendents, and education authority members and (2 staff assessment that assures the best teaching practices in the classrooms, may be contributing to the inability to improve our education system. With respect to these deficiencies, we may come to the conclusion that the inclusion of these competencies in the curriculum and evaluation is a superficial action to fullfill European education requirements, more than a real plan to improve teaching and learning processes, and therefore, learning results in our country.

  17. Results from LHCf Experiment

    Directory of Open Access Journals (Sweden)

    Tricomi Alessia

    2012-06-01

    Full Text Available The LHCf experiment has taken data in 2009 and 2010 p-p collisions at LHC at √s = 0.9 TeV and √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 1017 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.

  18. Results of hip resurfacing

    Science.gov (United States)

    Favetti, Fabio; Casella, Filippo; Papalia, Matteo; Panegrossi, Gabriele

    2011-01-01

    Background The renewed popularity of resurfacing hip arthroplasty in the last 10 years has generated a remarkable quantity of scientific contributions based on mid- and short-term follow-up. More than one paper has reported a consistent early revision rate as a consequence of biological or biomechanical failure. Two major complications are commonly described with resurfacing implants: avascular necrosis and femoral-neck fracture. A close relationship between these two events has been suggested, but not firmly demonstrated, whereas cementing technique seems to be better understood as potential cause of failure. Methods We performed an in vitro study in which four different resurfacing implants were evaluated with a simulated femoral head, two types of cement, (low and high viscosity) and two cementing techniques: direct (cement apposition directly on the femoral head) and indirect (cement poured into the femoral component). Results High-viscosity cement showed homogeneous distribution over the entire femoral head. Low-viscosity cement showed a massive polar concentration with insufficient, if not absent, distribution in the equatorial zone. Conclusion Polar cement concentration could be a risk factor for early implant failure due to two effects on the femoral head: biological (excessive local exothermic reaction could cause osteocyte necrosis) and biomechanical (which could lead to uneven load distribution on the femoral head). PMID:21234563

  19. Simpler images, better results

    Science.gov (United States)

    Chance, Britton

    1999-03-01

    The very rapid development of optical technology has followed a pattern similar to that of nuclear magnetic resonance: first, spectroscopy and then imaging. The accomplishments in spectroscopy have been significant--among them, early detection of hematomas and quantitative oximetry (assuming that time and frequency domain instruments are used). Imaging has progressed somewhat later. The first images were obtained in Japan and USA a few years ago, particularly of parietal stimulation of the human brain. Since then, rapid applications to breast and limb, together with higher resolution of the brain now make NIR imaging of functional activation and tumor detection readily available, reliable and affordable devices. The lecture has to do with the applications of imaging to these three areas, particularly to prefrontal imaging of cognitive function, of breast tumor detection, and of localized muscle activation in exercise. The imaging resolution achievable in functional activation appears to be FWHM of 4 mm. The time required for an image is a few seconds or even much less. Breast image detection at 50 microsecond(s) ec/pixel results in images obtainable in a few seconds or shorter times (bandwidths of the kHz are available). Finally, imaging of the body organs is under study in this laboratory, particularly in the in utero fetus. It appears that the photon migration theory now leads to the development of a wide number of images for human subject tissue spectroscopy and imaging.

  20. 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.

  1. ALOS-2 initial results

    Science.gov (United States)

    Kankaku, Yukihiro; Suzuki, Shinichi; Shimada, Masanobu

    2015-10-01

    The Advanced Land Observing Satellite-2 (ALOS-2) was launched from Tanegashima Space Center by H-IIA rocket successfully on 24th May 2014. ALOS-2 carries the Phased Array type L-band Synthetic Aperture Radar-2 (PALSAR-2) as the state-of-the-art L-band SAR system which succeeds to PALSAR onboard ALOS. PALSAR-2 uses almost whole bandwidth allocated for L-band active sensor of Earth Exploration Satellites Service specified by the Radio Regulation in order to realize the high resolution observation, and also, it transmits more than 6 kW power for lower Noise Equivalent Sigma Zero using 180 TRMs driven by Gallium Nitride (GaN) amplifier which is the first use in space. Furthermore, because ALOS-2 carries the SAR system only, PALSAR-2 antenna can be mounted under the satellite body. It enables to observe right-/left-looking observation by satellite maneuvering. And the high accuracy orbit control to maintain the satellite within 500 m radius tube against the reference orbit enables high coherence for the InSAR processing. Using these new technologies, ALOS-2 has been operating to fulfill the mission requirements such as disaster monitoring and so on. This document introduces the initial result of ALOS-2 from the first year operation.

  2. New results from VES

    CERN Document Server

    Dorofeev, V A

    1999-01-01

    The results of the patial wave analysis(PWA) of the pi+pi-pi- and omegapi-pi0 systems are presented. The a3 and a4(2040) signals are observed in the rho(770)pi and f2(1270)pi channels. Indications of the a1' meson existence was found in the 1+0+ rhopi S-wave. The decay branching ratio of the a2(1320)- to omegapi-pi0 was measured. The 2+1+ wave shows a broad bump at M~1.7GeV. The decays of the pi2(1670), a4(2040) and pi(1740) into omegarho- were found. The resonance in the b1(1235)pi wave with exotic quantum numbers jpc=1-+ at M~1.6 is observed and the simultaneous analysis of the 1-+ wave in the b1(1235)pi, etha'pi and rhopi final states is presented.

  3. [SENTIERI Project: results].

    Science.gov (United States)

    Crocetti, Emanuele; Pirastu, Roberta; Buzzoni, Carlotta; Minelli, Giada; Manno, Valerio; Bruno, Caterina; Fazzo, Lucia; Iavarone, Ivano; Pasetto, Roberto; Ricci, Paolo; Zona, Amerigo; Conti, Susanna; Comba, Pietro

    2014-01-01

    Of the 18 National Priority Contaminated Sites (NPCSs) analysed in this Report, some have a single source of environmental contamination (such as fluoro-edenite in Biancavilla). In most cases, however, we are looking at multiple heterogeneous sources of contamination. In this respect, the a priori causal evaluation of the association between diseases and environmental exposures in NPCSs, based on epidemiological evidence, can help trace the health impact back to specific types of environmental exposure. There are several cases in which the project's findings have been consistent with a priori evidence: stomach cancer (both genders, excess cancer incidence) in the Fidenza NPCS; stomach cancer (women, excess mortality, cancer incidence and hospital discharges) in the Laguna di Grado e Marano NPCS; excess hospitalisation from respiratory diseases in Brescia-Caffaro, Milazzo and Terni Papigno NPCSs; excesses for non-Hodgkin lymphomas and melanoma (incidence and hospitalisation in men and women) and breast cancer (incidence and hospital discharges, women) in Brescia-Caffaro NPCS. In preorder to properly evaluate the population's health profile, we must also observe whether results remain consistent for all three health outcomes or in both genders. The first is the case of excess mortality, cancer incidence and hospital discharges for bladder cancer (men) in Porto Torres and diseases of the urinary tract in the Basso bacino del fiume Chienti NPCS). Gender consistency is observed, for instance, for all cancer in Bolzano, Porto Torres, Venice, Litorale Domizio Flegreo, Priolo, and Taranto, for all causes in Taranto, Litorale Domizio Flegreo and Trieste. The health impact in the various NPCSs needs to be considered carefully and used as a springboard for further analytical research that could confirm and explain causal links to specific environmental exposures. The observations can, however, already be considered as a basis for mandatory primary prevention measures.

  4. Nonrecurrent PMP22-RAI1 contiguous gene deletions arise from replication-based mechanisms and result in Smith-Magenis syndrome with evident peripheral neuropathy.

    Science.gov (United States)

    Yuan, Bo; Neira, Juanita; Gu, Shen; Harel, Tamar; Liu, Pengfei; Briceño, Ignacio; Elsea, Sarah H; Gómez, Alberto; Potocki, Lorraine; Lupski, James R

    2016-10-01

    Hereditary neuropathy with liability to pressure palsies (HNPP) and Smith-Magenis syndrome (SMS) are genomic disorders associated with deletion copy number variants involving chromosome 17p12 and 17p11.2, respectively. Nonallelic homologous recombination (NAHR)-mediated recurrent deletions are responsible for the majority of HNPP and SMS cases; the rearrangement products encompass the key dosage-sensitive genes PMP22 and RAI1, respectively, and result in haploinsufficiency for these genes. Less frequently, nonrecurrent genomic rearrangements occur at this locus. Contiguous gene duplications encompassing both PMP22 and RAI1, i.e., PMP22-RAI1 duplications, have been investigated, and replication-based mechanisms rather than NAHR have been proposed for these rearrangements. In the current study, we report molecular and clinical characterizations of six subjects with the reciprocal phenomenon of deletions spanning both genes, i.e., PMP22-RAI1 deletions. Molecular studies utilizing high-resolution array comparative genomic hybridization and breakpoint junction sequencing identified mutational signatures that were suggestive of replication-based mechanisms. Systematic clinical studies revealed features consistent with SMS, including features of intellectual disability, speech and gross motor delays, behavioral problems and ocular abnormalities. Five out of six subjects presented clinical signs and/or objective electrophysiologic studies of peripheral neuropathy. Clinical profiling may improve the clinical management of this unique group of subjects, as the peripheral neuropathy can be more severe or of earlier onset as compared to SMS patients having the common recurrent deletion. Moreover, the current study, in combination with the previous report of PMP22-RAI1 duplications, contributes to the understanding of rare complex phenotypes involving multiple dosage-sensitive genes from a genetic mechanistic standpoint.

  5. Oncogenic BRAF(V600E Induces Clastogenesis and UVB Hypersensitivity

    Directory of Open Access Journals (Sweden)

    Dennis A. Simpson

    2015-06-01

    Full Text Available The oncogenic BRAF(V600E mutation is common in melanomas as well as moles. The roles that this mutation plays in the early events in the development of melanoma are poorly understood. This study demonstrates that expression of BRAF(V600E is not only clastogenic, but synergizes for clastogenesis caused by exposure to ultraviolet radiation in the 300 to 320 nM (UVB range. Expression of BRAF(V600E was associated with induction of Chk1 pS280 and a reduction in chromatin remodeling factors BRG1 and BAF180. These alterations in the Chk1 signaling pathway and SWI/SNF chromatin remodeling pathway may contribute to the clastogenesis and UVB sensitivity. These results emphasize the importance of preventing sunburns in children with developing moles.

  6. The mismatch repair system modulates curcumin sensitivity through induction of DNA strand breaks and activation of G2-M checkpoint.

    Science.gov (United States)

    Jiang, Zhihua; Jin, ShunQian; Yalowich, Jack C; Brown, Kevin D; Rajasekaran, Baskaran

    2010-03-01

    The highly conserved mismatch (MMR) repair system corrects postreplicative errors and modulates cellular responses to genotoxic agents. Here, we show that the MMR system strongly influences cellular sensitivity to curcumin. Compared with MMR-proficient cells, isogenically matched MMR-deficient cells displayed enhanced sensitivity to curcumin. Similarly, cells suppressed for MLH1 or MSH2 expression by RNA interference displayed increased curcumin sensitivity. Curcumin treatment generated comparable levels of reactive oxygen species and the mutagenic adduct 8-oxo-guanine in MMR-proficient and MMR-deficient cells; however, accumulation of gammaH2AX foci, a marker for DNA double-strand breaks (DSB), occurred only in MMR-positive cells in response to curcumin treatment. Additionally, MMR-positive cells showed activation of Chk1 and induction of G(2)-M cell cycle checkpoint following curcumin treatment and inhibition of Chk1 by UCN-01 abrogated Chk1 activation and heightened apoptosis in MMR-proficient cells. These results indicate that curcumin triggers the accumulation of DNA DSB and induction of a checkpoint response through a MMR-dependent mechanism. Conversely, in MMR-compromised cells, curcumin-induced DSB is significantly blunted, and as a result, cells fail to undergo cell cycle arrest, enter mitosis, and die through mitotic catastrophe. The results have potential therapeutic value, especially in the treatment of tumors with compromised MMR function.

  7. Atrazine Triggers DNA Damage Response and Induces DNA Double-Strand Breaks in MCF-10A Cells.

    Science.gov (United States)

    Huang, Peixin; Yang, John; Ning, Jie; Wang, Michael; Song, Qisheng

    2015-06-24

    Atrazine, a pre-emergent herbicide in the chloro-s-triazine family, has been widely used in crop lands and often detected in agriculture watersheds, which is considered as a potential threat to human health. Although atrazine and its metabolites showed an elevated incidence of mammary tumors in female Sprague-Dawley (SD) rats, no molecular evidence was found relevant to its carcinogenesis in humans. This study aims to determine whether atrazine could induce the expression of DNA damage response-related proteins in normal human breast epithelial cells (MCF-10A) and to examine the cytotoxicity of atrazine at a molecular level. Our results indicate that a short-term exposure of MCF-10A to an environmentally-detectable concentration of atrazine (0.1 µg/mL) significantly increased the expression of tumor necrosis factor receptor-1 (TNFR1) and phosphorylated Rad17 in the cells. Atrazine treatment increased H2AX phosphorylation (γH2AX) and the formation of γH2AX foci in the nuclei of MCF-10A cells. Atrazine also sequentially elevated DNA damage checkpoint proteins of ATM- and RAD3-related (ATR), ATRIP and phospho-Chk1, suggesting that atrazine could induce DNA double-strand breaks and trigger the DNA damage response ATR-Chk1 pathway in MCF-10A cells. Further investigations are needed to determine whether atrazine-triggered DNA double-strand breaks and DNA damage response ATR-Chk1 pathway occur in vivo.

  8. Induction of mitotic catastrophe by PKC inhibition in Nf1-deficient cells.

    Science.gov (United States)

    Zhou, Xiaodong; Kim, Sung-Hoon; Shen, Ling; Lee, Hyo-Jung; Chen, Changyan

    2014-01-01

    Mutations of tumor suppressor Nf1 gene deregulate Ras-mediated signaling, which confers the predisposition for developing benign or malignant tumors. Inhibition of protein kinase C (PKC) was shown to be in synergy with aberrant Ras for the induction of apoptosis in various types of cancer cells. However, it has not been investigated whether loss of PKC is lethal for Nf1-deficient cells. In this study, using HMG (3-hydroxy-3-methylgutaryl, a PKC inhibitor), we demonstrate that the inhibition of PKC by HMG treatment triggered a persistently mitotic arrest, resulting in the occurrence of mitotic catastrophe in Nf1-deficient ST8814 cells. However, the introduction of the Nf1 effective domain gene into ST8814 cells abolished this mitotic crisis. In addition, HMG injection significantly attenuated the growth of the xenografted ST8814 tumors. Moreover, Chk1 was phosphorylated, accompanied with the persistent increase of cyclin B1 expression in HMG-treated ST8814 cells. The knockdown of Chk1 by the siRNA prevented the Nf1-deficient cells from undergoing HMG-mediated mitotic arrest as well as mitotic catastrophe. Thus, our data suggested that the suppression of PKC activates the Chk1-mediated mitotic exit checkpoint in Nf1-deficient cells, leading to the induction of apoptosis via mitotic catastrophe. Collectively, the study indicates that targeting PKC may be a potential option for developing new strategies to treat Nf1-deficiency-related diseases.

  9. Tumor suppressor protein C53 antagonizes checkpoint kinases to promote cyclin-dependent kinase 1 activation.

    Science.gov (United States)

    Jiang, Hai; Wu, Jianchun; He, Chen; Yang, Wending; Li, Honglin

    2009-04-01

    Cyclin-dependent kinase 1 (Cdk1)/cyclin B1 complex is the driving force for mitotic entry, and its activation is tightly regulated by the G2/M checkpoint. We originally reported that a novel protein C53 (also known as Cdk5rap3 and LZAP) potentiates DNA damage-induced cell death by modulating the G2/M checkpoint. More recently, Wang et al. (2007) found that C53/LZAP may function as a tumor suppressor by way of inhibiting NF-kappaB signaling. We report here the identification of C53 protein as a novel regulator of Cdk1 activation. We found that knockdown of C53 protein causes delayed Cdk1 activation and mitotic entry. During DNA damage response, activation of checkpoint kinase 1 and 2 (Chk1 and Chk2) is partially inhibited by C53 overexpression. Intriguingly, we found that C53 interacts with Chk1 and antagonizes its function. Moreover, a portion of C53 protein is localized at the centrosome, and centrosome-targeting C53 potently promotes local Cdk1 activation. Taken together, our results strongly suggest that C53 is a novel negative regulator of checkpoint response. By counteracting Chk1, C53 promotes Cdk1 activation and mitotic entry in both unperturbed cell-cycle progression and DNA damage response.

  10. A tumor suppressor C53 protein antagonizes checkpoint kinases to promote cyclin-dependent kinase 1 activation

    Science.gov (United States)

    Jiang, Hai; Wu, Jianchun; He, Chen; Yang, Wending; Li, Honglin

    2009-01-01

    Cyclin dependent kinase 1 (Cdk1)/cyclin B1 complex is the driving force for mitotic entry, and its activation is tightly regulated by the G2/M checkpoint. We originally reported that a novel protein C53 (also known as Cdk5rap3 and LZAP) potentiates DNA damage-induced cell death by modulating the G2/M checkpoint (1). More recently, Wang et al (2007) found that C53/LZAP may function as a tumor suppressor via inhibiting NF-κB signaling (2). We report here identification of C53 protein as a novel regulator of Cdk1 activation. We found that knockdown of C53 protein causes delayed Cdk1 activation and mitotic entry. During DNA damage response, activation of checkpoint kinase 1 and 2 (Chk1 and Chk2) is partially inhibited by C53 overexrepsssion. Intriguingly, we found that C53 interacts with checkpoint kinase 1 (Chk1) and antagonizes its function. Moreover, a portion of C53 protein is localized at the centrosome, and centrosome-targeting C53 potently promotes local Cdk1 activation. Taken together, our results strongly suggest that C53 is a novel negative regulator of checkpoint response. By counteracting Chk1, C53 promotes Cdk1 activation and mitotic entry in both unperturbed cell cycle progression and DNA damage response. PMID:19223857

  11. Watershed Assessment, Tracking & Environmental ResultS (WATERS)

    Data.gov (United States)

    U.S. Environmental Protection Agency — The Watershed Assessment, Tracking & Environmental Results (WATERS) is an integrated information system for the nation's surface waters connecting Office of...

  12. 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.

  13. Testbeam Results of Endcap RPC's

    CERN Document Server

    Ahmed, Ijaz; Hoorani, Hafeez; Aftab, Zia; Jan, J. A; Shariq Khan, M; Solaija, Tariq

    2006-01-01

    In this paper, results are presented from the beamtest in 2002 of the full-scale RE-2/2 prototype RPC chamber assembled in Pakistan. The results are mainly related with the efficiency, time resolution, and rate capability of this non-oiled RPC. The CMS collaboration has imposed strict criteria on the performance parameters for RPC's. These results show that prototype RPC's meet with all the CMS criteria and are suitable for installation in CMS detector.

  14. 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).

  15. Quadriceps tendon rupture - treatment results

    Directory of Open Access Journals (Sweden)

    Popov Iva

    2013-01-01

    Full Text Available Introduction. Quadriceps tendon rupture is a rare but rather serious injury. If this injury is not promptly recognized and early operated, it may lead to disability. This research was aimed at pointing out the results and complications of the quadriceps tendon rupture surgical treatment. Material and Methods. This retrospective multicentric study was conducted in a group of 29 patients (mostly elderly men. Lysholm knee scoring scale was used to evaluate the surgical results. The post-operative results were compared in relation to the type of tendon rupture reconstructions (acute or chronic, various surgical techniques, type of injuries (unilateral or bilateral as well as the presence or absence of comorbid risk factors in the patients. Results. The average value of a Lysholm score was 87.6. Excellent and satisfactory Lysholm score results dominated in our sample of patients. Better post-operative results were recorded in the group of patients without risk factors, in case of a bilateral injury, and in case of an acute injury. The best result was obtained after performing the reconstruction using anchors, and the worst result came after using Codivilla technique. Discussion and Conclusion. Early diagnosis and surgical treatment are an absolute imperative in management of this injury. We have not proven that a certain surgical technique has an advantage over the others. A comorbid risk factor is related to a lower Lysholm score. Despite a few cases of complications, we can conclude that the surgical treatment yields satisfactory results.

  16. 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...

  17. ISOCAM experiment cryogenic test results

    Science.gov (United States)

    de Sa, L.; Collaudin, B.

    The thermal requirements for ISOCAM, an IR camera to be mounted aboard the ISO satellite, are reviewed, and model predictions are matched with test results. The degree of model validation suggested by analytical prediction vs test results is described. Predictions of thermal conduction through mounting screws, from ball bearings, and of the heat distribution in the rotor and stator of a cryogenic stepper motor correlate well with actual test results. It is shown that ISOCAM meets the thermal requirements necessary for successful on-orbit operation. The model predicted such phenomena as 'chopped' motor function and the twofold increase in temperature resulting from continuous motor operation.

  18. Some Results behind Dividend Problems

    Institute of Scientific and Technical Information of China (English)

    Ming Zhou; Li Wei; Jun-yi Guo

    2006-01-01

    We consider the basic dividend problem of the compound Poisson model with constant barrier strategy. Some results concealed behind the dividend problem are made explicit in the present work. Different methods and some of which are firstly given in this paper. All these results presented certain direct relationship between some important actuary variables in classical risk theory is also revealed.

  19. 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......-hardness of the plan verification problem, which strengthens previous results on the complexity of DEL model checking....

  20. Latest Electroweak Results from CDF

    Energy Technology Data Exchange (ETDEWEB)

    Lancaster, Mark

    2010-05-01

    The latest results in electroweak physics from proton anti-proton collisions at the Fermilab Tevatron recorded by the CDF detector are presented. The results provide constraints on parton distribution functions, the mass of the Higgs boson and beyond the Standard Model physics.

  1. Top physics results at CDF

    Energy Technology Data Exchange (ETDEWEB)

    Vickey, Trevor; /Illinois U., Urbana

    2005-05-01

    The most recent results on top quark physics at CDF are reported. Measurements of cross-section and mass are presented, and the status of single top quark production searches are discussed. The results obtained from probing various top quark properties are also presented.

