Science.gov

Sample records for pras robotsilma pikesele

  1. Comparing PRAs with operating experience

    SciTech Connect

    Picard, R.R.; Martz, H.F.

    1998-12-01

    Probabilistic Risk Assessment is widely used to estimate the frequencies of rare events, such as nuclear power plant accidents. An obvious question concerns the extent to which PRAs conform to operating experience--that is, do PRAs agree with reality? The authors discuss a formal methodology to address this issue and examine its performance using plant-specific data.

  2. Observations on seismic probabilistic risk assessments (PRAs)

    SciTech Connect

    Smith, P.D.

    1984-06-01

    In this paper we present observations on a number of issues related to seismic PRAs including: strengths and weaknesses of seismic PRAs; uncertainty, sensitivity and variability; common misconceptions; possible improvements in seismic safety acceptance criteria; recommended modifications to the NRC approach to safety goals; and major problems. Some specific examples are provided.

  3. Ischemia-Induced Changes of PRAS40 and p-PRAS40 Immunoreactivities in the Gerbil Hippocampal CA1 Region After Transient Cerebral Ischemia.

    PubMed

    Park, Joon Ha; Shin, Bich Na; Ahn, Ji Hyeon; Cho, Jeong-Hwi; Kim, In Hye; Kim, Dae Won; Won, Moo-Ho; Hong, Seongkweon; Cho, Jun Hwi; Lee, Choong-Hyun

    2016-07-01

    Proline-rich Akt substrate of 40-kDa (PRAS40) is one of the important interactive linkers between Akt and mTOR signaling pathways. The increase of PRAS40 is related with the reduction of brain damage induced by cerebral ischemia. In the present study, we investigated time-dependent changes in PRAS40 and phospho-PRAS40 (p-PRAS40) immunoreactivities in the hippocampal CA1 region of the gerbil after 5 min of transient cerebral ischemia. PRAS40 immunoreactivity in the CA1 region was decreased in pyramidal neurons from 12 h after ischemic insult in a time-dependent manner, and, at 5 days post-ischemia, PRAS40 immunoreactivity was newly expressed in astrocytes. p-PRAS40 immunoreactivity in the CA1 pyramidal neurons was hardly found 12 h and apparently detected again 1 and 2 days after ischemic insult. At 5 days post-ischemia, p-PRAS40 immunoreactivity in the CA1 pyramidal neurons was not found. These results indicate that ischemia-induced changes in PRAS40 and p-PRAS40 immunoreactivities in CA1 pyramidal neurons and astrocytes may be closely associated with delayed neuronal death in the hippocampal CA1 region following transient cerebral ischemia. PMID:26526334

  4. Pathological hypertrophy amelioration by PRAS40-mediated inhibition of mTORC1

    PubMed Central

    Völkers, Mirko; Toko, Haruhiro; Doroudgar, Shirin; Din, Shabana; Quijada, Pearl; Joyo, Anya Y.; Ornelas, Luis; Joyo, Eri; Thuerauf, Donna J.; Konstandin, Mathias H.; Gude, Natalie; Glembotski, Christopher C.; Sussman, Mark A.

    2013-01-01

    Mechanistic target of rapamycin complex 1 (mTORC1), necessary for cellular growth, is regulated by intracellular signaling mediating inhibition of mTORC1 activation. Among mTORC1 regulatory binding partners, the role of Proline Rich AKT Substrate of 40 kDa (PRAS40) in controlling mTORC1 activity and cellular growth in response to pathological and physiological stress in the heart has never been addressed. This report shows PRAS40 is regulated by AKT in cardiomyocytes and that AKT-driven phosphorylation relieves the inhibitory function of PRAS40. PRAS40 overexpression in vitro blocks mTORC1 in cardiomyocytes and decreases pathological growth. Cardiomyocyte-specific overexpression in vivo blunts pathological remodeling after pressure overload and preserves cardiac function. Inhibition of mTORC1 by PRAS40 preferentially promotes protective mTORC2 signaling in chronic diseased myocardium. In contrast, strong PRAS40 phosphorylation by AKT allows for physiological hypertrophy both in vitro and in vivo, whereas cardiomyocyte-specific overexpression of a PRAS40 mutant lacking capacity for AKT-phosphorylation inhibits physiological growth in vivo, demonstrating that AKT-mediated PRAS40 phosphorylation is necessary for induction of physiological hypertrophy. Therefore, PRAS40 phosphorylation acts as a molecular switch allowing mTORC1 activation during physiological growth, opening up unique possibilities for therapeutic regulation of the mTORC1 complex to mitigate pathologic myocardial hypertrophy by PRAS40. PMID:23842089

  5. PRAS40 prevents development of diabetic cardiomyopathy and improves hepatic insulin sensitivity in obesity

    PubMed Central

    Völkers, Mirko; Doroudgar, Shirin; Nguyen, Nathalie; Konstandin, Mathias H; Quijada, Pearl; Din, Shabana; Ornelas, Luis; Thuerauf, Donna J; Gude, Natalie; Friedrich, Kilian; Herzig, Stephan; Glembotski, Christopher C; Sussman, Mark A

    2014-01-01

    Diabetes is a multi-organ disease and diabetic cardiomyopathy can result in heart failure, which is a leading cause of morbidity and mortality in diabetic patients. In the liver, insulin resistance contributes to hyperglycaemia and hyperlipidaemia, which further worsens the metabolic profile. Defects in mTOR signalling are believed to contribute to metabolic dysfunctions in diabetic liver and hearts, but evidence is missing that mTOR activation is causal to the development of diabetic cardiomyopathy. This study shows that specific mTORC1 inhibition by PRAS40 prevents the development of diabetic cardiomyopathy. This phenotype was associated with improved metabolic function, blunted hypertrophic growth and preserved cardiac function. In addition PRAS40 treatment improves hepatic insulin sensitivity and reduces systemic hyperglycaemia in obese mice. Thus, unlike rapamycin, mTORC1 inhibition with PRAS40 improves metabolic profile in diabetic mice. These findings may open novel avenues for therapeutic strategies using PRAS40 directed against diabetic-related diseases. PMID:24408966

  6. GENERIC, COMPONENT FAILURE DATA BASE FOR LIGHT WATER AND LIQUID SODIUM REACTOR PRAs

    SciTech Connect

    S. A. Eide; S. V. Chmielewski; T. D. Swantz

    1990-02-01

    A comprehensive generic component failure data base has been developed for light water and liquid sodium reactor probabilistic risk assessments (PRAs) . The Nuclear Computerized Library for Assessing Reactor Reliability (NUCLARR) and the Centralized Reliability Data Organization (CREDO) data bases were used to generate component failure rates . Using this approach, most of the failure rates are based on actual plant data rather than existing estimates .

  7. Generic component failure data base for light water and liquid sodium reactor PRAs (probabilistic risk assessments)

    SciTech Connect

    Eide, S.A.; Chmielewski, S.V.; Swantz, T.D.

    1990-02-01

    A comprehensive generic component failure data base has been developed for light water and liquid sodium reactor probabilistic risk assessments (PRAs). The Nuclear Computerized Library for Assessing Reactor Reliability (NUCLARR) and the Centralized Reliability Data Organization (CREDO) data bases were used to generate component failure rates. Using this approach, most of the failure rates are based on actual plant data rather than existing estimates. 21 refs., 9 tabs.

  8. PRAS40 deregulates apoptosis in Ewing sarcoma family tumors by enhancing the insulin receptor/Akt and mTOR signaling pathways

    PubMed Central

    Lv, Dan; Liu, Jinye; Guo, Lianying; Wu, Dawei; Matsumoto, Ken; Huang, Lin

    2016-01-01

    EWS expression in Ewing sarcoma family tumors (ESFTs) is decreased due to the haploinsufficiency elicited by chromosomal translocation. The abnormal expression levels of EWS and its downstream factors contribute to the manifestation of ESFTs. Previously, we reported that increased Proline-rich Akt substrate of 40 kDa (PRAS40), which is encoded by an EWS mRNA target, promotes the development of ESFTs. However, the mechanism remains elusive. To clarify the role of PRAS40 in ESFTs, we silenced PRAS40 expression in ESFT cells using siRNAs and found increased levels of terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL)-positive cells. Cleaved caspase 3 levels and cytochrome C release were increased simultaneously. Furthermore, with PRAS40 knockdown, the phosphorylation of Akt and mTOR downstream factors, i.e., S6K and S6, was attenuated notably. Ectopic expression of PRAS40 increased Akt and S6 phosphorylation. Activation of Akt only partially reversed the apoptosis induced by PRAS40 knockdown, and downregulation of S6 phosphorylation by PRAS40 silencing could not be sufficiently restored via Akt activation. Searching the upstream factors in this pathway, the autophosphorylation of insulin receptor (IR) was found to be inhibited significantly by PRAS40 silencing but increased by PRAS40 overexpression. Therefore, PRAS40 may enhance IR phosphorylation to facilitate Akt and mTOR signaling leading to the apoptosis deregulation in ESFTs. Moreover, in vivo results confirmed that PRAS40 deletion suppressed the growth of ESFT xenografts and downregulated IR and S6 phosphorylation. Our findings suggest a novel functioning model for PRAS40, which represents a novel therapeutic target for ESFTs. PMID:27186418

  9. AKT inhibition overcomes rapamycin resistance by enhancing the repressive function of PRAS40 on mTORC1/4E-BP1 axis

    PubMed Central

    Mi, Wenting; Ye, Qing; Liu, Side; She, Qing-Bai

    2015-01-01

    The mTORC1 inhibitors, rapamycin and its analogs, are known to show only modest antitumor activity in clinic, but the underlying mechanisms remain largely elusive. Here, we found that activated AKT signaling is associated with rapamycin resistance in breast and colon cancers by sustained phosphorylation of the translational repressor 4E-BP1. Treatment of tumor cells with rapamycin or the AKT inhibitor MK2206 showed a limited activity in inhibiting 4E-BP1 phosphorylation, cap-dependent translation, cell growth and motility. However, treatment with both drugs resulted in profound effects in vitro and in vivo. Mechanistic investigation demonstrated that the combination treatment was required to effectively inhibit PRAS40 phosphorylation on both Ser183 and Thr246 mediated by mTORC1 and AKT respectively, and with the combined treatment, dephosphorylated PRAS40 binding to the raptor/mTOR complex was enhanced, leading to dramatic repression of mTORC1-regulated 4E-BP1 phosphorylation and translation. Knockdown of PRAS40 or 4E-BP1 expression markedly reduced the dependence of tumor cells on AKT/mTORC1 signaling for translation and survival. Together, these findings reveal a critical role of PRAS40 as an integrator of mTORC1 and AKT signaling for 4E-BP1-mediated translational regulation of tumor cell growth and motility, and highlight PRAS40 phosphorylation as a potential biomarker to evaluate the therapeutic response to mTOR/AKT inhibitors. PMID:25961827

  10. Tuberin and PRAS40 are anti-apoptotic gatekeepers during early human amniotic fluid stem-cell differentiation.

    PubMed

    Fuchs, Christiane; Rosner, Margit; Dolznig, Helmut; Mikula, Mario; Kramer, Nina; Hengstschläger, Markus

    2012-03-01

    Embryoid bodies (EBs) are three-dimensional multicellular aggregates allowing the in vitro investigation of stem-cell differentiation processes mimicking early embryogenesis. Human amniotic fluid stem (AFS) cells harbor high proliferation potential, do not raise the ethical issues of embryonic stem cells, have a lower risk for tumor development, do not need exogenic induction of pluripotency and are chromosomal stable. Starting from a single human AFS cell, EBs can be formed accompanied by the differentiation into cells of all three embryonic germ layers. Here, we report that siRNA-mediated knockdown of the endogenous tuberous sclerosis complex-2 (TSC2) gene product tuberin or of proline-rich Akt substrate of 40 kDa (PRAS40), the two major negative regulators of mammalian target of rapamycin (mTOR), leads to massive apoptotic cell death during EB development of human AFS cells without affecting the endodermal, mesodermal and ectodermal cell differentiation spectrum. Co-knockdown of endogenous mTOR demonstrated these effects to be mTOR-dependent. Our findings prove this enzyme cascade to be an essential anti-apoptotic gatekeeper of stem-cell differentiation during EB formation. These data allow new insights into the regulation of early stem-cell maintenance and differentiation and identify a new role of the tumor suppressor tuberin and the oncogenic protein PRAS40 with the relevance for a more detailed understanding of the pathogenesis of diseases associated with altered activities of these gene products. PMID:22090422

  11. Transfer in Marine Sediments of the Naturally Occurring Plasmid pRAS1 Encoding Multiple Antibiotic Resistance

    PubMed Central

    Sandaa, Ruth-Anne; Enger, Øivind

    1994-01-01

    The results of microcosm experiments performed with the fish-pathogenic bacterium Aeromonas salmonicida acting as a donor showed that promiscuous plasmid pRAS1, which encodes tetracycline resistance, is transferred at a high frequency in marine sediments even in the absence of a selective factor. The presence of oxytetracycline resulted in an increase in the transfer frequency compared with that of a microcosm to which no selective factor was added. Transfer frequencies of 3.4 × 10-1 transconjugant per recipient and 3.6 transconjugants per donor cell were obtained in a microcosm to which oxytetracycline had been added. Hybridization with a DNA probe specific for plasmid pRAS1 revealed that 45.8% of the oxytetracycline-resistant isolates obtained from a microcosm with no selective pressure carried the plasmid, while 86.8% of the isolates obtained from a microcosm to which oxytetracycline had been added carried the plasmid. Phenotypic characterization of the transconjugants revealed that the plasmid had been transferred to a variety of different biotypes in both microcosms. The diversity among the transconjugants isolated from the microcosm to which oxytetracycline had been added was substantially lower than the diversity among the transconjugants isolated from the microcosm to which no selective agent had been added. PMID:16349453

  12. MYO6 knockdown inhibits the growth and induces the apoptosis of prostate cancer cells by decreasing the phosphorylation of ERK1/2 and PRAS40.

    PubMed

    Wang, Dong; Zhu, Libing; Liao, Min; Zeng, Tengyue; Zhuo, Wenli; Yang, Shunliang; Wu, Weizhen

    2016-09-01

    Prostate cancer is the second most frequently diagnosed cancer among males around the world. Myosin VI (MYO6), as a motor protein, has been reported to be implicated in cancer-related cell migration and cellular functions. To investigate the role of MYO6 in prostate cancer, immunohistochemical analysis was firstly applied to prostate cancer tissues and revealed that MYO6 was closely related with the Gleason score in prostate cancer. Then we used specific short hairpin RNA (shRNA) to downregulate MYO6 expression in DU145 and PC-3 cells and found that decreased MYO6 expression significantly suppressed cell proliferation, as determined by MTT and colony formation assays. Flow cytometry confirmed that the suppression of MYO6 promoted cell cycle arrest at the G2/M and sub-G1 phase in the DU145 cells. Furthermore, PathScan intracellular signaling array analysis demonstrated that the phosphorylation of ERK1/2 and PRAS40 was downregulated in the DU145 cells following MYO6 knockdown. Knockdown of MYO6 downregulated the expression of AKT3 and upregulated the expression of PARP, as confirmed by western blot analysis. These results suggest that MYO6 plays an essential role in the progression of prostate cancer and silencing of MYO6 may be a promising therapeutic approach for prostate cancer. PMID:27431378

  13. PF573,228 inhibits vascular tumor cell growth, migration as well as angiogenesis, induces apoptosis and abrogates PRAS40 and S6RP phosphorylation.

    PubMed

    Mabeta, Peace

    2016-09-01

    PF573,228 is a compound that targets focal adhesion kinase (FAK), a non-receptor protein kinase, which is over-expressed in various tumors. The aim of this study was to evaluate the effects of PF573,228 on the cells derived from mouse vascular tumors, namely, endothelioma cells. The treatment of endothelioma cells with PF573,228 reduced their growth with an IC50 of approximately 4.6 μmol L-1 and inhibited cell migration with an IC50 of about 0.01 μmol L-1. Microscopic studies revealed morphological attributes of apoptosis. These observations were confirmed by ELISA, which showed increased caspase-3 activity. PF573,228 also inhibited angiogenesis in a dose-dependent manner, with an IC50 of approximately 3.7 μmol L-1, and abrogated the phosphorylation of cell survival proteins, proline-rich Akt substrate (PRAS40) and S6 ribosomal protein (S6RP). Array data further revealed that PF573,228 induced caspase-3 activation, thus promoting apoptosis. Since all the processes inhibited by PF573,228 provide important support to tumor survival and progression, the drug may have a potential role in the treatment of vascular tumors. PMID:27383888

  14. Detection of Variants of the pRAS3, pAB5S9, and pSN254 Plasmids in Aeromonas salmonicida subsp. salmonicida: Multidrug Resistance, Interspecies Exchanges, and Plasmid Reshaping

    PubMed Central

    Vincent, Antony T.; Trudel, Mélanie V.; Paquet, Valérie E.; Boyle, Brian; Tanaka, Katherine H.; Dallaire-Dufresne, Stéphanie; Daher, Rana K.; Frenette, Michel; Derome, Nicolas

    2014-01-01

    The ubiquitous water-borne Gram-negative bacterium Aeromonas salmonicida subsp. salmonicida is the causative agent of furunculosis, a worldwide disease in fish farms. Plasmids carrying antibiotic resistance genes have already been described for this bacterium. The aim of the present study was to identify and characterize additional multidrug resistance plasmids in A. salmonicida subsp. salmonicida. We sequenced the plasmids present in two multiple antibiotic-resistant isolates using high-throughput technologies. We also investigated 19 other isolates with various multidrug resistance profiles by genotyping PCR and assessed their resistance to tetracycline. We identified variants of the pAB5S9 and pSN254 plasmids that carry several antibiotic resistance genes and that have been previously reported in bacteria other than A. salmonicida subsp. salmonicida, which suggests a high level of interspecies exchange. Genotyping analyses and the antibiotic resistance profiles of the 19 other isolates support the idea that multiple versions of pAB5S9 and pSN254 exist in A. salmonicida subsp. salmonicida. We also identified variants of the pRAS3 plasmid. The present study revealed that A. salmonicida subsp. salmonicida harbors a wide variety of plasmids, which suggests that this ubiquitous bacterium may contribute to the spread of antibiotic resistance genes in the environment. PMID:25267667

  15. Detection of variants of the pRAS3, pAB5S9, and pSN254 plasmids in Aeromonas salmonicida subsp. salmonicida: multidrug resistance, interspecies exchanges, and plasmid reshaping.

    PubMed

    Vincent, Antony T; Trudel, Mélanie V; Paquet, Valérie E; Boyle, Brian; Tanaka, Katherine H; Dallaire-Dufresne, Stéphanie; Daher, Rana K; Frenette, Michel; Derome, Nicolas; Charette, Steve J

    2014-12-01

    The ubiquitous water-borne Gram-negative bacterium Aeromonas salmonicida subsp. salmonicida is the causative agent of furunculosis, a worldwide disease in fish farms. Plasmids carrying antibiotic resistance genes have already been described for this bacterium. The aim of the present study was to identify and characterize additional multidrug resistance plasmids in A. salmonicida subsp. salmonicida. We sequenced the plasmids present in two multiple antibiotic-resistant isolates using high-throughput technologies. We also investigated 19 other isolates with various multidrug resistance profiles by genotyping PCR and assessed their resistance to tetracycline. We identified variants of the pAB5S9 and pSN254 plasmids that carry several antibiotic resistance genes and that have been previously reported in bacteria other than A. salmonicida subsp. salmonicida, which suggests a high level of interspecies exchange. Genotyping analyses and the antibiotic resistance profiles of the 19 other isolates support the idea that multiple versions of pAB5S9 and pSN254 exist in A. salmonicida subsp. salmonicida. We also identified variants of the pRAS3 plasmid. The present study revealed that A. salmonicida subsp. salmonicida harbors a wide variety of plasmids, which suggests that this ubiquitous bacterium may contribute to the spread of antibiotic resistance genes in the environment. PMID:25267667

  16. Dynamic modeling of physical phenomena for PRAs using neural networks

    SciTech Connect

    Benjamin, A.S.; Brown, N.N.; Paez, T.L.

    1998-04-01

    In most probabilistic risk assessments, there is a set of accident scenarios that involves the physical responses of a system to environmental challenges. Examples include the effects of earthquakes and fires on the operability of a nuclear reactor safety system, the effects of fires and impacts on the safety integrity of a nuclear weapon, and the effects of human intrusions on the transport of radionuclides from an underground waste facility. The physical responses of the system to these challenges can be quite complex, and their evaluation may require the use of detailed computer codes that are very time consuming to execute. Yet, to perform meaningful probabilistic analyses, it is necessary to evaluate the responses for a large number of variations in the input parameters that describe the initial state of the system, the environments to which it is exposed, and the effects of human interaction. Because the uncertainties of the system response may be very large, it may also be necessary to perform these evaluations for various values of modeling parameters that have high uncertainties, such as material stiffnesses, surface emissivities, and ground permeabilities. The authors have been exploring the use of artificial neural networks (ANNs) as a means for estimating the physical responses of complex systems to phenomenological events such as those cited above. These networks are designed as mathematical constructs with adjustable parameters that can be trained so that the results obtained from the networks will simulate the results obtained from the detailed computer codes. The intent is for the networks to provide an adequate simulation of the detailed codes over a significant range of variables while requiring only a small fraction of the computer processing time required by the detailed codes. This enables the authors to integrate the physical response analyses into the probabilistic models in order to estimate the probabilities of various responses.

  17. Treatment of uncertainties associated with PRAs in risk-informed decision making (NUREG1855).

    SciTech Connect

    Wheeler, Timothy A.

    2010-06-01

    This document provides guidance on how to treat uncertainties associated with probabilistic risk assessment (PRA) in risk-informed decisionmaking. The objectives of this guidance include fostering an understanding of the uncertainties associated with PRA and their impact on the results of PRA and providing a pragmatic approach to addressing these uncertainties in the context of the decisionmaking. In implementing risk-informed decisionmaking, the U.S. Nuclear Regulatory Commission expects that appropriate consideration of uncertainty will be given in the analyses used to support the decision and in the interpretation of the findings of those analyses. To meet the objective of this document, it is necessary to understand the role that PRA results play in the context of the decision process. To define this context, this document provides an overview of the risk-informed decisionmaking process itself. With the context defined, this document describes the characteristics of a risk model and, in particular, a PRA. This description includes recognition that a PRA, being a probabilistic model, characterizes aleatory uncertainty that results from randomness associated with the events of the model. Because the focus of this document is epistemic uncertainty (i.e., uncertainties in the formulation of the PRA model), it provides guidance on identifying and describing the different types of sources of epistemic uncertainty and the different ways that they are treated. The different types of epistemic uncertainty are parameter, model, and completeness uncertainties. The final part of the guidance addresses the uncertainty in PRA results in the context of riskinformed decisionmaking and, in particular, the interpretation of the results of the uncertainty analysis when comparing PRA results with the acceptance criteria established for a specified application. In addition, guidance is provided for addressing completeness uncertainty in risk-informed decision making. Such consideration includes using a program of monitoring, feedback, and corrective action.

  18. Use of energy policy research and/or analysis in congressional decision making

    SciTech Connect

    Ahiarah, S.C.O.

    1985-01-01

    Regardless of what anyone thinks about it, policy science, as conceived by Lasswell, has become a discipline that is breeding new professionals who are producing policy researches and/or analyses decision making. But are they so used - is the intended marriage between PRA information and public policy decision making taking place. Many think they are, although others are skeptical. This study goes beyond the question of whether or not PRAs are used in public policy decision making, to investigate the purposes for which they are used therein. The public-policy decision making context selected is the legislative (congressional) decision making occasions in energy issues between 1979 and 1982; the objects of use are the energy PRAs from three congressional support agencies - the General Accounting Office, the Office of Technology Assessment, and the Congressional Budget Office. The findings are that when use is defined as congressional admission of the PRAs, all support agency PRAs are used, but when use is defined in terms of Congress Considering or adapting the PRAs in its decision making contexts, only a portion of all the support agency PRAs get used. The PRAs that are consideratively or adaptively used are more likely to be used for enlightenment, position support, and/or symbolic-propagandistic purposes.

  19. Applications of the International Space Station Probabilistic Risk Assessment Model

    NASA Technical Reports Server (NTRS)

    Grant, Warren; Lutomski, Michael G.

    2011-01-01

    Recently the International Space Station (ISS) has incorporated more Probabilistic Risk Assessments (PRAs) in the decision making process for significant issues. Future PRAs will have major impact to ISS and future spacecraft development and operations. These PRAs will have their foundation in the current complete ISS PRA model and the current PRA trade studies that are being analyzed as requested by ISS Program stakeholders. ISS PRAs have recently helped in the decision making process for determining reliability requirements for future NASA spacecraft and commercial spacecraft, making crew rescue decisions, as well as making operational requirements for ISS orbital orientation, planning Extravehicular activities (EVAs) and robotic operations. This paper will describe some applications of the ISS PRA model and how they impacted the final decision. This paper will discuss future analysis topics such as life extension, requirements of new commercial vehicles visiting ISS.

  20. The role of NUREG-1150 in accident management

    SciTech Connect

    Camp, A.L.; Cramond, W.R.; Sype, T.T.

    1988-01-01

    NUREG-1150 is being prepared by the NRC and its contractors to estimate the risk from five commercial light water reactors: Surry, Sequoyah, Peach Bottom, Grand Gulf, and Zion. Level 3 probabilistic risk assessments (PRAs) are being prepared for each of these plants. These PRAs provide a framework for evaluating accident management alternatives from a risk standpoint. This paper describes the accident management benefits that NUREG-1150 is providing.

  1. Probabilistic risk assessment (PRA): status report and guidance for regulatory application. Draft report for comment

    SciTech Connect

    1984-02-01

    This document describes the current status of the methodologies used in probabilistic risk assessment (PRA) and provides guidance for the application of the results of PRAs to the nuclear reactor regulatory process. The PRA studies that have been completed or are underway are reviewed. The levels of maturity of the methodologies used in a PRA are discussed. Insights derived from PRAs are listed. The potential uses of PRA results for regulatory purposes are discussed.

  2. Applications of the International Space Station Probabilistic Risk Assessment Model

    NASA Astrophysics Data System (ADS)

    Grant, W.; Lutomski, M.

    2012-01-01

    The International Space Station (ISS) program is continuing to expand the use of Probabilistic Risk Assessments (PRAs). The use of PRAs in the ISS decision making process has proven very successful over the past 8 years. PRAs are used in the decision making process to address significant operational and design issues as well as to identify, communicate, and mitigate risks. Future PRAs are expected to have major impacts on not only the ISS, but also future NASA programs and projects. Many of these PRAs will have their foundation in the current ISS PRA model and in PRA trade studies that are being developed for the ISS Program. ISS PRAs have supported: -Development of reliability requirements for future NASA and commercial spacecraft, -Determination of inherent risk for visiting vehicles, -Evaluation of potential crew rescue scenarios, -Operational requirements and alternatives, -Planning of Extravehicular activities (EV As) and, -Evaluation of robotics operations. This paper will describe some applications of the ISS PRA model and how they impacted the final decisions that were made.

  3. REFLECTIONS ON THE ROLE OF THE PHARMACY REGULATORY AUTHORITY IN ENHANCING QUALITY RELATED EVENT REPORTING IN COMMUNITY PHARMACIESi

    PubMed Central

    Boyle, Todd A.; Bishop, Andrea C.; Mahaffey, Thomas; MacKinnon, Neil J.; Ashcroft, Darren; Zwicker, Bev; Reid, Carolyn

    2016-01-01

    Background Given the demanding nature of providing pharmacy services, coupled with the expanded scope of practice of the professions in jurisdictions around the world, greater commitment to continuous quality improvement through adoption of quality related event (QRE) reporting is necessary to ensure patient safety. Pharmacy regulatory authorities (PRAs) are in a unique position to enhance QRE reporting and learning through the standardization of expected practice Objective This study aims to better understand the perceived roles of PRAs in enhancing QRE reporting and learning in community pharmacies and identifying regulatory best practices to execute such roles. Methods A purposive case sampling approach was used to identify PRA staff members from two groups (deputy registrars and pharmacy inspectors) in 10 Canadian jurisdictions to participate in focus groups in the fall of 2011. Focus groups were used to explore perceptions of the role of PRAs in enhancing and promoting QRE reporting and learning, and perceived barriers to effective implementation in practice. Thematic analysis was used to analyze the qualitative data. Results Two focus groups were conducted, one with seven deputy registrars/practice managers and one with nine pharmacy inspectors. Five themes were identified, including (1) defining QRE reporting and compliance, (2) navigating role conflict, (3) educating for enhanced QRE reporting and learning, (4) promoting the positive/removing the fear of QREs, and (5) tailoring QRE reporting and learning consistency. Conclusions Overall, participants perceived a strong role for PRAs in enhancing QRE reporting and learning and providing education for pharmacies to support their compliance with reporting standards. However, PRAs must navigate the conflict inherent in both educating and promoting a process for achieving a standard while simultaneously inspecting compliance to that standard. Ensuring pharmacies have autonomy in operationalizing standards may

  4. Generic safety insights for inspection of boiling water reactors

    SciTech Connect

    Higgins, J.C.; Taylor, J.H.; Fresco, A.N.; Hillman, B.M.

    1987-01-01

    As the number of operating nuclear power plants (NPPs) increases, safety inspection has increased in importance. Over the last 2 yr, probabilistic risk assessment (PRA) techniques have been developed to aid in the inspection process. Broad interest in generic PRA-based methods has arisen in the past year, since only approx. 25% of the US nuclear power plants have completed PRAs, and also, inspectors want PRA-based tools for these plants. This paper describes the Brookhaven National Lab. program to develop generic boiling water reactor (BWR) PRA-based inspection insights or inspection guidance designed to be applied to plants without PRAs.

  5. 6- and 14-Fluoro farnesyl diphosphate: mechanistic probes for the reaction catalysed by aristolochene synthase.

    PubMed

    Miller, David J; Yu, Fanglei; Knight, David W; Allemann, Rudolf K

    2009-03-01

    The catalytic mechanism of the enzyme aristolochene synthase from Penicillium roqueforti (PR-AS) has been probed with the farnesyl diphosphate analogues 6- and 14-fluoro farnesyl diphosphate (1a and 1c). Incubation of these analogues with PR-AS followed by analysis of the reaction products by GC-MS and NMR spectroscopy indicated that these synthetic FPP analogues were converted to the fluorinated germacrene A analogues 3b and 3c, respectively. In both cases the position of the fluorine atom prevented the formation of the eudesmane cation analogues 4b and 4c. These results highlight that germacrene A is an on-path reaction intermediate during PR-AS catalysis and shed light on the mechanism by which germacrene A is converted to eudesmane cation. They support the proposal that the role of PR-AS in the cyclisation is essentially passive in that it harnesses the inherent chemical reactivity present in the substrate by promoting the initial ionisation of farnesyl diphosphate and by acting as a productive template to steer the reaction through an effective series of cyclisations and rearrangements to (+)-aristolochene (7a). PMID:19225680

  6. A Regional Decision Support Scheme for Pest Risk Analysis in Southeast Asia.

    PubMed

    Soliman, T; MacLeod, A; Mumford, J D; Nghiem, T P L; Tan, H T W; Papworth, S K; Corlett, R T; Carrasco, L R

    2016-05-01

    A key justification to support plant health regulations is the ability of quarantine services to conduct pest risk analyses (PRA). Despite the supranational nature of biological invasions and the close proximity and connectivity of Southeast Asian countries, PRAs are conducted at the national level. Furthermore, some countries have limited experience in the development of PRAs, which may result in inadequate phytosanitary responses that put their plant resources at risk to pests vectored via international trade. We review existing decision support schemes for PRAs and, following international standards for phytosanitary measures, propose new methods that adapt existing practices to suit the unique characteristics of Southeast Asia. Using a formal written expert elicitation survey, a panel of regional scientific experts was asked to identify and rate unique traits of Southeast Asia with respect to PRA. Subsequently, an expert elicitation workshop with plant protection officials was conducted to verify the potential applicability of the developed methods. Rich biodiversity, shortage of trained personnel, social vulnerability, tropical climate, agriculture-dependent economies, high rates of land-use change, and difficulties in implementing risk management options were identified as challenging Southeast Asian traits. The developed methods emphasize local Southeast Asian conditions and could help support authorities responsible for carrying out PRAs within the region. These methods could also facilitate the creation of other PRA schemes in low- and middle-income tropical countries. PMID:26919665

  7. Initiating Events for Multi-Reactor Plant Sites

    SciTech Connect

    Muhlheim, Michael David; Flanagan, George F.; Poore, III, Willis P.

    2014-09-01

    Inherent in the design of modular reactors is the increased likelihood of events that initiate at a single reactor affecting another reactor. Because of the increased level of interactions between reactors, it is apparent that the Probabilistic Risk Assessments (PRAs) for modular reactor designs need to specifically address the increased interactions and dependencies.

  8. Generic risk insights for Westinghouse and Combustion Engineering pressurized water reactors

    SciTech Connect

    Travis, R.; Taylor, J.; Fresco, A. ); Chung, J. )

    1990-11-01

    A methodology has been developed to extract generic risk-based information from probabilistic risk assessments (PRAs) of Westinghouse and Combustion Engineering (CE) pressurized water reactors (PWRs) and apply the insights gained to Westinghouse and Ce plants have not been subjected to a PRA. The available PRAs (five Westinghouse plants and one CE plant) were examined to identify the most probable, i.e., dominant accident sequences at each plant. The goal was to include all sequences which represented at least 80% of core damage frequency. If the same plant specific dominant accident sequence appeared within this boundary in at least two plant PRAs, the sequence was considered to be a representative sequence. Eleven sequences met this definition. From these sequences, the most important component failures and human errors that contributed to each sequence have been prioritized. Guidance is provided to prioritize the representative sequences and modify selected basic events that have been shown to be sensitive to the plant specific design or operating variations of the contributing PRAs. This risk-based guidance can be used for utility and NRC activities including operator training maintenance, design review, and inspections.

  9. Methodology and application of surrogate plant PRA analysis to the Rancho Seco Power Plant: Final report

    SciTech Connect

    Gore, B.F.; Huenefeld, J.C.

    1987-07-01

    This report presents the development and the first application of generic probabilistic risk assessment (PRA) information for identifying systems and components important to public risk at nuclear power plants lacking plant-specific PRAs. A methodology is presented for using the results of PRAs for similar (surrogate) plants, along with plant-specific information about the plant of interest and the surrogate plants, to infer important failure modes for systems of the plant of interest. This methodology, and the rationale on which it is based, is presented in the context of its application to the Rancho Seco plant. The Rancho Seco plant has been analyzed using PRA information from two surrogate plants. This analysis has been used to guide development of considerable plant-specific information about Rancho Seco systems and components important to minimizing public risk, which is also presented herein.

  10. Generic safety insights for inspection of boiling water reactors

    SciTech Connect

    Higgins, J.C.; Taylor, J.H.; Fresco, A.N.; Hillman, B.M.

    1987-01-01

    As the number of operating nuclear power plants (NPP) increases, safety inspection has increased in importance. However, precisely what is important, and what is not important. What should one focus inspection efforts on. Over the last two years Probabilistic Risk Assessment (PR) techniques have been developed to aid in the inspection process. Broad interest in generic PRA-based methods has arisen in the past year, since only about 25% of the US nuclear power plants have completed PRAs, and also, inspectors want PRA-based tools for these plants. This paper describes the BNL program to develop generic BWR PRA-based inspection insights or inspection guidance designed to be applied to plants without PRAs.

  11. Contribution of Anticipated Transients Without Scram (ATWS) to core melt at United States nuclear power plants

    SciTech Connect

    Giachetti, R.T. , Ann Arbor, MI )

    1989-09-01

    This report looks at WASH-1400 and several other Probabilistic Risk Assessments (PRAs) and Probabilistic Safety Studies (PSSs) to determine the contribution of Anticipated Transients Without Scram (ATWS) events to the total core melt probability at eight nuclear power plants in the United States. After considering each plant individually, the results are compared from plant to plant to see if any generic conclusions regarding ATWS, or core melt in general, can be made. 8 refs., 34 tabs.

  12. Population pharmacokinetics and pharmacodynamics of prasugrel and clopidogrel in aspirin-treated patients with stable coronary artery disease.

    PubMed

    Ernest, C Steven; Small, David S; Rohatagi, Shashank; Salazar, Daniel E; Wallentin, Lars; Winters, Kenneth J; Wrishko, Rebecca E

    2008-12-01

    The aim of the current analysis was to characterize the population PK of prasugrel and clopidogrel metabolites, the resulting PD response, and identification of covariates for key PK/PD parameters. Aspirin-treated subjects with coronary artery disease were randomized to double-blind treatment with clopidogrel 600 mg loading dose (LD) followed by daily 75 mg maintenance dose (MD) or prasugrel 60 mg LD and daily 10 mg MD for 28 days. Plasma concentrations of prasugrel active metabolite (Pras-AM) and prasugrel's inactive thiolactone metabolite (Pras-thiolactone) were simultaneously fit to a multicompartmental model; a similar model adequately described clopidogrel's active metabolite (Clop-AM) PK. By linking to the PK model through the active metabolite concentrations, the PK/PD model characterized the irreversible inhibition of platelet aggregation through a sigmoidal Emax model. Although dose, sex, and weight were identified as significant covariates in the prasugrel PK model, only the effect of body weight produced significant changes in Pras-AM exposure. Generally, these factors resulted in only minor changes in Pras-AM exposures such that, overall, the change in the resulting maximal platelet aggregation (MPA) was predicted to be < or =10% points on average. The clopidogrel PK model included dose as a covariate indicating that a significantly less-than-proportional increase in Clop-AM exposure is expected over the dose range of 75-600 mg, thus, the model-predicted PD response is lower than might be anticipated given an 8-fold difference in dose and lower than that typically achieved following prasugrel 60 mg LD. The greater PD response with prasugrel compared with clopidogrel was accounted for by greater conversion of dose to active metabolite. PMID:19023649

  13. Ya??tmín Cqw?lqwilt Nixw, Ul Nixw, Ul Nixw, "I Need to Speak More, and More, and More": Okanagan-Colville (Interior Salish) Indigenous Second-Language Learners Share Our Filmed Narratives

    ERIC Educational Resources Information Center

    Johnson, Michele K.

    2014-01-01

    way', iskwíst, "my name is", S?ímla?xw, and I am from Penticton BC, Canada. kn sqilxw. I am a Syilx (Okanagan, Interior Salish) adult language learner. My cohort and I are midway in our language transformation to become proficient speakers. Our names are Prasát, S?ímla?xw, C'?r?tups, X?wnámx?wnam, Sta?qwálqs, and our Elder, S?amtíc'a?.…

  14. PRA (Probabilistic Risk Assessments) Participation versus Validation

    NASA Technical Reports Server (NTRS)

    DeMott, Diana; Banke, Richard

    2013-01-01

    Probabilistic Risk Assessments (PRAs) are performed for projects or programs where the consequences of failure are highly undesirable. PRAs primarily address the level of risk those projects or programs posed during operations. PRAs are often developed after the design has been completed. Design and operational details used to develop models include approved and accepted design information regarding equipment, components, systems and failure data. This methodology basically validates the risk parameters of the project or system design. For high risk or high dollar projects, using PRA methodologies during the design process provides new opportunities to influence the design early in the project life cycle to identify, eliminate or mitigate potential risks. Identifying risk drivers before the design has been set allows the design engineers to understand the inherent risk of their current design and consider potential risk mitigation changes. This can become an iterative process where the PRA model can be used to determine if the mitigation technique is effective in reducing risk. This can result in more efficient and cost effective design changes. PRA methodology can be used to assess the risk of design alternatives and can demonstrate how major design changes or program modifications impact the overall program or project risk. PRA has been used for the last two decades to validate risk predictions and acceptability. Providing risk information which can positively influence final system and equipment design the PRA tool can also participate in design development, providing a safe and cost effective product.

  15. Adequacy of human reliability data for addressing risk reduction issues at commercial nuclear power plants

    SciTech Connect

    Ryan, T.G.; O'Brien, J.N.; Spettell, C.M.

    1985-01-01

    This paper describes the results of an assessment of how well currently available Probabilistic Risk Assessment (PRA) data address a representative set of human risk issues of current concern to the US Nuclear Regulatory Commission (NRC). A three-step process was used to make that assessment. First, all Human Reliability Analysis (HRA) data included in 19 PRAs were identified, collected, and stored on a computer. Second, a list of human risk ''working level issues'' of concern to NRC was compiled. Finally, the HRA/PRA data which were collected from 19 PRAs were compared to the data needs to assess the extent to which currently available PRA data are useful in addressing human risk issues of concern to NRC. Less than 1% of the data needs were determined to be addressed by currently available PRA data. Findings indicate that PRA data could be far more useful in addressing human risk issues with modification of the development process and documentation structure of PRAs. In addition, information from non-PRA sources could be integrated with PRA data to address many other issues. 7 refs., 13 tabs.

  16. A paramagnetic molecular voltmeter.

    PubMed

    Surek, Jack T; Thomas, David D

    2008-01-01

    We have developed a general electron paramagnetic resonance (EPR) method to measure electrostatic potential at spin labels on proteins to millivolt accuracy. Electrostatic potential is fundamental to energy-transducing proteins like myosin, because molecular energy storage and retrieval is primarily electrostatic. Quantitative analysis of protein electrostatics demands a site-specific spectroscopic method sensitive to millivolt changes. Previous electrostatic potential studies on macromolecules fell short in sensitivity, accuracy and/or specificity. Our approach uses fast-relaxing charged and neutral paramagnetic relaxation agents (PRAs) to increase nitroxide spin label relaxation rate solely through collisional spin exchange. These PRAs were calibrated in experiments on small nitroxides of known structure and charge to account for differences in their relaxation efficiency. Nitroxide longitudinal (R(1)) and transverse (R(2)) relaxation rates were separated by applying lineshape analysis to progressive saturation spectra. The ratio of measured R(1) increases for each pair of charged and neutral PRAs measures the shift in local PRA concentration due to electrostatic potential. Voltage at the spin label is then calculated using the Boltzmann equation. Measured voltages for two small charged nitroxides agree with Debye-Hückel calculations. Voltage for spin-labeled myosin fragment S1 also agrees with calculation based on the pK shift of the reacted cysteine. PMID:17964835

  17. A Paramagnetic Molecular Voltmeter

    PubMed Central

    Surek, Jack T.; Thomas, David D.

    2008-01-01

    We have developed a general electron paramagnetic resonance (EPR) method to measure electrostatic potential at spin labels on proteins to millivolt accuracy. Electrostatic potential is fundamental to energy-transducing proteins like myosin, because molecular energy storage and retrieval is primarily electrostatic. Quantitative analysis of protein electrostatics demands a site-specific spectroscopic method sensitive to millivolt changes. Previous electrostatic potential studies on macromolecules fell short in sensitivity, accuracy and/or specificity. Our approach uses fast-relaxing charged and neutral paramagnetic relaxation agents (PRAs) to increase nitroxide spin label relaxation rate solely through collisional spin exchange. These PRAs were calibrated in experiments on small nitroxides of known structure and charge to account for differences in their relaxation efficiency. Nitroxide longitudinal (R1) and transverse (R2) relaxation rates were separated by applying lineshape analysis to progressive saturation spectra. The ratio of measured R1 increases for each pair of charged and neutral PRAs measures the shift in local PRA concentration due to electrostatic potential. Voltage at the spin label is then calculated using the Boltzmann equation. Measured voltages for two small charged nitroxides agree with Debye-Hückel calculations. Voltage for spin-labeled myosin fragment S1 also agrees with calculation based on the pK shift of the reacted cysteine. PMID:17964835

  18. Generic risk insights for General Electric boiling water reactors

    SciTech Connect

    Travis, R.; Taylor, J. ); Chung, J. . Office of Nuclear Reactor Regulation)

    1991-05-01

    A methodology has been developed to extract generic risk-based information from probabilistic risk assessments (PRAs) of General Electric boiling water rectors and applying the insights gained to plants that have not been subjected to a PRA. The available risk assessments (six plants) were examined to identify the most probable, i.e., dominant accident sequences at each plants. The goal was to include all sequences which represented at least 80% of core damage frequency. If the same plant specific dominant accident sequence appeared within this boundary in at least two plant PRAs, the sequence was considered to be a representative sequence. Eight sequences met this definition. From these sequences, the most important component failures and human error that contributed to each sequence have been prioritized. Guidance is provided to prioritize the representative sequences and modify selected basic events that have been shown to be sensitive to the plant specific design or operating variations of the contributing PRAs. This risk-based guidance can be used for utility and NRC activities including operator training, maintenance, design review, and inspections. 13 refs., 6 tabs.

  19. Preclinical pharmacology, antitumor activity and development of pharmacodynamic markers for the novel, potent AKT inhibitor CCT128930

    PubMed Central

    Yap, Timothy A.; Walton, Mike I.; Hunter, Lisa-Jane K.; Valenti, Melanie; de Haven Brandon, Alexis; Eve, Paul D.; Ruddle, Ruth; Heaton, Simon P.; Henley, Alan; Pickard, Lisa; Vijayaraghavan, Gowri; Caldwell, John J.; Thompson, Neil T.; Aherne, Wynne; Raynaud, Florence I.; Eccles, Suzanne A.; Workman, Paul; Collins, Ian; Garrett, Michelle D.

    2016-01-01

    AKT is frequently deregulated in cancer, making it an attractive anticancer drug target. CCT128930 is a novel ATP-competitive AKT inhibitor discovered using fragment and structure-based approaches. It is a potent, advanced lead pyrrolopyrimidine compound exhibiting selectivity for AKT over PKA, achieved by targeting a single amino acid difference. CCT128930 exhibited marked antiproliferative activity and inhibited the phosphorylation of a range of AKT substrates in multiple tumor cell lines in vitro, consistent with AKT inhibition. CCT128930 caused a G1 arrest in PTEN-null U87MG human glioblastoma cells, consistent with AKT pathway blockade. Pharmacokinetic studies established that potentially active concentrations of CCT128930 could be achieved in human tumor xenografts. Furthermore, CCT128930 also blocked the phosphorylation of several downstream AKT biomarkers in U87MG tumor xenografts, indicating AKT inhibition in vivo. Antitumor activity was observed with CCT128930 in U87MG and HER2-positive, PIK3CA-mutant BT474 human breast cancer xenografts, consistent with its pharmacokinetic and pharmacodynamic properties. A quantitative immunofluorescence assay to measure the phosphorylation and total protein expression of the AKT substrate PRAS40 in hair follicles is presented. Significant decreases in pThr246 PRAS40 occurred in CCT128930-treated mouse whisker follicles in vivo and human hair follicles treated ex vivo, with minimal changes in total PRAS40. In conclusion, CCT128930 is a novel, selective and potent AKT inhibitor, which blocks AKT activity in vitro and in vivo and induces marked antitumor responses. We have also developed a novel biomarker assay for the inhibition of AKT in human hair follicles, which is currently being employed in clinical trials. PMID:21191045

  20. Inhibition of Phospho-S6 Kinase, a Protein Involved in the Compensatory Adaptive Response, Increases the Efficacy of Paclitaxel in Reducing the Viability of Matrix-Attached Ovarian Cancer Cells

    PubMed Central

    Choi, Jeong In; Park, Sang Hi; Lee, Hee-Jin; Lee, Dae Woo; Lee, Hae Nam

    2016-01-01

    Objective To identify the proteins involved the compensatory adaptive response to paclitaxel in ovarian cancer cells and to determine whether inhibition of the compensatory adaptive response increases the efficacy of paclitaxel in decreasing the viability of cancer cells. Methods We used a reverse-phase protein array and western blot analysis to identify the proteins involved in the compensatory mechanism induced by paclitaxel in HeyA8 and SKOV3 ovarian cancer cells. We used a cell viability assay to examine whether inhibition of the proteins involved in the compensatory adaptive response influenced the effects of paclitaxel on cancer cell viability. All experiments were performed in three-dimensional cell cultures. Results Paclitaxel induced the upregulation of pS6 (S240/S244) and pS6 (S235/S236) in HeyA8 and SKOV3 cells, and pPRAS40 (T246) in HeyA8 cells. BX795 and CCT128930 were chosen as inhibitors of pS6 (S240/S244), pS6 (S235/S236), and pPRAS40 (T246). BX795 and CCT128930 decreased pS6 (S240/S244) and pS6 (S235/S236) expression in HeyA8 and SKOV3 cells. However, pPRAS40 (T246) expression was inhibited only by BX795 and not by CCT128930 in HeyA8 cells. Compared with paclitaxel alone, addition of BX795 or CCT128930 to paclitaxel was more effective in decreasing the viability of HeyA8 and SKOV3 cells. Conclusion Addition of BX795 or CCT128930 to inhibit pS6 (S240/S244) or pS6 (S235/S236) restricted the compensatory adaptive response to paclitaxel in HeyA8 and SKOV3 cells. These inhibitors increased the efficacy of paclitaxel in reducing cancer cell viability. PMID:27148873

  1. Auxiliary feedwater system risk-based inspection guide for the Diablo Canyon Unit 1 Nuclear Power Plant

    SciTech Connect

    Gore, B.F.; Vo, T.V.; Harrison, D.G.

    1990-08-01

    This document presents a compilation of auxiliary feedwater (AFW) system failure information which has been screened for risk significance in terms of failure frequency and degradation of system performance. It is a risk-prioritized listing of failure events and their causes that are significant enough to warrant consideration in inspection planning at Diablo Canyon. This information is presented to provide inspectors with increased resources for inspection planning at Diablo Canyon. The risk importance of various component failure modes was identified by analysis of the results of probabilistic risk assessments (PRAs) for many pressurized water reactors (PWRs). However, the component failure categories identified in PRAs are rather broad, because the failure data used in the PRAs is an aggregate of many individual failures having a variety of root causes. In order to help inspectors to focus on specific aspects of component operation, maintenance and design which might cause these failures, an extensive review of component failure information was performed to identify and rank the root causes of these component failures. Both Diablo Canyon and industry-wide failure information was analyzed. Failure causes were sorted on the basis of frequency of occurrence and seriousness of consequence, and categorized as common cause failures, human errors, design problems, or component failures. This information permits an inspector to concentrate on components important to the prevention of core damage. Other components which perform essential functions, but which are not included because of high reliability or redundancy, must also be addressed to ensure that degradation does not increase their failure probabilities, and hence their risk importances. 23 refs., 1 fig., 1 tab.

  2. Preclinical pharmacology, antitumor activity, and development of pharmacodynamic markers for the novel, potent AKT inhibitor CCT128930.

    PubMed

    Yap, Timothy A; Walton, Mike I; Hunter, Lisa-Jane K; Valenti, Melanie; de Haven Brandon, Alexis; Eve, Paul D; Ruddle, Ruth; Heaton, Simon P; Henley, Alan; Pickard, Lisa; Vijayaraghavan, Gowri; Caldwell, John J; Thompson, Neil T; Aherne, Wynne; Raynaud, Florence I; Eccles, Suzanne A; Workman, Paul; Collins, Ian; Garrett, Michelle D

    2011-02-01

    AKT is frequently deregulated in cancer, making it an attractive anticancer drug target. CCT128930 is a novel ATP-competitive AKT inhibitor discovered using fragment- and structure-based approaches. It is a potent, advanced lead pyrrolopyrimidine compound exhibiting selectivity for AKT over PKA, achieved by targeting a single amino acid difference. CCT128930 exhibited marked antiproliferative activity and inhibited the phosphorylation of a range of AKT substrates in multiple tumor cell lines in vitro, consistent with AKT inhibition. CCT128930 caused a G(1) arrest in PTEN-null U87MG human glioblastoma cells, consistent with AKT pathway blockade. Pharmacokinetic studies established that potentially active concentrations of CCT128930 could be achieved in human tumor xenografts. Furthermore, CCT128930 also blocked the phosphorylation of several downstream AKT biomarkers in U87MG tumor xenografts, indicating AKT inhibition in vivo. Antitumor activity was observed with CCT128930 in U87MG and HER2-positive, PIK3CA-mutant BT474 human breast cancer xenografts, consistent with its pharmacokinetic and pharmacodynamic properties. A quantitative immunofluorescence assay to measure the phosphorylation and total protein expression of the AKT substrate PRAS40 in hair follicles is presented. Significant decreases in pThr246 PRAS40 occurred in CCT128930-treated mouse whisker follicles in vivo and human hair follicles treated ex vivo, with minimal changes in total PRAS40. In conclusion, CCT128930 is a novel, selective, and potent AKT inhibitor that blocks AKT activity in vitro and in vivo and induces marked antitumor responses. We have also developed a novel biomarker assay for the inhibition of AKT in human hair follicles, which is currently being used in clinical trials. PMID:21191045

  3. Activation of PI3K/mTOR pathway occurs in most adult low-grade gliomas and predicts patient survival.

    PubMed

    McBride, Sean M; Perez, Daniel A; Polley, Mei-Yin; Vandenberg, Scott R; Smith, Justin S; Zheng, Shichun; Lamborn, Kathleen R; Wiencke, John K; Chang, Susan M; Prados, Michael D; Berger, Mitchel S; Stokoe, David; Haas-Kogan, Daphne A

    2010-03-01

    Recent evidence suggests the Akt-mTOR pathway may play a role in development of low-grade gliomas (LGG). We sought to evaluate whether activation of this pathway correlates with survival in LGG by examining expression patterns of proteins within this pathway. Forty-five LGG tumor specimens from newly diagnosed patients were analyzed for methylation of the putative 5'-promoter region of PTEN using methylation-specific PCR as well as phosphorylation of S6 and PRAS40 and expression of PTEN protein using immunohistochemistry. Relationships between molecular markers and overall survival (OS) were assessed using Kaplan-Meier methods and exact log-rank test. Correlation between molecular markers was determined using the Mann-Whitney U and Spearman Rank Correlation tests. Eight of the 26 patients with methylated PTEN died, as compared to 1 of 19 without methylation. There was a trend towards statistical significance, with PTEN methylated patients having decreased survival (P = 0.128). Eight of 29 patients that expressed phospho-S6 died, whereas all 9 patients lacking p-S6 expression were alive at last follow-up. There was an inverse relationship between expression of phospho-S6 and survival (P = 0.029). There was a trend towards decreased survival in patients expressing phospho-PRAS40 (P = 0.077). Analyses of relationships between molecular markers demonstrated a statistically significant positive correlation between expression of p-S6(235) and p-PRAS40 (P = 0.04); expression of p-S6(240) correlated positively with PTEN methylation (P = 0.04) and negatively with PTEN expression (P = 0.03). Survival of LGG patients correlates with phosphorylation of S6 protein. This relationship supports the use of selective mTOR inhibitors in the treatment of low grade glioma. PMID:19705067

  4. NADPH oxidases and reactive oxygen species at different stages of chronic hypoxia-induced pulmonary hypertension in newborn piglets

    PubMed Central

    Dennis, Kathleen E.; Aschner, J. L.; Milatovic, D.; Schmidt, J. W.; Aschner, M.; Kaplowitz, M. R.; Zhang, Y.

    2009-01-01

    Recently, we reported that reactive oxygen species (ROS) generated by NADPH oxidase (NOX) contribute to aberrant responses in pulmonary resistance arteries (PRAs) of piglets exposed to 3 days of hypoxia (Am J Physiol Lung Cell Mol Physiol 295: L881–L888, 2008). An objective of the present study was to determine whether NOX-derived ROS also contribute to altered PRA responses at a more advanced stage of pulmonary hypertension, after 10 days of hypoxia. We further wished to advance knowledge about the specific NOX and antioxidant enzymes that are altered at early and later stages of pulmonary hypertension. Piglets were raised in room air (control) or hypoxia for 3 or 10 days. Using a cannulated artery technique, we found that treatments with agents that inhibit NOX (apocynin) or remove ROS [an SOD mimetic (M40403) + polyethylene glycol-catalase] diminished responses to ACh in PRAs from piglets exposed to 10 days of hypoxia. Western blot analysis showed an increase in expression of NOX1 and the membrane fraction of p67phox. Expression of NOX4, SOD2, and catalase were unchanged, whereas expression of SOD1 was reduced, in arteries from piglets raised in hypoxia for 3 or 10 days. Markers of oxidant stress, F2-isoprostanes, measured by gas chromatography-mass spectrometry, were increased in PRAs from piglets raised in hypoxia for 3 days, but not 10 days. We conclude that ROS derived from some, but not all, NOX family members, as well as alterations in the antioxidant enzyme SOD1, contribute to aberrant PRA responses at an early and a more progressive stage of chronic hypoxia-induced pulmonary hypertension in newborn piglets. PMID:19592458

  5. Development and application of the dynamic system doctor to nuclear reactor probabilistic risk assessments.

    SciTech Connect

    Kunsman, David Marvin; Aldemir, Tunc; Rutt, Benjamin; Metzroth, Kyle; Catalyurek, Umit; Denning, Richard; Hakobyan, Aram; Dunagan, Sean C.

    2008-05-01

    This LDRD project has produced a tool that makes probabilistic risk assessments (PRAs) of nuclear reactors - analyses which are very resource intensive - more efficient. PRAs of nuclear reactors are being increasingly relied on by the United States Nuclear Regulatory Commission (U.S.N.R.C.) for licensing decisions for current and advanced reactors. Yet, PRAs are produced much as they were 20 years ago. The work here applied a modern systems analysis technique to the accident progression analysis portion of the PRA; the technique was a system-independent multi-task computer driver routine. Initially, the objective of the work was to fuse the accident progression event tree (APET) portion of a PRA to the dynamic system doctor (DSD) created by Ohio State University. Instead, during the initial efforts, it was found that the DSD could be linked directly to a detailed accident progression phenomenological simulation code - the type on which APET construction and analysis relies, albeit indirectly - and thereby directly create and analyze the APET. The expanded DSD computational architecture and infrastructure that was created during this effort is called ADAPT (Analysis of Dynamic Accident Progression Trees). ADAPT is a system software infrastructure that supports execution and analysis of multiple dynamic event-tree simulations on distributed environments. A simulator abstraction layer was developed, and a generic driver was implemented for executing simulators on a distributed environment. As a demonstration of the use of the methodological tool, ADAPT was applied to quantify the likelihood of competing accident progression pathways occurring for a particular accident scenario in a particular reactor type using MELCOR, an integrated severe accident analysis code developed at Sandia. (ADAPT was intentionally created with flexibility, however, and is not limited to interacting with only one code. With minor coding changes to input files, ADAPT can be linked to other

  6. Using Dynamic Master Logic Diagram for component partial failure analysis

    SciTech Connect

    Ni, T.; Modarres, M.

    1996-12-01

    A methodology using the Dynamic Master Logic Diagram (DMLD) for the evaluation of component partial failure is presented. Since past PRAs have not focused on partial failure effects, the reliability of components are only based on the binary state assumption, i.e. defining a component as fully failed or functioning. This paper is to develop an approach to predict and estimate the component partial failure on the basis of the fuzzy state assumption. One example of the application of this methodology with the reliability function diagram of a centrifugal pump is presented.

  7. Wind/Tornado Guidelines Study

    SciTech Connect

    Ng, D.S.; Holman, G.S.

    1991-10-01

    This report documents the strategy employed to develop recommended wind/tornado hazard design guidelines for a New Production Reactor (NRP) currently planned for either the Idaho National Engineering Laboratory (INEL) or the Savannah River (SR) site. The Wind/Tornado Working Group (WTWG), comprising six nationally recognized experts in structural engineering, wind engineering, and meteorology, formulated an independent set of guidelines based on site-specific wind/tornado hazard curves and state-of-the-art tornado missile technology. The basic philosophy was to select realistic wind and missile load specifications, and to meet performance goals by applying conservative structural response evaluation and acceptance criteria. Simplified probabilistic risk analyses (PRAs) for wind speeds and missile impact were performed to estimate annual damage risk frequencies for both the INEL and SR sites. These PRAs indicate that the guidelines will lead to facilities that meet the US Department of Energy (DOE) design requirements and that the Nuclear Regulatory Commission guidelines adopted by the DOE for design are adequate to meet the NPR safety goals.

  8. Selecting the seismic HRA approach for Savannah River Plant PRA revision 1

    SciTech Connect

    Papouchado, K.; Salaymeh, J.; Wingo, H.E.; Benhardt, H.C.; van Buijtenen, C.M.; Mitts, T.M.

    1993-10-01

    The Westinghouse Savannah River Company (WSRC) has prepared a level I probabilistic risk assessment (PRA), Rev. 0 of reactor operations for externally-initiated events including seismic events. The SRS PRA, Rev. 0 Seismic HRA received a critical review that expressed skepticism with the approach used for human reliability analysis because it had not been previously used and accepted in other published PRAs. This report provides a review of published probabilistic risk assessments (PRAs), the associated methodology guidance documents, and the psychological literature to identify parameters important to seismic human reliability analysis (HRA). It also describes a recommended approach for use in the Savannah River Site (SRS) PRA. The SRS seismic event PRA performs HRA to account for the contribution of human errors in the accident sequences. The HRA of human actions during and after a seismic event is an area subject to many uncertainties and involves significant analyst judgment. The approach recommended by this report is based on seismic HRA methods and associated issues and concerns identified from the review of these referenced documents that represent the current state-of-the- art knowledge and acceptance in the seismic HRA field.