  2. Spacelab Life Sciences 1 results

    Science.gov (United States)

    Seddon, Rhea

    1992-01-01

    Results are presented from the experiments conducted by the first Shuttle/Spacelab mission dedicated entirely to the life sciences, the Spacelab Life Sciences 1, launched on June 5, 1991. The experiments carried out during the 9-day flight included investigations of changes in the human cardiovascular, pulmonary, renal/endocrine, blood, and vestibular systems that were brought about by microgravity. Results were also obtained from the preflight and postflight complementary experiments performed on rats, which assessed the suitability of rodents as animal models for humans. Most results verified, or expanded on, the accepted theories of adaptation to zero gravity.

  3. 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.

  4. Results from NA61/SHINE

    Directory of Open Access Journals (Sweden)

    Unger M.

    2013-06-01

    Full Text Available In this paper we summarize recent results from NA61/SHINE relevant for heavy ion physics, neutrino oscillations and the interpretation of air showers induced by ultra-high energy cosmic rays.

  5. Retrospective Evaluation of Colonoscopy Results

    Directory of Open Access Journals (Sweden)

    Yaşar M et al.

    2010-09-01

    Full Text Available Aim: The aim of this study is the retrospective evaluation of colonoscopy results between 2005 January- 2009 December in General Surgery Department of Düzce University.Materials and Methods: Admitted to our department with lower gastrointestinal symptoms, and colonoscopy is indicated 500 male and 538 female total 1038 patients were performed flexible colonoscopic examinations after bowel cleansing.Results: According to results of colonoscopic findings, 42.9% No pathology, 32.5% Hemorrhoids, 17.6% Anal fissures were detected.Conclusion: As a result of this study, half of patients admitted to our surgical clinic with lower gastrointestinal complaints have no pathology and in the other half of patients have various pathologies such as hemorrhoids and anal fissures.

  6. Electroweak phase transition recent results

    CERN Document Server

    Csikor, Ferenc

    2000-01-01

    Recent results of four-dimensional (4d) lattice simulations on the finite temperature electroweak phase transition (EWPT) are discussed. The phase transition is of first order in the SU(2)-Higgs model below the end point Higgs mass 66.5$\\pm$1.4 GeV. For larger masses a rapid cross-over appears. This result completely agrees with the results of the dimensional reduction approach. Including the full Standard Model (SM) perturbatively the end point is at 72.1$\\pm$1.4 GeV. Combined with recent LEP Higgs mass lower bounds, this excludes any EWPT in the SM. A one-loop calculation of the static potential makes possible a precise comparison of the lattice and perturbative results. Recent 4d lattice studies of the Minimal Supersymmetric SM (MSSM) are also mentioned.

  7. PHENIX recent heavy flavor results

    Energy Technology Data Exchange (ETDEWEB)

    Lim, Sanghoon

    2014-06-15

    Cold nuclear matter (CNM) effects provide an important ingredient to interpret the results from heavy-ion collisions. Such effects include nuclear shadowing, intrinsic parton transverse momentum broadening, and initial patron energy loss. The measurement of heavy quark production is a good probe to study the CNM effects particularly on gluons, since heavy quarks are mainly produced via gluon fusions at RHIC energy. The PHENIX experiment has an ability to study the CNM effects by measuring leptons from heavy-flavor decay in a broad kinematic range. Comparisons of the results measured in different rapidity regions allow us to study modification of gluon density function in the Au nucleus depending on parton fractional momentum x. In addition, comparisons to the results from heavy-ion collisions (Au + Au and Cu + Cu) measured by PHENIX provide an insight into the role of CNM effects in such collisions. Recent PHENIX results on heavy quark production are discussed in this presentation.

  8. Heavy flavour results from ATLAS

    Directory of Open Access Journals (Sweden)

    Bell P. J.

    2012-06-01

    Full Text Available A selection of heavy-flavour physics results from the ATLAS experiment is presented, based on data collected in proton-proton collisions at the LHC during 2010. Differential cross-sections for the production of heavy flavours, charmonium and bottomonium states and D-mesons are presented and compared to various theoretical models. Results of B-hadron lifetime measurements are also reported.

  9. New CDF results on diffraction

    Energy Technology Data Exchange (ETDEWEB)

    Mesropian, Christina; /Rockefeller U.

    2006-12-01

    We report new diffraction results obtained by the CDF collaboration in proton-antiproton collisions at the Fermilab Tevatron collider at {radical}s=1.96 TeV. The first experimental evidence of exclusive dijet and diphoton production is presented. The exclusive results are discussed in context of the exclusive Higgs production at LHC. We also present the measurement of the Q{sup 2} and t dependence of the diffractive structure function.

  10. Selection of LHCb Physics Results

    Directory of Open Access Journals (Sweden)

    Schmidt Burkhard

    2013-05-01

    Full Text Available LHCb is a dedicated flavour physics experiment at the LHC searching for physics beyond the Standard Model through precision measurements of CP-violating observables and the study of very rare decays of beauty- and charm-flavoured hadrons. In this article a selection of recent LHCb results is presented. Unless otherwise stated, the results are based on an integrated luminosity of 1 fb−1 accumulated during the year 2011 at √s = 7 TeV.

  11. 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.

  12. 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...

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

    Science.gov (United States)

    Planck Collaboration; Adam, R.; Ade, P. A. R.; Aghanim, N.; Akrami, Y.; Alves, M. I. R.; Argüeso, F.; Arnaud, M.; Arroja, F.; Ashdown, M.; 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.; Benoît, A.; Benoit-Lévy, A.; Bernard, J.-P.; Bersanelli, M.; Bertincourt, B.; Bielewicz, P.; Bikmaev, I.; Bock, J. J.; Böhringer, H.; Bonaldi, A.; Bonavera, L.; Bond, J. R.; Borrill, J.; Bouchet, F. R.; Boulanger, F.; Bucher, M.; Burenin, R.; 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.; Chon, G.; 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.; Désert, F.-X.; Di Valentino, E.; Dickinson, C.; Diego, J. M.; Dolag, K.; Dole, H.; Donzelli, S.; Doré, 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.; Génova-Santos, R. T.; Gerbino, M.; Ghosh, T.; Giard, M.; Giraud-Héraud, Y.; Giusarma, E.; Gjerløw, E.; González-Nuevo, J.; Górski, 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-Versillé, S.; Hernández-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.; Ilić, S.; Jaffe, A. H.; Jaffe, T. R.; Jin, T.; Jones, W. C.; Juvela, M.; Karakci, A.; Keihänen, E.; Keskitalo, R.; Khamitov, I.; Kiiveri, K.; Kim, J.; Kisner, T. S.; Kneissl, R.; Knoche, J.; Knox, L.; Krachmalnicoff, N.; Kunz, M.; Kurki-Suonio, H.; Lacasa, F.; Lagache, G.; Lähteenmäki, A.; Lamarre, J.-M.; Langer, M.; Lasenby, A.; Lattanzi, M.; Lawrence, C. R.; Le Jeune, M.; Leahy, J. P.; Lellouch, E.; Leonardi, R.; León-Tavares, J.; Lesgourgues, J.; Levrier, F.; Lewis, A.; Liguori, M.; Lilje, P. B.; Lilley, M.; Linden-Vørnle, M.; Lindholm, V.; Liu, H.; López-Caniego, M.; Lubin, P. M.; Ma, Y.-Z.; Macías-Pérez, J. F.; Maggio, G.; Maino, D.; Mak, D. S. Y.; Mandolesi, N.; Mangilli, A.; Marchini, A.; Marcos-Caballero, A.; Marinucci, D.; Maris, M.; Marshall, D. J.; Martin, P. G.; Martinelli, M.; Martínez-González, 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.; Millea, M.; Mitra, S.; Miville-Deschênes, M.-A.; Molinari, D.; Moneti, A.; Montier, L.; Moreno, R.; Morgante, G.; Mortlock, D.; Moss, A.; Mottet, S.; Münchmeyer, M.; Munshi, D.; Murphy, J. A.; Narimani, A.; Naselsky, P.; Nastasi, A.; Nati, F.; Natoli, P.; Negrello, M.; Netterfield, C. B.; Nørgaard-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.; Prézeau, 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.; Rouillé d'Orfeuil, B.; Rowan-Robinson, M.; Rubiño-Martín, 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.; Sauvé, 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.; Tramonte, D.; Tristram, M.; Troja, A.; Trombetti, T.; Tucci, M.; Tuovinen, J.; Türler, M.; Umana, G.; Valenziano, L.; Valiviita, J.; Van Tent, F.; Vassallo, T.; Vibert, L.; 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.

    2016-09-01

    The European Space Agency's Planck satellite, which is dedicated to studying the early Universe and its subsequent evolution, was launched on 14 May 2009. It 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 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 Galactic and extragalactic sources (including separate catalogues of Sunyaev-Zeldovich clusters and Galactic cold clumps), and extensive simulations of signals and noise used in assessing uncertainties and the performance of the analysis methods. The likelihood code used to assess cosmological models 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, and modified gravity, and new results on low-frequency Galactic foregrounds.

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

    Science.gov (United States)

    Planck Collaboration; Ade, P. A. R.; Aghanim, N.; Alves, M. I. R.; Armitage-Caplan, C.; Arnaud, M.; Ashdown, M.; Atrio-Barandela, F.; Aumont, J.; Aussel, H.; Baccigalupi, C.; Banday, A. J.; Barreiro, R. B.; Barrena, R.; Bartelmann, M.; Bartlett, J. G.; Bartolo, N.; Basak, S.; Battaner, E.; Battye, R.; Benabed, K.; Benoît, A.; Benoit-Lévy, A.; Bernard, J.-P.; Bersanelli, M.; Bertincourt, B.; Bethermin, M.; Bielewicz, P.; Bikmaev, I.; Blanchard, A.; Bobin, J.; Bock, J. J.; Böhringer, H.; Bonaldi, A.; Bonavera, L.; Bond, J. R.; Borrill, J.; Bouchet, F. R.; Boulanger, F.; Bourdin, H.; Bowyer, J. W.; Bridges, M.; Brown, M. L.; Bucher, M.; Burenin, R.; Burigana, C.; Butler, R. C.; Calabrese, E.; Cappellini, B.; Cardoso, J.-F.; Carr, R.; Carvalho, P.; Casale, M.; Castex, G.; Catalano, A.; Challinor, A.; Chamballu, A.; Chary, R.-R.; Chen, X.; Chiang, H. C.; Chiang, L.-Y.; Chon, G.; Christensen, P. R.; Churazov, E.; Church, S.; Clemens, M.; Clements, D. L.; Colombi, S.; Colombo, L. P. L.; Combet, C.; Comis, B.; Couchot, F.; Coulais, A.; Crill, B. P.; Cruz, M.; Curto, A.; Cuttaia, F.; Da Silva, A.; Dahle, H.; Danese, L.; Davies, R. D.; Davis, R. J.; de Bernardis, P.; de Rosa, A.; de Zotti, G.; Déchelette, T.; Delabrouille, J.; Delouis, J.-M.; Démoclès, J.; Désert, F.-X.; Dick, J.; Dickinson, C.; Diego, J. M.; Dolag, K.; Dole, H.; Donzelli, S.; Doré, O.; Douspis, M.; Ducout, A.; Dunkley, J.; Dupac, X.; Efstathiou, G.; Elsner, F.; Enßlin, T. A.; Eriksen, H. K.; Fabre, O.; Falgarone, E.; Falvella, M. C.; Fantaye, Y.; Fergusson, J.; Filliard, C.; Finelli, F.; Flores-Cacho, I.; Foley, S.; Forni, O.; Fosalba, P.; Frailis, M.; Fraisse, A. A.; Franceschi, E.; Freschi, M.; Fromenteau, S.; Frommert, M.; Gaier, T. C.; Galeotta, S.; Gallegos, J.; Galli, S.; Gandolfo, B.; Ganga, K.; Gauthier, C.; Génova-Santos, R. T.; Ghosh, T.; Giard, M.; Giardino, G.; Gilfanov, M.; Girard, D.; Giraud-Héraud, Y.; Gjerløw, E.; González-Nuevo, J.; Górski, K. M.; Gratton, S.; Gregorio, A.; Gruppuso, A.; Gudmundsson, J. E.; Haissinski, J.; Hamann, J.; Hansen, F. K.; Hansen, M.; Hanson, D.; Harrison, D. L.; Heavens, A.; Helou, G.; Hempel, A.; Henrot-Versillé, S.; Hernández-Monteagudo, C.; Herranz, D.; Hildebrandt, S. R.; Hivon, E.; Ho, S.; Hobson, M.; Holmes, W. A.; Hornstrup, A.; Hou, Z.; Hovest, W.; Huey, G.; Huffenberger, K. M.; Hurier, G.; Ilić, S.; Jaffe, A. H.; Jaffe, T. R.; Jasche, J.; Jewell, J.; Jones, W. C.; Juvela, M.; Kalberla, P.; Kangaslahti, P.; Keihänen, E.; Kerp, J.; Keskitalo, R.; Khamitov, I.; Kiiveri, K.; Kim, J.; Kisner, T. S.; Kneissl, R.; Knoche, J.; Knox, L.; Kunz, M.; Kurki-Suonio, H.; Lacasa, F.; Lagache, G.; Lähteenmäki, A.; Lamarre, J.-M.; Langer, M.; Lasenby, A.; Lattanzi, M.; Laureijs, R. J.; Lavabre, A.; Lawrence, C. R.; Le Jeune, M.; Leach, S.; Leahy, J. P.; Leonardi, R.; León-Tavares, J.; Leroy, C.; Lesgourgues, J.; Lewis, A.; Li, C.; Liddle, A.; Liguori, M.; Lilje, P. B.; Linden-Vørnle, M.; Lindholm, V.; López-Caniego, M.; Lowe, S.; Lubin, P. M.; Macías-Pérez, J. F.; MacTavish, C. J.; Maffei, B.; Maggio, G.; Maino, D.; Mandolesi, N.; Mangilli, A.; Marcos-Caballero, A.; Marinucci, D.; Maris, M.; Marleau, F.; Marshall, D. J.; Martin, P. G.; Martínez-González, E.; Masi, S.; Massardi, M.; Matarrese, S.; Matsumura, T.; Matthai, F.; Maurin, L.; Mazzotta, P.; McDonald, A.; McEwen, J. D.; McGehee, P.; Mei, S.; Meinhold, P. R.; Melchiorri, A.; Melin, J.-B.; Mendes, L.; Menegoni, E.; Mennella, A.; Migliaccio, M.; Mikkelsen, K.; Millea, M.; Miniscalco, R.; Mitra, S.; Miville-Deschênes, M.-A.; Molinari, D.; Moneti, A.; Montier, L.; Morgante, G.; Morisset, N.; Mortlock, D.; Moss, A.; Munshi, D.; Murphy, J. A.; Naselsky, P.; Nati, F.; Natoli, P.; Negrello, M.; Nesvadba, N. P. H.; Netterfield, C. B.; Nørgaard-Nielsen, H. U.; North, C.; Noviello, F.; Novikov, D.; Novikov, I.; O'Dwyer, I. J.; Orieux, F.; Osborne, S.; O'Sullivan, C.; Oxborrow, C. A.; Paci, F.; Pagano, L.; Pajot, F.; Paladini, R.; Pandolfi, S.; Paoletti, D.; Partridge, B.; Pasian, F.; Patanchon, G.; Paykari, P.; Pearson, D.; Pearson, T. J.; Peel, M.; Peiris, H. V.; Perdereau, O.; Perotto, L.; Perrotta, F.; Pettorino, V.; Piacentini, F.; Piat, M.; Pierpaoli, E.; Pietrobon, D.; Plaszczynski, S.; Platania, P.; Pogosyan, D.; Pointecouteau, E.; Polenta, G.; Ponthieu, N.; Popa, L.; Poutanen, T.; Pratt, G. W.; Prézeau, G.; Prunet, S.; Puget, J.-L.; Pullen, A. R.; Rachen, J. P.; Racine, B.; Rahlin, A.; Räth, C.; Reach, W. T.; Rebolo, R.; Reinecke, M.; Remazeilles, M.; Renault, C.; Renzi, A.; Riazuelo, A.; Ricciardi, S.; Riller, T.; Ringeval, C.; Ristorcelli, I.; Robbers, G.; Rocha, G.; Roman, M.; Rosset, C.; Rossetti, M.; Roudier, G.; Rowan-Robinson, M.; Rubiño-Martín, J. A.; Ruiz-Granados, B.; Rusholme, B.; Salerno, E.; Sandri, M.; Sanselme, L.; Santos, D.; Savelainen, M.; Savini, G.; Schaefer, B. M.; Schiavon, F.; Scott, D.; Seiffert, M. D.; Serra, P.; Shellard, E. P. S.; Smith, K.; Smoot, G. F.; Souradeep, T.; Spencer, L. D.; Starck, J.-L.; Stolyarov, V.; Stompor, R.; Sudiwala, R.; Sunyaev, R.; Sureau, F.; Sutter, P.; Sutton, D.; Suur-Uski, A.-S.; Sygnet, J.-F.; Tauber, J. A.; Tavagnacco, D.; Taylor, D.; Terenzi, L.; Texier, D.; Toffolatti, L.; Tomasi, M.; Torre, J.-P.; Tristram, M.; Tucci, M.; Tuovinen, J.; Türler, M.; Tuttlebee, M.; Umana, G.; Valenziano, L.; Valiviita, J.; Van Tent, B.; Varis, J.; Vibert, L.; Viel, M.; Vielva, P.; Villa, F.; Vittorio, N.; Wade, L. A.; Wandelt, B. D.; Watson, C.; Watson, R.; Wehus, I. K.; Welikala, N.; Weller, J.; White, M.; White, S. D. M.; Wilkinson, A.; Winkel, B.; Xia, J.-Q.; Yvon, D.; Zacchei, A.; Zibin, J. P.; Zonca, A.

    2014-11-01

    The European Space Agency's Planck satellite, dedicated to studying the early Universe and its subsequent evolution, was launched 14 May 2009 and has been scanning the microwave and submillimetre sky continuously since 12 August 2009. In March 2013, ESA and the Planck Collaboration released the initial cosmology products based on the first 15.5 months of Planck data, along with a set of scientific and technical papers and a web-based explanatory supplement. This paper gives an overview of the mission and its performance, the processing, analysis, and characteristics of the data, the scientific results, and the science data products and papers in the release. The science products include maps of the cosmic microwave background (CMB) and diffuse extragalactic foregrounds, a catalogue of compact Galactic and extragalactic sources, and a list of sources detected through the Sunyaev-Zeldovich effect. The likelihood code used to assess cosmological models against the Planck data and a lensing likelihood are described. Scientific results include robust support for the standard six-parameter ΛCDM model of cosmology and improved measurements of its parameters, including a highly significant deviation from scale invariance of the primordial power spectrum. The Planck values for these parameters and others derived from them are significantly different from those previously determined. Several large-scale anomalies in the temperature distribution of the CMB, first detected by WMAP, are confirmed with higher confidence. Planck sets new limits on the number and mass of neutrinos, and has measured gravitational lensing of CMB anisotropies at greater than 25σ. Planck finds no evidence for non-Gaussianity in the CMB. Planck's results agree well with results from the measurements of baryon acoustic oscillations. Planck finds a lower Hubble constant than found in some more local measures. Some tension is also present between the amplitude of matter fluctuations (σ8) derived from

  15. Result-Based Public Governance

    DEFF Research Database (Denmark)

    Boll, Karen

    the performance measure that guides the inspectors’ inspection (or nudging) of the businesses. The analysis shows that although a result-based governance system is advocated on a strategic level, performance measures which are not ‘result-based’ are developed and used in the daily coordination of work. The paper......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...

  16. Overview of recent ALICE results

    Directory of Open Access Journals (Sweden)

    Arnaldi Roberta

    2014-01-01

    Full Text Available ALICE is the LHC experiment devoted to the study of heavy-ion collisions. While results from Pb-Pb collisions at √sNN = 2.76 TeV provide insight on the properties of the plasma of quarks and gluons, formed in nucleus-nucleus interactions, the study of p-Pb collisions at √sNN = 5.02 TeV allows a deeper understanding of cold nuclear matter effects. Therefore, p-Pb results turn out to be a powerful tool to provide a baseline for Pb-Pb, to correctly quantify how the various observables are affected by genuine hot medium effects. In this proceeding, a selection of the most recent ALICE results on the medium global properties and on heavy-flavour and quarkonium production will be discussed.

  17. Recent Beijing Spectroscopy (BES) results

    Institute of Scientific and Technical Information of China (English)

    LI WeiGuo

    2008-01-01

    Recent experimental results from Beijing Spectroscopy (BES) are reviewed,in-cluding the hadron spectroscopy from J/ψdecays,and a number of new states are found or confirmed,including σ,κ;X(1835),ωψ threshold enhancement in J/ψ→γωψ,a broad resbnance in J/ψ→K+K-π0,decay studies of ψ(2S) and χCJ,as well as the results of ψ(3770) non-DD decays.The current status of BEPCⅡ/BESⅢ,the major upgrade of BEPC/BESⅡ,is also reported.

  18. Recent QCD Results from ATLAS

    CERN Document Server

    Sinervo, Pekka; The ATLAS collaboration

    2016-01-01

    The ATLAS collaboration has performed studies of a wide range of QCD phenomena, from soft particle to hard photon and jet production. Among recent results are the measurement of Z event shape observables sensitive to the modelling of the underlying event, and the measurement of diffractive dijet production with a large rapidity gap, which tests the interplay of soft and hard phenomena. The inelastic pp cross section, a fundamental property of the strong interaction, is measured. Precision measurements of the isolated high pT inclusive photon cross section at cms energies of 8TeV test the theoretical predictions and constrain parton density functions. An overview of these results is given.

  19. 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....... We show that moving from epistemic preconditions to propositional preconditions makes it decidable, more precisely in EXPSPACE. The plan existence problem is PSPACE-complete when the underlying graphs are trees and NP-complete when they are chains (including singletons). We also show PSPACE......-hardness of the plan verification problem, which strengthens previous results on the complexity of DEL model checking....

  20. 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

  1. 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.

  2. Brain Glucose Transporter (Glut3) Haploinsufficiency Does Not Impair Mouse Brain Glucose Uptake

    OpenAIRE

    Stuart, Charles A.; Ross, Ian R.; Howell, Mary E. A.; McCurry, Melanie P.; Wood, Thomas G.; Ceci, Jeffrey D.; Kennel, Stephen J.; Wall, Jonathan

    2011-01-01

    Mouse brain expresses three principle glucose transporters. Glut1 is an endothelial marker and is the principal glucose transporter of the blood-brain barrier. Glut3 and Glut6 are expressed in glial cells and neural cells. A mouse line with a null allele for Glut3 has been developed. The Glut3−/− genotype is intrauterine lethal by seven days post-coitis, but the heterozygous (Glut3+/−) littermate survives, exhibiting rapid post-natal weight gain, but no seizures or other behavioral aberration...