  9. Developing new theoretical models of the formation of atomic collision cascades and subcascades in irradiated solids

    SciTech Connect

    Metelkin, E. V.; Ryazanov, A. I. Semenov, E. V.

    2008-09-15

    A new theoretical model is developed for the investigation of atomic collision cascades and subcascades in irradiated solids consisting of atoms of a single type. The model is based on an analytical description of the elastic collisions between moving atoms knocked out of the crystal lattice sites and the immobile atoms of the lattice. The description is based on the linear kinetic Boltzmann equation describing the retardation of primary recoil atoms (PRAs) in irradiated solids. The laws of conservation for the total number and the kinetic energy of moving atoms, which follow from the kinetic Boltzmann equation, are analyzed using the proposed model. An analytical solution is obtained for the stationary kinetic Boltzmann equation, which describes the retardation of PRAs for a given source responsible for their production. A kinetic equation for the moving atoms and the corresponding laws of conservation are also analyzed with allowance for the binding energy of atoms at the crystal lattice sites. A criterion for determining the threshold energy of subcascade formation in irradiated solids is formulated. Based on this criterion, the threshold energy of subcascade formation is calculated using the Thomas-Fermi potential. Formulas are presented for determining the mean size and number of subcascades formed in a solid as functions of the PRA energy.

  10. An overview of the evolution of human reliability analysis in the context of probabilistic risk assessment.

    SciTech Connect

    Bley, Dennis C.; Lois, Erasmia; Kolaczkowski, Alan M.; Forester, John Alan; Wreathall, John; Cooper, Susan E.

    2009-01-01

    Since the Reactor Safety Study in the early 1970's, human reliability analysis (HRA) has been evolving towards a better ability to account for the factors and conditions that can lead humans to take unsafe actions and thereby provide better estimates of the likelihood of human error for probabilistic risk assessments (PRAs). The purpose of this paper is to provide an overview of recent reviews of operational events and advances in the behavioral sciences that have impacted the evolution of HRA methods and contributed to improvements. The paper discusses the importance of human errors in complex human-technical systems, examines why humans contribute to accidents and unsafe conditions, and discusses how lessons learned over the years have changed the perspective and approach for modeling human behavior in PRAs of complicated domains such as nuclear power plants. It is argued that it has become increasingly more important to understand and model the more cognitive aspects of human performance and to address the broader range of factors that have been shown to influence human performance in complex domains. The paper concludes by addressing the current ability of HRA to adequately predict human failure events and their likelihood.

  11. What Becomes of Nuclear Risk Assessment in Light of Radiation Hormesis?

    PubMed Central

    Cuttler, Jerry M.

    2007-01-01

    A nuclear probabilistic risk or safety assessment (PRA or PSA) is a scientific calculation that uses assumptions and models to determine the likelihood of plant or fuel repository failures and the corresponding releases of radioactivity. Estimated radiation doses to the surrounding population are linked inappropriately to risks of cancer death and congenital malformations. Even though PRAs use very pessimistic assumptions, they demonstrate that nuclear power plants and fuel repositories are very safe compared with the health risks of other generating options or other risks that people readily accept. Because of the frightening negative images and the exaggerated safety and health concerns that are communicated, many people judge nuclear risks to be unacceptable and do not favour nuclear plants. Large-scale tests and experience with nuclear accidents demonstrate that even severe accidents expose the public to only low doses of radiation, and a century of research has demonstrated that such exposures are beneficial to health. A scientific basis for this phenomenon now exists. PRAs are valuable tools for improving plant designs, but if nuclear power is to play a significant role in meeting future energy needs, we must communicate its many real benefits and dispel the negative images formed by unscientific extrapolations of harmful effects at high doses. PMID:18648610

  12. Development status of an improved method for conducting an integrated HRA/PRA based on operating experience

    SciTech Connect

    Barriere, M.T.; Luckas, W.J.; Cooper, S.E.

    1995-04-01

    Since the early 1970s, Human Reliability Analysis (HRA) has been considered an integral part of Probabilistic Risk Assessments (PRAs). However, current limitations of existing HRA approaches become apparent when the role of the human is explicitly examined in the context of real nuclear power plant (NPP) events. Recent serious events indicate that human performance is a dominant source of plant risk. Development of new or improved HRA methodologies to more realistically represent human performance is recognized by the Nuclear Regulatory Commission (NRC) as a necessary means to increase the robustness of PRAs. In order to accomplish this objective, a Detailed HRA Project, under sponsorship of the NRC`s Office of Nuclear Regulatory Research (RES), was initiated in late February of 1992 by Brookhaven National Laboratory (BNL). The purpose of the BNL Detailed HRA project is to develop an improved method for HRA that enables a more realistic assessment of the human contribution to plant risk and can be fully integrated with PRA. This paper describes the research and development efforts of the project including: the development of a multidisciplinary HRA framework, the characterization and representation of errors of commission, and an approach for addressing human dependencies. Research implications and necessary development requirements are also discussed.

  13. Current and future applications of PRA in regulatory activities

    SciTech Connect

    Speis, T.P.; Murphy, J.A.; Cunningham, M.A.

    1995-04-01

    Probabilistic Risk Assessments (PRAs) have proven valuable in providing the regulators, the nuclear plant operators, and the reactor designers insights into plant safety, reliability, design and operation. Both the NRC Commissioners and the staff have grown to appreciate the valuable contributions PRAs can have in the regulatory arena, though I will admit the existence of some tendencies for strict adherence to the deterministic approach within the agency and the public at large. Any call for change, particularly one involving a major adjustment in approach to the regulation of nuclear power, will meet with a certain degree of resistance and retrenchment. Change can appear threatening and can cause some to question whether the safety mission is being fulfilled. This skepticism is completely appropriate and is, in fact, essential to a proper transition towards risk and performance-based approaches. Our task in the Office of Nuclear Regulatory Research is to increase the PRA knowledge base within the agency and develop appropriate guidance and methods needed to support the transitioning process.

  14. Methods for external event screening quantification: Risk Methods Integration and Evaluation Program (RMIEP) methods development

    SciTech Connect

    Ravindra, M.K.; Banon, H.

    1992-07-01

    In this report, the scoping quantification procedures for external events in probabilistic risk assessments of nuclear power plants are described. External event analysis in a PRA has three important goals; (1) the analysis should be complete in that all events are considered; (2) by following some selected screening criteria, the more significant events are identified for detailed analysis; (3) the selected events are analyzed in depth by taking into account the unique features of the events: hazard, fragility of structures and equipment, external-event initiated accident sequences, etc. Based on the above goals, external event analysis may be considered as a three-stage process: Stage I: Identification and Initial Screening of External Events; Stage II: Bounding Analysis; Stage III: Detailed Risk Analysis. In the present report, first, a review of published PRAs is given to focus on the significance and treatment of external events in full-scope PRAs. Except for seismic, flooding, fire, and extreme wind events, the contributions of other external events to plant risk have been found to be negligible. Second, scoping methods for external events not covered in detail in the NRC`s PRA Procedures Guide are provided. For this purpose, bounding analyses for transportation accidents, extreme winds and tornadoes, aircraft impacts, turbine missiles, and chemical release are described.

  15. Methods for external event screening quantification: Risk Methods Integration and Evaluation Program (RMIEP) methods development

    SciTech Connect

    Ravindra, M.K.; Banon, H. )

    1992-07-01

    In this report, the scoping quantification procedures for external events in probabilistic risk assessments of nuclear power plants are described. External event analysis in a PRA has three important goals; (1) the analysis should be complete in that all events are considered; (2) by following some selected screening criteria, the more significant events are identified for detailed analysis; (3) the selected events are analyzed in depth by taking into account the unique features of the events: hazard, fragility of structures and equipment, external-event initiated accident sequences, etc. Based on the above goals, external event analysis may be considered as a three-stage process: Stage I: Identification and Initial Screening of External Events; Stage II: Bounding Analysis; Stage III: Detailed Risk Analysis. In the present report, first, a review of published PRAs is given to focus on the significance and treatment of external events in full-scope PRAs. Except for seismic, flooding, fire, and extreme wind events, the contributions of other external events to plant risk have been found to be negligible. Second, scoping methods for external events not covered in detail in the NRC's PRA Procedures Guide are provided. For this purpose, bounding analyses for transportation accidents, extreme winds and tornadoes, aircraft impacts, turbine missiles, and chemical release are described.

  16. Seismic margin assessment of evolutionary light water reactors

    SciTech Connect

    Ali, S.A.; Bagchi, G.

    1996-12-01

    The objectives of the US Nuclear Regulatory Commission (NRC) staff`s review of the evolutionary light water reactors (ELWR) probabilistic risk assessment (PRA) are drawn from 10 CFR Part 52, the Commission`s Severe Reactor Accident Policy Statement regarding future designs and existing plants, the Commission`s Safety Goal Policy Statement, The Commission approved positions concerning the analyses of external and events contained in SECY-93-087, and NRC interest in the use of PRA to help improve future reactor designs. In general, these objectives have been achieved by the ELWR PRAs and the NRC staff`s review. The staff`s applicable regulation for the analysis of external events for the ELWR PRAs is as follows. The probabilistic risk assessment required by 10 CFR 52.47(a)(1)(v) must include an assessment of internal and external events. For external events, simplified probabilistic methods and margins methods may be used to assess the capacity of the standard design to withstand the effects of events such as fires and earthquakes. Traditional probabilistic techniques should be used to evaluate internal floods. For earthquakes, a seismic margin analysis must consider the effects of earthquakes with accelerations approximately one and two-thirds the acceleration of the safe-shutdown earthquake (SSE).

  17. Top-down and bottom-up definitions of human failure events in human reliability analysis

    SciTech Connect

    Boring, Ronald Laurids

    2014-10-01

    In the probabilistic risk assessments (PRAs) used in the nuclear industry, human failure events (HFEs) are determined as a subset of hardware failures, namely those hardware failures that could be triggered by human action or inaction. This approach is top-down, starting with hardware faults and deducing human contributions to those faults. Elsewhere, more traditionally human factors driven approaches would tend to look at opportunities for human errors first in a task analysis and then identify which of those errors is risk significant. The intersection of top-down and bottom-up approaches to defining HFEs has not been carefully studied. Ideally, both approaches should arrive at the same set of HFEs. This question is crucial, however, as human reliability analysis (HRA) methods are generalized to new domains like oil and gas. The HFEs used in nuclear PRAs tend to be top-down—defined as a subset of the PRA—whereas the HFEs used in petroleum quantitative risk assessments (QRAs) often tend to be bottom-up—derived from a task analysis conducted by human factors experts. The marriage of these approaches is necessary in order to ensure that HRA methods developed for top-down HFEs are also sufficient for bottom-up applications.

  18. Comparison between Canadian probabilistic safety assessment methods formulated by Atomic Energy of Canada limited and probabilistic risk assessment methods

    SciTech Connect

    Shapiro, H.S.; Smith, J.E.

    1989-03-01

    The procedures used by Atomic Energy of Canada Limited (AECL) to perform probabilistic safety assessments (PRAs) differ somewhat from conventionally accepted probabilistic risk assessment (PRA) procedures used elsewhere. In Canada, PSA is used by AECL as an audit tool for an evolving design. The purpose is to assess the safety of the plant in engineering terms. Thus, the PSA procedures are geared toward providing engineering feedback so that necessary changes can be made to the design at an early stage, input can be made to operating procedures, and test and maintenance programs can be optimized in terms of costs. Most PRAs, by contrast, are performed in plants that are already built. Their main purpose is to establish the core melt frequency and the risk to the public due to core melt. Also, any design modification is very expensive. The differences in purpose and timing between PSA and PRA have resulted in differences in methodology and scope. The PSA procedures are used on all plants being designed by AECL.

  19. What becomes of nuclear risk assessment in light of radiation hormesis?

    PubMed

    Cuttler, Jerry M

    2007-01-01

    A nuclear probabilistic risk or safety assessment (PRA or PSA) is a scientific calculation that uses assumptions and models to determine the likelihood of plant or fuel repository failures and the corresponding releases of radioactivity. Estimated radiation doses to the surrounding population are linked inappropriately to risks of cancer death and congenital malformations. Even though PRAs use very pessimistic assumptions, they demonstrate that nuclear power plants and fuel repositories are very safe compared with the health risks of other generating options or other risks that people readily accept. Because of the frightening negative images and the exaggerated safety and health concerns that are communicated, many people judge nuclear risks to be unacceptable and do not favour nuclear plants. Large-scale tests and experience with nuclear accidents demonstrate that even severe accidents expose the public to only low doses of radiation, and a century of research has demonstrated that such exposures are beneficial to health. A scientific basis for this phenomenon now exists. PRAs are valuable tools for improving plant designs, but if nuclear power is to play a significant role in meeting future energy needs, we must communicate its many real benefits and dispel the negative images formed by unscientific extrapolations of harmful effects at high doses. PMID:18648610

  20. Akt and β-catenin contribute to TMZ resistance and EMT of MGMT negative malignant glioma cell line.

    PubMed

    Yi, Guo-Zhong; Liu, Ya-Wei; Xiang, Wei; Wang, Hai; Chen, Zi-Yang; Xie, Si-di; Qi, Song-Tao

    2016-08-15

    Glioblastoma is one of the most lethal cancers in central nervous system, and some individual cells that cannot be isolated for surgical resection and also show treatment-resistance induce poor prognosis. Hence, in order to research these cells, we treated temozolomide (TMZ)-sensitive U87MG cells with 400μM TMZ in culture media for over 6months and established TMZ-resistant cell line designated as U87/TR. We detected the MGMT status through pyrosequencing and western blotting, and we also assessed the proliferation, migration, EMT-like changes and possible activated signaling pathways in U87/TR cells. Our results demonstrated that U87/TR was MGMT negative, which indicated that MGMT made no contribution for TMZ-resistance of U87/TR. And U87/TR cells displayed cell cycle arrest, higher capacity for migration and EMT-like changes including both phenotype and characteristic proteins. We also revealed that both β-catenin and the phosphorylation level of Akt and PRAS40 were increased in U87/TR, while we did not observe the phosphorylation of mTOR in U87/TR. It indicated that activation of Akt and Wnt/β-catenin pathways may be response for the chemo-resistance and increased invasion of U87/TR cells, and the phosphorylation of PRAS40 and inactivated mTOR may be related to cell cycle arrest in U87/TR cells. PMID:27423571

  1. Effect of Treatment With Tabalumab, a B Cell-Activating Factor Inhibitor, on Highly Sensitized Patients With End-Stage Renal Disease Awaiting Transplantation.

    PubMed

    Mujtaba, M A; Komocsar, W J; Nantz, E; Samaniego, M D; Henson, S L; Hague, J A; Lobashevsky, A L; Higgins, N G; Czader, M; Book, B K; Anderson, M D; Pescovitz, M D; Taber, T E

    2016-04-01

    B cell-activation factor (BAFF) is critical for B cell maturation. Inhibition of BAFF represents an appealing target for desensitization of sensitized end-stage renal disease (ESRD) patients. We conducted a Phase 2a, single-arm, open-label exploratory study investigating the effect of tabalumab (BAFF inhibitor) in patients with ESRD and calculated panel reactive antibodies (cPRAs) >50%. The treatment period duration was 24 weeks. Eighteen patients received tabalumab, at doses of 240-mg subcutaneous (SC) at Week 0 followed by 120-mg SC monthly for 5 additional months. Patients were followed for an additional 52 weeks. Immunopharmacologic effects were characterized through analysis of blood for HLA antibodies, BAFF concentrations, immunoglobulins, T and B cell subsets, as well as pre- and posttreatment tonsil and bone marrow biopsies. Significant reductions in cPRAs were observed at Weeks 16 (p = 0.043) and 36 (p = 0.004); however, absolute reductions were small (<5%). Expected pharmacologic changes in B cell subsets and immunoglobulin reductions were observed. Two tabalumab-related serious adverse events occurred (pneumonia, worsening of peripheral neuropathy), while the most common other adverse events were injection-site pain and hypotension. Three patients received matched deceased donor transplants during follow-up. Treatment with a BAFF inhibitor resulted in statistically significant, but not clinically meaningful reduction in the cPRA from baseline (NCT01200290, Clinicaltrials.gov). PMID:26780484

  2. Risk Insights Gained from Fire Incidents

    SciTech Connect

    Kazarians, Mardy; Nowlen, Steven P.

    1999-06-10

    There now exist close to 20 years of history in the application of Probabilistic Risk Assessment (PRA) for the analysis of fire risk at nuclear power plants. The current methods are based on various assumptions regarding fire phenomena, the impact of fire on equipment and operator response, and the overall progression of a fire event from initiation through final resolution. Over this same time period, a number of significant fire incidents have occurred at nuclear power plants around the world. Insights gained from US experience have been used in US studies as the statistical basis for establishing fire initiation frequencies both as a function of the plant area and the initiating fire source.To a lesser extent, the fire experience has also been used to assess the general severity and duration of fires. However, aside from these statistical analyses, the incidents have rarely been scrutinized in detail to verify the underlying assumptions of fire PRAs. This paper discusses an effort, under which a set of fire incidents are being reviewed in order to gain insights directly relevant to the methods, data, and assumptions that form the basis for current fire PRAs. The paper focuses on the objectives of the effort, the specific fire events being reviews methodology, and anticipated follow-on activities.

  3. A technique for human error analysis (ATHEANA)

    SciTech Connect

    Cooper, S.E.; Ramey-Smith, A.M.; Wreathall, J.; Parry, G.W.

    1996-05-01

    Probabilistic risk assessment (PRA) has become an important tool in the nuclear power industry, both for the Nuclear Regulatory Commission (NRC) and the operating utilities. Human reliability analysis (HRA) is a critical element of PRA; however, limitations in the analysis of human actions in PRAs have long been recognized as a constraint when using PRA. A multidisciplinary HRA framework has been developed with the objective of providing a structured approach for analyzing operating experience and understanding nuclear plant safety, human error, and the underlying factors that affect them. The concepts of the framework have matured into a rudimentary working HRA method. A trial application of the method has demonstrated that it is possible to identify potentially significant human failure events from actual operating experience which are not generally included in current PRAs, as well as to identify associated performance shaping factors and plant conditions that have an observable impact on the frequency of core damage. A general process was developed, albeit in preliminary form, that addresses the iterative steps of defining human failure events and estimating their probabilities using search schemes. Additionally, a knowledge- base was developed which describes the links between performance shaping factors and resulting unsafe actions.

  4. Multidisciplinary framework for human reliability analysis with an application to errors of commission and dependencies

    SciTech Connect

    Barriere, M.T.; Luckas, W.J.; Wreathall, J.; Cooper, S.E.; Bley, D.C.; Ramey-Smith, A.

    1995-08-01

    Since the early 1970s, human reliability analysis (HRA) has been considered to be an integral part of probabilistic risk assessments (PRAs). Nuclear power plant (NPP) events, from Three Mile Island through the mid-1980s, showed the importance of human performance to NPP risk. Recent events demonstrate that human performance continues to be a dominant source of risk. In light of these observations, the current limitations of existing HRA approaches become apparent when the role of humans is examined explicitly in the context of real NPP events. The development of new or improved HRA methodologies to more realistically represent human performance is recognized by the Nuclear Regulatory Commission (NRC) as a necessary means to increase the utility of PRAS. To accomplish this objective, an Improved HRA Project, sponsored by the NRC`s Office of Nuclear Regulatory Research (RES), was initiated in late February, 1992, at Brookhaven National Laboratory (BNL) to develop an improved method for HRA that more realistically assesses the human contribution to plant risk and can be fully integrated with PRA. This report describes the research efforts including the development of a multidisciplinary HRA framework, the characterization and representation of errors of commission, and an approach for addressing human dependencies. The implications of the research and necessary requirements for further development also are discussed.

  5. Review of Quantitative Software Reliability Methods

    SciTech Connect

    Chu, T.L.; Yue, M.; Martinez-Guridi, M.; Lehner, J.

    2010-09-17

    The current U.S. Nuclear Regulatory Commission (NRC) licensing process for digital systems rests on deterministic engineering criteria. In its 1995 probabilistic risk assessment (PRA) policy statement, the Commission encouraged the use of PRA technology in all regulatory matters to the extent supported by the state-of-the-art in PRA methods and data. Although many activities have been completed in the area of risk-informed regulation, the risk-informed analysis process for digital systems has not yet been satisfactorily developed. Since digital instrumentation and control (I&C) systems are expected to play an increasingly important role in nuclear power plant (NPP) safety, the NRC established a digital system research plan that defines a coherent set of research programs to support its regulatory needs. One of the research programs included in the NRC's digital system research plan addresses risk assessment methods and data for digital systems. Digital I&C systems have some unique characteristics, such as using software, and may have different failure causes and/or modes than analog I&C systems; hence, their incorporation into NPP PRAs entails special challenges. The objective of the NRC's digital system risk research is to identify and develop methods, analytical tools, and regulatory guidance for (1) including models of digital systems into NPP PRAs, and (2) using information on the risks of digital systems to support the NRC's risk-informed licensing and oversight activities. For several years, Brookhaven National Laboratory (BNL) has worked on NRC projects to investigate methods and tools for the probabilistic modeling of digital systems, as documented mainly in NUREG/CR-6962 and NUREG/CR-6997. However, the scope of this research principally focused on hardware failures, with limited reviews of software failure experience and software reliability methods. NRC also sponsored research at the Ohio State University investigating the modeling of digital systems

  6. NNSA / IAEA VVER reactor safety workshops. May 2002 - April 2003. Executive summary.

    SciTech Connect

    Evans, M.; Petri, M. C.

    2003-07-29

    Over the past year, the U.S. National Nuclear Security Administration (NNSA) has sponsored four workshops to compare the probabilistic risk assessments (PRAs) of Soviet-designed VVER power plants. The ''International Workshop on Safety of First-Generation VVER-440 Nuclear Power Plants'' was held on May 20-25, 2002, in Piestany, Slovakia. A short follow-on workshop was held in Bratislava, Slovakia, on November 5-6, 2002, to complete the work begun in May. Piestany was the location also for the ''International Workshop on Safety of Second-Generation VVER-440 Nuclear Power Plants'' (September 9-14, 2002) and the ''International Workshop on Safety of VVER-1000 Nuclear Power Plants'' (April 7-12, 2003). The four workshops were held in cooperation with the International Atomic Energy Agency (IAEA), the Nuclear Regulatory Authority of Slovakia (UJD), the Center for Nuclear Safety in Central and Eastern Europe (CENS), and Argonne National Laboratory (ANL). The objectives of the workshops were to identify the impact of the improvements on the core damage frequency; the contribution to the PRA results of different assumptions about events that can occur at the plants; and to understand, identify, and prioritize potential improvements in hardware and plant operation of VVER nuclear power plants. These objectives were achieved based on insights gained from recent PRAs completed by the plants and their technical support organizations. Nine first-generation VVER-440 plants (nominally of the VVER-440/230 design) are currently operating in Armenia, Bulgaria, Russia, and Slovakia. Sixteen VVER-440/213 plants are currently operating in the Czech Republic, Hungary, Russia, Slovakia, and Ukraine. Twenty-three VVER-1000 plants are currently operating in Bulgaria, the Czech Republic, Russia, and Ukraine. Eleven addition plants are in the advanced stages of construction in various parts of the world. The workshops reviewed the current configuration and safety status of each plant

  7. MicroRNA-214 Reduces Insulin-like Growth Factor-1 (IGF-1) Receptor Expression and Downstream mTORC1 Signaling in Renal Carcinoma Cells.

    PubMed

    Das, Falguni; Dey, Nirmalya; Bera, Amit; Kasinath, Balakuntalam S; Ghosh-Choudhury, Nandini; Choudhury, Goutam Ghosh

    2016-07-01

    Elevated IGF-1/insulin-like growth factor-1 receptor (IGF-1R) autocrine/paracrine signaling in patients with renal cell carcinoma is associated with poor prognosis of the disease independent of their von Hippel-Lindau (VHL) status. Increased expression of IGF-1R in renal cancer cells correlates with their potency of tumor development and progression. The mechanism by which expression of IGF-1R is increased in renal carcinoma is not known. We report that VHL-deficient and VHL-positive renal cancer cells possess significantly decreased levels of mature, pre-, and pri-miR-214 than normal proximal tubular epithelial cells. We identified an miR-214 recognition element in the 3'UTR of IGF-1R mRNA and confirmed its responsiveness to miR-214. Overexpression of miR-214 decreased the IGF-1R protein levels, resulting in the inhibition of Akt kinase activity in both types of renal cancer cells. IGF-1 provoked phosphorylation and inactivation of PRAS40 in an Akt-dependent manner, leading to the activation of mTORC1 signal transduction to increase phosphorylation of S6 kinase and 4EBP-1. Phosphorylation-deficient mutants of PRAS40 and 4EBP-1 significantly inhibited IGF-1R-driven proliferation of renal cancer cells. Expression of miR-214 suppressed IGF-1R-induced phosphorylation of PRAS40, S6 kinase, and 4EBP-1, indicating inhibition of mTORC1 activity. Finally, miR-214 significantly blocked IGF-1R-forced renal cancer cell proliferation, which was reversed by expression of 3'UTR-less IGF-1R and constitutively active mTORC1. Together, our results identify a reciprocal regulation of IGF-1R levels and miR-214 expression in renal cancer cells independent of VHL status. Our data provide evidence for a novel mechanism for IGF-1R-driven renal cancer cell proliferation involving miR-214 and mTORC1. PMID:27226530

  8. COMPARISON OF NOVORONEZH UNIT 5 NPP AND SOUTH UKRAINE UNIT 1 NPP LEVEL I PRA RESULTS.

    SciTech Connect

    MUSICKI,Z.; GINSBERG,T.

    2002-04-18

    This paper describes a study undertaken to explain the risk profile differences in the results of PRAs of two similar WER-1000 nuclear power plants. The risk profile differences are particularly significant in the area of small steam/feedwater line breaks, small-small LOCAs, support system initiators and containment bypass initiators. A top level (limited depth) approach was used in which we studied design differences, major assumptions, data differences, and also compared the two PRA analyses on an element-by-element basis in order to discern the major causative factors for the risk profile differences. We conclude that the major risk profile differences are due to differences in assumptions and engineering judgment (possibly combined with some design and data differences) involved in treatment of uncertain physical phenomena (primarily sump plugging in LOCAs and turbine building steaming effects in secondary system breaks). Additional major differences are attributable to support system characteristics.

  9. Evaluation of a microtiter system for identification of anaerobic bacteria.

    PubMed Central

    Savuto, P S; Ellner, P D

    1984-01-01

    The Anaerobe Combo Panel (American MicroScan, Mahwah, N.J.) was evaluated for its ability to identify anaerobic bacteria. The frozen, 96-well panel utilizes 24 biochemical reactions and four antimicrobial agents for species identification. The Anaerobe Combo Panel was used to test 114 clinical isolates of strict anaerobes. Reactions were read after 48 h, and the results were compared with those obtained with the PRAS II system (Scott Laboratories, Inc., Fiskeville, R.I.). Discrepancies between the two systems were resolved by gas-liquid chromatography. With the Anaerobe Combo Panel, 84% of the organisms were able to grow, and 89% of these were correctly identified to genus level and 78% to species level. The Anaerobe Combo Panel was easy to inoculate and read, but some of the reactions were difficult to interpret, and not all of the derived codes were found in the code book. PMID:6378969

  10. Enhanced Fire Events Database to Support Fire PRA

    SciTech Connect

    Patrick Baranowsky; Ken Canavan; Shawn St. Germain

    2010-06-01

    Abstract: This paper provides a description of the updated and enhanced Fire Events Data Base (FEDB) developed by the Electric Power Research Institute (EPRI) in cooperation with the U.S. Nuclear Regulatory Commission (NRC). The FEDB is the principal source of fire incident operational data for use in fire PRAs. It provides a comprehensive and consolidated source of fire incident information for nuclear power plants operating in the U.S. The database classification scheme identifies important attributes of fire incidents to characterize their nature, causal factors, and severity consistent with available data. The database provides sufficient detail to delineate important plant specific attributes of the incidents to the extent practical. A significant enhancement to the updated FEDB is the reorganization and refinement of the database structure and data fields and fire characterization details added to more rigorously capture the nature and magnitude of the fire and damage to the ignition source and nearby equipment and structures

  11. SAPHIRE 8 Software Quality Assurance Plan

    SciTech Connect

    Curtis Smith

    2010-02-01

    This Quality Assurance (QA) Plan documents the QA activities that will be managed by the INL related to JCN N6423. The NRC developed the SAPHIRE computer code for performing probabilistic risk assessments (PRAs) using a personal computer (PC) at the Idaho National Laboratory (INL) under Job Code Number (JCN) L1429. SAPHIRE started out as a feasibility study for a PRA code to be run on a desktop personal PC and evolved through several phases into a state-of-the-art PRA code. The developmental activity of SAPHIRE was the result of two concurrent important events: The tremendous expansion of PC software and hardware capability of the 90s and the onset of a risk-informed regulation era.

  12. The NRC's SPAR Models: Current Status, Future Development, and Modeling Issues

    SciTech Connect

    Robert F. Buell

    2008-09-01

    Probabilistic risk assessments (PRAs) play an increasingly important role in the regulatory framework of the U.S. nuclear power industry. The Nuclear Regulatory Commission (NRC) relies on a set of plant-specific Standardized Plant Analysis Risk (SPAR) models to provide critical risk-based input to the regulatory process. The Significance Determination Process (SDP), Management Directive 8.3 - NRC Incident Investigation Program, Accident Sequence Precursor (ASP) and Mitigating Systems Performance Index (MSPI) programs are among the regulatory initiatives that receive significant input from the SPAR models. Other uses of the SPAR models include: Screening & Resolution of Generic Safety Issues, License Amendment reviews and Notice of Enforcement Discretion (NOEDs). This paper presents the current status of SPAR model development activities, future development objectives, and issues related to the development, verification and maintenance of the SPAR models.

  13. Application of laboratory data from small-scale simulators to human performance issues in the nuclear industry

    SciTech Connect

    Spettell, C.M.

    1986-01-01

    Laboratory analogs of nuclear power plant tasks were simulated on personal computers in two experimental studies. Human performance data were collected during each experimental study. The goal of the first experiment was to validate a quantitative model of dependence among human errors during testing, calibration, and maintenance activities. This model, the Multiple Sequential Failure (MSF) model (NUREG/CR-2211) has been used to quantify dependent human error failure probabilities for human reliability analyses in Probabilistic Risk Assessments (PRAs). The goal of the second experiment was to examine the relationship among psychological and behavioral characteristics of individuals and their performance at controlling a simulated nuclear power plant. These studies demonstrated the usefulness of the experimental psychology approach for validating models of human performance at nuclear power plant tasks.

  14. Development of an improved HRA method: A technique for human error analysis (ATHEANA)

    SciTech Connect

    Taylor, J.H.; Luckas, W.J.; Wreathall, J.

    1996-03-01

    Probabilistic risk assessment (PRA) has become an increasingly important tool in the nuclear power industry, both for the Nuclear Regulatory Commission (NRC) and the operating utilities. The NRC recently published a final policy statement, SECY-95-126, encouraging the use of PRA in regulatory activities. Human reliability analysis (HRA), while a critical element of PRA, has limitations in the analysis of human actions in PRAs that have long been recognized as a constraint when using PRA. In fact, better integration of HRA into the PRA process has long been a NRC issue. Of particular concern, has been the omission of errors of commission - those errors that are associated with inappropriate interventions by operators with operating systems. To address these concerns, the NRC identified the need to develop an improved HRA method, so that human reliability can be better represented and integrated into PRA modeling and quantification.

  15. Discovery of 3-(3-(4-(1-Aminocyclobutyl)phenyl)-5-phenyl-3H-imidazo[4,5-b]pyridin-2-yl)pyridin-2-amine (ARQ 092): An Orally Bioavailable, Selective, and Potent Allosteric AKT Inhibitor.

    PubMed

    Lapierre, Jean-Marc; Eathiraj, Sudharshan; Vensel, David; Liu, Yanbin; Bull, Cathy O; Cornell-Kennon, Susan; Iimura, Shin; Kelleher, Eugene W; Kizer, Darin E; Koerner, Steffi; Makhija, Sapna; Matsuda, Akihisa; Moussa, Magdi; Namdev, Nivedita; Savage, Ronald E; Szwaya, Jeff; Volckova, Erika; Westlund, Neil; Wu, Hui; Schwartz, Brian

    2016-07-14

    The work in this paper describes the optimization of the 3-(3-phenyl-3H-imidazo[4,5-b]pyridin-2-yl)pyridin-2-amine chemical series as potent, selective allosteric inhibitors of AKT kinases, leading to the discovery of ARQ 092 (21a). The cocrystal structure of compound 21a bound to full-length AKT1 confirmed the allosteric mode of inhibition of this chemical class and the role of the cyclobutylamine moiety. Compound 21a demonstrated high enzymatic potency against AKT1, AKT2, and AKT3, as well as potent cellular inhibition of AKT activation and the phosphorylation of the downstream target PRAS40. Compound 21a also served as a potent inhibitor of the AKT1-E17K mutant protein and inhibited tumor growth in a human xenograft mouse model of endometrial adenocarcinoma. PMID:27305487

  16. Methods improvements incorporated into the SAPHIRE ASP models

    SciTech Connect

    Sattison, M.B.; Blackman, H.S.; Novack, S.D.

    1995-04-01

    The Office for Analysis and Evaluation of Operational Data (AEOD) has sought the assistance of the Idaho National Engineering Laboratory (INEL) to make some significant enhancements to the SAPHIRE-based Accident Sequence Precursor (ASP) models recently developed by the INEL. The challenge of this project is to provide the features of a full-scale PRA within the framework of the simplified ASP models. Some of these features include: (1) uncertainty analysis addressing the standard PRA uncertainties and the uncertainties unique to the ASP models and methods, (2) incorporation and proper quantification of individual human actions and the interaction among human actions, (3) enhanced treatment of common cause failures, and (4) extension of the ASP models to more closely mimic full-scale PRAs (inclusion of more initiators, explicitly modeling support system failures, etc.). This paper provides an overview of the methods being used to make the above improvements.

  17. Core damage frequency observations and insights of LWRs based on the IPEs

    SciTech Connect

    Dingman, S.E.; Camp, A.L.; Drouin, M.T.

    1995-04-01

    Seventy-eight plants are expected to submit Individual Plant Examinations (IPEs) for severe accident vulnerabilities to the US Nuclear Regulatory Commission (NRC). The majority of the plants have elected to perform full Level 1 probabilistic risk assessments (PRAs) to meet the intent of the IPEs. Because of this, it is possible to compare the results from the IPE submittals to determine general observations and {open_quotes}lessons learned{close_quotes} from the IPEs. The IPE Insights Program is performing this evaluation, and preliminary results are presented in this paper. The core damage frequency and core damage sequences are identified and compared for pressurized water reactors and boiling water reactors. Examination of the results indicates that variations among plant results are due to a combination of actual plant design/operational features and analysis approaches. The findings are consistent with previous NRC studies, such as WASH-1400 and NUREG-1150.

  18. Comparison of Novovoronezh Unit 5 NPP and South Ukraine Unit 1 NPP Level 1 PRA Results

    SciTech Connect

    Musicki, Zoran; Ginsberg, Ted

    2002-07-01

    This paper describes a study undertaken to explain the risk profile differences in the results of PRAs of two similar VVER-1000 nuclear power plants. The risk profile differences are particularly significant in the area of small steam/feedwater line breaks, small-small LOCAs, support system initiators and containment bypass initiators. A top level (limited depth) approach was used in which we studied design differences, major assumptions, data differences, and also compared the two PRA analyses on an element-by-element basis in order to discern the major causative factors for the risk profile differences. We conclude that the major risk profile differences are due to differences in assumptions and engineering judgment (possibly combined with some design and data differences) involved in treatment of uncertain physical phenomena (primarily sump plugging in LOCAs and turbine building steaming effects in secondary system breaks). Additional major differences are attributable to support system characteristics. (authors)

  19. Design, synthesis and biological evaluation of pyrazol-furan carboxamide analogues as novel Akt kinase inhibitors.

    PubMed

    Zhan, Wenhu; Xu, Lei; Dong, Xiaowu; Dong, Jun; Yi, Xiao; Ma, Xiaodong; Qiu, Ni; Li, Jia; Yang, Bo; Zhou, Yubo; Hu, Yongzhou

    2016-07-19

    A series of novel pyrazol-furan carboxamide analogues were designed, synthesized and biologically evaluated for their Akt1 inhibitory activities, as well as anti-proliferative efficacies against HCT116 and OVCAR-8 cell lines. Most compounds exhibited moderate to excellent Akt1 inhibitory activities, together with favorable cytotoxicities. Further kinase selectivity assay of the most promising compound 25e illustrated that it was also potent against the structurally related AGC kinases, including Akt2, Akt3, ROCK1 and PKA, but was specific over kinases from other subfamilies. In addition, the Western blot analysis indicated that 25e could significantly suppress the phosphorylation level of Akt substrate GSK3β in PC-3 cell. Moreover, 25e demonstrated a concentration-dependent inhibition of phosphorylation of PRAS40 in LNCaP cell, with IC50 value of 30.4 nM. PMID:27089211

  20. Development of partial failure analysis method in probability risk assessments

    SciTech Connect

    Ni, T.; Modarres, M.

    1996-12-01

    This paper presents a new approach to evaluate the partial failure effect on current Probability Risk Assessments (PRAs). An integrated methodology of the thermal-hydraulic analysis and fuzzy logic simulation using the Dynamic Master Logic Diagram (DMLD) was developed. The thermal-hydraulic analysis used in this approach is to identify partial operation effect of any PRA system function in a plant model. The DMLD is used to simulate the system performance of the partial failure effect and inspect all minimal cut sets of system functions. This methodology can be applied in the context of a full scope PRA to reduce core damage frequency. An example of this application of the approach is presented. The partial failure data used in the example is from a survey study of partial failure effects from the Nuclear Plant Reliability Data System (NPRDS).

  1. Systems analysis programs for hands-on integrated reliability evaluations (SAPHIRE) Version 5.0. Fault tree, event tree, and piping & instrumentation diagram (FEP) editors reference manual: Volume 7

    SciTech Connect

    McKay, M.K.; Skinner, N.L.; Wood, S.T.

    1994-07-01

    The Systems Analysis Programs for Hands-on Integrated Reliability Evaluations (SAPHIRE) refers to a set of several microcomputer programs that were developed to create and analyze probabilistic risk assessments (PRAs), primarily for nuclear power plants. The Fault Tree, Event Tree, and Piping and Instrumentation Diagram (FEP) editors allow the user to graphically build and edit fault trees, and event trees, and piping and instrumentation diagrams (P and IDs). The software is designed to enable the independent use of the graphical-based editors found in the Integrated Reliability and Risk Assessment System (IRRAS). FEP is comprised of three separate editors (Fault Tree, Event Tree, and Piping and Instrumentation Diagram) and a utility module. This reference manual provides a screen-by-screen guide of the entire FEP System.

  2. Systems Analysis Programs for Hands-on Integrated Reliability Evaluations (SAPHIRE) Tutorial

    SciTech Connect

    C. L. Smith; S. T. Beck; S. T. Wood

    2008-08-01

    The Systems Analysis Programs for Hands-on Integrated Reliability Evaluations (SAPHIRE) refers to a set of computer programs that were developed to create and analyze probabilistic risk assessment (PRAs). This volume is the tutorial manual for the SAPHIRE system. In this document, a series of lessons are provided that guide the user through basic steps common to most analyses preformed with SAPHIRE. The tutorial is divided into two major sections covering both basic and advanced features. The section covering basic topics contains lessons that lead the reader through development of a probabilistic hypothetical problem involving a vehicle accident, highlighting the program’s most fundamental features. The advanced features section contains additional lessons that expand on fundamental analysis features of SAPHIRE and provide insights into more complex analysis techniques. Together, these two elements provide an overview into the operation and capabilities of the SAPHIRE software.

  3. Handbook of methods for risk-based analysis of technical specifications

    SciTech Connect

    Samanta, P.K.; Kim, I.S.; Mankamo, T.; Vesely, W.E.

    1996-09-01

    Technical Specifications (TS) requirements for nuclear power plants define the Limiting Conditions for Operations (LCOs) and Surveillance Requirements (SRs) to assure safety during operation. In general, these requirements are based on deterministic analyses and engineering judgments. Improvements in these requirements are facilitated by the availability of plant-specific Probabilistic Risk Assessments (PRAs). The US Nuclear Regulatory Commission (USNRC) Office of Research sponsored research to develop systematic, risk-based methods to improve various aspects of TS requirements. A handbook of methods summarizing such risk-based approaches has been completed in 1994. It is expected that this handbook will provide valuable input to NRC`s present work in developing guidance for using PRA in risk-informed regulation. The handbook addresses reliability and risk-based methods for evaluating allowed outage times (AOTs), action statements requiring shutdown where shutdown risk may be substantial, surveillance test intervals (STIs), managing plant configurations, and scheduling maintenance.

  4. Core damage frequency observations and insights of LWRs based on the IPEs

    SciTech Connect

    Dingman, S.E.; Camp, A.L.; Drouin, M.T.; Kolaczkowski, A.; Darby, J.; LaChance, J.L.; Yakle, J.

    1995-01-01

    Seventy-eight plants are expected to submit Individual Plant Examinations (IPEs) for severe accident vulnerabilities to the U.S. Nuclear Regulatory Commission (NRC). The majority of the plants have elected to perform full Level 1 probabilistic risk assessments (PRAs) to meet the intent of the IPES. Because of this, it is possible to compare the results from the IPE submittals to determine general observations and {open_quotes}lessons learned{close_quotes} from the IPES. The IPE Insights Program is performing this evaluation, and preliminary results are presented in this paper. The core damage frequency and core damage sequences are identified and compared for pressurized water reactors and boiling water reactors. Examination of the results indicates that variations among plant results are due to a combination of actual plant design/operational features and analysis approaches. The findings are consistent with previous NRC studies, such as WASH-1400 and NUREG-1 150.

  5. A CNGB1 Frameshift Mutation in Papillon and Phalène Dogs with Progressive Retinal Atrophy

    PubMed Central

    Ahonen, Saija J.; Arumilli, Meharji; Lohi, Hannes

    2013-01-01

    Progressive retinal degenerations are the most common causes of complete blindness both in human and in dogs. Canine progressive retinal atrophy (PRA) or degeneration resembles human retinitis pigmentosa (RP) and is characterized by a progressive loss of rod photoreceptor cells followed by a loss of cone function. The primary clinical signs are detected as vision impairment in a dim light. Although several genes have been associated with PRAs, there are still PRAs of unknown genetic cause in many breeds, including Papillons and Phalènes. We have performed a genome wide association and linkage studies in cohort of 6 affected Papillons and Phalènes and 14 healthy control dogs to map a novel PRA locus on canine chromosome 2, with a 1.9 Mb shared homozygous region in the affected dogs. Parallel exome sequencing of a trio identified an indel mutation, including a 1-bp deletion, followed by a 6-bp insertion in the CNGB1 gene. This mutation causes a frameshift and premature stop codon leading to probable nonsense mediated decay (NMD) of the CNGB1 mRNA. The mutation segregated with the disease and was confirmed in a larger cohort of 145 Papillons and Phalènes (PFisher = 1.4×10−8) with a carrier frequency of 17.2 %. This breed specific mutation was not present in 334 healthy dogs from 10 other breeds or 121 PRA affected dogs from 44 other breeds. CNGB1 is important for the photoreceptor cell function its defects have been previously associated with retinal degeneration in both human and mouse. Our study indicates that a frameshift mutation in CNGB1 is a cause of PRA in Papillons and Phalènes and establishes the breed as a large functional animal model for further characterization of retinal CNGB1 biology and possible retinal gene therapy trials. This study enables also the development of a genetic test for breeding purposes. PMID:24015210

  6. cAMP-dependent activation of mammalian target of rapamycin (mTOR) in thyroid cells. Implication in mitogenesis and activation of CDK4.

    PubMed

    Blancquaert, Sara; Wang, Lifu; Paternot, Sabine; Coulonval, Katia; Dumont, Jacques E; Harris, Thurl E; Roger, Pierre P

    2010-07-01

    How cAMP-dependent protein kinases [protein kinase A (PKA)] transduce the mitogenic stimulus elicited by TSH in thyroid cells to late activation of cyclin D3-cyclin-dependent kinase 4 (CDK4) remains enigmatic. Here we show in PC Cl3 rat thyroid cells that TSH/cAMP, like insulin, activates the mammalian target of rapamycin (mTOR)-raptor complex (mTORC1) leading to phosphorylation of S6K1 and 4E-BP1. mTORC1-dependent S6K1 phosphorylation in response to both insulin and cAMP required amino acids, whereas inhibition of AMP-activated protein kinase and glycogen synthase kinase 3 enhanced insulin but not cAMP effects. Unlike insulin, TSH/cAMP did not activate protein kinase B or induce tuberous sclerosis complex 2 phosphorylation at T1462 and Y1571. However, like insulin, TSH/cAMP produced a stable increase in mTORC1 kinase activity that was associated with augmented 4E-BP1 binding to raptor. This could be caused in part by T246 phosphorylation of PRAS40, which was found as an in vitro substrate of PKA. Both in PC Cl3 cells and primary dog thyrocytes, rapamycin inhibited DNA synthesis and retinoblastoma protein phosphorylation induced by TSH and insulin. Although rapamycin reduced cyclin D3 accumulation, the abundance of cyclin D3-CDK4 complexes was not affected. However, rapamycin inhibited the activity of these complexes by decreasing the TSH and insulin-mediated stimulation of activating T172 phosphorylation of CDK4. We propose that mTORC1 activation by TSH, at least in part through PKA-dependent phosphorylation of PRAS40, crucially contributes to mediate cAMP-dependent mitogenesis by regulating CDK4 T172-phosphorylation. PMID:20484410

  7. A CNGB1 frameshift mutation in Papillon and Phalène dogs with progressive retinal atrophy.

    PubMed

    Ahonen, Saija J; Arumilli, Meharji; Lohi, Hannes

    2013-01-01

    Progressive retinal degenerations are the most common causes of complete blindness both in human and in dogs. Canine progressive retinal atrophy (PRA) or degeneration resembles human retinitis pigmentosa (RP) and is characterized by a progressive loss of rod photoreceptor cells followed by a loss of cone function. The primary clinical signs are detected as vision impairment in a dim light. Although several genes have been associated with PRAs, there are still PRAs of unknown genetic cause in many breeds, including Papillons and Phalènes. We have performed a genome wide association and linkage studies in cohort of 6 affected Papillons and Phalènes and 14 healthy control dogs to map a novel PRA locus on canine chromosome 2, with a 1.9 Mb shared homozygous region in the affected dogs. Parallel exome sequencing of a trio identified an indel mutation, including a 1-bp deletion, followed by a 6-bp insertion in the CNGB1 gene. This mutation causes a frameshift and premature stop codon leading to probable nonsense mediated decay (NMD) of the CNGB1 mRNA. The mutation segregated with the disease and was confirmed in a larger cohort of 145 Papillons and Phalènes (PFisher = 1.4×10(-8)) with a carrier frequency of 17.2 %. This breed specific mutation was not present in 334 healthy dogs from 10 other breeds or 121 PRA affected dogs from 44 other breeds. CNGB1 is important for the photoreceptor cell function its defects have been previously associated with retinal degeneration in both human and mouse. Our study indicates that a frameshift mutation in CNGB1 is a cause of PRA in Papillons and Phalènes and establishes the breed as a large functional animal model for further characterization of retinal CNGB1 biology and possible retinal gene therapy trials. This study enables also the development of a genetic test for breeding purposes. PMID:24015210

  8. Genotype-phenotype and genotype-origin correlations in children with mediterranean fever in Germany - an AID-net study.

    PubMed

    Jeske, M; Lohse, P; Kallinich, T; Berger, T; Rietschel, C; Holzinger, D; Kamlah, C; Lankisch, P; Berendes, R; Dueckers, G; Horneff, G; Lilienthal, E; Haas, J P; Giese, A; Dressler, F; Berrang, J; Braunewell, L; Neudorf, U; Niehues, T; Föll, D; Lainka, E

    2013-11-01

    Familial Mediterranean fever (FMF) is the most inherited common autoinflammatory disease (AID) with mutations in the MEFV (MEditerraneanFeVer) gene.The Mor- and Pras-Score modified for children and C-reactive protein (CRP) were used to assess FMF disease severity in Germany. We evaluate the applicability of the 2 severity scores and the correlations between ethnic origin, phenotype, and genotype.Among 242 children (median 5 age at diagnosis), we detected 431 pyrin mutations and 22 different sequence variants, including one new mutation (p.Gly488Asp). The 5 most -frequent alterations were p.Met694Val (55.2%), p.Met680lle (11.8%), p.Val726Ala (10%), p.Glu148Gln (7.9%) and p.Met694IIe (2.3%). The prevailing ancestries of 223 cases were Turkish (82.5%) and Lebanese (8.1%). Homozygous p.Met694Val substitution (30.2%) was associated with a more severe disease activity by Mor-Score, as well as with a higher mean CRP (74 mg/l) compared to patients with other mutations. Indeed, Mor- and Pras-Score were inconsistent with each other. A typical distribution of mutations in different ethnic populations was obvious, but not statistically verifiable due to the low number of cases.The homozygous p.Met694Val substitution was associated with a more severe disease activity in our German cohort. The common severity scores were inconsistent in -children. PMID:24158885

  9. Use Of Probabilistic Risk Assessment (PRA) In Expert Systems To Advise Nuclear Plant Operators And Managers

    NASA Astrophysics Data System (ADS)

    Uhrig, Robert E.

    1988-03-01

    The use of expert systems in nuclear power plants to provide advice to managers, supervisors and/or operators is a concept that is rapidly gaining acceptance. f2 Generally, expert systems rely on the expertise of human experts or knowledge that has been codified in publications, books, or regulations to provide advice under a wide variety of conditions. In this work, a probabilistic risk assessment (PRA)3 of a nuclear power plant performed previously is used to assess the safety status of nuclear power plants and to make recommendations to the plant personnel. Nuclear power plants have many redundant systems and can continue to operate when one or more of these systems is disabled or removed from service for maintenance or testing. PRAs provide a means of evaluating the risk to the public associated with the operation of nuclear power plants with components or systems out of service. While the choice of the "source term" and methodology in a PRA may influence the absolute probability and consequences of a core melt, the ratio of two PRA calculations for two configurations of the same plant, carried out on a consistent basis, can readily identify the increase in risk associated with going from one configuration to the other. PRISIM,4 a personal computer program to calculate the ratio of core melt probabilities described above (based on previously performed PRAs), has been developed under the sponsorship of the U.S. Nuclear Regulatory Commission (NRC). When one or several components are removed from service, PRISM then calculates the ratio of the core melt probabilities. The inference engine of the expert system then uses this ratio and a constant risk criterion,5 along with information from its knowledge base (which includes information from the PRA), to advise plant personnel as to what action, if any, should be taken.

  10. A suite of models to support the quantitative assessment of spread in pest risk analysis.

    PubMed

    Robinet, Christelle; Kehlenbeck, Hella; Kriticos, Darren J; Baker, Richard H A; Battisti, Andrea; Brunel, Sarah; Dupin, Maxime; Eyre, Dominic; Faccoli, Massimo; Ilieva, Zhenya; Kenis, Marc; Knight, Jon; Reynaud, Philippe; Yart, Annie; van der Werf, Wopke

    2012-01-01

    Pest Risk Analyses (PRAs) are conducted worldwide to decide whether and how exotic plant pests should be regulated to prevent invasion. There is an increasing demand for science-based risk mapping in PRA. Spread plays a key role in determining the potential distribution of pests, but there is no suitable spread modelling tool available for pest risk analysts. Existing models are species specific, biologically and technically complex, and data hungry. Here we present a set of four simple and generic spread models that can be parameterised with limited data. Simulations with these models generate maps of the potential expansion of an invasive species at continental scale. The models have one to three biological parameters. They differ in whether they treat spatial processes implicitly or explicitly, and in whether they consider pest density or pest presence/absence only. The four models represent four complementary perspectives on the process of invasion and, because they have different initial conditions, they can be considered as alternative scenarios. All models take into account habitat distribution and climate. We present an application of each of the four models to the western corn rootworm, Diabrotica virgifera virgifera, using historic data on its spread in Europe. Further tests as proof of concept were conducted with a broad range of taxa (insects, nematodes, plants, and plant pathogens). Pest risk analysts, the intended model users, found the model outputs to be generally credible and useful. The estimation of parameters from data requires insights into population dynamics theory, and this requires guidance. If used appropriately, these generic spread models provide a transparent and objective tool for evaluating the potential spread of pests in PRAs. Further work is needed to validate models, build familiarity in the user community and create a database of species parameters to help realize their potential in PRA practice. PMID:23056174

  11. Evaluation of potential severe accidents during low power and shutdown operations at Grand Gulf, Unit 1: Evaluation of severe accident risks for plant operational state 5 during a refueling outage. Supporting MELCOR calculations, Volume 6, Part 2

    SciTech Connect

    Kmetyk, L.N.; Brown, T.D.

    1995-03-01

    To gain a better understanding of the risk significance of low power and shutdown modes of operation, the Office of Nuclear Regulatory Research at the NRC established programs to investigate the likelihood and severity of postulated accidents that could occur during low power and shutdown (LP&S) modes of operation at commercial nuclear power plants. To investigate the likelihood of severe core damage accidents during off power conditions, probabilistic risk assessments (PRAs) were performed for two nuclear plants: Unit 1 of the Grand Gulf Nuclear Station, which is a BWR-6 Mark III boiling water reactor (BWR), and Unit 1 of the Surry Power Station, which is a three-loop, subatmospheric, pressurized water reactor (PWR). The analysis of the BWR was conducted at Sandia National Laboratories while the analysis of the PWR was performed at Brookhaven National Laboratory. This multi-volume report presents and discusses the results of the BWR analysis. The subject of this part presents the deterministic code calculations, performed with the MELCOR code, that were used to support the development and quantification of the PRA models. The background for the work documented in this report is summarized, including how deterministic codes are used in PRAS, why the MELCOR code is used, what the capabilities and features of MELCOR are, and how the code has been used by others in the past. Brief descriptions of the Grand Gulf plant and its configuration during LP&S operation and of the MELCOR input model developed for the Grand Gulf plant in its LP&S configuration are given.

  12. Hydrophobic motif site-phosphorylated protein kinase CβII between mTORC2 and Akt regulates high glucose-induced mesangial cell hypertrophy.

    PubMed

    Das, Falguni; Ghosh-Choudhury, Nandini; Mariappan, Meenalakshmi M; Kasinath, Balakuntalam S; Choudhury, Goutam Ghosh

    2016-04-01

    PKCβII controls the pathologic features of diabetic nephropathy, including glomerular mesangial cell hypertrophy. PKCβII contains the COOH-terminal hydrophobic motif site Ser-660. Whether this hydrophobic motif phosphorylation contributes to high glucose-induced mesangial cell hypertrophy has not been determined. Here we show that, in mesangial cells, high glucose increased phosphorylation of PKCβII at Ser-660 in a phosphatidylinositol 3-kinase (PI3-kinase)-dependent manner. Using siRNAs to downregulate PKCβII, dominant negative PKCβII, and PKCβII hydrophobic motif phosphorylation-deficient mutant, we found that PKCβII regulates activation of mechanistic target of rapamycin complex 1 (mTORC1) and mesangial cell hypertrophy by high glucose. PKCβII via its phosphorylation at Ser-660 regulated phosphorylation of Akt at both catalytic loop and hydrophobic motif sites, resulting in phosphorylation and inactivation of its substrate PRAS40. Specific inhibition of mTORC2 increased mTORC1 activity and induced mesangial cell hypertrophy. In contrast, inhibition of mTORC2 decreased the phosphorylation of PKCβII and Akt, leading to inhibition of PRAS40 phosphorylation and mTORC1 activity and prevented mesangial cell hypertrophy in response to high glucose; expression of constitutively active Akt or mTORC1 restored mesangial cell hypertrophy. Moreover, constitutively active PKCβII reversed the inhibition of high glucose-stimulated Akt phosphorylation and mesangial cell hypertrophy induced by suppression of mTORC2. Finally, using renal cortexes from type 1 diabetic mice, we found that increased phosphorylation of PKCβII at Ser-660 was associated with enhanced Akt phosphorylation and mTORC1 activation. Collectively, our findings identify a signaling route connecting PI3-kinase to mTORC2 to phosphorylate PKCβII at the hydrophobic motif site necessary for Akt phosphorylation and mTORC1 activation, leading to mesangial cell hypertrophy. PMID:26739493

  13. Standardized approach for developing probabilistic exposure factor distributions

    SciTech Connect

    Maddalena, Randy L.; McKone, Thomas E.; Sohn, Michael D.

    2003-03-01

    The effectiveness of a probabilistic risk assessment (PRA) depends critically on the quality of input information that is available to the risk assessor and specifically on the probabilistic exposure factor distributions that are developed and used in the exposure and risk models. Deriving probabilistic distributions for model inputs can be time consuming and subjective. The absence of a standard approach for developing these distributions can result in PRAs that are inconsistent and difficult to review by regulatory agencies. We present an approach that reduces subjectivity in the distribution development process without limiting the flexibility needed to prepare relevant PRAs. The approach requires two steps. First, we analyze data pooled at a population scale to (1) identify the most robust demographic variables within the population for a given exposure factor, (2) partition the population data into subsets based on these variables, and (3) construct archetypal distributions for each subpopulation. Second, we sample from these archetypal distributions according to site- or scenario-specific conditions to simulate exposure factor values and use these values to construct the scenario-specific input distribution. It is envisaged that the archetypal distributions from step 1 will be generally applicable so risk assessors will not have to repeatedly collect and analyze raw data for each new assessment. We demonstrate the approach for two commonly used exposure factors--body weight (BW) and exposure duration (ED)--using data for the U.S. population. For these factors we provide a first set of subpopulation based archetypal distributions along with methodology for using these distributions to construct relevant scenario-specific probabilistic exposure factor distributions.

  14. A Suite of Models to Support the Quantitative Assessment of Spread in Pest Risk Analysis

    PubMed Central

    Robinet, Christelle; Kehlenbeck, Hella; Kriticos, Darren J.; Baker, Richard H. A.; Battisti, Andrea; Brunel, Sarah; Dupin, Maxime; Eyre, Dominic; Faccoli, Massimo; Ilieva, Zhenya; Kenis, Marc; Knight, Jon; Reynaud, Philippe; Yart, Annie; van der Werf, Wopke

    2012-01-01

    Pest Risk Analyses (PRAs) are conducted worldwide to decide whether and how exotic plant pests should be regulated to prevent invasion. There is an increasing demand for science-based risk mapping in PRA. Spread plays a key role in determining the potential distribution of pests, but there is no suitable spread modelling tool available for pest risk analysts. Existing models are species specific, biologically and technically complex, and data hungry. Here we present a set of four simple and generic spread models that can be parameterised with limited data. Simulations with these models generate maps of the potential expansion of an invasive species at continental scale. The models have one to three biological parameters. They differ in whether they treat spatial processes implicitly or explicitly, and in whether they consider pest density or pest presence/absence only. The four models represent four complementary perspectives on the process of invasion and, because they have different initial conditions, they can be considered as alternative scenarios. All models take into account habitat distribution and climate. We present an application of each of the four models to the western corn rootworm, Diabrotica virgifera virgifera, using historic data on its spread in Europe. Further tests as proof of concept were conducted with a broad range of taxa (insects, nematodes, plants, and plant pathogens). Pest risk analysts, the intended model users, found the model outputs to be generally credible and useful. The estimation of parameters from data requires insights into population dynamics theory, and this requires guidance. If used appropriately, these generic spread models provide a transparent and objective tool for evaluating the potential spread of pests in PRAs. Further work is needed to validate models, build familiarity in the user community and create a database of species parameters to help realize their potential in PRA practice. PMID:23056174

  15. African Swine Fever in Uganda: Qualitative Evaluation of Three Surveillance Methods with Implications for Other Resource-Poor Settings

    PubMed Central

    Chenais, Erika; Sternberg-Lewerin, Susanna; Boqvist, Sofia; Emanuelson, Ulf; Aliro, Tonny; Tejler, Emma; Cocca, Giampaolo; Masembe, Charles; Ståhl, Karl

    2015-01-01

    Animal diseases impact negatively on households and on national economies. In low-income countries, this pertains especially to socio-economic effects on household level. To control animal diseases and mitigate their impact, it is necessary to understand the epidemiology of the disease in its local context. Such understanding, gained through disease surveillance, is often lacking in resource-poor settings. Alternative surveillance methods have been developed to overcome some of the hurdles obstructing surveillance. The objective of this study was to evaluate and qualitatively compare three methods for surveillance of acute infectious diseases using African swine fever in northern Uganda as an example. Report-driven outbreak investigations, participatory rural appraisals (PRAs), and a household survey using a smartphone application were evaluated. All three methods had good disease-detecting capacity, and each of them detected many more outbreaks compared to those reported to the World Organization for Animal Health during the same time period. Apparent mortality rates were similar for the three methods although highest for the report-driven outbreak investigations, followed by the PRAs, and then the household survey. The three methods have different characteristics and the method of choice will depend on the surveillance objective. The optimal situation might be achieved by a combination of the methods: outbreak detection via smartphone-based real-time surveillance, outbreak investigation for collection of biological samples, and a PRA for a better understanding of the epidemiology of the specific outbreak. All three methods require initial investments and continuous efforts. The sustainability of the surveillance system should, therefore, be carefully evaluated before making such investments. PMID:26664978

  16. Operative and technological management of super-large united power grids: lessons of major world's blackouts

    NASA Astrophysics Data System (ADS)

    Brinkis, K.; Kreslins, V.; Mutule, A.