  3. Delineation of EFTUD2 haploinsufficiency-related phenotypes through a series of 36 patients.

    Science.gov (United States)

    Lehalle, Daphné; Gordon, Christopher T; Oufadem, Myriam; Goudefroye, Géraldine; Boutaud, Lucile; Alessandri, Jean-Luc; Baena, Neus; Baujat, Geneviève; Baumann, Clarisse; Boute-Benejean, Odile; Caumes, Roseline; Decaestecker, Charles; Gaillard, Dominique; Goldenberg, Alice; Gonzales, Marie; Holder-Espinasse, Muriel; Jacquemont, Marie-Line; Lacombe, Didier; Manouvrier-Hanu, Sylvie; Marlin, Sandrine; Mathieu-Dramard, Michèle; Morin, Gilles; Pasquier, Laurent; Petit, Florence; Rio, Marlène; Smigiel, Robert; Thauvin-Robinet, Christel; Vasiljevic, Alexandre; Verloes, Alain; Malan, Valérie; Munnich, Arnold; de Pontual, Loïc; Vekemans, Michel; Lyonnet, Stanislas; Attié-Bitach, Tania; Amiel, Jeanne

    2014-04-01

    Mandibulofacial dysostosis, Guion-Almeida type (MFDGA) is a recently delineated multiple congenital anomalies/mental retardation syndrome characterized by the association of mandibulofacial dysostosis (MFD) with external ear malformations, hearing loss, cleft palate, choanal atresia, microcephaly, intellectual disability, oesophageal atresia (OA), congenital heart defects (CHDs), and radial ray defects. MFDGA emerges as a clinically recognizable entity, long underdiagnosed due to highly variable presentations. The main differential diagnoses are CHARGE and Feingold syndromes, oculoauriculovertebral spectrum, and other MFDs. EFTUD2, located on 17q21.31, encodes a component of the major spliceosome and is disease causing in MFDGA, due to heterozygous loss-of-function (LoF) mutations. Here, we describe a series of 36 cases of MFDGA, including 24 previously unreported cases, and we review the literature in order to delineate the clinical spectrum ascribed to EFTUD2 LoF. MFD, external ear anomalies, and intellectual deficiency occur at a higher frequency than microcephaly. We characterize the evolution of the facial gestalt at different ages and describe novel renal and cerebral malformations. The most frequent extracranial malformation in this series is OA, followed by CHDs and skeletal abnormalities. MFDGA is probably more frequent than other syndromic MFDs such as Nager or Miller syndromes. Although the wide spectrum of malformations complicates diagnosis, characteristic facial features provide a useful handle.

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

    NARCIS (Netherlands)

    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-beta) 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 irradiatio

  5. Effect of Brain-Derived Neurotrophic Factor Haploinsufficiency on Stress-Induced Remodeling of Hippocampal Neurons

    OpenAIRE

    Magariños, A.M.; Li, C. J.; Toth, J. Gal; Bath, K.G.; Jing, D; Lee, F S; MCEWEN, B. S.

    2011-01-01

    Chronic restraint stress (CRS) induces the remodeling (i.e., retraction and simplification) of the apical dendrites of hippocampal CA3 pyramidal neurons in rats, suggesting that intrahippocampal connectivity can be affected by a prolonged stressful challenge. Since the structural maintenance of neuronal dendritic arborizations and synaptic connectivity requires neurotrophic support, we investigated the potential role of brain derived neurotrophic factor (BDNF), a neurotrophin enriched in the ...

  6. Haploinsufficiency for AAGAB causes clinically heterogeneous forms of punctate palmoplantar keratoderma

    Science.gov (United States)

    Pohler, Elizabeth; Mamai, Ons; Hirst, Jennifer; Zamiri, Mozheh; Horn, Helen; Nomura, Toshifumi; Irvine, Alan D.; Moran, Benvon E.; Wilson, Neil J.; Smith, Frances J. D.; Goh, Christabelle S. M; Sandilands, Aileen; Cole, Christian; Barton, Geoffrey J.; Evans, Alan T.; Shimizu, Hiroshi; Akiyama, Masashi; Suehiro, Akihiro; Konohana, Izumi; Shboul, Mohammad; Teissier, Sebastien; Boussofara, Lobna; Denguezli, Mohamed; Saad, Ali; Gribaa, Moez; Dopping-Hepenstal, Patricia J.; McGrath, John A; Brown, Sara J.; Goudie, David R.; Reversade, Bruno; Munro, Colin S.; McLean, W. H. Irwin

    2012-01-01

    Palmoplantar keratodermas (PPKs) are a group of disorders that are diagnostically and therapeutically problematic in dermatogenetics1-3. Punctate PPKs are characterized by circumscribed hyperkeratotic lesions on palms and soles with considerable heterogeneity. In 18 families with autosomal dominant punctate PPK (OMIM #148600), we report heterozygous loss-of-function mutations in AAGAB, encoding alpha- and gamma-adaptin binding protein p34, at a previously linked locus on 15q22. p34, a cytosolic protein with a Rab-like GTPase domain, was shown to bind both clathrin adaptor protein complexes, indicative of a role in membrane traffic. Ultrastucturally, lesional epidermis showed abnormalities in intracellular vesicle biology. Immunohistochemistry showed hyperproliferation within the punctate lesions. Knockdown of p34 in keratinocytes led to increased cell division, which was linked to greatly increased epidermal growth factor receptor (EGFR) protein expression and tyrosine phosphorylation. We hypothesize that p34 deficiency may impair endocytic recycling of growth factor receptors such as EGFR, leading to increased signaling and proliferation. PMID:23064416

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

    Science.gov (United States)

    2016-07-01

    protein of >90% purity in a single step (Figure 2). Since the TET2 demethylase contain cysteine-rich DNA binding domains and the structure and...different cytosine derivatives. For each parent ion nucleoside (Q1), the most intense product ion (Q3) was detected. o What opportunities for

  8. 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...... 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...

  9. Results-based management - Developing one's key results areas (KRAs).

    Science.gov (United States)

    Kansal, Om Prakash; Goel, Sonu

    2015-01-01

    In spite of aspiring to be a good manager, we public health experts fail to evaluate ourselves against our personal and professional goals. The Key Result Areas (KRAs) or key performance indicators (KPIs) help us in setting our operational (day-to-day) and/or strategic (long-term) goals followed by grading ourselves at different times of our careers. These shall help in assessing our strengths and weaknesses. The weakest KRA should set the maximum extent to which one should use his/her skills and abilities to have the greatest impact on his/her career.

  10. 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.

  11. Electroweak results from hadron colliders

    Energy Technology Data Exchange (ETDEWEB)

    Marcel Demarteau

    1999-09-02

    A very brief summary of recent electroweak results from hadron colliders is given. The emphasis is placed on inclusive W{sup {+-}} and Z{sup 0} production, the measurement of the mass of the W boson and the measurement of trilinear gauge boson couplings.

  12. B0s Oscillation Results

    CERN Document Server

    Willocq, S

    2002-01-01

    We review new studies of the time dependence of B0s - B0s-bar mixing by the ALEPH, DELPHI and SLD Collaborations, with an emphasis on the different analysis methods used. Combining all available results yields a preliminary lower limit on the oscillation frequency of dms > 14.4 ps-1 at the 95% C.L.

  13. Some results in Diophantine approximation

    DEFF Research Database (Denmark)

    in the formal Laurent series over F3. The first paper is on intrinsic Diophantine approximation in the Cantor set in the formal Laurent series over F3. The summary contains a short motivation, the results of the paper and sketches of the proofs, mainly focusing on the ideas involved. The details of the proofs...

  14. Recent results from KLOE experiment

    CERN Document Server

    Ambrosino, F; Antonelli, M; Archilli, F; Bacci, C; Beltrame, P; Bencivenni, G; Bertolucci, S; Bini, C; Bloise, C; Bocchetta, S; Bossi, F; Branchini, P; Caloi, R; Campana, P; Capon, G; Capussela, T; Ceradini, F; Cesario, F; Chi, S; Chiefari, G; Ciambrone, P; Crucianelli, F; De Lucia, E; De Santis, A; De Simone, P; De Zorzi, G; Denig, A; Di Domenico, A; Di Donato, C; Di Micco, B; Doria, A; Dreucci, M; Felici, G; Ferrari, A; Ferrer, M L; Fiore, S; Forti, C; Franzini, P; Gatti, C; Gauzzi, P; Giovannella, S; Gorini, E; Graziani, E; Kluge, W; Kulikov, V; Lacava, F; Lanfranchi, G; Lee-Franzini, J; Leone, D; Martini, M; Massarotti, P; Mei, W; Meola, S; Miscetti, S; Moulson, M; Müller, S; Murtas, F; Napolitano, M; Nguyen, F; Palutan, M; Pasqualucci, E; Passeri, A; Patera, V; Perfetto, F; Primavera, M; Santangelo, P; Saracino, G; Sciascia, B; Sciubba, A; Sibidanov, A; Spadaro, T; Testa, M; Tortora, L; Valente, P; Venanzoni, G; Versaci, R; Xu, G

    2008-01-01

    We report the newest results from the KLOE experiment on hadronic physics, such as the parameters of scalars f0 and a0, the eta meson mass measurements and dynamics, the first observation of the eta -> p+p-e+e- rare decay, and study of e+e- -> omega p0 cross section around the phi resonance.

  15. 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.

  16. FFTF startup: status and results

    Energy Technology Data Exchange (ETDEWEB)

    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.

  17. ATLAS H(125) difermion results

    CERN Document Server

    Shabalina, Elizaveta; The ATLAS collaboration

    2016-01-01

    We present a summary of the recent measurements of the Standard Model Higgs production in fermionic decay modes. New results are presented for the dimuon Higgs decays, for Higgs decaying in a $b\\bar{b}$ pair in the VH and ttH production modes and in the VBF channel with photon production.

  18. Superconductivity resulting from antiferromagnetic states

    Energy Technology Data Exchange (ETDEWEB)

    Feng Shi-Ping (Department of Physics, Beijing Normal University (CN))

    1989-09-01

    When the dopping is low enough, the holes obey Bose statistics, Bose-Einstein condensation of these holes may lead to occurance of superconductivity. In this framework, we have calculated some physical quantities, the results are in qualitative agreement with experiments.

  19. Results from the AMANDA telescope

    CERN Document Server

    Bouhali, O

    2003-01-01

    We present results from the AMANDA high energy neutrino telescope located at the South Pole. They include measurements of the atmospheric neutrino flux, search for UHE point sources, and diffuse sources producing electromagnetic/hadronic showers at the detector or close to it. (4 refs).

  20. First Physics Results from ALICE

    Energy Technology Data Exchange (ETDEWEB)

    Peressounko, Dmitri [Russian Research Centre - RRC ' Kurchatov Institute' , Kurchatov sq.1, Moscow, 123182 (Russian Federation); Castillo Castellanos, Javier [service de physique nucleaire - SPhN, IRFU, CEA-Saclay, 91191 Gif-sur-Yvette Cedex (France); Belikov, Iouri [Institut Pluridisciplinaire Hubert Curien - IPHC, 23 rue du loess - BP28, 67037 Strasbourg cedex 2 (France)

    2010-07-01

    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 {radical}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)

  1. Results from the NOMAD experiment

    CERN Document Server

    Lupi, A

    2000-01-01

    he NOMAD experiment has been searching for νμ ↔ ντ oscillations by looking for the appearance of τ− in events from the CERN-SPS neutrino beam. With some improvements in the analysis techniques with respect to the previous published results and including data from 1995 to 1997, no evidence for oscillations is found, resulting in an updated limit in the oscillation probability of P(νμ↔ντ) < 0.6 × 10−3 at 90% C.L. This corresponds to a limit on the oscillation mixing angle of sin22θμτ < 1.2 × 10−3 for large Δm2.

  2. Basic results on braid groups

    CERN Document Server

    Gonzalez-Meneses, Juan

    2010-01-01

    These are Lecture Notes of a course given by the author at the French-Spanish School "Tresses in Pau", held in Pau (France) in October 2009. It is basically an introduction to distinct approaches and techniques that can be used to show results in braid groups. Using these techniques we provide several proofs of well known results in braid groups, namely the correctness of Artin's presentation, that the braid group is torsion free, or that its center is generated by the full twist. We also recall some solutions of the word and conjugacy problems, and that roots of a braid are always conjugate. We also describe the centralizer of a given braid. Most proofs are classical ones, using modern terminology. I have chosen those which I find simpler or more beautiful.

  3. Overview of recent ATLAS results

    CERN Document Server

    Nikolic-Audit, Irena; The ATLAS collaboration

    2013-01-01

    The ATLAS experiment at the LHC collider has been successfully taking data since the end of 2009 in proton-proton collisions at center of mass energies of 7 and 8 TeV, and in heavy ion collisions. The ATLAS detector has been designed to cover a wide range of physics topics, from the search for the Higgs boson (which will be covered in a separate contribution), precision measurements of Standard Model physics, heavy flavor physics, and to maximize the potential for the discovery of new physics. In this talk, some of the most important recent ATLAS results will be given for the Standard Model measurements, the searches for supersymetry and exotica and for the heavy ion results.

  4. 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.

  5. 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.

    2015-01-01

    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...

  6. LHC Results Highlights (CLASHEP 2013)

    CERN Document Server

    Gonzalez, O

    2015-01-01

    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.

  7. Recent results from ATLAS experiment

    CERN Document Server

    Smirnov, Sergei; The ATLAS collaboration

    2016-01-01

    The 2nd LHC run has started in 2015 with a pp centre-of-mass collision energy of 13 TeV and ATLAS has taken more than 20 fb-1 of data at the new energy by 2016 summer. In this talk, an overview is given on the ATLAS data taking and the improvements made to the ATLAS experiment during the 2-year shutdown 2013/2014. Selected new results from the recent data analysis from ATLAS is also presented.

  8. Open cherry picker simulation results

    Science.gov (United States)

    Nathan, C. A.

    1982-01-01

    The simulation program associated with a key piece of support equipment to be used to service satellites directly from the Shuttle is assessed. The Open Cherry Picker (OCP) is a manned platform mounted at the end of the remote manipulator system (RMS) and is used to enhance extra vehicular activities (EVA). The results of simulations performed on the Grumman Large Amplitude Space Simulator (LASS) and at the JSC Water Immersion Facility are summarized.

  9. Results from the B Factories

    Energy Technology Data Exchange (ETDEWEB)

    Bevan, A.; /Queen Mary, U. of London

    2009-01-08

    These proceedings are based on lectures given at the Helmholtz International Summer School Heavy Quark Physics at the Bogoliubov Laboratory of Theoretical Physics, Dubna, Russia, during August 2008. I review the current status of CP violation in B meson decays from the B factories. These results can be used, along with measurements of the sides of the Unitarity Triangle, to test the CKM mechanism. In addition I discuss experimental studies of B decays to final states with 'spin-one' particles.

  10. Top physics results with ATLAS

    CERN Document Server

    Massa, Lorenzo; The ATLAS collaboration

    2015-01-01

    This paper contains some of the most recent results on top-quark physics obtained by the ATLAS collaboration from the analysis of $pp$ collisions at $\\sqrt{s}=7$ TeV and 8 TeV at the Large Hadron Collider. Measurement of total and differential top-quark pair ($t\\bar{t}$), single top and $t\\bar{t}+\\gamma$ production cross sections and some top properties like mass, charge asymmetry and spin correlation are presented.

  11. 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.

  12. SPQR -- Spectroscopy: Prospects, Questions & Results

    Energy Technology Data Exchange (ETDEWEB)

    Pennington, Michael R. [JLAB

    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 strong coupling QCD. They reveal how this works.

  13. Results of the BSE experiment

    Science.gov (United States)

    Iwasaki, K.; Yamamoto, M.; Kurakake, Y.; Kinoshita, S.

    Results of satellite broadcasting experiments carried out using the BSE (Japan's Medium-scale Broadcasting Satellite for Experimental Purpose) are described. Consideration is given to the following experiments: the reception of radio waves from the satellite, radio wave attenuation and scattering, the uplink power control experiment, experiments with transportable earth stations, the transmission of FM-TV signals, and frequency sharing between the broadcasting satellite and broadcasting services in the 12 GHz band.

  14. PHENIX Spin Program, Recent Results

    CERN Document Server

    Bazilevsky, A; Aidala, C; Ajitanand, N N; Akiba, Y; Alexander, J; Amirikas, R; Aphecetche, L; Aronson, S H; Averbeck, R; Awes, T C; Azmoun, R; Babintsev, V; Baldisseri, Alberto; Barish, K N; Barnes, P D; Bassalleck, B; Bathe, S; Batsouli, S; Baublis, V; Bazilevsky, A; Belikov, S; Berdnikov, Yu A; Bhagavatula, S; Boissevain, J G; Borel, H; Borenstein, S R; Brooks, M L; Brown, D S; Bruner, N; Bucher, D; Büsching, H; Bumazhnov, V; Bunce, G; Burward-Hoy, J M; Butsyk, S; Camard, X; Chai, J S; Chand, P; Chang, W C; Chernichenko, S; Chi, C Y; Chiba, J; Chiu, M; Choi, I J; Choi, J; Choudhury, R K; Chujo, T; Cianciolo, V; Cobigo, Y; Cole, B A; Constantin, P; D'Enterria, D G; Dávid, G; Delagrange, H; Denisov, A; Deshpande, Abhay A; Desmond, E J; Devismes, A; Dietzsch, O; Drapier, O; Drees, A; Drees, K A; Du Rietz, R; Durum, A; Dutta, D; Efremenko, Yu V; El-Chenawi, K F; Enokizono, A; Enyo, H; Esumi, S; Ewell, L A; Fields, D E; Fleuret, F; Fokin, S L; Fox, B D; Fraenkel, Zeev; Frantz, J E; Franz, A; Frawley, A D; Fung, S Y; Garpman, S; Ghosh, K; Glenn, A; Gogiberidze, G; Gonin, M; Gosset, J; Goto, Y; Granier de Cassagnac, R; Grau, N; Greene, S V; Grosse-Perdekamp, M; Guryn, W; Gustafsson, Hans Åke; Hachiya, T; Haggerty, J S; Hamagaki, H; Hansen, A G; Hartouni, E P; Harvey, M; Hayano, R; Hayashi, N; He, X; Heffner, M; Hemmick, T K; Heuser, J M; Hibino, M; Hill, J C; Holzmann, W; Homma, K; Hong, B; Hoover, A; Ichihara, T; Ikonnikov, V V; Imai, K; Isenhower, D; Ishihara, M; Issah, M; Isupov, A; Jacak, B V; Jang, W Y; Jeong, Y; Jia, J; Jinnouchi, O; Johnson, B M; Johnson, S C; Joo, K S; Jouan, D; Kametani, S; Kamihara, N; Kang, J H; Kapoor, S S; Katou, K; Kelly, S; Khachaturov, B; Khanzadeev, A; Kikuchi, J; Kim, D H; Kim, D J; Kim, D W; Kim, E; Kim, G B; Kim, H J; Kistenev, E P; Kiyomichi, A; Kiyoyama, K; Klein-Bösing, C; Kobayashi, H; Kochenda, L; Kochetkov, V; Koehler, D; Kohama, T; Kopytine, M; Kotchetkov, D; Kozlov, A; Kroon, P J; Kuberg, C H; Kurita, K; Kuroki, Y; Kweon, M J; Kwon, Y; Kyle, G S; Lacey, R; Ladygin, V P; Lajoie, J G; Lebedev, A; Leckey, S; Lee, D M; Lee, S; Leitch, M J; Li, X H; Lim, H; Litvinenko, A G; Liu, M X; Liu, Y; Maguire, C F; Makdisi, Y I; Malakhov, A; Man'ko, V I; Mao, Y; Martínez, G; Marx, M D; Masui, H; Matathias, F; Matsumoto, T; McGaughey, P L; Melnikov, E A; Messer, F; Miake, Y; Milan, J; Miller, T E; Milov, A; Mioduszewski, S; Mischke, R E; Mishra, G C; Mitchell, J T; Mohanty, A K; Morrison, D P; Moss, J M; Muhlbacher, F; Mukhopadhyay, D; Muniruzzaman, M; Murata, J; Nagamiya, S; Nagle, J L; Nakamura, T; Nandi, B K; Nara, M; Newby, J; Nilsson, P; Nyanin, A S; Nystrand, J; O'Brien, E; Ogilvie, C A; Ohnishi, H; Ojha, I D; Okada, K; Ono, M; Onuchin, V A; Oskarsson, A; Otterlund, I; Oyama, K; Ozawa, K; Pal, D; Palounek, A P T; Pantuev, V S; Papavassiliou, V; Park, J; Parmar, A; Pate, S F; Peitzmann, T; Peng, J C; Peresedov, V; Pinkenburg, C; Pisani, R P; Plasil, F; Purschke, M L; Purwar, A K; Rak, J; Ravinovich, I; Read, K F; Reuter, M; Reygers, K; Riabov, V; Riabov, Y; Roche, G; Romana, A; Rosati, M; Rosnet, P; Ryu, S S; Sadler, M E; Saitô, N; Sakaguchi, T; Sakai, M; Sakai, S; Samsonov, V; Sanfratello, L; Santo, R; Sato, H D; Sato, S; Sawada, S; Schutz, Y; Semenov, V; Seto, R; Shaw, M R; Shea, T K; Shibata, T A; Shigaki, K; Shiina, T; Silva, C L; Silvermyr, D; Sim, K S; Singh, C P; Singh, V; Sivertz, M; Soldatov, A; Soltz, R A; Sondheim, W E; Sørensen, S P; Sourikova, I V; Staley, F; Stankus, P W; Stenlund, E; Stepanov, M; Ster, A; Stoll, S P; Sugitate, T; Sullivan, J P; Takagui, E M; Taketani, A; Tamai, M; Tanaka, K H; Tanaka, Y; Tanida, K; Tannenbaum, M J; Tarjan, P; Tepe, J D; Thomas, T L; Tojo, J; Torie, H A; Towell, R S; Tserruya, Itzhak; Tsuruoka, H; Tuli, S K; Tydesjo, H; Tyurin, N; van Hecke, H W; Velkovska, J; Velkovsky, M; Veszpremi, V; Villatte, L; Vinogradov, A A; Volkov, M A; Vznuzdaev, E A; Wang, X R; Watanabe, Y; White, S N; Wohn, F K; Woody, C L; Xie, W; Yang, Y; Yanovich, A A; Yokkaichi, S; Young, G R; Yushmanov, I E; Zajc, W A; Zhang, C; Zhou, S; Zhou, S J; Zolin, L S; Adler, S S; Bazilevsky, Alexander

    2005-01-01

    Acceleration of polarized protons in Relativistic Heavy Ion Collider (RHIC) provides unique tool to study the spin structure of the nucleon. We give a brief overview of the PHENIX program to investigate poorly known gluon and flavor decomposed see quark polarization in the proton, utilizing polarized proton collisions at RHIC. We report PHENIX first results on transverse single-spin asymmetry in pi0 and charged hadron production and longitudinal double-spin asymmetry in pi0 production at mid-rapidity.