    2014-02-01

    Power system (PS) blackouts still persist worldwide, evidencing that the existing protective structures need to be improved. The discussed requirements and criteria to be met for joint synchronous operation of large and super-large united PSs should be based on close co-ordination of operative and technological management of all PSs involved in order to ensure secure and stable electricity supply and minimise or avoid the threat of a total PS blackout. The authors analyse the July 2012 India blackout - the largest power outage in history, which affected over 620 million people, i.e. half of India's population and spread across its 22 states. The analysis is of a general character, being applicable also to similar blackouts that have occurred in Europe and worldwide since 2003. The authors summarise and develop the main principles and methods of operative and technological management aimed at preventing total blackouts in large and super-large PSs. Neskatoties uz sasniegumiem elektroenerģētikas jomā un energosistēmu nepārtrauktu modernizāciju, pasaulē regulāri notiek sabrukumu avārijas. Rakstā apskatīti lielu un superlielu energosistēmu apvienību savstarpējas sinhronas darbības nodrošinājuma prasības un kritēriji, kas pamatojas uz operatīvās un tehnoloģiskās vadības ciešu koordināciju starp energosistēmām. Savstarpējas sinhronas darbības nodrošinājuma prasībām un kritērijiem ir izšķiroša nozīme, lai panāktu elektroapgādes drošumu un stabilitāti katrā energosistēmā, kas darbojas apvienotas energosistēmas sastāvā. Šo prasību un kritēriju ievērošana sekmē totālo avāriju izcelšanās iespēju samazināšanu un to novēršanu. Indijas 2012.gada totālo avāriju un citu analogo avāriju Eiropā un Amerikā analīze un izvērtējums laika posmā no 2003.gada, deva iespēju apkopot un izstrādāt lielu un superlielu energosistēmu operatīvās un tehnoloģiskās vadības principus un metodoloģiju, lai novērstu vai

  17. Component Repair Times Obtained from MSPI Data

    SciTech Connect

    Eide, Steven A.

    2015-05-01

    Information concerning times to repair or restore equipment to service given a failure is valuable to probabilistic risk assessments (PRAs). Examples of such uses in modern PRAs include estimation of the probability of failing to restore a failed component within a specified time period (typically tied to recovering a mitigating system before core damage occurs at nuclear power plants) and the determination of mission times for support system initiating event (SSIE) fault tree models. Information on equipment repair or restoration times applicable to PRA modeling is limited and dated for U.S. commercial nuclear power plants. However, the Mitigating Systems Performance Index (MSPI) program covering all U.S. commercial nuclear power plants provides up-to-date information on restoration times for a limited set of component types. This paper describes the MSPI program data available and analyzes the data to obtain median and mean component restoration times as well as non-restoration cumulative probability curves. The MSPI program provides guidance for monitoring both planned and unplanned outages of trains of selected mitigating systems deemed important to safety. For systems included within the MSPI program, plants monitor both train UA and component unreliability (UR) against baseline values. If the combined system UA and UR increases sufficiently above established baseline results (converted to an estimated change in core damage frequency or CDF), a “white” (or worse) indicator is generated for that system. That in turn results in increased oversight by the US Nuclear Regulatory Commission (NRC) and can impact a plant’s insurance rating. Therefore, there is pressure to return MSPI program components to service as soon as possible after a failure occurs. Three sets of unplanned outages might be used to determine the component repair durations desired in this article: all unplanned outages for the train type that includes the component of interest, only

  18. The Importance of HRA in Human Space Flight: Understanding the Risks

    NASA Technical Reports Server (NTRS)

    Hamlin, Teri

    2010-01-01

    Human performance is critical to crew safety during space missions. Humans interact with hardware and software during ground processing, normal flight, and in response to events. Human interactions with hardware and software can cause Loss of Crew and/or Vehicle (LOCV) through improper actions, or may prevent LOCV through recovery and control actions. Humans have the ability to deal with complex situations and system interactions beyond the capability of machines. Human Reliability Analysis (HRA) is a method used to qualitatively and quantitatively assess the occurrence of human failures that affect availability and reliability of complex systems. Modeling human actions with their corresponding failure probabilities in a Probabilistic Risk Assessment (PRA) provides a more complete picture of system risks and risk contributions. A high-quality HRA can provide valuable information on potential areas for improvement, including training, procedures, human interfaces design, and the need for automation. Modeling human error has always been a challenge in part because performance data is not always readily available. For spaceflight, the challenge is amplified not only because of the small number of participants and limited amount of performance data available, but also due to the lack of definition of the unique factors influencing human performance in space. These factors, called performance shaping factors in HRA terminology, are used in HRA techniques to modify basic human error probabilities in order to capture the context of an analyzed task. Many of the human error modeling techniques were developed within the context of nuclear power plants and therefore the methodologies do not address spaceflight factors such as the effects of microgravity and longer duration missions. This presentation will describe the types of human error risks which have shown up as risk drivers in the Shuttle PRA which may be applicable to commercial space flight. As with other large PRAs

  19. 2009 Space Shuttle Probabilistic Risk Assessment Overview

    NASA Technical Reports Server (NTRS)

    Hamlin, Teri L.; Canga, Michael A.; Boyer, Roger L.; Thigpen, Eric B.

    2010-01-01

    Loss of a Space Shuttle during flight has severe consequences, including loss of a significant national asset; loss of national confidence and pride; and, most importantly, loss of human life. The Shuttle Probabilistic Risk Assessment (SPRA) is used to identify risk contributors and their significance; thus, assisting management in determining how to reduce risk. In 2006, an overview of the SPRA Iteration 2.1 was presented at PSAM 8 [1]. Like all successful PRAs, the SPRA is a living PRA and has undergone revisions since PSAM 8. The latest revision to the SPRA is Iteration 3. 1, and it will not be the last as the Shuttle program progresses and more is learned. This paper discusses the SPRA scope, overall methodology, and results, as well as provides risk insights. The scope, assumptions, uncertainties, and limitations of this assessment provide risk-informed perspective to aid management s decision-making process. In addition, this paper compares the Iteration 3.1 analysis and results to the Iteration 2.1 analysis and results presented at PSAM 8.

  20. Verification and validation of the SAPHIRE Version 4.0 PRA software package

    SciTech Connect

    Bolander, T.W.; Calley, M.B.; Capps, E.L.

    1994-02-01

    A verification and validation (V&V) process has been performed for the System Analysis Programs for Hands-on Integrated Reliability Evaluation (SAPHIRE). SAPHIRE is a set of four computer programs that the Nuclear Regulatory Commission (NRC) developed to perform probabilistic risk assessments (PRAs). These programs allow an analyst to create, quantify, and evaluate the risk associated with a facility or process being analyzed. The programs included in this set are Integrated Reliability and Risk Analysis System (IRRAS), System Analysis and Risk Assessment (SARA), Models and Results Database (MAR-D), and Fault Tree/Event Tree/Piping and Instrumentation Diagram (FEP) graphical editor. The V&V steps included a V&V plan to describe the process and criteria by which the V&V would be performed; a software requirements documentation review to determine the correctness, completeness, and traceability of the requirements; a user survey to determine the usefulness of the user documentation, identification and testing of vital and non-vital features, and documentation of the test results.

  1. Guidelines on the scope, content, and use of comprehensive risk assessment in the management of high-level nuclear waste transportation

    SciTech Connect

    Golding, D.; White, A.

    1990-12-01

    This report discusses the scope of risk assessment strategies in the management of the transport of high-level radioactive wastes. In spite of the shortcomings of probabilistic risk assessment(PRA), the Transportation Needs Assessment recommended this as the preferred methodology to assess the risks of high level nuclear waste (HLNW) transportation. A PRA also will need to heed the lessons learned from the development and application of PRA elsewhere, such as in the nuclear power industry. A set of guidelines will aid this endeavor by outlining the appropriate scope, content, and use of a risk assessment which is more responsive to the uncertainties, human-technical interactions, social forces, and iterative relationship with risk management strategies, than traditional PRAS. This more expansive definition, which encompasses but is not totally reliant on rigorous data requirements and quantitative probability estimates, we term Comprehensive Risk Assessment (CRA) Guidelines will be developed in three areas: the limitations of existing methodologies and suggested modifications; CRA as part of a flexible, effective, adaptive risk management system for HLNW transportation; and, the use of CRA in risk communication.

  2. A putative biomarker signature for clinically effective AKT inhibition: correlation of in vitro, in vivo and clinical data identifies the importance of modulation of the mTORC1 pathway

    PubMed Central

    Cheraghchi-Bashi, Azadeh; Salazar, Jean-Frederic; Gungor, Hatice; Saleem, Azeem; Cunnea, Paula; Rama, Nona; Salinas, Cristian; Mills, Gordon B.; Morris, Shannon R.; Kumar, Rakesh; Gabra, Hani; Stronach, Euan A.

    2015-01-01

    Our identification of dysregulation of the AKT pathway in ovarian cancer as a platinum resistance specific event led to a comprehensive analysis of in vitro, in vivo and clinical behaviour of the AKT inhibitor GSK2141795. Proteomic biomarker signatures correlating with effects of GSK2141795 were developed using in vitro and in vivo models, well characterised for related molecular, phenotypic and imaging endpoints. Signatures were validated in temporally paired biopsies from patients treated with GSK2141795 in a clinical study. GSK2141795 caused growth-arrest as single agent in vitro, enhanced cisplatin-induced apoptosis in vitro and reduced tumour volume in combination with platinum in vivo. GSK2141795 treatment in vitro and in vivo resulted in ~50-90% decrease in phospho-PRAS40 and 20-80% decrease in fluoro-deoxyglucose (FDG) uptake. Proteomic analysis of GSK2141795 in vitro and in vivo identified a signature of pathway inhibition including changes in AKT and p38 phosphorylation and total Bim, IGF1R, AR and YB1 levels. In patient biopsies, prior to treatment with GSK2141795 in a phase 1 clinical trial, this signature was predictive of post-treatment changes in the response marker CA125. Development of this signature represents an opportunity to demonstrate the clinical importance of AKT inhibition for re-sensitisation of platinum resistant ovarian cancer to platinum. PMID:26497682

  3. A putative biomarker signature for clinically effective AKT inhibition: correlation of in vitro, in vivo and clinical data identifies the importance of modulation of the mTORC1 pathway.

    PubMed

    Cheraghchi-Bashi, Azadeh; Parker, Christine A; Curry, Ed; Salazar, Jean-Frederic; Gungor, Hatice; Saleem, Azeem; Cunnea, Paula; Rama, Nona; Salinas, Cristian; Mills, Gordon B; Morris, Shannon R; Kumar, Rakesh; Gabra, Hani; Stronach, Euan A

    2015-12-01

    Our identification of dysregulation of the AKT pathway in ovarian cancer as a platinum resistance specific event led to a comprehensive analysis of in vitro, in vivo and clinical behaviour of the AKT inhibitor GSK2141795. Proteomic biomarker signatures correlating with effects of GSK2141795 were developed using in vitro and in vivo models, well characterised for related molecular, phenotypic and imaging endpoints. Signatures were validated in temporally paired biopsies from patients treated with GSK2141795 in a clinical study. GSK2141795 caused growth-arrest as single agent in vitro, enhanced cisplatin-induced apoptosis in vitro and reduced tumour volume in combination with platinum in vivo. GSK2141795 treatment in vitro and in vivo resulted in ~50-90% decrease in phospho-PRAS40 and 20-80% decrease in fluoro-deoxyglucose (FDG) uptake. Proteomic analysis of GSK2141795 in vitro and in vivo identified a signature of pathway inhibition including changes in AKT and p38 phosphorylation and total Bim, IGF1R, AR and YB1 levels. In patient biopsies, prior to treatment with GSK2141795 in a phase 1 clinical trial, this signature was predictive of post-treatment changes in the response marker CA125. Development of this signature represents an opportunity to demonstrate the clinical importance of AKT inhibition for re-sensitisation of platinum resistant ovarian cancer to platinum. PMID:26497682

  4. Identification of unique sensitizing targets for anti-inflammatory CDDO-Me in metastatic melanoma by a large-scale synthetic lethal RNAi screening

    PubMed Central

    Ekmekcioglu, Suhendan; Grimm, Elizabeth A.

    2013-01-01

    Summary CDDO-Me has been shown to exert potent anti-inflammatory activity for chronic kidney disease and antitumor activity for several tumors, including melanoma, in early clinical trials. To improve CDDO-Me response in melanoma, we utilized a large-scale synthetic lethal RNAi screen targeting 6,000 human druggable genes to identify targets that would sensitize melanoma cells to CDDO-Me. Based on screening results, five unique genes (GNPAT, SUMO1, SPINT2, FLI1, and SSX1) significantly potentiated the growth-inhibitory effects of CDDO-Me and induced apoptosis in A375, a BRAF mutated melanoma line (P<0.001). These five genes were then individually validated as targets to potentiate CDDO-Me activity, and related downstream signaling pathways of these genes were analyzed. In addition, the levels of phosphorylated Erk1/2, Akt, GSK-2, and PRAS40 were dramatically decreased by downregulating each of these five genes separately, suggesting a set of common mediators. Our findings indicate that GNPAT, SUMO1, SPINT2, FLI1, and SSX1 play critical roles in synergy with inflammation pathways in modulating melanoma cell survival, and could serve as sensitizing targets to enhance CDDO-Me efficacy in melanoma growth control. PMID:23020131

  5. SPAR Model Structural Efficiencies

    SciTech Connect

    John Schroeder; Dan Henry

    2013-04-01

    The Nuclear Regulatory Commission (NRC) and the Electric Power Research Institute (EPRI) are supporting initiatives aimed at improving the quality of probabilistic risk assessments (PRAs). Included in these initiatives are the resolution of key technical issues that are have been judged to have the most significant influence on the baseline core damage frequency of the NRC’s Standardized Plant Analysis Risk (SPAR) models and licensee PRA models. Previous work addressed issues associated with support system initiating event analysis and loss of off-site power/station blackout analysis. The key technical issues were: • Development of a standard methodology and implementation of support system initiating events • Treatment of loss of offsite power • Development of standard approach for emergency core cooling following containment failure Some of the related issues were not fully resolved. This project continues the effort to resolve outstanding issues. The work scope was intended to include substantial collaboration with EPRI; however, EPRI has had other higher priority initiatives to support. Therefore this project has addressed SPAR modeling issues. The issues addressed are • SPAR model transparency • Common cause failure modeling deficiencies and approaches • Ac and dc modeling deficiencies and approaches • Instrumentation and control system modeling deficiencies and approaches

  6. SAPHIRE 8 Volume 2 - Technical Reference

    SciTech Connect

    C. L. Smith; S. T. Wood; W. J. Galyean; J. A. Schroeder; M. B. Sattison

    2011-03-01

    The Systems Analysis Programs for Hands-on Integrated Reliability Evaluations (SAPHIRE) refers to a set of computer programs that were developed to create and analyze probabilistic risk assessment (PRAs). Herein information is provided on the principles used in the construction and operation of Version 8.0 of the SAPHIRE system. This report summarizes the fundamental mathematical concepts of sets and logic, fault trees, and probability. This volume then describes the algorithms used to construct a fault tree and to obtain the minimal cut sets. It gives the formulas used to obtain the probability of the top event from the minimal cut sets, and the formulas for probabilities that apply for various assumptions concerning reparability and mission time. It defines the measures of basic event importance that SAPHIRE can calculate. This volume gives an overview of uncertainty analysis using simple Monte Carlo sampling or Latin Hypercube sampling, and states the algorithms used by this program to generate random basic event probabilities from various distributions. Also covered are enhance capabilities such as seismic analysis, Workspace algorithms, cut set "recovery," end state manipulation, and use of "compound events."

  7. ATHEANA: {open_quotes}a technique for human error analysis{close_quotes} entering the implementation phase

    SciTech Connect

    Taylor, J.; O`Hara, J.; Luckas, W.

    1997-02-01

    Probabilistic Risk Assessment (PRA) has become an increasingly important tool in the nuclear power industry, both for the Nuclear Regulatory Commission (NRC) and the operating utilities. The NRC recently published a final policy statement, SECY-95-126, encouraging the use of PRA in regulatory activities. Human reliability analysis (HRA), while a critical element of PRA, has limitations in the analysis of human actions in PRAs that have long been recognized as a constraint when using PRA. In fact, better integration of HRA into the PRA process has long been a NRC issue. Of particular concern, has been the omission of errors of commission - those errors that are associated with inappropriate interventions by operators with operating systems. To address these concerns, the NRC identified the need to develop an improved HRA method, so that human reliability can be better represented and integrated into PRA modeling and quantification. The purpose of the Brookhaven National Laboratory (BNL) project, entitled `Improved HRA Method Based on Operating Experience` is to develop a new method for HRA which is supported by the analysis of risk-significant operating experience. This approach will allow a more realistic assessment and representation of the human contribution to plant risk, and thereby increase the utility of PRA. The project`s completed, ongoing, and future efforts fall into four phases: (1) Assessment phase (FY 92/93); (2) Analysis and Characterization phase (FY 93/94); (3) Development phase (FY 95/96); and (4) Implementation phase (FY 96/97 ongoing).

  8. Code cases for implementing risk-based inservice testing in the ASME OM code

    SciTech Connect

    Rowley, C.W.

    1996-12-01

    Historically inservice testing has been reasonably effective, but quite costly. Recent applications of plant PRAs to the scope of the IST program have demonstrated that of the 30 pumps and 500 valves in the typical plant IST program, less than half of the pumps and ten percent of the valves are risk significant. The way the ASME plans to tackle this overly-conservative scope for IST components is to use the PRA and plant expert panels to create a two tier IST component categorization scheme. The PRA provides the quantitative risk information and the plant expert panel blends the quantitative and deterministic information to place the IST component into one of two categories: More Safety Significant Component (MSSC) or Less Safety Significant Component (LSSC). With all the pumps and valves in the IST program placed in MSSC or LSSC categories, two different testing strategies will be applied. The testing strategies will be unique for the type of component, such as centrifugal pump, positive displacement pump, MOV, AOV, SOV, SRV, PORV, HOV, CV, and MV. A series of OM Code Cases are being developed to capture this process for a plant to use. One Code Case will be for Component Importance Ranking. The remaining Code Cases will develop the MSSC and LSSC testing strategy for type of component. These Code Cases are planned for publication in early 1997. Later, after some industry application of the Code Cases, the alternative Code Case requirements will gravitate to the ASME OM Code as appendices.

  9. Risk-ranking IST components into two categories

    SciTech Connect

    Rowley, C.W.

    1996-12-01

    The ASME has utilized several schemes for identifying the appropriate scope of components for inservice testing (IST). The initial scope was ASME Code Class 1/2/3, with all components treated equally. Later the ASME Operations and Maintenance (O&M) Committee decided to use safe shutdown and accident mitigation as the scoping criteria, but continued to treat all components equal inside that scope. Recently the ASME O&M Committee decided to recognize service condition of the component, hence the comprehensive pump test. Although probabilistic risk assessments (PRAs) are incredibly complex plant models and computer hardware and software intensive, they are a tool that can be utilized by many plant engineering organizations to analyze plant system and component applications. In 1992 the ASME O&M Committee got interested in using the PRA as a tool to categorize its pumps and valves. In 1994 the ASME O&M Committee commissioned the ASME Center for Research and Technology Development (CRTD) to develop a process that adapted the PRA technology to IST. In late 1995 that process was presented to the ASME O&M Committee. The process had three distinct portions: (1) risk-rank the IST components; (2) develop a more effective testing strategy for More Safety Significant Components; and (3) develop a more economic testing strategy for Less Safety Significant Components.

  10. Removal of criticality accident alarm systems at the Y-12 Plant waste management facilities

    SciTech Connect

    Marble, R.C.; Taylor, R.G.

    1998-09-01

    This paper discusses why criticality accident alarm systems (CAASs) were installed in certain waste management buildings at the Y-12 Plant, why the plant now wants to remove them, and what steps were taken to allow the US Department of Energy (DOE) to authorize the removal of the systems. To begin with, the systems in question were installed in the mid- to late-1980s. Some of the facilities were new, and there was no operating experience with the processes. A CAAS, although expensive, is an absolute necessity where criticality accidents are credible. But, they are a superfluous and unnecessary expense in those facilities where it has been determined that a criticality accident is incredible (defined as having a probability of <1 {times} 10{sup {minus}6}/yr). The PRAs have been performed to evaluate six Y-12 Plant waste management facilities, five storage facilities, and a nondestructive analysis facility, with an additional study now being performed on the West End Treatment Facility. The results to date have shown that the probability of various criticality accident scenarios at these facilities is <1 {times} 10{sup {minus}6}/yr and that the CAASs are not needed in these facilities.

  11. Phosphoproteomics reveals resveratrol-dependent inhibition of Akt/mTORC1/S6K1 signaling.

    PubMed

    Alayev, Anya; Doubleday, Peter F; Berger, Sara Malka; Ballif, Bryan A; Holz, Marina K

    2014-12-01

    Resveratrol, a plant-derived polyphenol, regulates many cellular processes, including cell proliferation, aging and autophagy. However, the molecular mechanisms of resveratrol action in cells are not completely understood. Intriguingly, resveratrol treatment of cells growing in nutrient-rich conditions induces autophagy, while acute resveratrol treatment of cells in a serum-deprived state inhibits autophagy. In this study, we performed a phosphoproteomic analysis after applying resveratrol to serum-starved cells with the goal of identifying the acute signaling events initiated by resveratrol in a serum-deprived state. We determined that resveratrol in serum-starved conditions reduces the phosphorylation of several proteins belonging to the mTORC1 signaling pathway, most significantly, PRAS40 at T246 and S183. Under these same conditions, we also found that resveratrol altered the phosphorylation of several proteins involved in various biological processes, most notably transcriptional modulators, represented by p53, FOXA1, and AATF. Together these data provide a more comprehensive view of both the spectrum of phosphoproteins upon which resveratrol acts as well as the potential mechanisms by which it inhibits autophagy in serum-deprived cells. PMID:25311616

  12. Risk-informed regulation and safety management of nuclear power plants--on the prevention of severe accidents.

    PubMed

    Himanen, Risto; Julin, Ari; Jänkälä, Kalle; Holmberg, Jan-Erik; Virolainen, Reino

    2012-11-01

    There are four operating nuclear power plant (NPP) units in Finland. The Teollisuuden Voima (TVO) power company has two 840 MWe BWR units supplied by Asea-Atom at the Olkiluoto site. The Fortum corporation (formerly IVO) has two 500 MWe VVER 440/213 units at the Loviisa site. In addition, a 1600 MWe European Pressurized Water Reactor supplied by AREVA NP (formerly the Framatome ANP--Siemens AG Consortium) is under construction at the Olkiluoto site. Recently, the Finnish Parliament ratified the government Decision in Principle that the utilities' applications to build two new NPP units are in line with the total good of the society. The Finnish utilities, Fenno power company, and TVO company are in progress of qualifying the type of the new nuclear builds. In Finland, risk-informed applications are formally integrated in the regulatory process of NPPs that are already in the early design phase and these are to run through the construction and operation phases all through the entire plant service time. A plant-specific full-scope probabilistic risk assessment (PRA) is required for each NPP. PRAs shall cover internal events, area events (fires, floods), and external events such as harsh weather conditions and seismic events in all operating modes. Special attention is devoted to the use of various risk-informed PRA applications in the licensing of Olkiluoto 3 NPP. PMID:23035957

  13. Targeting TORC1/2 enhances sensitivity to EGFR inhibitors in head and neck cancer preclinical models.

    PubMed

    Cassell, Andre; Freilino, Maria L; Lee, Jessica; Barr, Sharon; Wang, Lin; Panahandeh, Mary C; Thomas, Sufi M; Grandis, Jennifer R

    2012-11-01

    Head and neck squamous cell carcinoma (HNSCC) is characterized by overexpression of the epidermal growth factor receptor (EGFR) where treatments targeting EGFR have met with limited clinical success. Elucidation of the key downstream-pathways that remain activated in the setting of EGFR blockade may reveal new therapeutic targets. The present study was undertaken to test the hypothesis that inhibition of the mammalian target of rapamycin (mTOR) complex would enhance the effects of EGFR blockade in HNSCC preclinical models. Treatment of HNSCC cell lines with the newly developed TORC1/TORC2 inhibitor OSI-027/ASP4876 resulted in dose-dependent inhibition of proliferation with abrogation of phosphorylation of known downstream targets including phospho-AKT (Ser473), phospho-4E-BP1, phospho-p70s6K, and phospho-PRAS40. Furthermore, combined treatment with OSI-027 and erlotinib resulted in enhanced biochemical effects and synergistic growth inhibition in vitro. Treatment of mice bearing HNSCC xenografts with a combination of the Food and Drug Administration (FDA)-approved EGFR inhibitor cetuximab and OSI-027 demonstrated a significant reduction of tumor volumes compared with either treatment alone. These findings suggest that TORC1/TORC2 inhibition in conjunction with EGFR blockade represents a plausible therapeutic strategy for HNSCC. PMID:23226094

  14. Progesterone Receptor A Stability Is Mediated by Glycogen Synthase Kinase-3β in the Brca1-deficient Mammary Gland*

    PubMed Central

    Wang, Shaohui; Li, Ying; Hsu, Pang-Hung; Lee, Sou-Ying; Kim, Yoon; Lee, Eva Y.-H. P.

    2013-01-01

    Germ line mutations of the BRCA1 gene increase the risk of breast and ovarian cancer, but the basis of this tissue-specific tumor predisposition is not fully understood. Previously, we reported that the progesterone receptors are stabilized in Brca1-deficient mammary epithelial cells, and treating with anti-progesterone delays mammary tumorigenesis in Brca1/p53 conditional knock-out mice, suggesting that the progesterone has a critical role in breast carcinogenesis. To further explore how the stability of progesterone receptor is modulated, here, we have found that glycogen synthase kinase (GSK)-3β phosphorylation of progesterone receptor-A (PR-A) facilitates its ubiquitination. GSK-3β-mediated phosphorylation of serine 390 in PR-A regulates its subsequent ubiquitination and protein stability. Expression of PR-AS390A mutant in the human breast epithelial cells, MCF-10A, results in enhanced proliferation and formation of aberrant acini structure in the three-dimensional culture. Consistently, reduction of phosphorylation of serine 390 of PR-A and GSK-3β activity is observed in the Brca1-deficient mammary gland. Taken together, these results provide important aspects of tissue specificity of BRCA1-mediated suppression of breast carcinogenesis. PMID:23880761

  15. Evaluation of severe accident risks: Methodology for the containment, source term, consequence, and risk integration analyses; Volume 1, Revision 1

    SciTech Connect

    Gorham, E.D.; Breeding, R.J.; Brown, T.D.; Harper, F.T.; Helton, J.C.; Murfin, W.B.; Hora, S.C.

    1993-12-01

    NUREG-1150 examines the risk to the public from five nuclear power plants. The NUREG-1150 plant studies are Level III probabilistic risk assessments (PRAs) and, as such, they consist of four analysis components: accident frequency analysis, accident progression analysis, source term analysis, and consequence analysis. This volume summarizes the methods utilized in performing the last three components and the assembly of these analyses into an overall risk assessment. The NUREG-1150 analysis approach is based on the following ideas: (1) general and relatively fast-running models for the individual analysis components, (2) well-defined interfaces between the individual analysis components, (3) use of Monte Carlo techniques together with an efficient sampling procedure to propagate uncertainties, (4) use of expert panels to develop distributions for important phenomenological issues, and (5) automation of the overall analysis. Many features of the new analysis procedures were adopted to facilitate a comprehensive treatment of uncertainty in the complete risk analysis. Uncertainties in the accident frequency, accident progression and source term analyses were included in the overall uncertainty assessment. The uncertainties in the consequence analysis were not included in this assessment. A large effort was devoted to the development of procedures for obtaining expert opinion and the execution of these procedures to quantify parameters and phenomena for which there is large uncertainty and divergent opinions in the reactor safety community.

  16. Taking aim at Alzheimer’s disease through the mammalian target of rapamycin

    PubMed Central

    Maiese, Kenneth

    2014-01-01

    A significant portion of the world’s population suffers from sporadic Alzheimer’s disease (AD) with available present therapies limited to symptomatic care that does not alter disease progression. Over the next decade, advancing age of the global population will dramatically increase the incidence of AD and severely impact health care resources, necessitating novel, safe, and efficacious strategies for AD. The mammalian target of rapamycin (mTOR) and its protein complexes mTOR Complex 1 (mTORC1) and mTOR Complex 2 (mTORC2) offer exciting and unique avenues of intervention for AD through the oversight of programmed cell death pathways of apoptosis, autophagy, and necroptosis. mTOR modulates multi-faceted signal transduction pathways that involve phosphoinositide 3-kinase (PI 3-K), protein kinase B (Akt), hamartin (tuberous sclerosis 1)/tuberin (tuberous sclerosis 2) (TSC1/TSC2) complex, proline-rich Akt substrate 40 kDa (PRAS40), and p70 ribosomal S6 kinase (p70S6K) and can interface with the neuroprotective pathways of growth factors, sirtuins, wingless, fork-head transcription factors, and glycogen synthase kinase-3β. With the ability of mTOR to broadly impact cellular function, clinical strategies for AD that implement mTOR must achieve parallel objectives of protecting neuronal, vascular, and immune cell survival in conjunction with preserving networks that determine memory and cognitive function. PMID:25105207

  17. Depressurization as an accident management strategy to minimize the consequences of direct containment heating

    SciTech Connect

    Hanson, D.J.; Golden, D.W.; Chambers, R.; Miller, J.D.; Hallbert, B.P.; Dobbe, C.A. )

    1990-10-01

    Probabilistic Risk Assessments (PRAs) have identified severe accidents for nuclear power plants that have the potential to cause failure of the containment through direct containment heating (DCH). Prevention of DCH or mitigation of its effects may be possible using accident management strategies that intentionally depressurize the reactor coolant system (RCS). The effectiveness of intentional depressurization during a station blackout TMLB' sequence was evaluated considering the phenomenological behavior, hardware performance, and operational performance. Phenomenological behavior was calculated using the SCDAP/RELAP5 severe accident analysis code. Two strategies to mitigate DCH by depressurization of the RCS were considered. One strategy, called early depressurization, assumed that the reactor head vent and pressurizer power-operated relief valves (PORVs) were latched open at steam generator dryout. The second strategy, called late depression, assumed that the head vent and PORVs were latched open at a core exit temperature of {approximately}922 K (1200{degree}F). Depressurization of the RCS to a low value that may mitigate DCH was predicted prior to reactor pressure vessel breach for both early and late depressurization. The strategy of late depressurization is preferred over early depressurization because there are greater opportunities to recover plant functions prior to core damage and because failure uncertainties are lessened. 22 refs., 38 figs., 6 tabs.

  18. Risk-based maintenance modeling. Prioritization of maintenance importances and quantification of maintenance effectiveness

    SciTech Connect

    Vesely, W.E.; Rezos, J.T.

    1995-09-01

    This report describes methods for prioritizing the risk importances of maintenances using a Probabilistic Risk Assessment (PRA). Approaches then are described for quantifying their reliability and risk effects. Two different PRA importance measures, minimal cutset importances and risk reduction importances, were used to prioritize maintenances; the findings show that both give similar results if appropriate criteria are used. The justifications for the particular importance measures also are developed. The methods developed to quantify the reliability and risk effects of maintenance actions are extensions of the usual reliability models now used in PRAs. These extended models consider degraded states of the component, and quantify the benefits of maintenance in correcting degradations and preventing failures. The negative effects of maintenance, including downtimes, also are included. These models are specific types of Markov models. The data for these models can be obtained from plant maintenance logs and from the Nuclear Plant Reliability Data System (NPRDS). To explore the potential usefulness of these models, the authors analyzed a range of postulated values of input data. These models were used to examine maintenance effects on a components reliability and performance for various maintenance programs and component data. Maintenance schedules were analyzed to optimize the component`s availability. In specific cases, the effects of maintenance were found to be large.

  19. Mechanistic Target of Rapamycin Complex 2 Protects the Heart From Ischemic Damage

    PubMed Central

    Völkers, Mirko; Konstandin, Mathias H.; Doroudgar, Shirin; Toko, Haruhiro; Quijada, Pearl; Din, Shabana; Joyo, Anya; Ornelas, Luis; Samse, Kaitleen; Thuerauf, Donna J.; Gude, Natalie; Glembotski, Christopher C.; Sussman, Mark A.

    2014-01-01

    Background The mechanistic target of rapamycin (mTOR) comprises 2 structurally distinct multiprotein complexes, mTOR complexes 1 and 2 (mTORC1 and mTORC2). Deregulation of mTOR signaling occurs during and contributes to the severity of myocardial damage from ischemic heart disease. However, the relative roles of mTORC1 versus mTORC2 in the pathogenesis of ischemic damage are unknown. Methods and Results Combined pharmacological and molecular approaches were used to alter the balance of mTORC1 and mTORC2 signaling in cultured cardiac myocytes and in mouse hearts subjected to conditions that mimic ischemic heart disease. The importance of mTOR signaling in cardiac protection was demonstrated by pharmacological inhibition of both mTORC1 and mTORC2 with Torin1, which led to increased cardiomyocyte apoptosis and tissue damage after myocardial infarction. Predominant mTORC1 signaling mediated by suppression of mTORC2 with Rictor similarly increased cardiomyocyte apoptosis and tissue damage after myocardial infarction. In comparison, preferentially shifting toward mTORC2 signaling by inhibition of mTORC1 with PRAS40 led to decreased cardiomyocyte apoptosis and tissue damage after myocardial infarction. Conclusions These results suggest that selectively increasing mTORC2 while concurrently inhibiting mTORC1 signaling is a novel therapeutic approach for the treatment of ischemic heart disease. PMID:24008870

  20. Systems Analysis Programs for Hands-On Integrated Reliability Evaluations.

    Energy Science and Technology Software Center (ESTSC)

    2014-08-01

    Version 00 The U.S. Nuclear Regulatory Commission (NRC) has developed a powerful personal computer (PC) software application for performing probabilistic risk assessments (PRAs), called Systems Analysis Programs for Hands-on Integrated Reliability Evaluations (SAPHIRE) Version 8. Using SAPHIRE 8 on a PC, an analyst can perform a PRA for any complex system, facility, or process. Regarding nuclear power plants, SAPHIRE can be used to model a plant's response to initiating events, quantify associated core damage frequencies,more » and identify important contributors to core damage (Level 1 PRA). It can also be used to evaluate containment failure and release models for severe accident conditions, given that core damage has occurred (Level 2 PRA). It can be used for a PRA assuming that the reactor is at full power, at low power, or at shutdown conditions. Furthermore, it can be used to analyze both internal and external initiating events, and it has special features for transforming models built for internal event analysis to models for external event analysis. It can also be used in a limited manner to quantify risk for release consequences to both the public and the environment (Level 3 PRA). For all of these models, SAPHIRE can evaluate the uncertainty inherent in the probabilistic models. SAPHIRE has evolved with advances in computer technology.« less

  1. Pseudo-Reference-Based Assembly of Vertebrate Transcriptomes

    PubMed Central

    Nam, Kyoungwoo; Jeong, Heesu; Nam, Jin-Wu

    2016-01-01

    High-throughput RNA sequencing (RNA-seq) provides a comprehensive picture of the transcriptome, including the identity, structure, quantity, and variability of expressed transcripts in cells, through the assembly of sequenced short RNA-seq reads. Although the reference-based approach guarantees the high quality of the resulting transcriptome, this approach is only applicable when the relevant reference genome is present. Here, we developed a pseudo-reference-based assembly (PRA) that reconstructs a transcriptome based on a linear regression function of the optimized mapping parameters and genetic distances of the closest species. Using the linear model, we reconstructed transcriptomes of four different aves, the white leg horn, turkey, duck, and zebra finch, with the Gallus gallus genome as a pseudo-reference, and of three primates, the chimpanzee, gorilla, and macaque, with the human genome as a pseudo-reference. The resulting transcriptomes show that the PRAs outperformed the de novo approach for species with within about 10% mutation rate among orthologous transcriptomes, enough to cover distantly related species as far as chicken and duck. Taken together, we suggest that the PRA method can be used as a tool for reconstructing transcriptome maps of vertebrates whose genomes have not yet been sequenced. PMID:26927182

  2. Interpretation of risk significance of passive component aging using probabilistic structural analysis

    SciTech Connect

    Phillips, J.H. ); Atwood, C.L. )

    1993-01-01

    The probabilistic risk assessments (PRAs) being developed at most nuclear power plants to calculate the risk of core damage generally focus on the possible failure of active components. Except as initiating events, the possible failure of passive components is given little consideration. The NRC is sponsoring a project at INEL to investigate the risk significance of passive components as they age. For this project, we developed a technique to calculate the failure probability of passive components over time, and demonstrated the technique by applying it to a weld in the auxiliary feedwater (AFW) system. A decreasing yearly rupture rate for this weld was calculated instead of the increasing rupture rate trend one might expect. We attribute this result to infant mortality; that is, most of those initial flaws that will eventually lead to rupture will do so early in life. This means that although each weld in a population may be wearing out, the population as a whole can exhibit a decreasing rupture rate. This observation has implications for passive components in commercial nuclear plants and other facilities where aging is a concern. For the population of passive components that exhibit a decreasing failure rate, risk increase is not a concern. The next step of the work is to identify the attributes that contribute to this decreasing rate, and to determine any attributes that would contribute to an increasing failure rate and thus to an increased risk.

  3. Interpretation of risk significance of passive component aging using probabilistic structural analysis

    SciTech Connect

    Phillips, J.H.; Atwood, C.L.

    1993-05-01

    The probabilistic risk assessments (PRAs) being developed at most nuclear power plants to calculate the risk of core damage generally focus on the possible failure of active components. Except as initiating events, the possible failure of passive components is given little consideration. The NRC is sponsoring a project at INEL to investigate the risk significance of passive components as they age. For this project, we developed a technique to calculate the failure probability of passive components over time, and demonstrated the technique by applying it to a weld in the auxiliary feedwater (AFW) system. A decreasing yearly rupture rate for this weld was calculated instead of the increasing rupture rate trend one might expect. We attribute this result to infant mortality; that is, most of those initial flaws that will eventually lead to rupture will do so early in life. This means that although each weld in a population may be wearing out, the population as a whole can exhibit a decreasing rupture rate. This observation has implications for passive components in commercial nuclear plants and other facilities where aging is a concern. For the population of passive components that exhibit a decreasing failure rate, risk increase is not a concern. The next step of the work is to identify the attributes that contribute to this decreasing rate, and to determine any attributes that would contribute to an increasing failure rate and thus to an increased risk.

  4. Assessment of the impact of degraded shear wall stiffnesses on seismic plant risk and seismic design loads

    SciTech Connect

    Klamerus, E.W.; Bohn, M.P.; Johnson, J.J.; Asfura, A.P.; Doyle, D.J.

    1994-02-01

    Test results sponsored by the USNRC have shown that reinforced shear wall (Seismic Category I) structures exhibit stiffnesses and natural frequencies which are smaller than those calculated in the design process. The USNRC has sponsored Sandia National Labs to perform an evaluation of the effects of the reduced frequencies on several existing seismic PRAs in order to determine the seismic risk implications inherent in these test results. This report presents the results for the re-evaluation of the seismic risk for three nuclear power plants: the Peach Bottom Atomic Power Station, the Zion Nuclear Power Plant, and Arkansas Nuclear One -- Unit 1 (ANO-1). Increases in core damage frequencies for seismic initiated events at Peach Bottom were 25 to 30 percent (depending on whether LLNL or EPRI hazard curves were used). At the ANO-1 site, the corresponding increases in plant risk were 10 percent (for each set of hazard curves). Finally, at Zion, there was essentially no change in the computed core damage frequency when the reduction in shear wall stiffness was included. In addition, an evaluation of deterministic ``design-like`` structural dynamic calculations with and without the shear stiffness reductions was made. Deterministic loads calculated for these two cases typically increased on the order of 10 to 20 percent for the affected structures.

  5. Summary of core damage frequency from internal initiators: Peach Bottom

    SciTech Connect

    Kolaczkowski, A.M.; Lambright, J.A.; Cathey, N.

    1986-01-01

    Probabilistic risk assessments (PRAs) based on internal initiators are being conducted on a number of reference plants to provide the US Nuclear Regulatory Commission (NRC) with updated information about light-water reactor risk. The results of these analyses will be used by the NRC to prepare NUREG-1150 which will examine the NRC's current perception of risk. Peach Bottom has been chosen as one of the reference plants. The Peach Bottom Atomic Power Station has two boiling water reactor (BWR) units, each with a capacity of 1150 MW(e). The reactors are each housed in a Mark I containment. Peach Bottom Unit 2 analyzed here, was studied before as part of WASH-1400. A number of plant features tend to be important in determining the nature and frequency of the core melt scenarios for Peach Bottom. These features include the recent above-average diesel generator performance history, the single emergency service water system for both units, the numerous emergency core cooling systems, recent procedure modifications and the low volume containment.

  6. Fire PRA requantification studies. Final report

    SciTech Connect

    Parkinson, W.

    1993-03-01

    This report describes the requantification of two existing fire probabilistic risk assessments (PRAs) using a fire PRA method and data that are being developed by the Electric Power Research Institute (EPRI). The two existing studies are the Seabrook Station Probabilistic Safety Assessment that was made in 1983 and the 1989 NUREG-1150 analysis of the Peach Bottom Plant. Except for the fire methods and data, the original assumptions were used. The results from the requantification show that there were excessive conservatisms in the original studies. The principal reason for a hundredfold reduction in the Peach Bottom core- damage frequency is the determination that no electrical cabinet fire in a switchgear room would damage both offsite power feeds. Past studies often overestimated the heat release from electrical cabinet fires. EPRI`s electrical cabinet heat release rates are based on tests that were conducted for Sandia`s fire research program. The rates are supported by the experience in the EPRI Fire Events Database for U.S. nuclear plants. Test data and fire event experience also removed excessive conservatisms in the Peach Bottom control and cable spreading rooms, and the Seabrook primary component cooling pump, turbine building relay and cable spreading rooms. The EPRI fire PRA method and data will show that there are excessive conservatisms in studies that were made for many plants and can benefit them accordingly.

  7. Using Generic Data to Establish Dormancy Failure Rates

    NASA Technical Reports Server (NTRS)

    Reistle, Bruce

    2014-01-01

    Many hardware items are dormant prior to being operated. The dormant period might be especially long, for example during missions to the moon or Mars. In missions with long dormant periods the risk incurred during dormancy can exceed the active risk contribution. Probabilistic Risk Assessments (PRAs) need to account for the dormant risk contribution as well as the active contribution. A typical method for calculating a dormant failure rate is to multiply the active failure rate by a constant, the dormancy factor. For example, some practitioners use a heuristic and divide the active failure rate by 30 to obtain an estimate of the dormant failure rate. To obtain a more empirical estimate of the dormancy factor, this paper uses the recently updated database NPRD-2011 [1] to arrive at a set of distributions for the dormancy factor. The resulting dormancy factor distributions are significantly different depending on whether the item is electrical, mechanical, or electro-mechanical. Additionally, this paper will show that using a heuristic constant fails to capture the uncertainty of the possible dormancy factors.

  8. Regulation of Akt during torpor in the hibernating ground squirrel, Ictidomys tridecemlineatus

    PubMed Central

    McMullen, David C.

    2010-01-01

    The 13-lined ground squirrel (Ictidomys tridecemlineatus) is capable of entering into extended periods of torpor during winter hibernation. The state of torpor represents a hypometabolic shift wherein the rate of oxygen consuming processes are strongly repressed in an effort to maintain cellular homeostasis as the availability of food energy becomes limited. We are interested in studying hibernation/torpor because of the robust state of tolerance to constrained oxygen delivery, oligemia, and hypothermia achieved by the tissues of hibernating mammals. The role of the serine/threonine kinase Akt (also known as PKB) has been examined in torpor in previous studies. However, this is the first study that examines the level of Akt phosphorylation in the liver during the two transition phases of the hibernation cycle: entrance into torpor, and the subsequent arousal from torpor. Our results indicate that Akt is activated in the squirrel liver by phosphorylation of two key residues (Thr308 and Ser473) during entrance into torpor and arousal from torpor. Moreover, we observed increased phosphorylation of key substrates of Akt during the two transition stages of torpor. Finally, this study reports the novel finding that PRAS40, a component of the TORC1 multi-protein complex and a potentially important modulator of metabolism, is regulated during torpor. PMID:20352231

  9. Targeting TORC1/2 Enhances Sensitivity to EGFR Inhibitors in Head and Neck Cancer Preclinical Models1

    PubMed Central

    Cassell, Andre; Freilino, Maria L; Lee, Jessica; Barr, Sharon; Wang, Lin; Panahandeh, Mary C; Thomas, Sufi M; Grandis, Jennifer R

    2012-01-01

    Head and neck squamous cell carcinoma (HNSCC) is characterized by overexpression of the epidermal growth factor receptor (EGFR) where treatments targeting EGFR have met with limited clinical success. Elucidation of the key downstream-pathways that remain activated in the setting of EGFR blockade may reveal new therapeutic targets. The present study was undertaken to test the hypothesis that inhibition of the mammalian target of rapamycin (mTOR) complex would enhance the effects of EGFR blockade in HNSCC preclinical models. Treatment of HNSCC cell lines with the newly developed TORC1/TORC2 inhibitor OSI-027/ASP4876 resulted in dose-dependent inhibition of proliferation with abrogation of phosphorylation of known downstream targets including phospho-AKT (Ser473), phospho-4E-BP1, phospho-p70s6K, and phospho-PRAS40. Furthermore, combined treatment with OSI-027 and erlotinib resulted in enhanced biochemical effects and synergistic growth inhibition in vitro. Treatment of mice bearing HNSCC xenografts with a combination of the Food and Drug Administration (FDA)-approved EGFR inhibitor cetuximab and OSI-027 demonstrated a significant reduction of tumor volumes compared with either treatment alone. These findings suggest that TORC1/TORC2 inhibition in conjunction with EGFR blockade represents a plausible therapeutic strategy for HNSCC. PMID:23226094

  10. BacMam-enabled LanthaScreen cellular assays for PI3K/Akt pathway compound profiling in disease-relevant cell backgrounds.

    PubMed

    Carlson, Coby B; Mashock, Michael J; Bi, Kun

    2010-03-01

    The authors recently reported the development and application of multiple LanthaScreen cellular assays to interrogate specific steps within the PI3K/Akt pathway. The importance of this signaling cascade in regulating fundamental aspects of cell growth and survival, as well as in the progression of cancer, underscores the need for portable cell-based assays for compound profiling in multiple disease-relevant cell backgrounds. To meet this need, the authors have now expanded their LanthaScreen assay platform across a variety of cell types using a gene delivery technology known as BacMam. Here, they have demonstrated the successful detection of Akt-dependent phosphorylation of PRAS40 at Thr246 in 10 different cell lines harboring mutations known to activate the PI3K/Akt pathway. In addition, they generated inhibitory profiles of 17 known pathway inhibitors in these same cells to validate the approach of using the BacMam-enabled LanthaScreen cellular assay format to rapidly profile compounds in disease-relevant cell types. Importantly, their results provide a broad illustration of how the genetic alterations that affect PI3K/Akt signaling can also influence the inhibitory profile of a given compound. PMID:20145103

  11. Pseudo-Reference-Based Assembly of Vertebrate Transcriptomes.

    PubMed

    Nam, Kyoungwoo; Jeong, Heesu; Nam, Jin-Wu

    2016-01-01

    High-throughput RNA sequencing (RNA-seq) provides a comprehensive picture of the transcriptome, including the identity, structure, quantity, and variability of expressed transcripts in cells, through the assembly of sequenced short RNA-seq reads. Although the reference-based approach guarantees the high quality of the resulting transcriptome, this approach is only applicable when the relevant reference genome is present. Here, we developed a pseudo-reference-based assembly (PRA) that reconstructs a transcriptome based on a linear regression function of the optimized mapping parameters and genetic distances of the closest species. Using the linear model, we reconstructed transcriptomes of four different aves, the white leg horn, turkey, duck, and zebra finch, with the Gallus gallus genome as a pseudo-reference, and of three primates, the chimpanzee, gorilla, and macaque, with the human genome as a pseudo-reference. The resulting transcriptomes show that the PRAs outperformed the de novo approach for species with within about 10% mutation rate among orthologous transcriptomes, enough to cover distantly related species as far as chicken and duck. Taken together, we suggest that the PRA method can be used as a tool for reconstructing transcriptome maps of vertebrates whose genomes have not yet been sequenced. PMID:26927182

  12. Dynamical systems probabilistic risk assessment.

    SciTech Connect

    Denman, Matthew R.; Ames, Arlo Leroy

    2014-03-01

    Probabilistic Risk Assessment (PRA) is the primary tool used to risk-inform nuclear power regulatory and licensing activities. Risk-informed regulations are intended to reduce inherent conservatism in regulatory metrics (e.g., allowable operating conditions and technical specifications) which are built into the regulatory framework by quantifying both the total risk profile as well as the change in the risk profile caused by an event or action (e.g., in-service inspection procedures or power uprates). Dynamical Systems (DS) analysis has been used to understand unintended time-dependent feedbacks in both industrial and organizational settings. In dynamical systems analysis, feedback loops can be characterized and studied as a function of time to describe the changes to the reliability of plant Structures, Systems and Components (SSCs). While DS has been used in many subject areas, some even within the PRA community, it has not been applied toward creating long-time horizon, dynamic PRAs (with time scales ranging between days and decades depending upon the analysis). Understanding slowly developing dynamic effects, such as wear-out, on SSC reliabilities may be instrumental in ensuring a safely and reliably operating nuclear fleet. Improving the estimation of a plant's continuously changing risk profile will allow for more meaningful risk insights, greater stakeholder confidence in risk insights, and increased operational flexibility.

  13. Ursolic acid stimulates mTORC1 signaling after resistance exercise in rat skeletal muscle.

    PubMed

    Ogasawara, Riki; Sato, Koji; Higashida, Kazuhiko; Nakazato, Koichi; Fujita, Satoshi

    2013-09-15

    A recent study identified ursolic acid (UA) as a potent stimulator of muscle protein anabolism via PI3K/Akt signaling, thereby suggesting that UA can increase Akt-independent mTOR complex 1 (mTORC1) activation induced by resistance exercise via Akt signaling. The purpose of the present study was to investigate the effect of UA on resistance exercise-induced mTORC1 activation. The right gastrocnemius muscle of male Sprague-Dawley rats aged 11 wk was isometrically exercised via percutaneous electrical stimulation (stimulating ten 3-s contractions per set for 5 sets), while the left gastrocnemius muscle served as the control. UA or placebo (PLA; corn oil only) was injected intraperitoneally immediately after exercise. The rats were killed 1 or 6 h after the completion of exercise and the target tissues removed immediately. With placebo injection, the phosphorylation of p70(S6K) at Thr(389) increased 1 h after resistance exercise but attenuated to the control levels 6 h after the exercise. On the other hand, the augmented phosphorylation of p70(S6K) was maintained even 6 h after exercise when UA was injected immediately after exercise. A similar trend of prolonged phosphorylation was observed in PRAS40 Thr(246), whereas UA alone or resistance exercise alone did not alter its phosphorylation level at 6 h after intervention. These results indicate that UA is able to sustain resistance exercise-induced mTORC1 activity. PMID:23900420

  14. Survey and evaluation of aging risk assessment methods and applications

    SciTech Connect

    Sanzo, D.L.; Kvam, P.; Apostolakis, G.; Wu, J.; Milici, T.; Ghoniem, N.; Guarro, S.

    1993-11-01

    The Nuclear Regulatory Commission (NRC) initiated the nuclear power plant aging research (NPAR) program about 6 years ago to gather information about nuclear power plant aging. Since then, this program has collected a significant amount of information, largely qualitative, on plant aging and its potential effects on plant safety. However, this body of knowledge has not yet been integrated into formalisms that can be used effectively and systematically to assess plant risk resulting from aging, although models for assessing the effect of increasing failure rates on core damage frequency have been proposed. The purpose of this review is to survey the work conducted to address the aging of systems, structures, and components (SSCs) of nuclear power plants (NPPs), as well as the associated data bases. The review takes a critical look at the need to revise probabilistic risk assessment (PRAs) so that they will include the contribution to risk from plant aging, the adequacy of existing methods for evaluating this contribution, and the adequacy of the data that have been used in these evaluation methods. A preliminary framework is identified for integrating the aging of SSCs into the PRA, including the identification of needed data for such an integration.

  15. Report on the Dagstuhl Seminar on Visualization and Monitoring of Network Traffic

    SciTech Connect

    Keim, Daniel; Pras, Aiko; Schonwalder, Jurgen; Wong, Pak C.; Mansmann, Florian

    2011-01-26

    The Dagstuhl Seminar on Visualization and Monitoring of Network Traffic [1] took place May 17-20, 2009 in Dagstuhl, Germany. Dagstuhl seminars promote personal interaction and open discussion of results as well as new ideas. Unlike at most conferences, the focus is not solely on the presentation of established results but to equal parts on results, ideas, sketches, and open problems. The aim of this particular seminar was to bring together experts from the information visualization community and the networking community in order to discuss the state of the art of monitoring and visualization of network traffic. People from the different research communities involved jointly organized the seminar. The co-chairs of the seminar from the networking community were Aiko Pras (University of Twente) and Jürgen Schönwälder (Jacobs University Bremen). The co-chairs from the visualization community were Daniel A. Keim (University of Konstanz) and Pak Chung Wong (Pacific Northwest National Lab). Florian Mansmann (University of Konstanz) helped with producing this report. The seminar was organized and supported by Schloss Dagstuhl and the EC IST-EMANICS Network of Excellence [1].

  16. Synergistic effect of anti-platelet and anti-inflammation of drug-coated Co-Cr substrates for prevention of initial in-stent restenosis.

    PubMed

    Lih, Eugene; Jung, Jee Won; Joung, Yoon Ki; Ahn, Dong June; Han, Dong Keun

    2016-04-01

    Antiplatelet and antithrombotic therapies are systematically considered to prevent restenosis following coronary stent implantation. Currently, patients receiving medicated stents are prescribed to orally take anticoagulants and antiplatelet drugs such as aspirin (ASP) and prasugrel (PRAS). Propolis (PROP) known as a natural organic compound was recently evaluated for its antiplatelet activity, antibiotics and immunomodulatory activities. In this study, antiplatelet drug-coated Co-Cr substrates were prepared with biodegradable poly(d,l-lactide) (PDLLA) containing ASP, PRA, or PROP using electrospray and the blood compatibility of the different substrates was investigated by measuring protein adsorption and platelet adhesion. In addition, the anti-inflammatory properties of the modified Co-Cr surfaces were assessed by measuring IL-8 and IL-6 expression levels in human endothelial cell cultures. Drug-coated surfaces were found to resist the adsorption of fibrinogen when compared to bare Co-Cr or PDLLA-coated Co-Cr. Interestingly, ASP- and PROP-containing substrates not only showed reduced adhesion of platelets and delayed coagulation time, but also drastically reduced the expression level of IL-8 and IL-6. Such results are supported that ASP- or PROP-coated Co-Cr can be potentially used as a stent material to mitigate early stage of restenosis. The developed coating materials might be an interesting alternative to systemic anticoagulant therapies prescribed after stent implantation. PMID:26774572

  17. Enabling systematic interrogation of protein-protein interactions in live cells with a versatile ultra-high-throughput biosensor platform.

    PubMed

    Mo, Xiu-Lei; Luo, Yin; Ivanov, Andrei A; Su, Rina; Havel, Jonathan J; Li, Zenggang; Khuri, Fadlo R; Du, Yuhong; Fu, Haian

    2016-06-01

    Large-scale genomics studies have generated vast resources for in-depth understanding of vital biological and pathological processes. A rising challenge is to leverage such enormous information to rapidly decipher the intricate protein-protein interactions (PPIs) for functional characterization and therapeutic interventions. While a number of powerful technologies have been employed to detect PPIs, a singular PPI biosensor platform with both high sensitivity and robustness in a mammalian cell environment remains to be established. Here we describe the development and integration of a highly sensitive NanoLuc luciferase-based bioluminescence resonance energy transfer technology, termed BRET(n), which enables ultra-high-throughput (uHTS) PPI detection in live cells with streamlined co-expression of biosensors in a miniaturized format. We further demonstrate the application of BRET(n) in uHTS format in chemical biology research, including the discovery of chemical probes that disrupt PRAS40 dimerization and pathway connectivity profiling among core members of the Hippo signaling pathway. Such hippo pathway profiling not only confirmed previously reported PPIs, but also revealed two novel interactions, suggesting new mechanisms for regulation of Hippo signaling. Our BRET(n) biosensor platform with uHTS capability is expected to accelerate systematic PPI network mapping and PPI modulator-based drug discovery. PMID:26578655

  18. mTOR inhibition as a Therapeutic Strategy in the Management of Urologic Malignancies

    PubMed Central

    Garcia, Jorge A.; Danielpour, David

    2008-01-01

    The mammalian target of rapamycin (mTOR) is a protein kinase that regulates protein translation, cell growth and apoptosis. Recently, there has been an enormous increase in our understanding on molecular mechanisms underlying the therapeutics of rapamycin in cancer. Alterations in the pathway regulating mTOR occur in many solid malignancies including prostate, bladder and kidney cancer; and in-vitro and in-vivo models of prostate and bladder cancer have established the importance of the mTOR pathway in control of cancer progression and metastasis. Temsirolimus (Torisel™) and everolimus (RAD-001), two ester analogues of rapamycin, as well as rapamycin itself have clear antitumor activity in in-vitro and in-vivo models, and are under clinical trial investigations for prostate and bladder cancer. Phase II and III trials have already established the clinical efficacy of temsirolimus in renal cancer, and current renal trials are evaluating the combined effects of VEGF and mTOR inhibition. Ongoing studies in prostate and bladder cancer will soon define the activity and safety profiles of everolimus and temsirolimus. Recent molecular advances have uncovered a startling complexity in the macromolecular function of mTOR complexes, with the identification of new mTOR partners (raptor, rictor, FKBP38, PRAS40 and mSIN1), putative cancer therapeutic/prognostic targets for future clinical trials. PMID:18566209

  19. Systems analysis programs for hands-on integrated reliability evaluations (SAPHIRE), Version 5.0

    SciTech Connect

    Russell, K.D.; Kvarfordt, K.J.; Hoffman, C.L.

    1995-10-01

    The Systems Analysis Programs for Hands-on Integrated Reliability Evaluations (SAPHIRE) refers to a set of several microcomputer programs that were developed to create and analyze probabilistic risk assessments (PRAs), primarily for nuclear power plants. The Graphical Evaluation Module (GEM) is a special application tool designed for evaluation of operational occurrences using the Accident Sequence Precursor (ASP) program methods. GEM provides the capability for an analyst to quickly and easily perform conditional core damage probability (CCDP) calculations. The analyst can then use the CCDP calculations to determine if the occurrence of an initiating event or a condition adversely impacts safety. It uses models and data developed in the SAPHIRE specially for the ASP program. GEM requires more data than that normally provided in SAPHIRE and will not perform properly with other models or data bases. This is the first release of GEM and the developers of GEM welcome user comments and feedback that will generate ideas for improvements to future versions. GEM is designated as version 5.0 to track GEM codes along with the other SAPHIRE codes as the GEM relies on the same, shared database structure.

  20. Eliciting and Combining Decision Criteria Using a Limited Palette of Utility Functions and Uncertainty Distributions: Illustrated by Application to Pest Risk Analysis.