  15. Digital coincidence counting - initial results

    Science.gov (United States)

    Butcher, K. S. A.; Watt, G. C.; Alexiev, D.; van der Gaast, H.; Davies, J.; Mo, Li; Wyllie, H. A.; Keightley, J. D.; Smith, D.; Woods, M. J.

    2000-08-01

    Digital Coincidence Counting (DCC) is a new technique in radiation metrology, based on the older method of analogue coincidence counting. It has been developed by the Australian Nuclear Science and Technology Organisation (ANSTO), in collaboration with the National Physical Laboratory (NPL) of the United Kingdom, as a faster more reliable means of determining the activity of ionising radiation samples. The technique employs a dual channel analogue-to-digital converter acquisition system for collecting pulse information from a 4π beta detector and an NaI(Tl) gamma detector. The digitised pulse information is stored on a high-speed hard disk and timing information for both channels is also stored. The data may subsequently be recalled and analysed using software-based algorithms. In this letter we describe some recent results obtained with the new acquistion hardware being tested at ANSTO. The system is fully operational and is now in routine use. Results for 60Co and 22Na radiation activity calibrations are presented, initial results with 153Sm are also briefly mentioned.

  16. 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.

  17. ISO: highlights of recent results

    Science.gov (United States)

    Metcalfe, L.; Salama, A.

    ESA's Infrared Space Observatory (ISO) mission, operating in the wavelength range from 2.5 to 240 microns, made over 26000 scientific observations during its 2.5 year operational lifetime. ISO's results broke new ground on all scales. New asteroid counts and improved asteroid thermophysical models augmented important advances in Solar System chemistry to comprise a striking body of results addressing our planetary system. In turn, parallels between the chemical composition of Solar System dust and dust around other stars revealed by the comparison of stellar spectra with cometary spectra, together with results on the incidence and stability of stellar disks, recall the birth of our Solar System and point to fundamental similarities with other star systems. Numerous important facts concerning the chemistry of the ISM have unfolded, such as the ubiquity of water and of the probably-organic carriers of the Unidentified Infrared Bands (UIBs). The large systematic body of data on galactic stars has permitted fascinating advances in the characterisation of important aspects of stellar evolution. Investigations of nearby normal galaxies complement template specimens of interacting galaxies. These in turn exemplify galaxy evolutionary processes in the early Universe associated with a huge burst of dust-obscured star formation at redshifts of just below one. This global surge of star formation has vital implications for the interpretation and explanation of major components of the Extragalactic Background Light (EBL) and for charting the global history of star formation and the relative importance of sources which derive their energy from accretion processes. Representative examples of key aspects of ISO's recent scientific output will be presented, once again affirming ISO's place at the forefront of successful space-borne astronomy missions.

  18. 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.

  19. Treasury, the Resultant Flow Business

    Directory of Open Access Journals (Sweden)

    Luciana Spineanu-Georgescu

    2010-12-01

    Full Text Available Treasury expresses the result of all activities of the enterprise and how to comply with the requirements of financial balance. All operations which the undertaking is found out immediately and forward the form of cash flow. The enterprise is a system which, in turn, is characterized by economic, social and financial structure. Inside and outside the company are born a lot of flows, a point mentioned in the previous chapter, from which the money have a role and an important place.

  20. 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.

  1. 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.

  2. Results from IceCube

    Directory of Open Access Journals (Sweden)

    DeYoung Tyce

    2016-01-01

    Full Text Available Data from the IceCube Neutrino Observatory have revealed the existence of a flux of high energy neutrinos of extraterrestrial origin, which is observed in a number of analyses spanning different energy ranges, fields of view, and neutrino flavors. The current data are consistent with an isotropic, equal-flavor flux described by a simple power law spectrum, but deviations from this simple model cannot yet be constrained with high precision. The existing observations in this area are reviewed, along with recent results on dark matter searches and observations of cosmic rays.

  3. 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.

  4. ATLAS Run II Exotics Results

    CERN Document Server

    ATLAS Collaboration; The ATLAS collaboration

    2016-01-01

    While Standard Model is in a good shape especially after Higgs boson discovery, there are a lot of questions beyond SM. The ATLAS detector is performing about 50 Exotics searches addressed these questions. This talk is discussing some of them with datasets collected during the 2015-2016 LHC run from 3 fb^-1 to 18 fb^-1 of proton-proton collisions at 13 TeV centre of mass energy . Results on searches for resonances decaying into vector boson or fermions, for vector like quarks, for dark matter, and for other new phenomena using these data will be presented.

  5. Overview of recent ALICE results

    Science.gov (United States)

    Gunji, Taku

    2016-12-01

    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 pT hadrons, electromagnetic probes, small system physics, and the upgrade program. This paper highlights some of the selected results.

  6. Heel pain--operative results.

    Science.gov (United States)

    Baxter, D E; Thigpen, C M

    1984-01-01

    In 6 years through 1982, the authors performed 34 operative cases in 26 patients with recalcitrant heel pain. The operative procedure involves an isolated neurolysis of the mixed nerve supplying the abductor digiti quinti muscle as it passes beneath the abductor hallucis muscle and beneath the medial ridge of the calcaneus. The deep fascia of the abductor hallucis muscle is released routinely, and an impinging heel spur or tight plantar fascia is partially removed or released if it is causing entrapment of the nerve. The biomechanical pathogenesis of heel pain in relation to pes planus and pes cavus predisposing to an entrapment neuropathy is described, and the anatomy of the heel in relation to the nerve distribution is clarified and well illustrated. Of the 34 operated heels, 32 had good results and two had poor results. Heel pain can cause total disability in the working population and may jeopardize one's employment or professional athletic career. The authors believe operative treatment has a place in the care of recalcitrant heel pain and that an entrapment neuropathy is an etiological factor in heel pain.

  7. Toxocariasis Resulting in Seeming Allergy

    Directory of Open Access Journals (Sweden)

    Rosanna Qualizza

    2009-09-01

    Full Text Available Toxocara canis is an intestinal nematode affecting dogs and cats that causes human infestations by ingestion of embryonated eggs excreted in dogs' faeces. Humans are transport hosts, in whom the larvae do not develop to adult worms, but may migrate to various tissues and organs, and survive for several years, giving rise to several clinical symptoms, which include allergy-like presentations. We report three cases presenting as dermatitis, rhinitis, asthma, and conjunctivitis which were diagnosed and unsuccessfully treated as allergy. The correct diagnosis was established after detecting anti-Toxocara antibodies by Western blotting. All clinical symptoms showed improvement after starting treatment with mebendazole and subsequent courses of the antiparasitic drug resulted in full recovery. This suggests the possible role of Toxocara canis in inducing chronic symptoms of allergic type. This is particularly important for asthma, where it has been demonstrated that Toxocara canis infection causes allergic inflammation in the lungs associated with bronchial hyperreactivity. On the other hand, in our patients with asthma and with dermatitis the positive results from allergy tests were a confounding factor in delaying the correct diagnosis, which was finally obtained by the detection of antibodies to Toxocara canis.

  8. 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.

  9. 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.

  10. Indication and results of xeromammography

    Energy Technology Data Exchange (ETDEWEB)

    Willgeroth, F.

    1982-12-01

    The prognosis of breast cancer depends decisively on the time of the diagnosis. So far, survival rates could not be significantly improved. One can expect the best results from an earlier diagnosis. Above all film and Xero-mammography and enforced self examination can contribute to discover carcinoma in an earlier stage. The number of cancer cases that can be discovered this way is low. Film-mammography is preferred in Germany, Xero-mammography in the USA. Both techniques are equal with respect to their diagnostic power, if they are used under optimal technical conditions. The dose load in Xero-mammography is lower compared with mammography with foil-less materal test films. Low-dose film mammographies with and without screen are techniques with an even lower exposure. They do not appear mature in a technological sense. It is not clear whether the high filtration Xero-mammography with negative development technique can yield the same diagnostic results with a radiation exposure of the same order because larger comparative tests are still lacking.

  11. Recent Results from Telescope Array

    CERN Document Server

    Fukushima, M

    2015-01-01

    The Telescope Array (TA) is an experiment to observe Ultra-High Energy Cosmic Rays (UHECRs). TA's recent results, the energy spectrum and anisotropy based on the 6-year surface array data, and the primary composition obtained from the shower maximum Xmax are reported. The spectrum demonstrates a clear dip and cutoff. The shape of the spectrum is well described by the energy loss of extra-galactic protons interacting with the cosmic microwave background (CMB). Above the cutoff, a medium-scale (20 degrees radius) flux enhancement was observed near the Ursa-Major. A chance probability of creating this hotspot from the isotropic flux is 4.0 sigma. The measured Xmax is consistent with the primary being proton or light nuclei for energies 10^18.2 eV - 10^19.2 eV.

  12. CMS results on exclusive production

    CERN Document Server

    Khakzad, Mohsen

    2016-01-01

    A search for exclusive or quasi-exclusive $\\gamma\\gamma \\rightarrow W^{+}W^{-}$ production, ${\\rm pp} \\rightarrow {\\rm p}^{(*)} W^{+}W^{-} {\\rm p}^{(*)} \\rightarrow {\\rm p}^{(*)} \\mu^{\\pm} {\\rm e}^{\\mp} {\\rm p}^{(*)}$, at $\\sqrt{s}$ = 8 TeV (7 TeV) are reported using data corresponding to an integrated luminosity of 19.7 $\\rm {fb}^{-1}$ (5.5$\\rm {fb}^{-1}$), respectively. In this study, we look for any deviations that there might be from the Standard Model, and the results are used to set limits on the Anomalous Quartic Gauge Couplings. We also report a measurement of the exclusive production of pairs of charged pions in proton-proton collisions. The differential cross sections for $\\pi^{+}\\pi^{-}$ pairs as a function of the pion pair invariant mass is measured and compared to several phenomenological predictions.

  13. 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.

  14. First results on fast baking

    Science.gov (United States)

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

    2006-07-01

    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 120 °C. With such treatment, the intrinsic quality factor Q0 is improved at high fields. Assuming the oxygen diffusion is involved in this phenomenon, we have developed the “fast baking” (145 °C/3 h) 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.

  15. Airfreight forecasting methodology and results

    Science.gov (United States)

    1978-01-01

    A series of econometric behavioral equations was developed to explain and forecast the evolution of airfreight traffic demand for the total U.S. domestic airfreight system, the total U.S. international airfreight system, and the total scheduled international cargo traffic carried by the top 44 foreign airlines. The basic explanatory variables used in these macromodels were the real gross national products of the countries involved and a measure of relative transportation costs. The results of the econometric analysis reveal that the models explain more than 99 percent of the historical evolution of freight traffic. The long term traffic forecasts generated with these models are based on scenarios of the likely economic outlook in the United States and 31 major foreign countries.

  16. Initial Blackbeard power survey results

    Energy Technology Data Exchange (ETDEWEB)

    Murphy, T.; Devenport, J.; Holden, D.

    1996-06-01

    The Blackbeard broadband VHF radio receiver is in low-earth orbit aboard the ALEXIS satellite. The receiver has been used to measure the transmitted power in four VHF bands (55.2-75.8, 28.0-94.8, 132.3-152.2, and 107.7-166.0 MHz) over quiet and noisy parts of the earth. The authors present the results of the survey and discuss their implications. They find that there are remote ocean areas over which the observed spectrum is largely free of man-made interference, but that the spectrum over most of the earth is dominated by broadcast VHF signals. The signal characteristics observed over a given area are quite constant when observed at different times of day and at intervals of several weeks to months. It appears that in many cases the bulk of the signal power is coming from a small number of sources.

  17. 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.

  18. 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.

  19. 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)

  20. 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.

  1. 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)

  2. TFTR D-T results

    Energy Technology Data Exchange (ETDEWEB)

    Meade, D.M.

    1995-03-01

    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 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 {approximately} 20 MW of tritium and 14 MW of deuterium neutral beams into the TFTR produced a plasma with a T/D density ratio of {approximately} 1 and yielded a maximum fusion power of {approximately} 9.2 MW. The fusion power density in the core of the plasma was {approximately} 1.8 MW m{sup {minus}3} approximating that expected in a D-T fusion reactor. A TFTR plasma with T/D density ratio of {approximately} 1 was found to have {approximately} 20% higher energy confinement time than a comparable D plasma, indicating a confinement scaling with average ion mass, A, of {tau}{sub E} {approximately} A{sup 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 {approx} 5% loss of alpha particles 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.

  3. RESULTS OF SUPPLEMENTAL MST STUDIES

    Energy Technology Data Exchange (ETDEWEB)

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

    2006-07-24

    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

  4. 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...

  5. Unfavourable results in craniofacial surgery

    Directory of Open Access Journals (Sweden)

    Ramesh Kumar Sharma

    2013-01-01

    Full Text Available Craniofacial surgery is one of the newer subspecialties of plastic surgery and owes its birth to the pioneering work of Paul Tessier in the late sixties. Since then this challenging specialty work has been taken up by many centres around the word including India. Initial reports in late eighties and early nineties showed morbidity and mortality ranging from 1.6% to 4.3%. However over past few decades, with improved instrumentations, safer anaesthesia and cumulative experience of surgeons the morbidity and mortality has been brought down to as low as 0.1% in many centres in USA. In our centre at Post-graduate Institute, Chandigarh, the mortality rate is about 0.8% (4 out of 480 cases. The learning curve in this surgery is rather steep but with experience and a well-coordinated team work, results in this complex subspecialty can be improved. The infection is a major cause for worry but can be easily prevented by sound surgical principles and placing a vascularised tissue barrier between the extradural space and the nasopharynx/sinus mucosa.

  6. 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).

  7. Preliminary results of ANAIS-25

    CERN Document Server

    Amaré, J; Cuesta, C; García, E; Ginestra, C; Martínez, M; Oliván, M A; Ortigoza, Y; de Solórzano, A Ortiz; Pobes, C; Puimedón, J; Sarsa, M L; Villar, P; Villar, J A

    2013-01-01

    The ANAIS (Annual Modulation with NaI(Tl) Scintillators) experiment aims at the confirmation of the DAMA/LIBRA signal using the same target and technique at the Canfranc Underground Laboratory. 250 kg of ultrapure NaI(Tl) crystals will be used as a target, divided into 20 modules, each coupled to two photomultipliers. Two NaI(Tl) crystals of 12.5 kg each, grown by Alpha Spectra from a powder having a potassium level under the limit of our analytical techniques, form the ANAIS-25 set-up. The background contributions are being carefully studied and preliminary results are presented: their natural potassium content in the bulk has been quantified, as well as the uranium and thorium radioactive chains presence in the bulk through the discrimination of the corresponding alpha events by PSA, and due to the fast commissioning, the contribution from cosmogenic activated isotopes is clearly identified and their decay observed along the first months of data taking. Following the procedures established with ANAIS-0 and ...

  8. 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.

  9. 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...

  10. J-PARC Commissioning Results

    CERN Document Server

    Hasegawa, Kazuo

    2005-01-01

    The J-PARC (Japan Proton Accelerator Research Complex)comprises a 400-MeV linac, a 3-GeV rapid-cycling synchrotron (RCS), a 50-GeV main ring synchrotron (MR) and experimental facilities. A peak current of 30 mA was accelerated up to 20 MeV of the DTL beam commissioning at the KEK site. The buildings and conventional facilities will be completed in succession in the Japanese Fiscal Year 2005, when the installation of the accelerator components will be actually started at Tokai site. The beam commissioning of the 181 MeV linac will be started in September, 2006, followed by the RCS and MR beam commissioning. To achieve the high beam power with low beam loss, the J-PARC accelerators are based on many newly developed technologies; pi-mode stabilizing loops in the RFQ, RF choppers in the medium energy beam transport, magnetic alloy loaded RF cavities in the synchrotrons, etc. The recent results of the developments of these new technologies, the present construction status and the commissioning schedule will be pre...

  11. EUPORIAS: plans and preliminary results

    Science.gov (United States)

    Buontempo, C.

    2013-12-01

    Recent advances in our understanding and ability to forecast climate variability have meant that skilful predictions are beginning to be routinely made on seasonal to decadal (s2d) timescales. Such forecasts have the potential to be of great value to a wide range of decision-making, where outcomes are strongly influenced by variations in the climate. In 2012 the European Commission funded EUPORIAS, a four year long project to develop prototype end-to-end climate impact prediction services operating on a seasonal to decadal timescale, and assess their value in informing decision-making. EUPORIAS commenced on 1 November 2012, coordinated by the UK Met Office leading a consortium of 24 organisations representing world-class European climate research and climate service centres, expertise in impacts assessments and seasonal predictions, two United Nations agencies, specialists in new media, and commercial companies in climate-vulnerable sectors such as energy, water and tourism. The poster describes the setup of the project, its main outcome and some of the very preliminary results.

  12. Recent QCD results from ATLAS

    CERN Document Server

    Pleskot, Vojtech; The ATLAS collaboration

    2016-01-01

    ATLAS has has performed several measurements of phenomena connected to QCD at soft scales or at the transition to the hard regime. These include the measurements at different centre-of-mass energies in Run-1 and Run-2 of the elastic, inelastic and total cross sections in pp collisions, the properties of minimum bias and the underlying event interactions, particle production and their correlations, as well as of diffractive and exclusive events. These results are sensitive to non-perturbative models of soft QCD. Jet and photon production cross sections have been measured differentially for inclusive and multi-object final states at 7, 8 and 13 TeV pp collisions with the ATLAS detector and are compared to expectations based on next-to-leading order QCD calculations as well as Monte Carlo simulations. Further studies of jet production properties include the measurements of jet properties, and the determination of the strong coupling constant alpha_s. These measurements provide direct probes of short-distance phy...

  13. Protein expression studies of desmoplakin mutations in cardiomyopathy patients reveal different molecular disease mechanisms

    DEFF Research Database (Denmark)

    Rasmussen, T B; Hansen, Jakob; Nissen, P H;

    2013-01-01

    identified and included haploinsufficiency, dominant-negative effects, or a combination hereof. Furthermore, the results suggest that the keratinocytes cultured from patients are a valuable and easily accessible resource to elucidate the effects of desmosomal gene mutations in humans....

  14. 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.

  15. 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.

  16. NCV Flow Diagnostic Test Results

    Science.gov (United States)

    Cappuccio, Mina

    1999-01-01

    There were two objectives for this test. First, was to assess the reasons why there is approximately 1.5 drag counts (cts) discrepancy between measured and computed drag improvement of the Non-linear Cruise Validation (NCV) over the Technology Concept Airplane (TCA) wing body (WB) configurations. The Navier-Stokes (N-S) pre-test predictions from Boeing Commercial Airplane Group (BCAG) show 4.5 drag cts of improvement for NCV over TCA at a lift coefficient (CL) of 0. I at Mach 2.4. The pre-test predictions from Boeing Phantom Works - Long Beach, BPW-LB, show 3.75 drag cts of improvement. BCAG used OVERFLOW and BPW-LB used CFL3D. The first test entry to validate the improvement was held at the NASA Langley Research Center (LARC) UPV;T, test number 1687. The experimental results showed that the drag improvement was only 2.6 cts, not accounting for laminar run and trip drag. This is approximately 1.5 cts less than predicted computationally. In addition to the low Reynolds Number (RN) test, there was a high RN test in the Boeing Supersonic Wind Tunnel (BSWT) of NCV and TCA. BSV@T test 647 showed that the drag improvement of NCV over TCA was also 2.6 cts, but this did account for laminar run and trip drag. Every effort needed to be done to assess if the improvement measured in LaRC UPWT and BSWT was correct. The second objective, once the first objective was met, was to assess the performance increment of NCV over TCA accounting for the associated laminar run and trip drag corrections in LaRC UPWT. We know that the configurations tested have laminar flow on portions of the wing and have trip drag due to the mechanisms used to force the flow to go from laminar to turbulent aft of the transition location.

  17. 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.

  18. 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

  19. Results of nonendoscopic endonasal dacryocystorhinostomy

    Directory of Open Access Journals (Sweden)

    Preechawai P

    2012-08-01

    Full Text Available Passorn PreechawaiDepartment of Ophthalmology, Faculty of Medicine, Prince of Songkla University, Hat Yai, Songkhla, ThailandBackground: Surgical scarring on the face and disrupted anatomy in the medial canthal area following external dacryocystorhinostomy (DCR can be avoided by an endonasal approach. This study examined the outcome of direct visualization endonasal DCR, performed by young surgeons and residents.Methods: A retrospective case series of 75 consecutive endonasal DCRs performed under direct visualization from July 2002 to July 2004 were reviewed. Surgery was performed by surgeons and residents who had received no special training in the procedure. Full success was defined as no symptoms of tearing after surgery and anatomical patency with fluorescein flow on nasal endoscopy or patency to lacrimal syringing. Partial success was defined as a tearing decrease compared with prior to surgery and with anatomical patency, and failure was defined as no significant improvement in persistent tearing. The average follow-up duration was 26.83 ± 16.26 (range 6–55 months.Results: Seventy-five DCRs were performed on 63 patients (four male, 59 female of mean age 49.44 ± 16.63 (range 21–85 years. The surgery was successful in 54/75 eyes (72%, 37/54 eyes (68.5%, and 30/42 eyes (71.4% at 6, 12, and 24 months, respectively. Partial success was achieved in 13/75 (17.3%, 9/54 (16.7%, and 9/42 (21.4%, and the failure rates were 10.7%, 14.8%, and 7.1% at 6, 12, and 24 months, respectively. The overall functional success with this technique was 74.7% and the overall anatomical patency was 92.0%. There were no serious complications arising from the surgery; three minor complications were documented, ie, an incorrectly placed silicone tube in the lower canaliculus, tube prolapse, and postoperative bleeding which needed nasal packing and eventually a developed retention cyst in the nasal cavity.Conclusion: Endonasal DCR under direct visualization is a

  20. Recent Opportunity Microscopic Imager Results

    Science.gov (United States)

    Herkenhoff, K. E.; Arvidson, R. E.; Jolliff, B. L.; Yingst, R.; Team, A.