    PubMed

    Holt, Johnson; Leach, Adrian W; Schrader, Gritta; Petter, Françoise; Macleod, Alan; van der Gaag, Dirk Jan; Baker, Richard H A; Mumford, John D

    2013-07-01

    Utility functions in the form of tables or matrices have often been used to combine discretely rated decision-making criteria. Matrix elements are usually specified individually, so no one rule or principle can be easily stated for the utility function as a whole. A series of five matrices are presented that aggregate criteria two at a time using simple rules that express a varying degree of constraint of the lower rating over the higher. A further nine possible matrices were obtained by using a different rule either side of the main axis of the matrix to describe situations where the criteria have a differential influence on the outcome. Uncertainties in the criteria are represented by three alternative frequency distributions from which the assessors select the most appropriate. The output of the utility function is a distribution of rating frequencies that is dependent on the distributions of the input criteria. In pest risk analysis (PRA), seven of these utility functions were required to mimic the logic by which assessors for the European and Mediterranean Plant Protection Organization arrive at an overall rating of pest risk. The framework enables the development of PRAs that are consistent and easy to understand, criticize, compare, and change. When tested in workshops, PRA practitioners thought that the approach accorded with both the logic and the level of resolution that they used in the risk assessments. PMID:23834916

  1. Systems Analysis Programs for Hands-On Integrated Reliability Evaluations.

    SciTech Connect

    2014-08-01

    Version 00 The U.S. Nuclear Regulatory Commission (NRC) has developed a powerful personal computer (PC) software application for performing probabilistic risk assessments (PRAs), called Systems Analysis Programs for Hands-on Integrated Reliability Evaluations (SAPHIRE) Version 8. Using SAPHIRE 8 on a PC, an analyst can perform a PRA for any complex system, facility, or process. Regarding nuclear power plants, SAPHIRE can be used to model a plant's response to initiating events, quantify associated core damage frequencies, and identify important contributors to core damage (Level 1 PRA). It can also be used to evaluate containment failure and release models for severe accident conditions, given that core damage has occurred (Level 2 PRA). It can be used for a PRA assuming that the reactor is at full power, at low power, or at shutdown conditions. Furthermore, it can be used to analyze both internal and external initiating events, and it has special features for transforming models built for internal event analysis to models for external event analysis. It can also be used in a limited manner to quantify risk for release consequences to both the public and the environment (Level 3 PRA). For all of these models, SAPHIRE can evaluate the uncertainty inherent in the probabilistic models. SAPHIRE has evolved with advances in computer technology.

  2. A RE-LOOK AT THE US NRC SAFETY GOALS

    SciTech Connect

    mubayi v.

    2013-09-22

    Since they were adopted in 1986, the US NRC’s Safety Goals have played a valuable role as a de facto risk acceptance criterion against which the predicted performance of a commercial nuclear power reactor can be evaluated and assessed. The current safety goals are cast in terms of risk metrics called quantitative health objectives (QHOs), limiting numerical values of the risks of the early and latent health effects of accidental releases of radioactivity to the offsite population. However, while demonstrating compliance with current safety goals has been an important step in assessing the acceptance of the risk posed by LWRs, new or somewhat different goals may be needed that go beyond the current early fatality and latent cancer fatality QHOs in assessing reactor risk. Natural phenomena such as hurricanes seem to be suitable candidates for establishing a background rate to derive a risk goal as their order of magnitude cost of damages is similar to those estimated in severe accident Level 3 PRAs done for nuclear power plants. This paper obtains a risk goal that could have a wider applicability, compared to the current QHOs, as a technology-neutral goal applicable to future reactors and multi-unit sites.

  3. Analysis of loss of off-site power with a PWR at shutdown

    SciTech Connect

    Chu, T.L.; Yoon, W.H.; Fitzpatrick, R.G.

    1987-01-01

    In many probabilistic risk assessments (PRAs), loss of offsite power (LOOP) when a nuclear power plant is operating was found to be a significant contributor to core damage. The purpose of this study is to provide an analysis of a LOOP event that occurs while a pressurized water reactor (PWR) is shut down. The importance of such an analysis was recognized as part of a study to evaluate the core damage frequency due to a loss of decay heat removal (DHR) capability during an outage. When a PWR is in a shutdown condition, there are relatively few technical specification requirements on the operability of safety systems. In fact, some safety systems are intentionally disabled, i.e., the safety injection system and nonoperating charging pumps. Another problem when the reactor is shut down is that the reactor coolant system (RCS) may be partially drained and the steam generators may be unavailable. To determine the time available for operator actions, given that a LOOP occurs during shutdown and the DHR capability is lost, a simple thermal model has been developed. Similar calculations have been performed for other phases of refueling and maintenance outages. A total core damage frequency due to LOOP while the plant is in shutdown has been calculated to be 5.9 x 10/sup -6//yr. This is approximately twice the core damage frequency calculated for LOOP when the plant is at power.

  4. Undercar Electrical Generator for Railway Passenger Cars: Improvement of Efficiency / Dzelzceļa Pasažieru Zemvagona Elektriskā Ģeneratora Efektivitātes Uzlabošana

    NASA Astrophysics Data System (ADS)

    Levin, N.; Kamolins, E.; Gusakov, A.; Pugachev, V.

    2013-04-01

    Passenger cars of the railway transport are being constantly improved, thus becoming ever more comfortable for public conveyance. These cars are fitted with air conditioners, installations for heating and forced ventilation, heaters, refrigerators; lighting, radio and TV sets; communication equipment, etc. All the listed fittings need continuous and secure electricity supply from a primary independent source. The paper considers the possibilities of meeting requirements for particular power supply systems - first of all for undercar generators. At operation of such a high-power generator under rugged conditions it should be highly reliable, possessing a reasonable mass and high efficiency. The existing designs of these generators still do not meet the listed requirements in full measure. To improve the efficiency of the undercar generator it is proposed to integrate its excitation winding into the armature one, thus reducing the copper consumption, losses and mass, while - which is the most important - considerably raising reliability of the generator and its availability factor. Dzelzceļa transporta pasažieru vilcienu vagoni nepārtraukti tiek pilnveidoti ar mērķi paaugstināt pasažieru komforta līmeni pārvadājumu laikā. Šādi pasažieru vagoni aprīkoti ar gaisa kondicionēšanas, apsildes, ventilācijas, ūdens uzsildīšanas, saldēšanas, apgaismes, radio, televīzijas, sakaru u.c. iekārtām. Visām pieminētajām iekārtām to darbības laikā ir nepieciešama nepārtraukta un droša elektroenerģijas apgāde no primāra neatkarīga avota. Darbā tiek izskatīta elektroapgādes sistēma, kura spētu nodrošināt izvirzītās prasības. Pie šīs sistēmas, pirmkārt, pieder zemvagona ģenerators. Tam ir jābūt paaugstinātas jaudas, smagos darba apstākļos jānodrošina augsts drošums, ar pieņemamu masu un augstu lietderības koeficientu. Šādu ģeneratoru esošās konstrukcijas pilnā mērā nespēj nodrošināt iepriekš minētās pras

  5. Lentivirus-mediated knockdown of eukaryotic translation initiation factor 3 subunit D inhibits proliferation of HCT116 colon cancer cells.

    PubMed

    Yu, Xiaojun; Zheng, Bo'an; Chai, Rui

    2014-01-01

    Dysregulation of protein synthesis is emerging as a major contributory factor in cancer development. eIF3D (eukaryotic translation initiation factor 3 subunit D) is one member of the eIF3 (eukaryotic translation initiation factor 3) family, which is essential for initiation of protein synthesis in eukaryotic cells. Acquaintance with eIF3D is little since it has been identified as a dispensable subunit of eIF3 complex. Recently, eIF3D was found to embed somatic mutations in human colorectal cancers, indicating its importance for tumour progression. To further probe into its action in colon cancer, we utilized lentivirus-mediated RNA interference to knock down eIF3D expression in one colon cancer cell line HCT116. Knockdown of eIF3D in HCT116 cells significantly inhibited cell proliferation and colony formation in vitro. Flow cytometry analysis indicated that depletion of eIF3D led to cell-cycle arrest in the G2/M phase, and induced an excess accumulation of HCT116 cells in the sub-G1 phase representing apoptotic cells. Signalling pathways responsible for cell growth and apoptosis have also been found altered after eIF3D silencing, such as AMPKα (AMP-activated protein kinase alpha), Bad, PRAS40 [proline-rich Akt (PKB) substrate of 40 kDa], SAPK (stress-activated protein kinase)/JNK (c-Jun N-terminal kinase), GSK3β and PARP [poly(ADP-ribose) polymerase]. Taken together, these findings suggest that eIF3D might play an important role in colon cancer progression. PMID:25370813

  6. Phosphoproteomic Profiling of In Vivo Signaling in Liver by the Mammalian Target of Rapamycin Complex 1 (mTORC1)

    PubMed Central

    Demirkan, Gokhan; Yu, Kebing; Boylan, Joan M.; Salomon, Arthur R.; Gruppuso, Philip A.

    2011-01-01

    Background Our understanding of signal transduction networks in the physiological context of an organism remains limited, partly due to the technical challenge of identifying serine/threonine phosphorylated peptides from complex tissue samples. In the present study, we focused on signaling through the mammalian target of rapamycin (mTOR) complex 1 (mTORC1), which is at the center of a nutrient- and growth factor-responsive cell signaling network. Though studied extensively, the mechanisms involved in many mTORC1 biological functions remain poorly understood. Methodology/Principal Findings We developed a phosphoproteomic strategy to purify, enrich and identify phosphopeptides from rat liver homogenates. Using the anticancer drug rapamycin, the only known target of which is mTORC1, we characterized signaling in liver from rats in which the complex was maximally activated by refeeding following 48 hr of starvation. Using protein and peptide fractionation methods, TiO2 affinity purification of phosphopeptides and mass spectrometry, we reproducibly identified and quantified over four thousand phosphopeptides. Along with 5 known rapamycin-sensitive phosphorylation events, we identified 62 new rapamycin-responsive candidate phosphorylation sites. Among these were PRAS40, gephyrin, and AMP kinase 2. We observed similar proportions of increased and reduced phosphorylation in response to rapamycin. Gene ontology analysis revealed over-representation of mTOR pathway components among rapamycin-sensitive phosphopeptide candidates. Conclusions/Significance In addition to identifying potential new mTORC1-mediated phosphorylation events, and providing information relevant to the biology of this signaling network, our experimental and analytical approaches indicate the feasibility of large-scale phosphoproteomic profiling of tissue samples to study physiological signaling events in vivo. PMID:21738781

  7. Natural Compounds as Potential Treatments of NF2-Deficient Schwannoma and Meningioma: Cucurbitacin D and Goyazensolide

    PubMed Central

    Spear, Samuel A.; Burns, Sarah S.; Oblinger, Janet L.; Ren, Yulin; Pan, Li; Kinghorn, A. Douglas; Welling, D. Bradley; Chang, Long-Sheng

    2015-01-01

    Hypothesis Cucurbitacin D and goyazensolide, two plant-derived natural compounds, possess potent growth-inhibitory activity in schwannoma and meningioma cells. Background Currently, no FDA-approved drugs are available for neurofibromatosis type 2 (NF2)-associated schwannomas and meningiomas. Selected natural compounds with antineoplastic activity, such as cucurbitacin and goyazensolide, may be developed as potential treatments for these tumors. Methods The Nf2-deficient mouse schwannoma Sch10545 and human benign meningioma Ben-Men-1 cells were treated with various concentrations of cucurbitacin D and goyazensolide. The effect on cell proliferation was determined using resazurin assays. Flow cytometry was used to assess the cell cycle profiles. Western blot analysis was performed to investigate the expression of various signal molecules related to the cell cycle and the AKT pathway. Results Cucurbitacin D inhibited proliferation of Sch10545 cells (IC50 ~0.75 μM) and Ben-Men-1 cells (IC50 ~0.2 μM). Goyazensolide also reduced cell proliferation of Sch10545 cells (IC50 ~0.9 μM) and Ben-Men-1 cells (IC50 ~1 μM). The G2/M population increased in both Sch10545 and Ben-Men-1 cells treated with cucurbitacin D or goyazensolide around the IC50. Cucurbitacin and goyazensolide substantially reduced the levels of cyclins E and A in treated Sch10545 and Ben-Men-1 cells. Cucurbitacin D also inhibited cyclin B, phospho-AKT and phospho-PRAS40 expression. In addition, goyazensolide reduced the levels of phospho-AKT and NFκB and increased the expression of pro-apoptotic Bim in Sch10545 and Ben-Men-1 cells. Conclusions Both cucurbitacin D and goyazensolide effectively inhibit proliferation of NF2-deficient schwannoma and meningioma cells, suggesting that these natural compounds should be further evaluated as potential treatments for NF2-related tumors. PMID:23928514

  8. Distribution and Replication of the Pathogenicity Plasmid pPATH in Diverse Populations of the Gall-Forming Bacterium Pantoea agglomerans▿ † ‡

    PubMed Central

    Weinthal, Dan M.; Barash, Isaac; Panijel, Mary; Valinsky, Lea; Gaba, Victor; Manulis-Sasson, Shulamit

    2007-01-01

    Pantoea agglomerans has been transformed from a commensal bacterium into two related gall-forming pathovars by acquisition of pPATH plasmids containing a pathogenicity island (PAI). This PAI harbors an hrp/hrc gene cluster, type III effectors, and phytohormone biosynthetic genes. DNA typing by pulsed-field gel electrophoresis revealed two major groups of P. agglomerans pv. gypsophilae and one group of P. agglomerans pv. betae. The pPATH plasmids of the different groups had nearly identical replicons (98% identity), and the RepA protein showed the highest level of similarity with IncN plasmid proteins. A series of plasmids, designated pRAs, in which the whole replicon region (2,170 bp) or deleted derivatives of it were ligated with nptI were generated for replicon analysis. A basic 929-bp replicon (pRA6) was sufficient for replication in Escherichia coli and in nonpathogenic P. agglomerans. However, the whole replicon region (pRA1) was necessary for expulsion of the pPATH plasmid, which resulted in the loss of pathogenicity. The presence of direct repeats in the replicon region suggests that the pPATH plasmid is an iteron plasmid and that the repeats may regulate its replication. The pPATH plasmids are nonconjugative but exhibit a broad host range, as shown by replication of pRA1 in Erwinia, Pseudomonas, and Xanthomonas. Restriction fragment length polymorphism analyses indicated that the PAIs in the two groups of P. agglomerans pv. gypsophilae are similar but different from those in P. agglomerans pv. betae. The results could indicate that the pPATH plasmids evolved from a common ancestral mobilizable plasmid that was transferred into different strains of P. agglomerans. PMID:17921271

  9. Low Molecular Weight Fraction of Commercial Human Serum Albumin Induces Morphologic and Transcriptional Changes of Bone Marrow-Derived Mesenchymal Stem Cells.

    PubMed

    Bar-Or, David; Thomas, Gregory W; Rael, Leonard T; Gersch, Elizabeth D; Rubinstein, Pablo; Brody, Edward

    2015-08-01

    Osteoarthritis (OA) is the most common chronic disease of the joint; however, the therapeutic options for severe OA are limited. The low molecular weight fraction of commercial 5% human serum albumin (LMWF5A) has been shown to have anti-inflammatory properties that are mediated, in part, by a diketopiperazine that is present in the albumin preparation and that was demonstrated to be safe and effective in reducing pain and improving function when administered intra-articularly in a phase III clinical trial. In the present study, bone marrow-derived mesenchymal stem cells (BMMSCs) exposed to LMWF5A exhibited an elongated phenotype with diffuse intracellular F-actin, pronounced migratory leading edges, and filopodia-like projections. In addition, LMWF5A promoted chondrogenic condensation in "micromass" culture, concurrent with the upregulation of collagen 2α1 mRNA. Furthermore, the transcription of the CXCR4-CXCL12 axis was significantly regulated in a manner conducive to migration and homing. Several transcription factors involved in stem cell differentiation were also found to bind oligonucleotide response element probes following exposure to LMWF5A. Finally, a rapid increase in PRAS40 phosphorylation was observed following treatment, potentially resulting in the activation mTORC1. Proteomic analysis of synovial fluid taken from a preliminary set of patients indicated that at 12 weeks following administration of LMWF5A, a microenvironment exists in the knee conducive to stem cell infiltration, self-renewal, and differentiation, in addition to indications of remodeling with a reduction in inflammation. Taken together, these findings imply that LMWF5A treatment may prime stem cells for both mobilization and chondrogenic differentiation, potentially explaining some of the beneficial effects achieved in clinical trials. PMID:26041739

  10. PI3K/Akt promotes feedforward mTORC2 activation through IKKα

    PubMed Central

    Dan, Han C.; Antonia, Ricardo J.; Baldwin, Albert S.

    2016-01-01

    The ser-thr Akt plays a critical role in the regulation of cell survival, cell growth and proliferation, as well as energy metabolism and is dysregulated in many cancers. The regulation of Akt activity depends on the phosphorylation at two sites: (i) Thr308 in the activation loop by phosphoinositide-dependent kinase-1 (PDK1) and (ii) Ser473 hydrophobic motif at the carboxyl terminus by a second activity termed PDK2, which is the mTORC2 complex composed of mTOR, rictor, and Sin1. Previously we demonstrated that IKKα, a component of the IKK complex that controls NF-κB activation, participates in the Akt-dependent regulation of mTORC1. Here we have explored a potential involvement of IKKα in controlling Akt activity and whether this may involve mTORC2. The experiments show that IKKα associates with mTORC2 in several cancer cells in a manner dependent on PI3K/Akt activity and that IKKα positively promotes Akt phosphorylation at Ser473 and at Thr308. Moreover, IKKα enhances mTORC2 kinase activity directed to Akt on Ser473 and Akt-mediated phosphorylation of FOXO3a and GSK3β, but not other Akt-associated targets such as TSC2 and PRAS40, indicating the existence of multiple mechanisms of Akt activation in cells. In addition, loss of IKKα suppresses growth factor-induced Akt activation associated with mTORC1 inhibition. These results indicate that IKKα serves as a feedforward regulator of mTORC2 and that IKKα could serve as a key therapeutic target to block mTORC2 and Akt activation in some cancers. PMID:27027448

  11. Differences in growth, fillet quality, and fatty acid metabolism-related gene expression between juvenile male and female rainbow trout.

    PubMed

    Manor, Meghan L; Cleveland, Beth M; Kenney, P Brett; Yao, Jianbo; Leeds, Tim

    2015-04-01

    Sexual maturation occurs at the expense of stored energy and nutrients, including lipids; however, little is known regarding sex effects on nutrient regulatory mechanisms in rainbow trout prior to maturity. Thirty-two, 14-month-old, male and female rainbow trout were sampled for growth, carcass yield, fillet composition, and gene expression of liver, white muscle, and visceral adipose tissue. Growth parameters, including gonadosomatic index, were not affected by sex. Females had higher percent separable muscle yield, but there were no sex effects on fillet proximate composition. Fillet shear force indicated females produce firmer fillets than males. Male livers had greater expression of three cofactors within the mTOR signaling pathway that act to inhibit TORC1 assembly; mo25, rictor, and pras40. Male liver also exhibited increased expression of β-oxidation genes cpt1b and ehhadh. These findings are indicative of increased mitochondrial β-oxidation in male liver. Females exhibited increased expression of the mTOR cofactor raptor in white muscle and had higher expression levels of several genes within the fatty acid synthesis pathway, including gpat, srebp1, scd1, and cd36. Female muscle also had increased expression of β-oxidation genes cpt1d and cpt2. Increased expression of both fatty acid synthesis and β-oxidation genes suggests female muscle may have greater fatty acid turnover. Differences between sexes were primarily associated with variation of gene expression within the mTOR signaling pathway. Overall, data suggest there is differential regulation of gene expression in male and female rainbow trout tissues prior to the onset of sexual maturity that may lead to nutrient repartitioning during maturation. PMID:25673423

  12. Primary hyperaldosteronism, a mediator of progressive renal disease in cats.

    PubMed

    Javadi, S; Djajadiningrat-Laanen, S C; Kooistra, H S; van Dongen, A M; Voorhout, G; van Sluijs, F J; van den Ingh, T S G A M; Boer, W H; Rijnberk, A

    2005-01-01

    In recent years, there has been renewed interest in primary hyperaldosteronism, particularly because of its possible role in the progression of kidney disease. While most studies have concerned humans and experimental animal models, we here report on the occurrence of a spontaneous form of (non-tumorous) primary hyperaldosteronism in cats. At presentation, the main physical features of 11 elderly cats were hypokalemic paroxysmal flaccid paresis and loss of vision due to retinal detachment with hemorrhages. Primary hyperaldosteronism was diagnosed on the basis of plasma concentrations of aldosterone (PAC) and plasma renin activity (PRA), and the calculation of the PAC:PRA ratio. In all animals, PACs were at the upper end or higher than the reference range. The PRAs were at the lower end of the reference range, and the PAC:PRA ratios exceeded the reference range. Diagnostic imaging by ultrasonography and computed tomography revealed no or only very minor changes in the adrenals compatible with nodular hyperplasia. Adrenal gland histopathology revealed extensive micronodular hyperplasia extending from zona glomerulosa into the zona fasciculata and reticularis. In three cats, plasma urea and creatinine concentrations were normal when hyperaldosteronism was diagnosed but thereafter increased to above the upper limit of the respective reference range. In the other eight cats, urea and creatinine concentrations were raised at first examination and gradually further increased. Even in end-stage renal insufficiency, there was a tendency to hypophosphatemia rather than to hyperphosphatemia. The histopathological changes in the kidneys mimicked those of humans with hyperaldosteronism: hyaline arteriolar sclerosis, glomerular sclerosis, tubular atrophy and interstitial fibrosis. The non-tumorous form of primary hyperaldosteronism in cats has many similarities with "idiopathic" primary hyperaldosteronism in humans. The condition is associated with progressive renal disease

  13. Driving neural regeneration through the mammalian target of rapamycin.

    PubMed

    Maiese, Kenneth

    2014-08-01

    Neurodegenerative disorders affect more than 30 million individuals throughout the world and lead to significant disability as well as death. These statistics will increase almost exponentially as the lifespan and age of individuals increase globally and individuals become more susceptible to acute disorders such as stroke as well as chronic diseases that involve cognitive loss, Alzheimer's disease, and Parkinson's disease. Current therapies for such disorders are effective only for a small subset of individuals or provide symptomatic relief but do not alter disease progression. One exciting therapeutic approach that may turn the tide for addressing neurodegenerative disorders involves the mammalian target of rapamycin (mTOR). mTOR is a component of the protein complexes mTOR Complex 1 (mTORC1) and mTOR Complex 2 (mTORC2) that are ubiquitous throughout the body and control multiple functions such as gene transcription, metabolism, cell survival, and cell senescence. mTOR through its relationship with phosphoinositide 3-kinase (PI 3-K) and protein kinase B (Akt) and multiple downstream signaling pathways such as p70 ribosomal S6 kinase (p70S6K) and proline rich Akt substrate 40 kDa (PRAS40) promotes neuronal cell regeneration through stem cell renewal and oversees critical pathways such as apoptosis, autophagy, and necroptosis to foster protection against neurodegenerative disorders. Targeting by mTOR of specific pathways that drive long-term potentiation, synaptic plasticity, and β-amyloid toxicity may offer new strategies for disorders such as stroke and Alzheimer's disease. Overall, mTOR is an essential neuroprotective pathway but must be carefully targeted to maximize clinical efficacy and eliminate any clinical toxic side effects. PMID:25317149

  14. Downscaling Pest Risk Analyses: Identifying Current and Future Potentially Suitable Habitats for Parthenium hysterophorus with Particular Reference to Europe and North Africa.

    PubMed

    Kriticos, Darren J; Brunel, Sarah; Ota, Noboru; Fried, Guillaume; Oude Lansink, Alfons G J M; Panetta, F Dane; Prasad, T V Ramachandra; Shabbir, Asad; Yaacoby, Tuvia

    2015-01-01

    Pest Risk Assessments (PRAs) routinely employ climatic niche models to identify endangered areas. Typically, these models consider only climatic factors, ignoring the 'Swiss Cheese' nature of species ranges due to the interplay of climatic and habitat factors. As part of a PRA conducted for the European and Mediterranean Plant Protection Organization, we developed a climatic niche model for Parthenium hysterophorus, explicitly including the effects of irrigation where it was known to be practiced. We then downscaled the climatic risk model using two different methods to identify the suitable habitat types: expert opinion (following the EPPO PRA guidelines) and inferred from the global spatial distribution. The PRA revealed a substantial risk to the EPPO region and Central and Western Africa, highlighting the desirability of avoiding an invasion by P. hysterophorus. We also consider the effects of climate change on the modelled risks. The climate change scenario indicated the risk of substantial further spread of P. hysterophorus in temperate northern hemisphere regions (North America, Europe and the northern Middle East), and also high elevation equatorial regions (Western Brazil, Central Africa, and South East Asia) if minimum temperatures increase substantially. Downscaling the climate model using habitat factors resulted in substantial (approximately 22-53%) reductions in the areas estimated to be endangered. Applying expert assessments as to suitable habitat classes resulted in the greatest reduction in the estimated endangered area, whereas inferring suitable habitats factors from distribution data identified more land use classes and a larger endangered area. Despite some scaling issues with using a globally conformal Land Use Systems dataset, the inferential downscaling method shows promise as a routine addition to the PRA toolkit, as either a direct model component, or simply as a means of better informing an expert assessment of the suitable habitat types

  15. Unified Model of Multiple Wind Turbines

    NASA Astrophysics Data System (ADS)

    Mutule, A.; Kochukov, O.

    2014-08-01

    An approach is proposed to the modelling of wind farms in the electric power system long-term planning. It allows a specialist to perform calculations based on scanty information and offers a set of ready-to-use data for easy, fast, and precise modelling. The authors exemplify the calculations of wind speed probability density and power curves and give an idea for relevant corrections. They also show how to pass from a single wind turbine model to the unified model of multiple wind turbines which would meet the requirements of long-term planning tasks. The paper presents the data on wind farms that are operating in UK and Oceania Rakstā ir apskatīta vēja elektrostaciju modelēšana ilgtermiņa attīstības plānošanas uzdevumos. Modelēšana tika veikta, izmantojot ierobežotu datu apjomu, kuri bija piejami lietotājam. Gatavie dati deva iespēju veikt ātru un precīzu modelēšanu. Raksts piedāva metodi kā pāriet no viena vēja ģeneratora modeli uz vēja elektrostaciju (vairāki vēja ģeneratori) modeli, kas atbilst ilgtermiņa attīstības plānošanas prasībām. Rakstā atspoguļoti dati no Okeānijas un Lielbritānijas eksistējošām vēja elektrostacijām

  16. The Flavones Apigenin and Luteolin Induce FOXO1 Translocation but Inhibit Gluconeogenic and Lipogenic Gene Expression in Human Cells

    PubMed Central

    Bumke-Vogt, Christiane; Osterhoff, Martin A.; Borchert, Andrea; Guzman-Perez, Valentina; Sarem, Zeinab; Birkenfeld, Andreas L.; Bähr, Volker; Pfeiffer, Andreas F. H.

    2014-01-01

    The flavones apigenin (4′,5,7,-trihydroxyflavone) and luteolin (3′,4′,5,7,-tetrahydroxyflavone) are plant secondary metabolites with antioxidant, antiinflammatory, and anticancer activities. We evaluated their impact on cell signaling pathways related to insulin-resistance and type 2 diabetes. Apigenin and luteolin were identified in our U-2 OS (human osteosarcoma) cell screening assay for micronutrients triggering rapid intracellular translocation of the forkhead box transcription factor O1 (FOXO1), an important mediator of insulin signal transduction. Insulin reversed the translocation of FOXO1 as shown by live cell imaging. The impact on the expression of target genes was evaluated in HepG2 (human hepatoma) cells. The mRNA-expression of the gluconeogenic enzymes phosphoenolpyruvate carboxykinase (PEPCK) and glucose-6-phosphatase (G6Pc), the lipogenic enzymes fatty-acid synthase (FASN) and acetyl-CoA-carboxylase (ACC) were down-regulated by both flavones with smaller effective dosages of apigenin than for luteolin. PKB/AKT-, PRAS40-, p70S6K-, and S6-phosphorylation was reduced by apigenin and luteolin but not that of the insulin-like growth factor receptor IGF-1R by apigenin indicating a direct inhibition of the PKB/AKT-signaling pathway distal to the IGF-1 receptor. N-acetyl-L-cysteine did not prevent FOXO1 nuclear translocation induced by apigenin and luteolin, suggesting that these flavones do not act via oxidative stress. The roles of FOXO1, FOXO3a, AKT, sirtuin1 (SIRT1), and nuclear factor (erythroid-derived2)-like2 (NRF2), investigated by siRNA knockdown, showed differential patterns of signal pathways involved and a role of NRF2 in the inhibition of gluconeogenic enzyme expression. We conclude that these flavones show an antidiabetic potential due to reduction of gluconeogenic and lipogenic capacity despite inhibition of the PKB/AKT pathway which justifies detailed investigation in vivo. PMID:25136826

  17. Safety analysis, risk assessment, and risk acceptance criteria

    SciTech Connect

    Jamali, K.; Stack, D.W.; Sullivan, L.H.; Sanzo, D.L.

    1997-08-01

    This paper discusses a number of topics that relate safety analysis as documented in the Department of Energy (DOE) safety analysis reports (SARs), probabilistic risk assessments (PRA) as characterized primarily in the context of the techniques that have assumed some level of formality in commercial nuclear power plant applications, and risk acceptance criteria as an outgrowth of PRA applications. DOE SARs of interest are those that are prepared for DOE facilities under DOE Order 5480.23 and the implementing guidance in DOE STD-3009-94. It must be noted that the primary area of application for DOE STD-3009 is existing DOE facilities and that certain modifications of the STD-3009 approach are necessary in SARs for new facilities. Moreover, it is the hazard analysis (HA) and accident analysis (AA) portions of these SARs that are relevant to the present discussions. Although PRAs can be qualitative in nature, PRA as used in this paper refers more generally to all quantitative risk assessments and their underlying methods. HA as used in this paper refers more generally to all qualitative risk assessments and their underlying methods that have been in use in hazardous facilities other than nuclear power plants. This discussion includes both quantitative and qualitative risk assessment methods. PRA has been used, improved, developed, and refined since the Reactor Safety Study (WASH-1400) was published in 1975 by the Nuclear Regulatory Commission (NRC). Much debate has ensued since WASH-1400 on exactly what the role of PRA should be in plant design, reactor licensing, `ensuring` plant and process safety, and a large number of other decisions that must be made for potentially hazardous activities. Of particular interest in this area is whether the risks quantified using PRA should be compared with numerical risk acceptance criteria (RACs) to determine whether a facility is `safe.` Use of RACs requires quantitative estimates of consequence frequency and magnitude.