    2013-12-01

    Opportunity. The extremely soft bedrock exposed at a Whitewater Lake outcrop target dubbed 'Azilda' is mostly fine-grained, with dispersed 2-5 mm-diameter spherules and resistant veins. This target was easily abraded by the RAT, exposing a sandstone-like texture, but the sorting of grains is difficult to determine at MI resolution. Darker, erosion-resistant veneers, similar to desert varnishes on Earth, appear to record aqueous alteration that post-dates the formation of the Ca sulfate veins; they likely contain the nontronite that is observed by CRISM in this area. The inferred neutral pH and relatively low temperature of the fluids involved in these phases of alteration would have provided a habitable environment for life if it existed on Mars at that time. Because Opportunity can no longer directly sense phyllosilicate mineralogy with the MiniTES or Mössbauer spectrometers, it is focusing on characterizing the chemistry with the APXS and texture with the MI of potential phyllosilicate host rocks. The Athena MI continues to return useful images of Mars that are being used to study the textures of rocks and soils at Endeavour crater. Exploration by Opportunity continues, with the rover approaching 'Solander Point' and more exposures of phyllosilicates detected from orbit; the latest MI results will be presented at the conference.

  1. A preliminary study on the radiation-resistance mechanism in ovarian cancer

    Directory of Open Access Journals (Sweden)

    Qi Liao

    2013-01-01

    Full Text Available Aim: The present study was designed to explore the radiation-resistance mechanism by interfering in checkpoints kinase 1 (CHK1 and DNA-activated protein kinase (DNA-PK genes with short hairpin RNA (shRNA transfection into Skov3 cells derived from ovarian cancer and HeLa cells derived from cervical cancer. Materials and Methods: The cultured Skov3 and HeLa cells were transfected with plasmid vectors containing CHK1 shRNA and DNA-PK shRNA, respectively, through Lipofectimine™ 2000 mediation, and cultured for 20 hours before exposure to 2 Gy X-radiation. The cells were harvested 4 and 28 after X-irradiation respectively then washed 3 times with PBS. These cells were stained with Annexin V/PI and applied by flow cytometer to analyze alteration of apoptosis with software CellQuest. Results: The apoptotic response in Skov3 cells to X-radiation was significantly lower than that in HeLa cells at 4 hour (t = 15.22, P < 0.001 and 28 hours (t = 15.78, P < 0.001 of post-irradiation. The shRNA might not affect the apoptosis of Skov3 and HeLa cells, while shRNA-transfection significantly enhanced the apoptotic response in Skov3 cells to X-radiation as compared with that in HeLa cells. Conclusions: The present work suggests that the CHK1 and DNA-PK genes are very likely to play a role in developing a radiation resistance in ovarian cancer.

  2. Atrazine Triggers DNA Damage Response and Induces DNA Double-Strand Breaks in MCF-10A Cells

    Directory of Open Access Journals (Sweden)

    Peixin Huang

    2015-06-01

    Full Text Available Atrazine, a pre-emergent herbicide in the chloro-s-triazine family, has been widely used in crop lands and often detected in agriculture watersheds, which is considered as a potential threat to human health. Although atrazine and its metabolites showed an elevated incidence of mammary tumors in female Sprague–Dawley (SD rats, no molecular evidence was found relevant to its carcinogenesis in humans. This study aims to determine whether atrazine could induce the expression of DNA damage response-related proteins in normal human breast epithelial cells (MCF-10A and to examine the cytotoxicity of atrazine at a molecular level. Our results indicate that a short-term exposure of MCF-10A to an environmentally-detectable concentration of atrazine (0.1 µg/mL significantly increased the expression of tumor necrosis factor receptor-1 (TNFR1 and phosphorylated Rad17 in the cells. Atrazine treatment increased H2AX phosphorylation (γH2AX and the formation of γH2AX foci in the nuclei of MCF-10A cells. Atrazine also sequentially elevated DNA damage checkpoint proteins of ATM- and RAD3-related (ATR, ATRIP and phospho-Chk1, suggesting that atrazine could induce DNA double-strand breaks and trigger the DNA damage response ATR-Chk1 pathway in MCF-10A cells. Further investigations are needed to determine whether atrazine-triggered DNA double-strand breaks and DNA damage response ATR-Chk1 pathway occur in vivo.

  3. 16 CFR 1610.8 - Reporting results.

    Science.gov (United States)

    2010-01-01

    ... FLAMMABILITY OF CLOTHING TEXTILES The Standard § 1610.8 Reporting results. (a) The reported result shall be the classification before or after refurbishing, whichever is the more severe; and based on this result, the textile... results for each specimen that is burned. (1) For Plain Surface Textile Fabrics: DNIDid not...

  4. Results of Evolution Supervised by Genetic Algorithms

    CERN Document Server

    Jäntschi, Lorentz; Bălan, Mugur C; Sestraş, Radu E

    2010-01-01

    A series of results of evolution supervised by genetic algorithms with interest to agricultural and horticultural fields are reviewed. New obtained original results from the use of genetic algorithms on structure-activity relationships are reported.

  5. NEW RESULTS ON ESTIMATES FOR SINGULAR VALUES

    Institute of Scientific and Technical Information of China (English)

    2000-01-01

    New results are provided to estimate matrix singular values in terms of partial absolute deleted row sums and column sums. Illustrative examples are presented to show comparisons with results in literature.

  6. Some Oscillation Results for Linear Hamiltonian Systems

    Directory of Open Access Journals (Sweden)

    Nan Wang

    2012-01-01

    oscillation criteria are established for the system. These criteria extend and improve some results that have been required before. An interesting example is included to illustrate the importance of our results.

  7. Presidential General Election Results - 2012 - Direct Download

    Data.gov (United States)

    U.S. Geological Survey, Department of the Interior — This map layer portrays Presidential general election results for 2012, with results reported by county or county equivalent, for the 50 United States and the...

  8. A Brief Syntactic Research on Resultative Construction

    Institute of Scientific and Technical Information of China (English)

    邱林林

    2008-01-01

    <正>This article will deal with Resultative Construction syntactically.First of all,the Unaccusative Hypothesis will be introduced,and the ideas of different scholars(mainly Levin and Rappaport) towards the question--whether the resultative construction can serve as diagnostic test to tell unergative verbs and unaccusative verbs apart--will be presented.The second focus of the article is about the differences that tell resultative constructions apart from depicitive construction and secondary predication construction.

  9. Setting Priorities Personal Values, Organizational Results

    CERN Document Server

    (CCL), Center for Creative Leadership

    2011-01-01

    To be a successful leader, you need to get results. To get results, you need to set priorities. This book can help you do a better job of setting priorities, recognizing the personal values that motivate your decision making, the probable trade-offs and consequences of your decisions, and the importance of aligning your priorities with your organization's expectations. In this way you can successfully meet organizational objectives and consistently produce results.

  10. Recent Results from the ZEUS Experiment

    CERN Document Server

    Smith, W H; Abramowicz, H; Adamczyk, L; Adamus, M; Adler, V; Aghuzumtsyan, G; Antonioli, P; Antonov, A; Arneodo, M; Bailey, D S; Bamberger, A; Barakbaev, A N; Barbagli, G; Barbi, M; Bari, G; Barreiro, F; Bartsch, D; Basile, M; Bauerdick, L A T; Behrens, U; Bell, M; Bellagamba, L; Benen, A; Bertolin, A; Bhadra, S; Bloch, I; Bodmann, B; Bold, T; Boos, E G; Borras, K; Boscherini, D; Brock, I; Brook, N H; Brugnera, R; Brümmer, N; Bruni, A; Bruni, G; Bussey, P J; Butterworth, J M; Bylsma, B; Caldwell, A; Capua, M; Cara Romeo, G; Carli, T; Carlin, R; Catterall, C D; Chekanov, S; Chiochia, V; Chwastowski, J; Ciborowski, J; Ciesielski, R; Cifarelli, Luisa; Cindolo, F; Cloth, P; Cole, J E; Collins-Tooth, C; Contin, A; Cooper-Sarkar, A M; Coppola, N; Cormack, C; Corradi, M; Corriveau, F; Cottrell, A; D'Agostini, Giulio; Dal Corso, F; Danilov, P; Dannheim, D; De Pasquale, S; Dementiev, R K; Derrick, M; Deshpande, Abhay A; Devenish, R C E; Dhawan, S; Dolgoshein, B A; Doyle, A T; Drews, G; Durkin, L S; Dusini, S; Eisenberg, Y; Ermolov, P F; Eskreys, Andrzej; Ferrando, J; Ferrero, M I; Figiel, J; Filges, D; Foster, B; Foudas, C; Fourletov, S; Fourletova, J; Fricke, U; Fusayasu, T; Gabareen, A; Gallo, E; Garfagnini, A; Geiser, A; Genta, C; Gialas, I; Giusti, P; Gladilin, L K; Gladkov, D; Glasman, C; Gliga, S; Goers, S; Golubkov, Yu A; Goncalo, R; González, O; Göttlicher, P; Grabowska-Bold, I; Grijpink, S; Grzelak, G; Gutsche, O; Gwenlan, C; Haas, T; Hain, W; Hall-Wilton, R; Hamatsu, R; Hamilton, J; Hanlon, S; Hart, J C; Hartmann, H; Hartner, G; Hartner, G F; Heaphy, E A; Heath, G P; Heath, H F; Helbich, M; Heusch, C A; Hilger, E; Hillert, S; Hirose, T; Hochman, D; Holm, U; Iacobucci, G; Iga, Y; Inuzuka, M; Irrgang, P; Jakob, H P; Jones, T W; Kagawa, S; Kahle, B; Kaji, H; Kananov, S; Kappes, A; Kataoka, Y; Yamazaki, M; Katkov, I I; Katz, U F; Kcira, D; Khein, L A; Kim, J Y; Kim, Y K; Kind, O; Kisielewska, D; Kitamura, S; Klimek, K; Koffeman, E; Kohno, T; Kooijman, P; Koop, T; Korzhav, I A; Kotanski, A; Kötz, U; Kowal, A M; Kowal, M; Kowalski, H; Kowalski, T; Krakauer, D; Kramberger, G; Kreisel, A; Krumnack, N; Kuze, M; Kuzmin, V A; Labarga, L; Labes, H; Lainesse, J; Lammers, S; Lee, J H; Lee, S W; Lelas, D; Levchenko, B B; Levman, G M; Levy, A; Li, L; Lightwood, M S; Lim, H; Lim, I T; Limentani, S; Ling, T Y; Liu, X; Löhr, B; Lohrmann, E; Loizides, J H; Long, K R; Longhin, A; Lukina, O Yu; Lupi, A; Luzniak, P; Maddox, E; Magill, S; Mankel, R; Margotti, A; Marini, G; Martin, J F; Mastroberardino, A; Matsuzawa, K; Mattingly, M C K; McCubbin, N A; Mellado, B; Melzer-Pellmann, I A; Menary, S R; Metlica, F; Meyer, U; Milite, M; Mirea, A; Monaco, V; Montanari, A; Moritz, M; Musgrave, B; Nagano, K; Nania, R; Nguyen, C N; Nigro, A; Ning, Y; Nishimura, T; Notz, D; Nowak, R J; Oh, B Y; Olkiewicz, K; Pac, M Y; Padhi, S; Paganis, S; Palmonari, F; Parenti, A; Park, I H; Patel, S; Paul, E; Pavel, N; Pawlak, J M; Pelfer, P G; Pellegrino, A; Pesci, A; Petrucci, M C; Piotrzkowski, K; Plucinsky, P P; Pokrovskiy, N S; Polini, A; Posocco, M; Proskuryakov, A S; Przybycien, M B; Rautenberg, J; Raval, A; Reeder, D D; Ren, Z; Renner, R; Repond, J; Riveline, U; Karshon, M; Robins, S; Rodrigues, E; Rosin, M; Rurua, L; Ruspa, M; Sacchi, R; Salehi, H; Sartorelli, G; Savin, A A; Saxon, D H; Schagen, S; Schioppa, M; Schlenstedt, S; Schmidke, W B; Schneekloth, U; Sciulli, F; Scott, J; Selonke, F; Shcheglova, L M; Skillicorn, I O; Slominski, W; Soares, M; Solano, A; Son, D; Sosnovtsev, V V; Stairs, D G; Stanco, L; Standage, J; Stifutkin, A; Stoesslein, U; Stonjek, S; Stopa, P; Straub, P B; Suchkov, S; Susinno, G; Suszycki, L; Sutton, M R; Sztuk, J; Szuba, D; Szuba, J; Tandler, J; Tapper, A D; Tapper, R J; Tassi, E; Tawara, T; Terron, J; Tiecke, H G; Tokushuku, K; Tsurugai, T; Turcato, M; Tymieniecka, T; Ukleja, A; Ukleja, J; Vázquez, M; Velthuis, J J; Vlasov, N N; Voss, K C; Walczak, R; Walsh, R; Wang, M; Weber, A; Wessoleck, H; West, B J; Whitmore, J J; Wick, K; Wiggers, L; Wills, H H; Wing, M; Wolf, G; Yamada, S; Yamashita, T; Yoshida, R; Youngman, C; Zawiejski, L; Zeuner, W; Zhautykov, B O; Zichichi, A; Ziegler, A; Zotkin, S A; De Wolf, E; Del Peso, J

    2004-01-01

    A summary of recent results from ZEUS is presented. New ZEUS results from HERA-1 data include Structure Functions, QCD fits, analysis of hadronic final states, precision measurements of alpha_s, production of heavy flavor mesons and baryons and studies of diffraction. Results from the new HERA-II running include the measurement of the cross section for polarized charged current events and charm events tagged with the new ZEUS vertex detector.

  11. New results on jet fragmentation at CDF

    Energy Technology Data Exchange (ETDEWEB)

    Jindariani, Sergo; /Florida U.

    2006-12-01

    Presented are the latest results of jet fragmentation studies at the Tevatron using the CDF Run II detector. Studies include the distribution of transverse momenta (Kt) of particles jets, two-particle momentum correlations, and indirectly global event shapes in p{bar p} collisions. Results are discussed within the context of recent Next-to-Leading Log calculations as well as earlier experimental results from the Tevatron and e{sup +}e{sup -} colliders.

  12. Review of Tevatron Results: Top quark physics

    CERN Document Server

    Gerber, Cecilia E

    2014-01-01

    We present results on top quark physics from the CDF and D0 collaborations at the Fermilab Tevatron proton anti-proton collider. These include legacy results from Run II that were published or submitted for publication before mid-2014, as well as a summary of Run I results. The historical perspective of the discovery of the top quark in Run I is also described.

  13. Reproducibility of AMPLICOR enterovirus PCR test results.

    OpenAIRE

    1997-01-01

    The reproducibility of AMPLICOR enterovirus PCR test results was determined with clinical samples of cerebrospinal fluid, serum, urine, and throat and rectal swabs. Among 608 samples from which duplicate aliquots were run simultaneously, only seven pairs gave discordant results. Among 104 samples from which duplicate aliquots were run in separate assays, no discordance was seen. Overall, the reproducibility of test kit results was 99% (705 of 712).

  14. 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.

  15. GNO Solar Neutrino Observations: Results for GNOI

    OpenAIRE

    GNO Collaboration; Altmann, M; Balata, M.; Belli, P.; Bellotti, E.(Dipartimento di Fisica, Università Milano Bicocca, Milan, Italy); Bernabei, R.; Burkert, E; Cattadori, C.; Cerichelli, G.; Chiarini, M; Cribier, M.; D'Angelo, S; Del Re, G.; Ebert, K.H.; Feilitzsch, F. v.

    2000-01-01

    We report the first GNO solar neutrino results for the measuring period GNOI, solar exposure time May 20, 1998 till January 12, 2000. In the present analysis, counting results for solar runs SR1 - SR19 were used till April 4, 2000. With counting completed for all but the last 3 runs (SR17 - SR19), the GNO I result is [65.8 +10.2 -9.6 (stat.) +3.4 -3.6 (syst.)]SNU (1sigma) or [65.8 + 10.7 -10.2 (incl. syst.)]SNU (1sigma) with errors combined. This may be compared to the result for Gallex(I-IV)...

  16. Generalized Common Fixed Point Results with Applications

    Directory of Open Access Journals (Sweden)

    Marwan Amin Kutbi

    2014-01-01

    Full Text Available We obtained some generalized common fixed point results in the context of complex valued metric spaces. Moreover, we proved an existence theorem for the common solution for two Urysohn integral equations. Examples are presented to support our results.

  17. Annual results 2004; Resultats annuels 2004

    Energy Technology Data Exchange (ETDEWEB)

    NONE

    2005-07-01

    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.)

  18. Review of Recent Results in Charm Physics

    CERN Document Server

    Engelfried, J

    2003-01-01

    A biased review of recent results in charm physics is presented. New results on D0 anti-D0 mixing, rare decays of D0 and D+/-, scalar resonances in D+ and Ds decays, and new decay modes and mass measurements in Lambda_c, Xi_c, Omega_c, and Xi_cc are discussed.

  19. Modeling clicks beyond the first result page

    NARCIS (Netherlands)

    Chuklin, A.; Serdyukov, P.; de Rijke, M.

    2013-01-01

    Most modern web search engines yield a list of documents of a fixed length (usually 10) in response to a user query. The next ten search results are usually available in one click. These documents either replace the current result page or are appended to the end. Hence, in order to examine more docu

  20. Recent Electroweak Results from the LHC

    CERN Document Server

    Helary, Louis; The ATLAS collaboration

    2016-01-01

    Slides for conference Aspen 2016. The talk is about recent Electroweak results at the LHC. It is focused on multi-boson physics and boson EWK production. It is supposed to summarize results from ATLAS, CMS and LHCb, but given the topic it contains only material from ATLAS and CMS.

  1. ANISOTROPIC BIQUADRATIC ELEMENT WITH SUPERCLOSE RESULT

    Institute of Scientific and Technical Information of China (English)

    Dongyang SHI; Shipeng MAO; Hui LIANG

    2006-01-01

    The main aim of this paper is to study the convergence of biquadratic finite element for the second order problem on anisotropic meshes. By using some novel approaches and techniques, the optimal error estimates are obtained. At the same time, the anisotropic superclose results are also achieved. Furthermore, the numerical results are given to demonstrate our theoretical analysis.

  2. Two convergence results for continuous descent methods

    Directory of Open Access Journals (Sweden)

    Simeon Reich

    2003-03-01

    Full Text Available We consider continuous descent methods for the minimization of convex functionals defined on general Banach space. We establish two convergence results for methods which are generated by regular vector fields. Since the complement of the set of regular vector fields is $sigma$-porous, we conclude that our results apply to most vector fields in the sense of Baire's categories.

  3. Students' Homework and TIMSS 2003 Mathematics Results

    Science.gov (United States)

    Mikk, Jaan

    2006-01-01

    An aspect of the complex relationship between students homework and academic achievement (Cooper, Robinson, and Patall, 2006) was examined by correlating TIMSS 2003 mathematics results with the data about homework in 46 countries of the TIMSS study. The TIMSS results had no statistically significant correlation with the teachers' emphasis on…

  4. IPE results as compared with NUREG-1150

    Energy Technology Data Exchange (ETDEWEB)

    Pratt, W.T.; Lehner, J. [Brookhaven National Lab., Upton, NY (United States); Camp, A. [Sandia National Lab., Albuqurque, NM (United States); Chow, E. [Nuclear Regulatory Commission, Rockville, MD (United States)

    1995-12-31

    In 1990, the NRC published NUREG-1150 which assessed the risks for five U.S. nuclear power plants. This paper provides a comparison of the results and perspectives obtained from the NUREG-1150 study to those obtained form the Individual Plant Examination (IPE) program. Specifically, results and perspectives on core damage frequency and containment performance are compared.

  5. Experimental results on quadratic assignment problem

    Directory of Open Access Journals (Sweden)

    N.P. Nikolov

    1999-08-01

    Full Text Available The paper presents experimental results on quadratic assignment problem. The "scanning area" method formulated for radioelectronic equipment design is applied. For all more complex tests ours results are better or coincident with the ones known in literature. Conclusion concerning the effectiveness of method are given.

  6. Tablet PCs, Academic Results and Educational Inequalities

    Science.gov (United States)

    Ferrer, Ferran; Belvis, Esther; Pamies, Jordi

    2011-01-01

    This article is the result of a study carried out in 2008 and 2009 by a team from the Autonomous University of Barcelona in order to evaluate the implementation of the Digital Whiteboard Program in public schools in the region of Aragon (Spain). The following pages present some of the results obtained during the study. More specifically, this…

  7. On degree phrases and result clauses

    NARCIS (Netherlands)

    Rijkhoek, Paulien Dea

    1998-01-01

    This dissertation consists of two parts, one on degree phrases and one on result clauses. Sentence (1) below exemplifies a result clause construction: (1) Zij had zo mooi gezongen dat het publiek er stil van was she has so beautifully sang that the audience there silent of was ‘She had sung so beaut

  8. Format SPARQL Query Results into HTML Report

    Directory of Open Access Journals (Sweden)

    Dr Sunitha Abburu

    2013-07-01

    Full Text Available SPARQL is one of the powerful query language for querying semantic data. It is recognized by the W3C as a query language for RDF. As an efficient query language for RDF, it has defined several query result formats such as CSV, TSV and XML etc. These formats are not attractive, understandable and readable. The results need to be converted in an appropriate format so that user can easily understand. The above formats require additional transformations or tool support to represent the query result in user readable format. The main aim of this paper is to propose a method to build HTML report dynamically for SPARQL query results. This enables SPARQL query result display, in HTML report format easily, in an attractive understandable format without the support of any additional or external tools or transformation.

  9. GNO Solar Neutrino Observations Results for GNOI

    CERN Document Server

    Altmann, M; Belli, P; Bellotti, E; Bernabei, R; Burkert, E; Cattadori, C; Cerichelli, G; Chiarini, M; Cribier, Michel; Re, G D; Ebert, K H; Von Feilitzsch, F; Ferrari, N; Hampel, W; Handt, J; Henrich, E; Heusser, G; Kiko, J; Kirsten, T; Lachenmaier, T; Lanfranchi, J; Laubenstein, M; Motta, D; Rau, W; Richter, H; Wänninger, S; Wójcik, M; Zanotti, L

    2000-01-01

    We report the first GNO solar neutrino results for the measuring period GNOI, solar exposure time May 20, 1998 till January 12, 2000. In the present analysis, counting results for solar runs SR1 - SR19 were used till April 4, 2000. With counting completed for all but the last 3 runs (SR17 - SR19), the GNO I result is [65.8 +10.2 -9.6 (stat.) +3.4 -3.6 (syst.)]SNU (1sigma) or [65.8 + 10.7 -10.2 (incl. syst.)]SNU (1sigma) with errors combined. This may be compared to the result for Gallex(I-IV), which is [77.5 +7.6 -7.8 (incl. syst.)] SNU (1sigma). A combined result from both GNOI and Gallex(I-IV) together is [74.1 + 6.7 -6.8 (incl. syst.)] SNU (1sigma).

  10. Results Processing in Heterogeneous Digital Libraries

    Institute of Scientific and Technical Information of China (English)

    2002-01-01

    In the heterogeneous digital libraries, users are allowed to have access to data of different modalities, from different information sources, and ranked by different criteria. This paper,which assumes that each information retrieval model is satisfactory in its own context, proposes two results processing methods: Ranking by Sources (RBS) and Simply Merging Results (SMR). It defines satisfied ranking, which satisfies most source rankings, and satisfied distance to indicate how a specific source ranking suits the satisfied ranking. RBS ranks sources by their satisfied distances and groups the results by sources. SMR, using source scoring function distributions, substitutes normalized scores for original scores from sources, and then merges the results using these normalized scores. The results show they are very feasible and efficient in the heterogeneous environment

  11. Uniform dimension results for Gaussian random fields

    Institute of Scientific and Technical Information of China (English)

    WU DongSheng; XIAO YiMin

    2009-01-01

    Let X = {X(t), t ∈ RN} be a Gaussian random field with values in Rd defined by x(t) = (x1(t),…,xd(t)), At∈RN.(1)The properties of space and time anisotropy of X and their connections to uniform Hausdorff dimension results are discussed. It is shown that in general the uniform Hausdorff dimension result does not hold for the image sets of a space-anisotropic Gaussian random field X. When X is an (N, d)-Gaussian random field as in (1), where X1,..., Xd are independent copies of a real valued, centered Gaussian random field Xo which is anisotropic in the time variable. We establish uniform Hausdorff dimension results for the image sets of X. These results extend the corresponding results on one-dimensional Brownian motion, fractional Brownian motion and the Brownian sheet.

  12. Explicit Optimal Hardness via Gaussian stability results

    CERN Document Server

    De, Anindya

    2012-01-01

    The results of Raghavendra (2008) show that assuming Khot's Unique Games Conjecture (2002), for every constraint satisfaction problem there exists a generic semi-definite program that achieves the optimal approximation factor. This result is existential as it does not provide an explicit optimal rounding procedure nor does it allow to calculate exactly the Unique Games hardness of the problem. Obtaining an explicit optimal approximation scheme and the corresponding approximation factor is a difficult challenge for each specific approximation problem. An approach for determining the exact approximation factor and the corresponding optimal rounding was established in the analysis of MAX-CUT (KKMO 2004) and the use of the Invariance Principle (MOO 2005). However, this approach crucially relies on results explicitly proving optimal partitions in Gaussian space. Until recently, Borell's result (Borell 1985) was the only non-trivial Gaussian partition result known. In this paper we derive the first explicit optimal...

  13. Uniform dimension results for Gaussian random fields

    Institute of Scientific and Technical Information of China (English)

    2009-01-01

    Let X = {X(t),t ∈ RN} be a Gaussian random field with values in Rd defined by X(t) =(X1(t),...,Xd(t)), t ∈ RN.(1) The properties of space and time anisotropy of X and their connections to uniform Hausdorff dimension results are discussed.It is shown that in general the uniform Hausdorff dimension result does not hold for the image sets of a space-anisotropic Gaussian random field X.When X is an(N,d)-Gaussian random field as in(1),where X1,...,Xd are independent copies of a real valued,centered Gaussian random field X0 which is anisotropic in the time variable.We establish uniform Hausdorff dimension results for the image sets of X.These results extend the corresponding results on one-dimensional Brownian motion,fractional Brownian motion and the Brownian sheet.

  14. Mutations in Snail Family Genes Enhance Craniosynostosis of Twist1 Haplo-insufficient Mice: Implications for Saethre-Chotzen Syndrome

    OpenAIRE

    2005-01-01

    In Drosophila, mutations in the Twist gene interact with mutations in the Snail gene. We show that the mouse Twist1 mutation interacts with Snai1 and Snai2 mutations to enhance aberrant cranial suture fusion, demonstrating that genetic interactions between genes of the Twist and Snail families have been conserved during evolution.

  15. 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

    organotypic cultures significantly reduced activity-dependent phosphorylated extracellular signal-regulated kinase (pERK) levels. In contrast, constructs expressing p.W362R, p.P562L, or the previously described p.R579X had no significant effect on pERK levels. These experiments suggest that the de novo...

  16. The effect of losartan therapy on ventricular function in Marfan patients with haploinsufficient or dominant negative FBN1 mutations

    NARCIS (Netherlands)

    den Hartog, A. W.; Franken, R.; van den Berg, M. P.; Zwinderman, A. H.; Timmermans, J.; Scholte, A. J.; de Waard, V.; Spijkerboer, A. M.; Pals, G.; Mulder, B. J. M.; Groenink, M.

    2016-01-01

    Background Mild biventricular dysfunction is often present in patients with Marfan syndrome. Losartan has been shown to reduce aortic dilatation in patients with Marfan syndrome. This study assesses the effect of losartan on ventricular volume and function in genetically classified subgroups of asym

  17. Loss-of-function mutations in TNFAIP3 leading to A20 haploinsufficiency cause an early-onset autoinflammatory disease

    NARCIS (Netherlands)

    Zhou, Qing; Wang, Hongying; Schwartz, Daniella M; Stoffels, Monique; Park, Yong Hwan; Zhang, Yuan; Yang, Dan; Demirkaya, Erkan; Takeuchi, Masaki; Tsai, Wanxia Li; Lyons, Jonathan J; Yu, Xiaomin; Ouyang, Claudia; Chen, Celeste; Chin, David T; Zaal, Kristien; Chandrasekharappa, Settara C; P Hanson, Eric; Yu, Zhen; Mullikin, James C; Hasni, Sarfaraz A; Wertz, Ingrid E; Ombrello, Amanda K; Stone, Deborah L; Hoffmann, Patrycja; Jones, Anne; Barham, Beverly K; Leavis, Helen L; van Royen, Annet; Sibley, Cailin; Batu, Ezgi D; Gül, Ahmet; Siegel, Richard M; Boehm, Manfred; Milner, Joshua D; Ozen, Seza; Gadina, Massimo; Chae, JaeJin; Laxer, Ronald M; Kastner, Daniel L; Aksentijevich, Ivona

    2015-01-01

    Systemic autoinflammatory diseases are driven by abnormal activation of innate immunity. Herein we describe a new disease caused by high-penetrance heterozygous germline mutations in TNFAIP3, which encodes the NF-κB regulatory protein A20, in six unrelated families with early-onset systemic inflamma

  18. Mutations in snail family genes enhance craniosynostosis of Twist1 haplo-insufficient mice: implications for Saethre-Chotzen Syndrome.

    Science.gov (United States)

    Oram, Kathleen F; Gridley, Thomas

    2005-06-01

    In Drosophila, mutations in the Twist gene interact with mutations in the Snail gene. We show that the mouse Twist1 mutation interacts with Snai1 and Snai2 mutations to enhance aberrant cranial suture fusion, demonstrating that genetic interactions between genes of the Twist and Snail families have been conserved during evolution.

  19. Haploinsufficiency of novel FOXG1B variants in a patient with severe mental retardation, brain malformations and microcephaly

    DEFF Research Database (Denmark)

    Shoichet, Sarah A; Kunde, Stella-Amrei; Viertel, Petra;

    2005-01-01

    We have investigated the chromosome abnormalities in a female patient exhibiting a severe cognitive disability associated with complete agenesis of the corpus callosum and microcephaly. The patient carries a balanced de novo translocation t(2;14)(p22;q12), together with a neighbouring 720 kb inve...

  20. 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...

  1. IceCube Results and PINGU Perspectives

    DEFF Research Database (Denmark)

    Koskinen, David Jason

    2015-01-01

    The last three years of IceCube operation with the completed detector have resulted in a plethora of results, including the first observation of high energy astrophysical neutrinos, tests of a possible neutrino flux from atmospheric charm meson decay, and competitive results of neutrino oscillati...... from atmospheric muon neutrino disappearance. Based on the success of IceCube, a new low energy in-fill, known as the Precision IceCube Next Generation Upgrade, is being proposed with the primary physics goal of resolving the ordering of the neutrino mass hierarchy....

  2. Semantic Clustering of Search Engine Results

    Directory of Open Access Journals (Sweden)

    Sara Saad Soliman

    2015-01-01

    Full Text Available This paper presents a novel approach for search engine results clustering that relies on the semantics of the retrieved documents rather than the terms in those documents. The proposed approach takes into consideration both lexical and semantics similarities among documents and applies activation spreading technique in order to generate semantically meaningful clusters. This approach allows documents that are semantically similar to be clustered together rather than clustering documents based on similar terms. A prototype is implemented and several experiments are conducted to test the prospered solution. The result of the experiment confirmed that the proposed solution achieves remarkable results in terms of precision.

  3. Exact Results for the BTZ Black Hole

    CERN Document Server

    Birmingham, Daniel; Sen, S; Birmingham, Danny; Sachs, Ivo; Sen, Siddhartha

    2001-01-01

    In this review, we summarize exact results for the three-dimensional BTZ black hole. We use rigorous mathematical results to clarify the general structure and properties of this black hole spacetime and its microscopic description. In particular, we study the formation of the black hole by point particle collisions, leading to an exact analytic determination of the Choptuik scaling parameter. We also show that a `No Hair Theorem' follows immediately from a mathematical theorem of hyperbolic geometry, due to Sullivan. A microscopic understanding of the Bekenstein-Hawking entropy, and decay rate for massless scalars, is shown to follow from standard results of conformal field theory.

  4. Unfavourable results with distraction in craniofacial skeleton

    Directory of Open Access Journals (Sweden)

    Rajiv Agarwal

    2013-01-01

    Full Text Available Distraction osteogenesis has revolutionised the management of craniofacial abnormalities. The technique however requires precise planning, patient selection, execution and follow-up to achieve consistent and positive results and to avoid unfavourable results. The unfavourable results with craniofacial distraction stem from many factors ranging from improper patient selection, planning and use of inappropriate distraction device and vector. The present study analyses the current standards and techniques of distraction and details in depth the various errors and complications that may occur due to this technique. The commonly observed complications of distraction have been detailed along with measures and suggestions to avoid them in clinical practice.

  5. Unfavourable results in skull base surgery

    Directory of Open Access Journals (Sweden)

    Hemen Jaju

    2013-01-01

    Full Text Available Treatment of skull base tumors involves multiple specialities. The lesions are usually advanced and the treatment is often associated with unfavorable results, which may be functional and/or aesthetic. Here we have done an analysis for the complications and unfavorable results of 546 cases treated surgically by a single craniofacial surgeon over a period of 14 years. The major morbidity ranges from death to permanent impairment of vital organ functions (brain, eye, nose, infections, tissue losses, flap failures, treatment associated complications, psychosocial issues, and aesthesis besides others. This article is aimed at bringing forth these unfavorable results and how to avoid them.

  6. First scientific results from the Estonian Grid

    CERN Document Server

    Hektor, A; Kadastik, M; Skaburskas, K; Teder, H; Hektor, Andi; Anton, Lauri; Kadastik, Mario; Skaburskas, Konstantin; Teder, Hardi

    2004-01-01

    We present first scientific results, technical details and recent developments in the Estonian Grid. Ideas and concepts behind Grid technology are described. We mention some most crucial parts of a Grid system, as well as some unique possibilities in the Estonian situation. Scientific applications currently running on Estonian Grid are listed. We discuss the first scientific computations and results the Estonian Grid. The computations show that the middleware is well chosen and the Estonian Grid has remarkable stability and scalability. The authors present the collected results and experiences of the development of the Estonian Grid and add some ideas of the near future of the Estonian Grid.

  7. Semantic Clustering of Search Engine Results.

    Science.gov (United States)

    Soliman, Sara Saad; El-Sayed, Maged F; Hassan, Yasser F

    2015-01-01

    This paper presents a novel approach for search engine results clustering that relies on the semantics of the retrieved documents rather than the terms in those documents. The proposed approach takes into consideration both lexical and semantics similarities among documents and applies activation spreading technique in order to generate semantically meaningful clusters. This approach allows documents that are semantically similar to be clustered together rather than clustering documents based on similar terms. A prototype is implemented and several experiments are conducted to test the prospered solution. The result of the experiment confirmed that the proposed solution achieves remarkable results in terms of precision.

  8. Review of Physics Results from the Tevatron

    Energy Technology Data Exchange (ETDEWEB)

    Bandurin, D. [Virginia U.; Bernardi, G. [Paris U., VI-VII; Gerber, C. [Chicago U., EFI; Junk, T. [Fermilab; Juste, A. [Barcelona, IFAE; Kotwal, A. [Duke U.; Lewis, J. [Fermilab; Mesropian, C. [Rockefeller U.; Schellman, H. [Northwestern U.; Sekaric, J. [Kansas U.; Toback, D. [Texas A-M; Van Kooten, R. [Indiana U.; Vellidis, C. [Fermilab; Zivkovic, L. [Clemson U.

    2015-02-27

    We present a comprehensive review of the physics results obtained by the CDF and D0 collaborations up to summer 2014, with emphasis on those achieved in the Run II of the Tevatron collider which delivered a total integrated luminosity of ~10 fb$^{-1}$ at $\\sqrt{s} = 1.96~{\\rm TeV}$. The results are presented in six main physics topics: QCD, Heavy Flavor, Electroweak, Top quark, Higgs boson and searches for New Particles and Interactions. The characteristics of the accelerator, detectors, and the techniques used to achieve these results are also briefly summarized.

  9. v-Src Causes Chromosome Bridges in a Caffeine-Sensitive Manner by Generating DNA Damage.

    Science.gov (United States)

    Ikeuchi, Masayoshi; Fukumoto, Yasunori; Honda, Takuya; Kuga, Takahisa; Saito, Youhei; Yamaguchi, Naoto; Nakayama, Yuji

    2016-06-02

    An increase in Src activity is commonly observed in epithelial cancers. Aberrant activation of the kinase activity is associated with malignant progression. However, the mechanisms that underlie the Src-induced malignant progression of cancer are not completely understood. We show here that v-Src, an oncogene that was first identified from a Rous sarcoma virus and a mutant variant of c-Src, leads to an increase in the number of anaphase and telophase cells having chromosome bridges. v-Src increases the number of γH2AX foci, and this increase is inhibited by treatment with PP2, a Src kinase inhibitor. v-Src induces the phosphorylation of KAP1 at Ser824, Chk2 at Thr68, and Chk1 at Ser345, suggesting the activation of the ATM/ATR pathway. Caffeine decreases the number of cells having chromosome bridges at a concentration incapable of inhibiting Chk1 phosphorylation at Ser345. These results suggest that v-Src induces chromosome bridges via generation of DNA damage and the subsequent DNA damage response, possibly by homologous recombination. A chromosome bridge gives rise to the accumulation of DNA damage directly through chromosome breakage and indirectly through cytokinesis failure-induced multinucleation. We propose that v-Src-induced chromosome bridge formation is one of the causes of the v-Src-induced malignant progression of cancer cells.

  10. WEE1 inhibition targets cell cycle checkpoints for triple negative breast cancers to overcome cisplatin resistance

    Science.gov (United States)

    Zheng, Hongping; Shao, Fangyuan; Martin, Scots; Xu, Xiaoling; Deng, Chu-Xia

    2017-01-01

    Cisplatin is one of the most commonly used therapeutic drugs for cancer therapy, yet prolonged cisplatin treatment frequently results in drug resistance. To enhance therapeutic effect of cisplatin, we conducted a high throughput screening using a kinase library containing 704 kinases against triple negative breast cancer (TNBC) cells. We demonstrated that cisplatin activates ATR, CHK1 and WEE1, which shut down DNA replication and attenuate cisplatin induced-lethality. WEE1 inhibition sensitizes TNBCs and cisplatin resistant cancer cells to cisplatin-induced lethality, because it not only impairs DNA replication checkpoint more profoundly than inhibition of ATR or CHK1, but also defects G2-M cell cycle checkpoint. Finally, we demonstrated that combined cisplatin treatment and WEE1 inhibition synergistically inhibits xenograft cancer growth accompanied by markedly reduced expression of TNBC signature genes. Thus targeting DNA replication and G2-M cell cycle checkpoint simultaneously by cisplatin and WEE1 inhibition is promising for TNBCs treatment, and for overcoming their cisplatin resistance. PMID:28262781

  11. Isocorydine inhibits cell proliferation in hepatocellular carcinoma cell lines by inducing G2/m cell cycle arrest and apoptosis.

    Directory of Open Access Journals (Sweden)

    Hefen Sun

    Full Text Available The treatment of human hepatocellular carcinoma (HCC cell lines with (+-isocorydine, which was isolated and purified from Papaveraceae sp. plants, resulted in a growth inhibitory effect caused by the induction of G2/M phase cell cycle arrest and apoptosis. We report that isocorydine induces G2/M phase arrest by increasing cyclin B1 and p-CDK1 expression levels, which was caused by decreasing the expression and inhibiting the activation of Cdc25C. The phosphorylation levels of Chk1 and Chk2 were increased after ICD treatment. Furthermore, G2/M arrest induced by ICD can be disrupted by Chk1 siRNA but not by Chk2 siRNA. In addition, isocorydine treatment led to a decrease in the percentage of CD133(+ PLC/PRF/5 cells. Interestingly, isocorydine treatment dramatically decreased the tumorigenicity of SMMC-7721 and Huh7 cells. These findings indicate that isocorydine might be a potential therapeutic drug for the chemotherapeutic treatment of HCC.

  12. Ral A, via activating the mitotic checkpoint, sensitizes cells lacking a functional Nf1 to apoptosis in the absence of protein kinase C.

    Science.gov (United States)

    Ganapathy, Suthakar; Fagman, Johan B; Shen, Ling; Yu, Tianqi; Zhou, Xiaodong; Dai, Wei; Makriyannis, Alexandros; Chen, Changyan

    2016-12-20

    Nf1 mutations or deletions are suggested to underlie the tumor predisposition of NF1 (neurofibromatosis type 1) and few treatments are available for treating NF1 patients with advanced malignant tumors. Aberrant activation of Ras in Nf1-deficient conditions is responsible for the promotion of tumorigenesis in NF1. PKC is proven to be an important factor in supporting the viability of Nf1-defected cells, but the molecular mechanisms are not fully understood. In this study, we demonstrate that the inhibition of protein kinase C (PKC) by 1-O-Hexadecyl-2-O-methyl-rac-glycerol (HMG, a PKC inhibitor) preferentially sensitizes Nf1-defected cells to apoptosis, via triggering a persistent mitotic arrest. In this process, Ral A is activated. Subsequently, Chk1 is phosphorylated and translocated to the nucleus. Silencing Ral A significantly blocks Chk1 nuclear translocation and releases HMG-treated Nf1-deficient cells from mitotic arrest, resulting in the reduction of the magnitude of apoptosis. Thus, our study reveals that PKC is able to maintain the homeostasis or viability of Nf1-defected cells and may serve as a potential target for developing new therapeutic strategies.

  13. Tumor suppressor protein C53 antagonizes checkpoint kinases to promote cyclin-dependent kinase 1 activation

    Institute of Scientific and Technical Information of China (English)

    Hai Jiang; Jianchun Wu; Chen He; Wending Yang; Honglin Li

    2009-01-01

    Cyclin-dependent kinase 1 (Cdk1)/cyclin B1 complex is the driving force for mitotic entry, and its activation is tightly regulated by the G2/M checkpoint. We originally reported that a novel protein C53 (also known as Cdk5rap3 and LZAP) potentiates DNA damage-induced cell death by modulating the G2/M checkpoint. More recently, Wang et al. (2007) found that C53/LZAP may function as a tumor suppressor by way of inhibiting NF-kB signaling. We report here the identification of C53 protein as a novel regulator of Cdk1 activation. We found that knockdown of C53 protein causes delayed Cdkl activation and mitotic entry. During DNA damage response, activation of checkpoint kinase 1 and 2 (Chk1 and Chk2) is partially inhibited by C53 overexpression. Intriguingly, we found that C53 interacts with Chkl and antagonizes its function. Moreover, a portion of C53 protein is localized at the centrosome, and centrosome-targeting C53 potently promotes local Cdk1 activation. Taken together, our results strongly suggest that C53 is a novel negative regulator of checkpoint response. By counteracting Chk1, C53 promotes Cdk1 activation and mitotic entry in both unperturbed cell-cycle progression and DNA damage response.

  14. Contribution of ATM and ATR kinase pathways to p53-mediated response in etoposide and methyl methanesulfonate induced DNA damage.

    Science.gov (United States)

    Sun, Bin; Ross, Susan M; Rowley, Sean; Adeleye, Yeyejide; Clewell, Rebecca A

    2017-03-01

    p53 is a key integrator of cellular response to DNA damage, supporting post-translational repair and driving transcription-mediated responses including cell cycle arrest, apoptosis, and repair. DNA damage sensing kinases recognize different types of DNA damage and initiate specific responses through various post-translational modifications of p53. This study evaluated chemical specificity of the p53 pathway response by manipulating p53 or its upstream kinases and assessing the effect on DNA damage and cellular responses to prototype chemicals: etoposide (ETP, topoisomerase II inhibitor) and methyl methane sulfonate (MMS, alkylating agent). p53-deficient cells demonstrated reduced accumulation of the p53 target proteins MDM2, p21, and Wip1; reduced apoptotic response; and increased DNA damage (p-H2AX and micronuclei) with both chemicals. However, p53 was not essential for cell cycle arrest in HT1080 or HCT116 cells. The two chemicals induced different patterns of kinase activation, particularly in terms of Chk 1, Chk 2, p38, and ERK 1/2. However, inhibition of the ATM pathway showed a greater effect on p53 activtation, apoptosis, and accumulation of DNA damage than ATR-Chk 1 or the MAP kinases regardless of the chemical used. These results indicate that ATM is the predominant upstream kinase responsible for activation of the p53-mediated DNA damage response for both MMS and ETP, though the downstream kinase response is markedly different. Environ. Mol. Mutagen. 58:72-83, 2017. © 2017 Wiley Periodicals, Inc.

  15. Differential regulation of p21 (waf1) protein half-life by DNA damage and Nutlin-3 in p53 wild-type tumors and its therapeutic implications.

    Science.gov (United States)

    Chang, Li-Ju; Eastman, Alan

    2012-09-01

    DNA damage induces the canonical p53 pathway including elevation of p21 (waf1) resulting in arrest of cell cycle progression. This can protect cells from subsequent Chk1 inhibition. Some p53 wild-type cancer cells such as HCT116 and U2OS exhibit attenuated p21 (waf1) induction upon DNA damage due to translational inhibition, and are incapable of maintaining arrest upon Chk1 inhibition. The purpose of this study was to determine whether this attenuated p21 (waf1) induction also occurred with the non-DNA damaging agent Nutlin-3 which induces p53 by disrupting binding to its negative regulator MDM2. We find that Nutlin-3 circumvented the attenuated induction of p21 (waf1) protein by increasing its half-life which led to G 1 and G 2 arrest in both cell lines. Interestingly, the p21 (waf1) protein half-life remained short on Nutlin-3 in p53 wild-type MCF10A cells; these cells achieve high p21 (waf1) levels through transcriptional upregulation. Consequently, all three p53 wild-type cells but not p53 mutant MDA-MB-231 cancer cells were protected from subsequent incubation with a combination of DNA damage plus a checkpoint inhibitor.

  16. WEE1 inhibition targets cell cycle checkpoints for triple negative breast cancers to overcome cisplatin resistance.

    Science.gov (United States)

    Zheng, Hongping; Shao, Fangyuan; Martin, Scots; Xu, Xiaoling; Deng, Chu-Xia

    2017-03-06

    Cisplatin is one of the most commonly used therapeutic drugs for cancer therapy, yet prolonged cisplatin treatment frequently results in drug resistance. To enhance therapeutic effect of cisplatin, we conducted a high throughput screening using a kinase library containing 704 kinases against triple negative breast cancer (TNBC) cells. We demonstrated that cisplatin activates ATR, CHK1 and WEE1, which shut down DNA replication and attenuate cisplatin induced-lethality. WEE1 inhibition sensitizes TNBCs and cisplatin resistant cancer cells to cisplatin-induced lethality, because it not only impairs DNA replication checkpoint more profoundly than inhibition of ATR or CHK1, but also defects G2-M cell cycle checkpoint. Finally, we demonstrated that combined cisplatin treatment and WEE1 inhibition synergistically inhibits xenograft cancer growth accompanied by markedly reduced expression of TNBC signature genes. Thus targeting DNA replication and G2-M cell cycle checkpoint simultaneously by cisplatin and WEE1 inhibition is promising for TNBCs treatment, and for overcoming their cisplatin resistance.

  17. Zbrowse: an interactive GWAS results browser

    Directory of Open Access Journals (Sweden)

    Greg R. Ziegler

    2015-05-01

    Full Text Available The growing number of genotyped populations, the advent of high-throughput phenotyping techniques and the development of GWAS analysis software has rapidly accelerated the number of GWAS experimental results. Candidate gene discovery from these results files is often tedious, involving many manual steps searching for genes in windows around a significant SNP. This problem rapidly becomes more complex when an analyst wishes to compare multiple GWAS studies for pleiotropic or environment specific effects. To this end, we have developed a fast and intuitive interactive browser for the viewing of GWAS results with a focus on an ability to compare results across multiple traits or experiments. The software can easily be run on a desktop computer with software that bioinformaticians are likely already familiar with. Additionally, the software can be hosted or embedded on a server for easy access by anyone with a modern web browser.

  18. Search Result Diversification Based on Query Facets

    Institute of Scientific and Technical Information of China (English)

    胡莎; 窦志成; 王晓捷; 继荣

    2015-01-01

    In search engines, different users may search for different information by issuing the same query. To satisfy more users with limited search results, search result diversification re-ranks the results to cover as many user intents as possible. Most existing intent-aware diversification algorithms recognize user intents as subtopics, each of which is usually a word, a phrase, or a piece of description. In this paper, we leverage query facets to understand user intents in diversification, where each facet contains a group of words or phrases that explain an underlying intent of a query. We generate subtopics based on query facets and propose faceted diversification approaches. Experimental results on the public TREC 2009 dataset show that our faceted approaches outperform state-of-the-art diversification models.

  19. Analytic results for the Tsallis thermodynamic variables

    CERN Document Server

    Bhattacharyya, Trambak; Mogliacci, Sylvain

    2016-01-01

    We analytically investigate the thermodynamic variables of a hot and dense system, in the framework of the Tsallis non-extensive classical statistics. After a brief review, we start by recalling the corresponding massless limits for all the thermodynamic variables. We then present the detail of calculation for the exact massive result regarding the pressure -- valid for all values of the $q$-parameter -- as well as the Tsallis $T$-, $\\mu$- and $m$- parameters, the former characterizing the non-extensivity of the system. The results for other thermodynamic variables, in the massive case, readily follow from appropriate differentiations of the pressure, for which we provide the necessary formulas. For the convenience of the reader, we tabulate all of our results. A special emphasis is put on the method used in order to perform these computations, which happens to reduce cumbersome momentum integrals into simpler ones. Numerical consistency between our analytic results and the corresponding usual numerical integ...

  20. Highlights of Recent Results with Clas

    CERN Document Server

    Burkert, V D

    2005-01-01

    Recent results on the study of the electromagnetic structure of nucleon resonances, the spin structure of proton and neutrons at small and intermediate photon virtualities, and the search for exotic pentaquark baryons are presented.

  1. CRUMP 2003 Selected Water Sample Results

    Data.gov (United States)

    U.S. Environmental Protection Agency — Point locations and water sampling results performed in 2003 by the Church Rock Uranium Monitoring Project (CRUMP) a consortium of organizations (Navajo Nation...

  2. Innovation Impact: Breakthrough Research Results (Brochure)

    Energy Technology Data Exchange (ETDEWEB)

    2013-07-01

    The Innovation Impact brochure captures key breakthrough results across NREL's primary areas of renewable energy and energy efficiency research: solar, wind, bioenergy, transportation, buildings, analysis, and manufacturing technologies.

  3. Focus on Communication: NIH Research to Results

    Science.gov (United States)

    ... Current Issue Past Issues Special Section: Focus on Communication NIH Research to Results Past Issues / Fall 2008 ... grew new hair cells. Read More "Focus on Communication" Articles Living with Hearing Loss / Anatomy of the ...

  4. Results from CMS on Higgs boson physics

    CERN Document Server

    Azzurri, Paolo

    2017-01-01

    A selection of measurements and results of Higgs physics obtained by the CMS experiment are presented, obtained with proton collision data collected in 2015 and 2016 at the center-of-mass energy of 13 TeV.

  5. Some Results on the Simultaneous Approximation

    Institute of Scientific and Technical Information of China (English)

    M. R. Haddadi∗

    2014-01-01

    In this paper, we give some result on the simultaneous proximinal subset and simultaneous Chebyshev in the uniformly convex Banach space. Also we give relation between fixed point theory and simultaneous proximity.

  6. The journal of irreproducible results II

    CERN Document Server

    Scherr, George H

    1997-01-01

    Compilation of offbeat science papers from the Journal of Irreproducible Results, including: Emotion in the Rat Face; Foamy Beer; Cooking with Potential Energy; The Large-Cake Cutting Problem; Siamese Twinning in Gummy Bears; much more.

  7. MedlinePlus Survey Results 2015

    Science.gov (United States)

    ... page: https://medlineplus.gov/survey/index.html MedlinePlus Survey Results 2015 To use the sharing features on ... government sites in the "Information/News" category. Other survey question responses: What best describes your role in ...

  8. Common Diagnostic Test Results Over the Years

    Directory of Open Access Journals (Sweden)

    Aruvee Eve

    2016-12-01

    Full Text Available In this article, common test results over the years 2000 – 2016 are analysed. The test questions for new entrants were based on secondary school mathematics. The students took the test in the first lesson of the higher mathematics course. The test results were analysed by years, by tasks and by specialities, and their differences were found. The test results’ dependence on state-exams score was studied and other types of dependence were looked at.

  9. Bent functions results and applications to cryptography

    CERN Document Server

    Tokareva, Natalia

    2015-01-01

    Bent Functions: Results and Applications to Cryptography offers a unique survey of the objects of discrete mathematics known as Boolean bent functions. As these maximal, nonlinear Boolean functions and their generalizations have many theoretical and practical applications in combinatorics, coding theory, and cryptography, the text provides a detailed survey of their main results, presenting a systematic overview of their generalizations and applications, and considering open problems in classification and systematization of bent functions. The text is appropriate for novices and advanced

  10. Rare earth optogalvanic spectroscopy: preliminary results

    Energy Technology Data Exchange (ETDEWEB)

    Destro, Marcelo G.; Neri, Jose W.; Rodrigues, Nicolau A.S.; Silveira, Carlos A.B.; Riva, Rudimar [Instituto de Estudos Avancados (IEAv/EFO), Sao Jose dos Campos, SP (Brazil). Div. de Fotonica]. E-mail: destro@ieav.cta.br; Victor, Alessandro R. [Instituto Tecnologico de Aeronautica (ITA), Sao Jose dos Campos, SP (Brazil)

    2008-07-01

    The IEAv has special interest in the studies of rare earth isotope applications in laser medium and integrated optics as well as aerospace research. We are starting to work with Ytterbium, Erbium, Dysprosium and Neodymium laser selective photoionization research. This paper describes the preliminary results of emission and optogalvanic spectroscopy obtained from a Neodymium hollow cathode lamps. Furthermore these results were used to setup our laser systems to work to leads a Nd isotopes selective laser photoionization. (author)

  11. Quantum chromodynamics results from HERA and JLAB

    Indian Academy of Sciences (India)

    Katja Krüger

    2012-10-01

    Recent QCD results from electron–proton interactions at HERA and JLAB are presented. Inclusive cross-section measurements as well as studies of the hadronic final state like jet production or the production of heavy quarks are discussed. The results are compared with perturbative QCD predictions and their impact on the determination of the parton density functions of the proton as well as of the strong coupling α s is discussed.

  12. Some results on stability of difference systems

    Directory of Open Access Journals (Sweden)

    Xiao-Song Yang

    2002-01-01

    Full Text Available This paper presents some new results on existence and stability of equilibrium or periodic points for difference systems. First sufficient conditions of existence of asymptotically stable equilibrium point as well as the asymptotic stability of given equilibrium point are given for second order or delay difference systems. Then some similar results on existence of asymptotically stable periodic (equilibrium points to general difference systems are presented.

  13. Results from STAR experiment at RHIC

    Indian Academy of Sciences (India)

    Bedangadas Mohanty; STAR Collaboration

    2006-11-01

    We present some of the important experimental results from nucleus–nucleus collision studies carried out by the STAR experiment at Relativistic Heavy Ion Collider (RHIC). The results suggests that central Au+Au collisions at RHIC has produced a dense and rapidly thermalizing matter with initial energy densities above the critical values predicted by lattice QCD for establishment of a quark-gluon plasma (QGP).

  14. Preliminary results of noise radar experiments

    Science.gov (United States)

    Malanowski, Mateusz; Contartese, Clara; Maslikowski, Lukasz; Baczyk, Marcin; Kulpa, Krzysztof

    2009-06-01

    The paper describes the first results of noise radar experiments carried out at Warsaw University of Technology. The radar system was built with Commercial Off-The-Shelf (COTS) components: log-periodic antennas, an arbitrary waveform generator and a two-channel spectrum analyzer. The radar operated in the continuous-wave mode, and the aim was to detect moving targets in the received signal. The paper shows the system setup as well as the numerical results obtained from the recorded signals.

  15. Visualizing search results: evaluating an iconic visualization

    Science.gov (United States)

    Erfani Joorabchi, M.; Dalvandi, A.; Seifi, H.; Bartram, L.; Shaw, C. D.

    2010-01-01

    Commercial websites offer many items to potential site users. However, most current websites display results of a search in text lists, or as lists sorted on one or two single criteria. Finding the best item in a text list based on multi-priority criteria is an exhausting task, especially for long lists. Visualizing search results and enabling users to perceive the tradeoffs among the results based on multiple priorities may ease this process. To investigate this, two different techniques for displaying and sorting search results are studied in this paper; Text, and XY Iconic Visualization. The goal is to determine which technique for representing search results would be the most efficient one for a website user. We conducted a user study to compare the usability of the two techniques. Collected data is in the form of participants' task responses, a satisfaction questionnaire, qualitative observations, and participants' comments. According to the results, iconic visualization is better for overview (it gives a good overview in a short amount of time) and search with more than two criteria, while text-based performs better for displaying details.

  16. Proximal clavicle excision: an analysis of results.

    Science.gov (United States)

    Acus, R W; Bell, R H; Fisher, D L

    1995-01-01

    Medial clavicle excision has been reported by several authors, but few cases are documented, and long-term follow-up information is lacking. The purpose of this study was to examine the long-term results of medial clavicle excision in regard to function, pain, cosmesis, and complications. Fifteen patients ranging in age from 18 to 64 years (average 43 years) were evaluated an average of 4.6 years (range 1 to 14 years) after proximal clavicle excision. The indications for excision were unstable anterior subluxation/dislocation of the sternoclavicular joint (four cases), unstable posterior dislocation (one case), sternoclavicular osteoarthritis (nine cases), and proximal clavicle osteomyelitis (one case). An average of 2.9 cm of the medial clavicle was excised (range 1 to 4 cm). Fourteen of the 15 patients received significant relief of pain. On a strict grading scale four patients had an excellent result, five a good result, four a fair result, and two a poor result. Regeneration of the clavicle appeared to contribute to a poor result. No operative complications occurred. These findings aid our understanding of surgical options and outcome in the treatment of sternoclavicular joint disease.

  17. Web Search Results Summarization Using Similarity Assessment

    Directory of Open Access Journals (Sweden)

    Sawant V.V.

    2014-06-01

    Full Text Available Now day’s internet has become part of our life, the WWW is most important service of internet because it allows presenting information such as document, imaging etc. The WWW grows rapidly and caters to a diversified levels and categories of users. For user specified results web search results are extracted. Millions of information pouring online, users has no time to surf the contents completely .Moreover the information available is repeated or duplicated in nature. This issue has created the necessity to restructure the search results that could yield results summarized. The proposed approach comprises of different feature extraction of web pages. Web page visual similarity assessment has been employed to address the problems in different fields including phishing, web archiving, web search engine etc. In this approach, initially by enters user query the number of search results get stored. The Earth Mover's Distance is used to assessment of web page visual similarity, in this technique take the web page as a low resolution image, create signature of that web page image with color and co-ordinate features .Calculate the distance between web pages by applying EMD method. Compute the Layout Similarity value by using tag comparison algorithm and template comparison algorithm. Textual similarity is computed by using cosine similarity, and hyperlink analysis is performed to compute outward links. The final similarity value is calculated by fusion of layout, text, hyperlink and EMD value. Once the similarity matrix is found clustering is employed with the help of connected component. Finally group of similar web pages i.e. summarized results get displayed to user. Experiment conducted to demonstrate the effectiveness of four methods to generate summarized result on different web pages and user queries also.

  18. Predictive aging results in radiation environments

    Science.gov (United States)

    Gillen, Kenneth T.; Clough, Roger L.

    1993-06-01

    We have previously derived a time-temperature-dose rate superposition methodology, which, when applicable, can be used to predict polymer degradation versus dose rate, temperature and exposure time. This methodology results in predictive capabilities at the low dose rates and long time periods appropriate, for instance, to ambient nuclear power plant environments. The methodology was successfully applied to several polymeric cable materials and then verified for two of the materials by comparisons of the model predictions with 12 year, low-dose-rate aging data on these materials from a nuclear environment. In this paper, we provide a more detailed discussion of the methodology and apply it to data obtained on a number of additional nuclear power plant cable insulation (a hypalon, a silicone rubber and two ethylene-tetrafluoroethylenes) and jacket (a hypalon) materials. We then show that the predicted, low-dose-rate results for our materials are in excellent agreement with long-term (7-9 year) low-dose-rate results recently obtained for the same material types actually aged under bnuclear power plant conditions. Based on a combination of the modelling and long-term results, we find indications of reasonably similar degradation responses among several different commercial formulations for each of the following "generic" materials: hypalon, ethylene-tetrafluoroethylene, silicone rubber and PVC. If such "generic" behavior can be further substantiated through modelling and long-term results on additional formulations, predictions of cable life for other commercial materials of the same generic types would be greatly facilitated.

  19. Planck 2015 results: XIII. Cosmological parameters

    DEFF Research Database (Denmark)

    Ade, P. A R; Aghanim, N.; Arnaud, M.

    2016-01-01

    on annihilating dark matter and on possible deviations from the standard recombination history. In neither case do we find no evidence for new physics. The Planck results for base ΛCDM are in good agreement with baryon acoustic oscillation data and with the JLA sample of Type Ia supernovae. However......This paper presents cosmological results based on full-mission Planck observations of temperature and polarization anisotropies of the cosmic microwave background (CMB) radiation. Our results are in very good agreement with the 2013 analysis of the Planck nominal-mission temperature data......, but with increased precision. The temperature and polarization power spectra are consistent with the standard spatially-flat 6-parameter ΛCDM cosmology with a power-law spectrum of adiabatic scalar perturbations (denoted "base ΛCDM" in this paper). From the Planck temperature data combined with Planck lensing...

  20. New and Improved Results from Daya Bay

    CERN Document Server

    CERN. Geneva

    2017-01-01

    Despite the great progress achieved in the last decades, neutrinos remain among the least understood fundamental particles to have been experimentally observed. The Daya Bay Reactor Neutrino Experiment consists of eight identically designed detectors placed underground at different baselines from three groups of nuclear reactors in China, a configuration that is ideally suited for studying the properties of these elusive particles. In this talk I will review the improved results released last summer by the Daya Bay collaboration. These results include (i) a precision measurement of the θ13 mixing angle and the effective mass splitting in the electron antineutrino disappearance channel with a dataset comprising more than 2.5 million antineutrino interactions, (ii) a high-statistics measurement of the absolute flux and spectrum of reactor-produced electron antineutrinos, and (iii) a search for light sterile neutrino mixing performed with more than three times the statistics of the previous result. I w...

  1. Results from the Double Chooz experiment

    Directory of Open Access Journals (Sweden)

    Kaneda Michiru

    2016-01-01

    Full Text Available Recent results from the Double Chooz experiment on the neutrino mixing angle θ13 are presented. Two detectors are located at distances of 400m and 1050m from the reactor cores of the Chooz nuclear power plant, to measure the original neutrino flux from the reactor cores and the disappearance of neutrinos, respectively. The Far Detector has taken data since 2011 while the Near Detector started the data taking in 2014. The latest far detector only result with gadolinium capture events is sin2 2θ13=0.090+0.032.-0.029. Studies using hydrogen capture events also have been improved and the combined result of gadolinium and hydrogen capture events is obtained as sin2 2θ13 = 0.088 ± 0.033.

  2. Livermore Big Trees Park: 1998 Results

    Energy Technology Data Exchange (ETDEWEB)

    Mac Queen, D; Gallegos, G; Surano, K

    2002-04-18

    This report is an in-depth study of results from environmental sampling conducted in 1998 by the Lawrence Livermore National Laboratory (LLNL) at Big Trees Park in the city of Livermore. The purpose of the sampling was to determine the extent and origin of plutonium found in soil at concentrations above fallout-background levels in the park. This report describes the sampling that was conducted, the chemical and radio-chemical analyses of the samples, the quality control assessments and statistical analyses of the analytical results, and LLNL's interpretations of the results. It includes a number of data analyses not presented in LLNL's previous reports on Big Trees Park.

  3. Adaptive structures - Test hardware and experimental results

    Science.gov (United States)

    Wada, Ben K.; Fanson, James L.; Chen, Gun-Shing; Kuo, Chin-Po

    1990-01-01

    The facilities and procedures used at JPL to test adaptive structures such as the large deployable reflector (LDR) are described and preliminary results are reported. The applications of adaptive structures in future NASA missions are outlined, and the techniques which are employed to modify damping, stiffness, and isolation characteristics, as well as geometric changes, are listed. The development of adaptive structures is shown to be effective as a result of new actuators and sensors, and examples are listed for categories such as fiber optics, shape-memory materials, piezoelectrics, and electrorheological fluids. Some ground test results are described for laboratory truss structures and truss test beds, which are shown to be efficient and easy to assemble in space. Adaptive structures are shown to be important for precision space structures such as the LDR, and can alleviate ground test requirements.

  4. Preliminary results in surgery of Parkinson's disease.

    Science.gov (United States)

    Nasser, J A; Confort, C I; Ferraz, A; Bouza, A A

    1998-09-01

    The authors present the preliminary results of 20 patients selected to be operated on between January 1996 and April 1997. These patients presented one of the present indications for stereotactic posteroventral pallidotomy (PVP), such as: rigidity, akinesia/bradykinesia, gait dysfunction, drug induced dyskinesias and tremor. Every patient of this protocol was evaluated by: UPDRS score, Schwab and England scale, Hoehn and Yahr Staging Scale before and after surgery. The results in 3 months showed a remarkable improvement after PVP (P < 0.01) in all functional assessments, except for facial expression, speech and posture. The morbidity was 5%. 5 patients (25%) who were in Hoehn and Yahr 5 underwent a bilateral simultaneous PVP. In 5 patients (25%), who had tremor, during the PVP, VIM thalamotomy was added. These preliminary results, suggest that PVP is highly effective for PD symptoms.

  5. Efficient Diversification of Web Search Results

    CERN Document Server

    Capannini, Gabriele; Perego, Raffaele; Silvestri, Fabrizio

    2011-01-01

    In this paper we analyze the efficiency of various search results diversification methods. While efficacy of diversification approaches has been deeply investigated in the past, response time and scalability issues have been rarely addressed. A unified framework for studying performance and feasibility of result diversification solutions is thus proposed. First we define a new methodology for detecting when, and how, query results need to be diversified. To this purpose, we rely on the concept of "query refinement" to estimate the probability of a query to be ambiguous. Then, relying on this novel ambiguity detection method, we deploy and compare on a standard test set, three different diversification methods: IASelect, xQuAD, and OptSelect. While the first two are recent state-of-the-art proposals, the latter is an original algorithm introduced in this paper. We evaluate both the efficiency and the effectiveness of our approach against its competitors by using the standard TREC Web diversification track test...

  6. Heavy Ion results from RHIC-BNL

    Directory of Open Access Journals (Sweden)

    Esumi Shinlchi

    2013-05-01

    Full Text Available Recent results from heavy ion collision experiments from RHIC at BNL are presented and discussed in terms of Quark Gluon Plasm properties, such as partonic collectivity and partonic energy loss. The experimental results with direct photons and heavy quarks have given important additional insights of the plasma on top of what has been known with light hadrons. Higher order event anisotropies and the related results have provided the geometrical, temporal and dynamical information of the plasma. The beam energy dependence of the various measurements could reveal the structure of QCD phase diagram and possibly the critical point in the diagram, where the properties of phase transition are expected to change drastically.

  7. How to present and publish research results

    Directory of Open Access Journals (Sweden)

    Dekanski Aleksandar

    2014-01-01

    Full Text Available The end of each research is to present its results to the public, especially to those who are engaged in similar research. This is particularly true for scientific research. Scientific paper is written report that contains a presentation of the results of the original scientific research. Its format is defined by centuries-old tradition of writing, the editorial practices of the publishers, scientific ethics, accepted standards and requirements of modern printing and publishing. Unfortunately, the experience of the publishers and editors of scientific books and journals show that a large number of submitted contributions are not meeting the minimum requirements to be even considered. This article indicates the most important principles that one should have in mind during creation of full text paper or presentation of scientific results.

  8. Nebraska wind resource assessment first year results

    Energy Technology Data Exchange (ETDEWEB)

    Hurley, P.J.F.; Vilhauer, R. [RLA Consulting, Inc., Bothell, WA (United States); Stooksbury, D. [Univ. of Nebraska, Lincoln, NE (United States)

    1996-12-31

    This paper presents the preliminary results from a wind resource assessment program in Nebraska sponsored by the Nebraska Power Association. During the first year the measured annual wind speed at 40 meters ranged from 6.5 - 7.5 m/s (14.6 - 16.8 mph) at eight stations across the state. The site selection process is discussed as well as an overview of the site characteristics at the monitoring locations. Results from the first year monitoring period including data recovery rate, directionality, average wind speeds, wind shear, and turbulence intensity are presented. Results from the eight sites are qualitatively compared with other midwest and west coast locations. 5 figs., 2 tabs.

  9. An overview of recent ATLAS results

    CERN Document Server

    Nikolic-Audit, Irena; The ATLAS collaboration

    2013-01-01

    The ATLAS experiment at the LHC collider has been successfully taking data since the end of 2009, both in proton-proton collisions at center of mass energies of 7 and 8 TeV, and in heavy ion collisions. The ATLAS detector has been designed to cover a wide range of physics topics, from the search for the Higgs boson, precision measurements of Standard Model physics, heavy flavor physics, and to maximize the potential for the discovery of new physics. In this presentation, some of the most important recent ATLAS results will be given for the Standard Model measurements, for the searches for supersymmetry and exotica, and for the heavy ion results. All of the results concerning the properties of the newly discovered Higgs boson are presented in a separate contribution by IlyaTsukerman \\cite{higgs} in these proceedings.

  10. Annotating images by mining image search results.

    Science.gov (United States)

    Wang, Xin-Jing; Zhang, Lei; Li, Xirong; Ma, Wei-Ying

    2008-11-01

    Although it has been studied for years by the computer vision and machine learning communities, image annotation is still far from practical. In this paper, we propose a novel attempt at model-free image annotation, which is a data-driven approach that annotates images by mining their search results. Some 2.4 million images with their surrounding text are collected from a few photo forums to support this approach. The entire process is formulated in a divide-and-conquer framework where a query keyword is provided along with the uncaptioned image to improve both the effectiveness and efficiency. This is helpful when the collected data set is not dense everywhere. In this sense, our approach contains three steps: 1) the search process to discover visually and semantically similar search results, 2) the mining process to identify salient terms from textual descriptions of the search results, and 3) the annotation rejection process to filter out noisy terms yielded by Step 2. To ensure real-time annotation, two key techniques are leveraged-one is to map the high-dimensional image visual features into hash codes, the other is to implement it as a distributed system, of which the search and mining processes are provided as Web services. As a typical result, the entire process finishes in less than 1 second. Since no training data set is required, our approach enables annotating with unlimited vocabulary and is highly scalable and robust to outliers. Experimental results on both real Web images and a benchmark image data set show the effectiveness and efficiency of the proposed algorithm. It is also worth noting that, although the entire approach is illustrated within the divide-and conquer framework, a query keyword is not crucial to our current implementation. We provide experimental results to prove this.

  11. Latest results from the Pierre Auger Observatory

    Directory of Open Access Journals (Sweden)

    Lhenry-Yvon Isabelle

    2016-01-01

    Full Text Available The Pierre Auger Observatory has been designed to investigate the origin and nature of Ultra High Energy Cosmic Rays (UHECR with energies from 1017 to 1020 eV. In this paper we will review some of the most recent results obtained from data of the Pierre Auger Observatory, namely the spectrum of cosmic rays, the anisotropies in arrival directions and the studies related to mass composition and to the number of muons measured at the ground. We will also discuss the implication of these results for assembling a consistent description of the composition, origin and propagation of cosmic rays.

  12. First results of the CAKE experiment

    Energy Technology Data Exchange (ETDEWEB)

    Chiarusi, T. E-mail: chiarusi@bo.infn.it; Bottazzi, E.; Cecchini, S.; Di Ferdinando, D.; Giacomelli, G.; Kumar, A.; Patrizii, L.; Togo, V.; Valieri, C

    2003-06-01

    We present the preliminary results of the cosmic abundances below the knee energies (CAKE) experiment for the study of the primary cosmic-ray composition and for the search of exotic particles in the primary cosmic radiation. CAKE uses CR39[reg] and Lexan nuclear track detectors, which were calibrated with beams of 158 A GeV Pb ions and 1 A GeV Fe ions at the CERN and BNL accelerators, respectively. Results based on the analysis of a first data sample are shown.

  13. Latest results from the Pierre Auger Observatory

    Science.gov (United States)

    Lhenry-Yvon, Isabelle

    2016-07-01

    The Pierre Auger Observatory has been designed to investigate the origin and nature of Ultra High Energy Cosmic Rays (UHECR) with energies from 1017 to 1020 eV. In this paper we will review some of the most recent results obtained from data of the Pierre Auger Observatory, namely the spectrum of cosmic rays, the anisotropies in arrival directions and the studies related to mass composition and to the number of muons measured at the ground. We will also discuss the implication of these results for assembling a consistent description of the composition, origin and propagation of cosmic rays.

  14. Scientific results of the Mars Pathfinder mission.

    Science.gov (United States)

    Golombek, M. P.

    1999-02-01

    The author, project scientist of the Mars Pathfinder mision, presents a summary of the most important scientific results from the space probe, which descended to the Martian surface on July 4, 1997. These results include the strong evidence for catastrophic water floods in the history of the planet; close-up studies of the morphology and mineralogy of Martian rocks; the characteristics, chemistry, and origin of the magnetic dust particles deposited on the Martian surface; and meteorological measurements of temperature fluctuations, pressure variations, and wind velocities.

  15. SMART-1 results and future lunar exploration

    Science.gov (United States)

    Foing, Bernard H.

    2008-04-01

    We present some highlights from SMART-1's science and technology payload, and the relevance of SMART-1 results and lessons for future lunar exploration. SMART-1 is the first ESA mission that reached the Moon. It is the first of Small Missions for Advanced Research and Technology. It has fulfilled its technology objectives to demonstrate Solar Electric Primary Propulsion (SEP) and to test new technologies for spacecraft and instruments. After a 15-month cruise with primary SEP and successful technology demonstration, the SMART-1 science and exploration phase, provided first lunar orbit results. The mission has been extended one year and ended with an impact on 3 September 2006.

  16. Establishing precision and accuracy in PDV results

    Energy Technology Data Exchange (ETDEWEB)

    Briggs, Matthew E. [Los Alamos National Lab. (LANL), Los Alamos, NM (United States); Howard, Marylesa [National Security Technologies, LLC. (NSTec), North Las Vegas, NV (United States); Diaz, Abel [National Security Technologies, LLC. (NSTec), Los Alamos, NM (United States)

    2016-04-19

    We need to know uncertainties and systematic errors because we create and compare against archival weapons data, we constrain the models, and we provide scientific results. Good estimates of precision from the data record are available and should be incorporated into existing results; reanalysis of valuable data is suggested. Estimates of systematic errors are largely absent. The original work by Jensen et al. using gun shots for window corrections, and the integrated velocity comparison with X-rays by Schultz are two examples where any systematic errors appear to be <1% level.

  17. BSM Higgs results from ATLAS and CMS

    Directory of Open Access Journals (Sweden)

    Flechl Martin

    2013-11-01

    Full Text Available Résumé. Searches for Higgs bosons in different extensions of the Standard Model (SM are presented. These include the Minimal Supersymmetric extension of the SM (MSSM, the next-to-MSSM (NMSSM, models with additional scalar singlets, doublets, or triplets, and generic searches for models with couplings modified with respect to the SM or for non-SM Higgs boson decay channels. Results are based on data collected by the ATLAS and CMS experiments in 2011 and 2012 at the LHC. No excess is found in any of the searches and thus the resulting exclusion limits are given.

  18. Some Results on Halo Research at RIBLL

    Institute of Scientific and Technical Information of China (English)

    2001-01-01

    Last years,several experiments about halo nuclei were performed at RIBLL.On the analyzing and fitting the data by using Glauber theory with some assumptions,following some results were deduced.1.~8B shows a proton halo structure.The reaction cross section σR of 54 MeV/u~8B on Si was measured as 1634±49 mb.The density distribution of ~8B was studied through a fitting procedure on the enhancement of the σR at low energies including the high energy data by using Glauber theory.The result shows a long tail ...

  19. Latest results in rare decays at LHCb

    CERN Document Server

    Kreps, Michal

    2014-01-01

    Recent results from the LHCb experiment on decays governed by $b \\rightarrow s\\mu^+\\mu^-$ or $b\\rightarrow s\\gamma$ transitions are reviewed. The updated isospin asymmetry in $B \\rightarrow K^{(*)} \\mu^+\\mu^-$ decay are in good agreement with the Standard Model. Results of the angular analysis of $B \\rightarrow K\\mu^+ \\mu^-$ decay help to exclude large cancellation between left- and right-handed couplings in the $B^0_s \\rightarrow \\mu^+\\mu^-$ decay. Finally using the decay $B^+ \\rightarrow K^+\\pi^-\\pi^+\\gamma$, nonzero photon polarization is observed for the first time in $b\\rightarrow s\\gamma$ transitions.

  20. [Preliminary results of treatment with aflibercept].

    Science.gov (United States)

    Blăjan, Codruta; Nicula, D; Rusu, Ioana

    2014-01-01

    The paper presents the first results concerning the Aflibercept (Eylea) treatment, the last antiVEGF approved for treatment of the age related macular degeneration (AMD), neovascular form and for macular edema due to the central retinal vein occlusion. The treatment was applied to patients presenting AMD, ME and other diseases: myopic and idiopatic choroidal neovascularisation, central serous choroidopathy (CSC) or diabetic macular edema (DME). The results were good: improvement of the visual acuity, resolution of the intraretinal fluids and macular edema. Although we did not notice major side-effects, resistance or tachyphylaxis, we noticed some recurrences.

  1. Recent QCD Results from the Tevatron

    Energy Technology Data Exchange (ETDEWEB)

    Vellidis, Costas [Fermilab

    2015-10-10

    Four years after the shutdown of the Tevatron proton-antiproton collider, the two Tevatron experiments, CDF and DZero, continue producing important results that test the theory of the strong interaction, Quantum Chromodynamics (QCD). The experiments exploit the advantages of the data sample acquired during the Tevatron Run II, stemming from the unique pp initial state, the clean environment at the relatively low Tevatron instantaneous luminosities, and the good understanding of the data sample after many years of calibrations and optimizations. A summary of results using the full integrated luminosity is presented, focusing on measurements of prompt photon production, weak boson production associated with jets, and non-perturbative QCD processes.

  2. Predictions of High Energy Experimental Results

    Directory of Open Access Journals (Sweden)

    Comay E.

    2010-10-01

    Full Text Available Eight predictions of high energy experimental results are presented. The predictions contain the $Sigma ^+$ charge radius and results of two kinds of experiments using energetic pionic beams. In addition, predictions of the failure to find the following objects are presented: glueballs, pentaquarks, Strange Quark Matter, magnetic monopoles searched by their direct interaction with charges and the Higgs boson. The first seven predictions rely on the Regular Charge-Monopole Theory and the last one relies on mathematical inconsistencies of the Higgs Lagrangian density.

  3. Quark Hadron Duality - Recent Jefferson Lab Results

    CERN Document Server

    Niculescu, Ioana

    2015-01-01

    The duality between the partonic and hadronic descriptions of electron--nucleon scattering is a remarkable feature of nuclear interactions. When averaged over appropriate energy intervals the cross section at low energy which is dominated by nucleon resonances resembles the smooth behavior expected from perturbative QCD. Recent Jefferson Lab results indicate that quark-hadron duality is present in a variety of observables, not just the proton F2 structure function. An overview of recent results, especially local quark-hadron duality on the neutron, are presented here.

  4. Excited random walks: results, methods, open problems

    CERN Document Server

    Kosygina, Elena

    2012-01-01

    We consider a class of self-interacting random walks in deterministic or random environments, known as excited random walks or cookie walks, on the d-dimensional integer lattice. The main purpose of this paper is two-fold: to give a survey of known results and some of the methods and to present several new results. The latter include functional limit theorems for transient one-dimensional excited random walks in bounded i.i.d. cookie environments as well as some zero-one laws. Several open problems are stated.

  5. First results of the CAKE experiment

    CERN Document Server

    Chiarusi, T; Cecchini, S; Di Ferdinando, D; Giacomelli, G; Kumar, A; Patrizii, L; Togo, V; Valieri, C

    2003-01-01

    We present the preliminary results of the cosmic abundances below the knee energies (CAKE) experiment for the study of the primary cosmic- ray composition and for the search of exotic particles in the primary cosmic radiation. CAKE uses CR39** registered trademark and Lexan nuclear track detectors, which were calibrated with beams of 158 A Ge V Pb ions and 1 A GeV Fe ions at the CERN and BNL accelerators, respectively. Results based on the analysis of a first data sample are shown.

  6. Resummed Results for Hadron Collider Observables

    Science.gov (United States)

    McAslan, Heather

    2016-07-01

    Event shapes are invaluable QCD tools for theoretical calculations and experimental measurements. We revise the definition of these observables in e+e- annihilation and in hadron collisions, and give a review of the state-of-the-art results for their resummation. Then we detail how recent work on the re-summation of event shapes in electron-positron annihilation can provide us with the tools to extend resummation of generic hadronic event shapes to NNLL accuracy. We match our findings to fixed-order results at NNLO accuracy, showing the sizeable effects of resummation in the relevant regions of phase space.

  7. Resummed Results for Hadron Collider Observables

    Directory of Open Access Journals (Sweden)

    McAslan Heather

    2016-01-01

    Full Text Available Event shapes are invaluable QCD tools for theoretical calculations and experimental measurements. We revise the definition of these observables in e+e− annihilation and in hadron collisions, and give a review of the state-of-the-art results for their resummation. Then we detail how recent work on the re-summation of event shapes in electron-positron annihilation can provide us with the tools to extend resummation of generic hadronic event shapes to NNLL accuracy. We match our findings to fixed-order results at NNLO accuracy, showing the sizeable effects of resummation in the relevant regions of phase space.

  8. Latest oscillation results from T2K

    CERN Document Server

    Khabibullin, Marat

    2011-01-01

    The latest oscillation results obtained in the off-axis accelerator neutrino experiment T2K are presented. In the data sample, corresponding to 1.43 x 10^20 protons on target, 6 electron neutrino candidate events pass the selection criteria, while the expected number of background events for sin^2 2\\theta_{13}=0 is 1.5 \\pm 0.3 (syst.). The probability to observe six or more candidate events due to background is 0.7%, equivalent to 2.5-sigma significance. In the muon neutrino disappearance analysis the obtained atmospheric oscillation parameters are consistent with results from the Super-Kamiokande and MINOS experiments.

  9. Some recent results of the CODALEMA experiment

    CERN Document Server

    Rebai, Ahmed

    2012-01-01

    Codalema is one of the experiments devoted to the detection of ultra high energy cosmic rays by the radio method. The main objective is to study the features of the radio signal induced by the development in the atmosphere of extensive air showers (EAS) generated by cosmic rays in the energy range of 10 PeV-1 EeV . After a brief presentation of the detector features, the main results obtained are reported (emission mechanism, lateral distribution of the electric field, energy calibration, etc.). The first studies of the radio wave front curvature are discussed as new preliminary results.

  10. Some New Results on Transition Probability

    Institute of Scientific and Technical Information of China (English)

    Yu Quan XIE

    2008-01-01

    In this paper, we study the basic properties of stationary transition probability of Markov processes on a general measurable space (E, ε), such as the continuity, maximum probability, zero point, positive probability set standardization, and obtain a series of important results such as Continuity Theorem, Representation Theorem, Levy Theorem and so on. These results are very useful for us to study stationary tri-point transition probability on a general measurable space (E, ε). Our main tools such as Egoroff's Theorem, Vitali-Hahn-Saks's Theorem and the theory of atomic set and well-posedness of measure are also very interesting and fashionable.

  11. Quark Hadron Duality - Recent Jefferson Lab Results

    Energy Technology Data Exchange (ETDEWEB)

    Niculescu, Maria Ioana [James Madison Univ., Harrisonburg, VA (United States); Thomas Jefferson National Accelerator Facility (TJNAF), Newport News, VA (United States)

    2016-08-01

    The duality between the partonic and hadronic descriptions of electron--nucleon scattering is a remarkable feature of nuclear interactions. When averaged over appropriate energy intervals the cross section at low energy which is dominated by nucleon resonances resembles the smooth behavior expected from perturbative QCD. Recent Jefferson Lab results indicate that quark-hadron duality is present in a variety of observables, not just the proton F2 structure function. An overview of recent results, especially local quark-hadron duality on the neutron, are presented here.

  12. Recent Results of the CMS Experiment

    Science.gov (United States)

    Dorigo, Tommaso

    2016-11-01

    The CMS experiment has produced a large number of new measurements with data collected during Run 1 by the CERN Large Hadron Collider (LHC). In this report a few results in Higgs and top physics will be mentioned. After a shutdown in 2013 and 2014, the LHC restarted proton-proton collisions at the unprecedented center-of-mass energy of 13 TeV in June 2015. The data collected until August 2015 have yielded interesting events and allowed the extraction of the first results of searches at the high-energy end of mass spectra, where the effect of the higher collision energy is largest.

  13. Results from combined CMS-TOTEM data

    CERN Document Server

    Sen, Sercan

    2016-01-01

    The combined data taking of the CMS and TOTEM experiments allows to characterize hadronic final states in an extremely wide pseudo-rapidity range and opens up a window to a rich diffractive/forward physics program. In this paper, the trigger strategy of the common data taking is described, and the physics results from combined CMS-TOTEM data is presented.

  14. SOME RESULTS OF MODULAR LIE SUPERALGEBRAS

    Institute of Scientific and Technical Information of China (English)

    2006-01-01

    In the present article, the authors give some properties on subinvariant subalgebras of modular Lie superalgebras and obtain the derivation tower theorem of modular Lie superalgebras, which is analogous to the automorphism tower theorem of finite groups.Moreover, they announce and prove some results of modular complete Lie superalgebras.

  15. A partially static turbine - first experimental results

    Energy Technology Data Exchange (ETDEWEB)

    Grassmann, H.; Bet, F.; Cabras, G.; Ceschia, M.; Cobai, D.; DelPapa, C. [Universitadi Udine (Italy). Dpto. di Fisica

    2003-09-01

    Recently it has been shown in a fluidodynamic simulation, that a wing-profiled structure of rather small size placed in the vicinity of a wind turbine augments the power of the wind turbine. In this paper we present the first experimental results from a prototype. (author)

  16. Reverberation Mapping Results from MDM Observatory

    DEFF Research Database (Denmark)

    Denney, Kelly D.; Peterson, B. M.; Pogge, R. W.

    2010-01-01

    . We present results from a multi-month reverberation mapping campaign undertaken primarily at MDM Observatory with supporting observations from around the world. We measure BLR radii and black hole masses for six objects. The primary goal of this campaign was to obtain either new or improved Hß...

  17. Reverberation Mapping Results from MDM Observatory

    DEFF Research Database (Denmark)

    Denney, Kelly D.; Peterson, B. M.; Pogge, R. W.

    2009-01-01

    We present results from a multi-month reverberation mapping campaign undertaken primarily at MDM Observatory with supporting observations from around the world. We measure broad line region (BLR) radii and black hole masses for six objects. A velocity-resolved analysis of the H_beta response shows...

  18. STABILITY RESULTS FOR GENERALIZED CONTRACTIVE MAPPINGS

    Institute of Scientific and Technical Information of China (English)

    2000-01-01

    Using a more general contractive definition, this paper continues the study on T-stable Ishikawa iteration procedure and generalizes most of the results of Harder and Hicks[1], Osilike[5] and Rhoades[6-8]. A note on [6][8] is also presented.

  19. Complaint studies: Methodological considerations and a result

    DEFF Research Database (Denmark)

    Juhl, Hans Jørn; Poulsen, Carsten Stig; Thøgersen, John

    are developed, ranging from the Rasch model via latent structure analysis with several correlated latent variables to suggestions about a comprehensive framework, combining Fishbein-Ajzen's Theory of Planned Behaviour and latent trait models. The empirical results show that the propensity to complain in Denmark...

  20. Diversifying Search Results with Popular Subtopics

    Science.gov (United States)

    2009-10-25

    previous results on diversity task. Carbonell and Goldstein [2] firstly introduced a preliminary model for diversity based reranking–maximal marginal...Data Mining, pages 5–14, New York, NY, USA, 2009. ACM. [2] J. Carbonell and J. Goldstein. The use of mmr, diversity-based reranking for reordering