  18. Guides d'ondes infrarouges pour applications en télécommunications, capteurs chimiques et biochimiques

    NASA Astrophysics Data System (ADS)

    Smektala, F.; Bureau, B.; Adam, J. L.; Lucas, J.

    2002-06-01

    Les énergies de phonons élevés des verres à base de silice limitent leurs applications dans l'infrarouge. Il devient donc incontournable de créer des verres à plus faible énergie de phonons pour développer une optique passive guidée opérationnelle dans l'IR moyen et pour réaliser de nouveaux guide d'ondes optiques activés par des lanthanides pouvant jouer le rôle soit d'amplificateurs optiques soit de fibres lasers. Les compositions de verres stables répondant à ces critères sont exceptionnelles et appartiennent aux familles chimiques des fluorures et des chalcogénures. Les verres de fluorures, convenablement dopés par des terres rares, ont permis la réalisation d'amplificateurs optiques opérant dans la fenêtre télecom de la silice (1.3 μm avec le praséodyme, 1.45 μm avec le thulium et 1.55 μm avec l'erbium. Les verres de chalcogénures permettent la réalisation de fibres opérationnelles jusqu'à 12 μm mais seulement pour des applications courtes distances telles que le transport d'énergie moyenne, la radiométrie à l'ambiante et la spectrométrie IR déportée par fibre optique de molécules chimiques ou de tissus biologiques.

  19. Conducting an Efficient Proactive Risk Assessment Prior to CPOE Implementation in an Intensive Care Unit

    PubMed Central

    Hundt, Ann Schoofs; Adams, Jean A.; Schmid, J. Andrew; Musser, Linda M.; Walker, James M.; Wetterneck, Tosha B; Douglas, Stephen V.; Paris, Bonnie L.; Carayon, Pascale

    2012-01-01

    Purpose To develop, conduct, and evaluate a proactive risk assessment (PRA) of the design and implementation of CPOE in an ICU. Methods We developed a PRA method based on issues identified from documented experience with conventional PRA methods and the constraints of an organization about to implement CPOE in an intensive care unit. The PRA method consists of three phases: planning (three months), team (one five-hour meeting), and evaluation (short- and long-term). Results Sixteen unique relevant vulnerabilities were identified as a result of the PRA team’s efforts. Negative consequences resulting from the vulnerabilities included potential patient safety and quality of care issues, non-compliance with regulatory requirements, increases in cognitive burden on CPOE users, and/or worker inconvenience or distress. Actions taken to address the vulnerabilities included redesign of the technology, process (workflow) redesign, user training, and/or ongoing monitoring. Verbal and written evaluation by the team members indicated that the PRA method was useful and that participants were willing to participate in future PRAs. Long-term evaluation was accomplished by monitoring an ongoing “issues list” of CPOE problems identified by or reported to IT staff. Vulnerabilities identified by the team were either resolved prior to CPOE implementation (n = 7) or shortly thereafter (n = 9). No other issues were identified beside those identified by the team. Conclusions Generally positive results from the various evaluations including a long-term evaluation demonstrate the value of developing an efficient PRA method that meets organizational and contextual requirements and constraints. PMID:22608242

  20. Hypoxia upregulates Rab11-family interacting protein 4 through HIF-1α to promote the metastasis of hepatocellular carcinoma.

    PubMed

    Hu, F; Deng, X; Yang, X; Jin, H; Gu, D; Lv, X; Wang, C; Zhang, Y; Huo, X; Shen, Q; Luo, Q; Zhao, F; Ge, T; Zhao, F; Chu, W; Shu, H; Yao, M; Fan, J; Qin, W

    2015-12-01

    Hypoxic microenvironment is a powerful driving force for the invasion and metastasis of hepatocellular carcinoma (HCC). Hypoxia-inducible factor 1α (HIF-1α), as a crucial regulator of transcriptional responses to hypoxia, induces the expression of multiple target genes involved in different steps of HCC metastatic process. It is critical to find target genes associated with metastasis under hypoxia for shedding new light on molecular mechanism of HCC metastasis. In this study, we uncovered that hypoxia could induce the upregulation of Rab11-family interacting protein 4 (Rab11-FIP4) and activation of Rab11-FIP4 promoter by HIF-1α. The overexpression of Rab11-FIP4 significantly enhanced the mobility and invasiveness of HCC cells in vitro, also contributed to distant lung metastasis in vivo, whereas silencing of Rab11-FIP4 decreased the ability of migration and invasion in HCC cells in vitro and suppressed lung metastasis in vivo. Rab11-FIP4 facilitated HCC metastasis through the phosphorylation of PRAS40, which was regulated by mTOR. Furthermore, the expression level of Rab11-FIP4 was significantly increased in HCC tissues and high expression of Rab11-FIP4 was closely correlated with vascular invasion and poor prognosis in HCC patients. A markedly positive correlation between the expression of Rab11-FIP4 and HIF-1α was observed in HCC tissues and combination of Rab11-FIP4 and HIF-1α was a more valuable predictor of poor prognosis for HCC patients. In conclusion, Rab11-FIP4 is a target gene of HIF-1α and has a pro-metastatic role in HCC, suggesting that Rab11-FIP4 may be a promising candidate target for HCC treatment. PMID:25745995

  1. Evaluation of potential severe accidents during low power and shutdown operations at Grand Gulf, Unit 1: Evaluation of severe accident risks for plant operational state 5 during a refueling outage. Main report and appendices, Volume 6, Part 1

    SciTech Connect

    Brown, T.D.; Kmetyk, L.N.; Whitehead, D.; Miller, L.; Forester, J.; Johnson, J.

    1995-03-01

    Traditionally, probabilistic risk assessments (PRAS) of severe accidents in nuclear power plants have considered initiating events potentially occurring only during full power operation. Recent studies and operational experience have, however, implied that accidents during low power and shutdown could be significant contributors to risk. In response to this concern, in 1989 the Nuclear Regulatory Commission (NRC) initiated an extensive program to carefully examine the potential risks during low power and shutdown operations. Two plants, Surry (pressurized water reactor) and Grand Gulf (boiling water reactor), were selected as the plants to be studied. The program consists of two parallel projects being performed by Brookhaven National Laboratory (Surry) and Sandia National Laboratories (Grand Gulf). The program objectives include assessing the risks of severe accidents initiated during plant operational states other than full power operation and comparing the estimated risks with the risk associated with accidents initiated during full power operation as assessed in NUREG-1150. The scope of the program is that of a Level-3 PRA. The subject of this report is the PRA of the Grand Gulf Nuclear Station, Unit 1. The Grand Gulf plant utilizes a 3833 MWt BUR-6 boiling water reactor housed in a Mark III containment. The Grand Gulf plant is located near Port Gibson, Mississippi. The regime of shutdown analyzed in this study was plant operational state (POS) 5 during a refueling outage, which is approximately Cold Shutdown as defined by Grand Gulf Technical Specifications. The entire PRA of POS 5 is documented in a multi-volume NUREG report (NUREG/CR-6143). The internal events accident sequence analysis (Level 1) is documented in Volume 2. The Level 1 internal fire and internal flood analyses are documented in Vols 3 and 4, respectively.

  2. Human event observations in the individual plant examinations

    SciTech Connect

    Forester, J.

    1995-01-01

    A major objective of the Nuclear Regulatory Commission`s (NRC) Individual Plant Examination (IPE) Insights Program is to identify the important determinants of core damage frequency (CDF) for the different reactor and containment types and plant designs as indicated in the IPEs. The human reliability analysis (HRA) is a critical component of the probabilistic risk assessments (PRAS) which were done for the IPES. The determination and selection of human actions for incorporation into the event and fault tree models and the quantification of their failure probabilities can have an important impact on the resulting estimates of CDF and risk. Therefore, two important goals of the NRCs IPE Insights Program are (1) to determine the extent to which human actions and their corresponding failure probabilities influenced the results of the IPEs and (2) to identify which factors played significant roles in determining the differences and similarities in the results of the HRA analyses across the different plants. To obtain the relevant information, the NRC`s IPE database, which contains information on plant design, CDF, and containment performance obtained from the IPES, was used in conjunction with a systematic examination of the HRA analyses and results from the IPES. Regarding the extent to which the results of the HRA analyses were significant contributors to the plants` CDFs, examinations of several different measures indicated that while individual human actions could have important influences on CDF for particular initiators, the HRA results did not appear to be the most significant driver of plant risk (CDF). Another finding was that while there were relatively wide variations in the calculated human error probabilities (HEPs) for similar events across plants, there was no evidence for any systematic variation as a function of the HRA methods used in the analyses.

  3. Improved Sampling Algorithms in the Risk-Informed Safety Margin Characterization Toolkit

    SciTech Connect

    Mandelli, Diego; Smith, Curtis Lee; Alfonsi, Andrea; Rabiti, Cristian; Cogliati, Joshua Joseph

    2015-09-01

    The RISMC approach is developing advanced set of methodologies and algorithms in order to perform Probabilistic Risk Analyses (PRAs). In contrast to classical PRA methods, which are based on Event-Tree and Fault-Tree methods, the RISMC approach largely employs system simulator codes applied to stochastic analysis tools. The basic idea is to randomly perturb (by employing sampling algorithms) timing and sequencing of events and internal parameters of the system codes (i.e., uncertain parameters) in order to estimate stochastic parameters such as core damage probability. This approach applied to complex systems such as nuclear power plants requires to perform a series of computationally expensive simulation runs given a large set of uncertain parameters. These types of analysis are affected by two issues. Firstly, the space of the possible solutions (a.k.a., the issue space or the response surface) can be sampled only very sparsely, and this precludes the ability to fully analyze the impact of uncertainties on the system dynamics. Secondly, large amounts of data are generated and tools to generate knowledge from such data sets are not yet available. This report focuses on the first issue and in particular employs novel methods that optimize the information generated by the sampling process by sampling unexplored and risk-significant regions of the issue space: adaptive (smart) sampling algorithms. They infer system response from surrogate models constructed from existing samples and predict the most relevant location of the next sample. It is therefore possible to understand features of the issue space with a small number of carefully selected samples. In this report, we will present how it is possible to perform adaptive sampling using the RISMC toolkit and highlight the advantages compared to more classical sampling approaches such Monte-Carlo. We will employ RAVEN to perform such statistical analyses using both analytical cases but also another RISMC code: RELAP-7.

  4. Using experts feedback in clinical case resolution and arbitration as accuracy diagnosis methodology.

    PubMed

    Rodríguez-González, Alejandro; Torres-Niño, Javier; Valencia-Garcia, Rafael; Mayer, Miguel A; Alor-Hernandez, Giner

    2013-09-01

    This paper proposes a new methodology for assessing the efficiency of medical diagnostic systems and clinical decision support systems by using the feedback/opinions of medical experts. The methodology behind this work is based on a comparison between the expert feedback that has helped solve different clinical cases and the expert system that has evaluated these same cases. Once the results are returned, an arbitration process is carried out in order to ensure the correctness of the results provided by both methods. Once this process has been completed, the results are analyzed using Precision, Recall, Accuracy, Specificity and Matthews Correlation Coefficient (MCC) (PRAS-M) metrics. When the methodology is applied, the results obtained from a real diagnostic system allow researchers to establish the accuracy of the system based on objective facts. The methodology returns enough information to analyze the system's behavior for each disease in the knowledge base or across the entire knowledge base. It also returns data on the efficiency of the different assessors involved in the evaluation process, analyzing their behavior in the diagnostic process. The proposed work facilitates the evaluation of medical diagnostic systems, having a reliable process based on objective facts. The methodology presented in this research makes it possible to identify the main characteristics that define a medical diagnostic system and their values, allowing for system improvement. A good example of the results provided by the application of the methodology is shown in this paper. A diagnosis system was evaluated by means of this methodology, yielding positive results (statistically significant) when comparing the system with the assessors that participated in the evaluation process of the system through metrics such as recall (+27.54%) and MCC (+32.19%). These results demonstrate the real applicability of the methodology used. PMID:23816170

  5. Critical review of Ayurvedic Varṇya herbs and their tyrosinase inhibition effect

    PubMed Central

    Sharma, Khemchand; Joshi, Namrata; Goyal, Chinky

    2015-01-01

    Introduction: The aspiration for light skin (fair complexion) is becoming pronounced in a greater number of people in the present times with natural products being more in demand than their synthetic counterparts. Research in the area of skin-lightening agents is an expanding field with the knowledge being updated regularly. In Ayurveda, varṇya, raktaprasādana, tvacya are few terms specifying skin lightening with respect to its modern counterpart i.e., Tyrosinase inhibition, the most commonly reported method of skin lightening. Aim: The present review is undertaken for screening twenty herbs from Varṇya Mahākaṣāya, Lodhrādi varṇya gaṇa, Elādi varṇa prasādana gaṇa and few varṇya formulations to evaluate their probable modes of action through which the skin lightening is effected as per both Ayurveda and biomedical concepts. Materials and Methods: Critical review of herbs to show varṇya property is compiled from various Ayurvedic texts as well as from multiple articles on the internet to justify their skin lightening property on the basis of data collected. Result and Conclusion: All the twenty herbs reviewed are found to act as varṇya directly (citation as varṇya) or indirectly (alleviation of pitta and rakta) as per Ayurveda and to interfere in melanogenesis pathway through tyrosinase inhibition as per biomedicine. This shows their potential to act as good skin whitening agents. Śuṇṭhi being a part of many varṇya formulations, is the only herb among all reviewed in the present study found to exhibit tyrosinase inhibition without any Ayurvedic citation of varṇya property. PMID:26600663

  6. Downscaling Pest Risk Analyses: Identifying Current and Future Potentially Suitable Habitats for Parthenium hysterophorus with Particular Reference to Europe and North Africa

    PubMed Central

    Kriticos, Darren J.; Brunel, Sarah; Ota, Noboru; Fried, Guillaume; Oude Lansink, Alfons G. J. M.; Panetta, F. Dane; Prasad, T. V. Ramachandra; Shabbir, Asad; Yaacoby, Tuvia

    2015-01-01

    Pest Risk Assessments (PRAs) routinely employ climatic niche models to identify endangered areas. Typically, these models consider only climatic factors, ignoring the ‘Swiss Cheese’ nature of species ranges due to the interplay of climatic and habitat factors. As part of a PRA conducted for the European and Mediterranean Plant Protection Organization, we developed a climatic niche model for Parthenium hysterophorus, explicitly including the effects of irrigation where it was known to be practiced. We then downscaled the climatic risk model using two different methods to identify the suitable habitat types: expert opinion (following the EPPO PRA guidelines) and inferred from the global spatial distribution. The PRA revealed a substantial risk to the EPPO region and Central and Western Africa, highlighting the desirability of avoiding an invasion by P. hysterophorus. We also consider the effects of climate change on the modelled risks. The climate change scenario indicated the risk of substantial further spread of P. hysterophorus in temperate northern hemisphere regions (North America, Europe and the northern Middle East), and also high elevation equatorial regions (Western Brazil, Central Africa, and South East Asia) if minimum temperatures increase substantially. Downscaling the climate model using habitat factors resulted in substantial (approximately 22–53%) reductions in the areas estimated to be endangered. Applying expert assessments as to suitable habitat classes resulted in the greatest reduction in the estimated endangered area, whereas inferring suitable habitats factors from distribution data identified more land use classes and a larger endangered area. Despite some scaling issues with using a globally conformal Land Use Systems dataset, the inferential downscaling method shows promise as a routine addition to the PRA toolkit, as either a direct model component, or simply as a means of better informing an expert assessment of the suitable habitat

  7. A risk methodology to evaluate sensitvity of plant risk to human errors

    SciTech Connect

    Samanta, P.; Wong, S.; Higgins, J.; Haber, S.; Luckas, W.

    1988-01-01

    This paper presents an evaluation of sensitivity of plant risk parameters, namely the core melt frequency and the accident sequence frequencies, to the human errors involved in various aspects of nuclear power plant operations. Results are provided using the Oconee-3 Probabilistic Risk Assessment model as an example application of the risk methodology described herein. Sensitivity analyses in probabilistic risk assessment (PRA) involve three areas: (1) a determination of the set of input parameters; in this case, various categories of human errors signifying aspects of plant operation, (2) the range over which the input parameters vary, and (3) an assessment of the sensitivity of the plant risk parameters to the input parameters which, in this case, consist of all postulated human errors, or categories of human errors. The methodology presents a categorization scheme where human errors are categorized in terms of types of activity, location, personnel involved, etc., to relate the significance of sensitivity of risk parameters to specific aspects of human performance in the nuclear plant. Ranges of variability for human errors have been developed considering the various known causes of uncertainty in human error probability estimates in PRAs. The sensitivity of the risk parameters are assessed using the event/fault tree methodology of the PRA. The results of the risk-based sensitivity evaluation using the Oconee-3 PRA as an example show the quantitative impact on the plant risk level due to variations in human error probabilities. The relative effects of various human error categories and human error sorts within the categories are also presented to identify and characterize significant human errors for effective risk management in nuclear power plant operational activities. 8 refs., 10 figs., 4 tabs.

  8. Testosterone regulation of Akt/mTORC1/FoxO3a Signaling in Skeletal Muscle

    PubMed Central

    White, James P.; Gao, Song; Puppa, Melissa J.; Sato, Shuichi; Welle, Stephen L.; Carson, James A.

    2012-01-01

    Low endogenous testosterone production, known as hypogonadism is commonly associated with conditions inducing muscle wasting. Akt signaling can control skeletal muscle mass through mTOR regulation of protein synthesis and FoxO regulation of protein degradation, and this pathway has been previously identified as a target of androgen signaling. However, the testosterone sensitivity of Akt/mTOR signaling requires further understanding in order to grasp the significance of varied testosterone levels seen with wasting disease on muscle protein turnover regulation. Therefore, the purpose of this study is to determine the effect of androgen availability on muscle Akt/mTORC1/FoxO3a regulation in skeletal muscle and cultured C2C12 myotubes. C57BL/6 mice were either castrated for 42 days or castrated and treated with the nandrolone decanoate (ND) (6 mg/kg bw/wk). Testosterone loss (TL) significantly decreased volitional grip strength, body weight, and gastrocnemius (GAS) muscle mass, and ND reversed these changes. Related to muscle mass regulation, TL decreased muscle IGF-1 mRNA, the rate of myofibrillar protein synthesis, Akt phosphorylation, and the phosphorylation of Akt targets, GSK3β, PRAS40 and FoxO3a. TL induced expression of FoxO transcriptional targets, MuRF1, atrogin1 and REDD1. Muscle AMPK and raptor phosphorylation, mTOR inhibitors, were not altered by low testosterone. ND restored IGF-1 expression and Akt/mTORC1 signaling while repressing expression of FoxO transcriptional targets. Testosterone (T) sensitivity of Akt/mTORC1 signaling was examined in C2C12 myotubes, and mTOR phosphorylation was induced independent of Akt activation at low T concentrations, while a higher T concentration was required to activate Akt signaling. Interestingly, low concentration T was sufficient to amplify myotube mTOR and Akt signaling after 24h of T withdrawal, demonstrating the potential in cultured myotubes for a T initiated positive feedback mechanism to amplify Akt

  9. Incorporating Equipment Condition Assessment in Risk Monitors for Advanced Small Modular Reactors

    SciTech Connect

    Coble, Jamie B.; Coles, Garill A.; Meyer, Ryan M.; Ramuhalli, Pradeep

    2013-10-01

    Advanced small modular reactors (aSMRs) can complement the current fleet of large light-water reactors in the USA for baseload and peak demand power production and process heat applications (e.g., water desalination, shale oil extraction, hydrogen production). The day-to-day costs of aSMRs are expected to be dominated by operations and maintenance (O&M); however, the effect of diverse operating missions and unit modularity on O&M is not fully understood. These costs could potentially be reduced by optimized scheduling, with risk-informed scheduling of maintenance, repair, and replacement of equipment. Currently, most nuclear power plants have a “living” probabilistic risk assessment (PRA), which reflects the as-operated, as-modified plant and combine event probabilities with population-based probability of failure (POF) for key components. “Risk monitors” extend the PRA by incorporating the actual and dynamic plant configuration (equipment availability, operating regime, environmental conditions, etc.) into risk assessment. In fact, PRAs are more integrated into plant management in today’s nuclear power plants than at any other time in the history of nuclear power. However, population-based POF curves are still used to populate fault trees; this approach neglects the time-varying condition of equipment that is relied on during standard and non-standard configurations. Equipment condition monitoring techniques can be used to estimate the component POF. Incorporating this unit-specific estimate of POF in the risk monitor can provide a more accurate estimate of risk in different operating and maintenance configurations. This enhanced risk assessment will be especially important for aSMRs that have advanced component designs, which don’t have an available operating history to draw from, and often use passive design features, which present challenges to PRA. This paper presents the requirements and technical gaps for developing a framework to integrate unit

  10. Accelerated Tumor Growth Mediated by Sub-lytic Levels of Antibody-Induced Complement Activation is Associated with Activation of the PI3K/AKT Survival Pathway

    PubMed Central

    Wu, Xiaohong; Ragupathi, Govind; Panageas, Katherine; Hong, Feng; Livingston, Philip O.

    2013-01-01

    Purpose We addressed the possibility that low levels of tumor cell bound antibodies targeting gangliosides might accelerate tumor growth. Experimental Design To test this hypothesis, we treated mice with a range of mAb doses against GM2, GD2, GD3 and CD20 after challenge with tumors expressing these antigens and tested the activity of the same mAbs in-vitro. We also explored the mechanisms behind the complement-mediated tumor growth acceleration that we observed and an approach to overcome it. Results Serologically detectable levels of IgM-mAb against GM2 are able to delay or prevent tumor growth of high GM2-expressing cell lines both in-vitro and in a SCID mouse model, while very low levels of this mAb resulted in slight but consistent acceleration of tumor growth in both settings. Surprisingly, this is not restricted to IgM antibodies targeting GM2 but consistent against IgG-mAb targeting GD3 as well. These findings were mirrored by in-vitro studies with antibodies against these antigens as well as GD2 and CD20 (with Rituxan), and shown to be complement-dependent in all cases. Complement-mediated accelerated growth of cultured tumor cell lines initiated by low mAb levels was associated with activation of the PI3K/AKT survival pathway and significantly elevated levels of both p-AKT and p-PRAS40. This complement-mediated PI3K-activation and accelerated tumor growth in-vitro and in-vivo are eliminated by PI3K-inhibitors NVP-BEZ235 and Wortmannin. These PI3K-inhibitors also significantly increased efficacy of high doses of these 4 mAbs. Conclusion Our findings suggest that manipulation of the PI3K/AKT pathway and its signaling network can significantly increase the potency of passively administered mAbs and vaccine-induced-antibodies targeting a variety of tumor-cell-surface-antigens. PMID:23833306

  11. Effects of a brief high-fat diet and acute exercise on the mTORC1 and IKK/NF-κB pathways in rat skeletal muscle

    PubMed Central

    Castorena, Carlos M.; Arias, Edward B.; Sharma, Naveen; Cartee, Gregory D.

    2016-01-01

    One exercise session can improve subsequent insulin-stimulated glucose uptake by skeletal muscle in healthy and insulin-resistant individuals. Our first aim was to determine whether a brief (2 weeks) high-fat diet (HFD) that caused muscle insulin resistance would activate the mammalian target of rapamycin complex 1 (mTORC1) and/or inhibitor of κB kinase/nuclear factor κB (IKK/NF-κB) pathways, which are potentially linked to induction of insulin resistance. Our second aim was to determine whether acute exercise that improved insulin-stimulated glucose uptake by muscles would attenuate activation of these pathways. We compared HFD-fed rats with rats fed a low-fat diet (LFD). Some animals from each diet group were sedentary and others were studied 3 h postexercise, when insulin-stimulated glucose uptake was increased. The results did not provide evidence that brief HFD activated either the mTORC1 (including phosphorylation of mTORSer2448, TSC2Ser939, p70S6KThr412, and RPS6Ser235/236) or the IKK/NF-κB (including abundance of IκBα or phosphorylation of NF-κBSer536, IKKα/βSer177/181, and IκBSer32) pathway in insulin-resistant muscles. Exercise did not oppose the activation of either pathway, as evidenced by no attenuation of phosphorylation of key proteins in the IKK/NF-κB pathway (NF-κBSer536, IKKα/βSer177/181, and IκBSer32), unaltered IκBα abundance, and no attenuation of phosphorylation of key proteins in the mTORC1 pathway (mTORSer2448, TSC2Ser939, and RPS6Ser235/236). Instead, exercise induced greater phosphorylation of 2 proteins of the mTORC1 pathway (PRAS40Thr246 and p70S6KThr412) in insulin-stimulated muscles, regardless of diet. Insulin resistance induced by a brief HFD was not attributable to greater activation of the mTORC1 or the IKK/NF-κB pathway in muscle, and exercise-induced improvement in insulin sensitivity was not attributable to attenuated activation of these pathways in muscle. PMID:25706655

  12. Identification and Assessment of Material Models for Age-Related Degradation of Structures and Passive Components in Nuclear Power Plants

    SciTech Connect

    Nie,J.; Braverman, J.; Hofmayer, C.; Kim, M. K.; Choi, I-K.

    2009-04-27

    When performing seismic safety assessments of nuclear power plants (NPPs), the potential effects of age-related degradation on structures, systems, and components (SSCs) should be considered. To address the issue of aging degradation, the Korea Atomic Energy Research Institute (KAERI) has embarked on a five-year research project to develop a realistic seismic risk evaluation system which will include the consideration of aging of structures and components in NPPs. Three specific areas that are included in the KAERI research project, related to seismic probabilistic risk assessment (PRA), are probabilistic seismic hazard analysis, seismic fragility analysis including the effects of aging, and a plant seismic risk analysis. To support the development of seismic capability evaluation technology for degraded structures and components, KAERI entered into a collaboration agreement with Brookhaven National Laboratory (BNL) in 2007. The collaborative research effort is intended to continue over a five year period with the goal of developing seismic fragility analysis methods that consider the potential effects of age-related degradation of SSCs, and using these results as input to seismic PRAs. In the Year 1 scope of work BNL collected and reviewed degradation occurrences in US NPPs and identified important aging characteristics needed for the seismic capability evaluations that will be performed in the subsequent evaluations in the years that follow. This information is presented in the Annual Report for the Year 1 Task, identified as BNL Report-81741-2008 and also designated as KAERI/RR-2931/2008. The report presents results of the statistical and trending analysis of this data and compares the results to prior aging studies. In addition, the report provides a description of U.S. current regulatory requirements, regulatory guidance documents, generic communications, industry standards and guidance, and past research related to aging degradation of SSCs. This report

  13. Impact of mTORC1 inhibition on keratinocyte proliferation during skin tumor promotion in wild-type and BK5.AktWT mice.

    PubMed

    Rho, Okkyung; Kiguchi, Kaoru; Jiang, Guiyu; DiGiovanni, John

    2014-11-01

    In this study, we examined the impact of rapamycin on mTORC1 signaling during 12-O-tetradecanoylphorbol-13-acetate (TPA)-induced keratinocyte proliferation and skin tumor promotion in both wild-type (FVB/N) and BK5.Akt(WT) mice. TPA activated mTORC1 signaling in a time-dependent manner in cultured primary mouse keratinocytes and a mouse keratinocyte cell line. Early activation (15-30 min) of mTORC1 signaling induced by TPA was mediated in part by PKC activation, whereas later activation (2-4 h) was mediated by activation of EGFR and Akt. BK5.Akt(WT) transgenic mice, where Akt1 is overexpressed in basal epidermis, are highly sensitive to TPA-induced epidermal proliferation and two-stage skin carcinogenesis. Targeting mTORC1 with rapamycin effectively inhibited TPA-induced epidermal hyperplasia and hyperproliferation as well as tumor promotion in a dose-dependent manner in both wild-type and BK5.Akt(WT) mice. A significant expansion (∼threefold) of the label retaining cell (LRC) population per hair follicle was observed in BK5.Akt(WT) mice compared to FVB/N mice. There was also a significant increase in K15 expressing cells in the hair follicle of transgenic mice that coincided with expression of phospho-Akt, phospho-S6K, and phospho-PRAS40, suggesting an important role of mTORC1 signaling in bulge-region keratinocyte stem cell (KSC) homeostasis. After 2 weeks of TPA treatment, LRCs had moved upward into the interfollicular epidermis from the bulge region of both wild-type and BK5.Akt(WT) mice. TPA-mediated LRC proliferation and migration was significantly inhibited by rapamycin. Collectively, the current data indicate that signaling through mTORC1 contributes significantly to the process of skin tumor promotion through effects on proliferation of the target cells for tumor development. PMID:24114993

  14. Johnson Space Center's Risk and Reliability Analysis Group 2008 Annual Report

    NASA Technical Reports Server (NTRS)

    Valentine, Mark; Boyer, Roger; Cross, Bob; Hamlin, Teri; Roelant, Henk; Stewart, Mike; Bigler, Mark; Winter, Scott; Reistle, Bruce; Heydorn,Dick

    2009-01-01

    as well as performing major probabilistic assessments used to support flight rationale and help establish program requirements. During 2008, the Analysis Group performed more than 70 assessments. Although all these assessments were important, some were instrumental in the decisionmaking processes for the Shuttle and Constellation Programs. Two of the more significant tasks were the Space Transportation System (STS)-122 Low Level Cutoff PRA for the SSP and the Orion Pad Abort One (PA-1) PRA for the CxP. These two activities, along with the numerous other tasks the Analysis Group performed in 2008, are summarized in this report. This report also highlights several ongoing and upcoming efforts to provide crucial statistical and probabilistic assessments, such as the Extravehicular Activity (EVA) PRA for the Hubble Space Telescope service mission and the first fully integrated PRAs for the CxP's Lunar Sortie and ISS missions.

  15. Effects of a brief high-fat diet and acute exercise on the mTORC1 and IKK/NF-κB pathways in rat skeletal muscle.

    PubMed

    Castorena, Carlos M; Arias, Edward B; Sharma, Naveen; Cartee, Gregory D

    2015-03-01

    One exercise session can improve subsequent insulin-stimulated glucose uptake by skeletal muscle in healthy and insulin-resistant individuals. Our first aim was to determine whether a brief (2 weeks) high-fat diet (HFD) that caused muscle insulin resistance would activate the mammalian target of rapamycin complex 1 (mTORC1) and/or inhibitor of κB kinase/nuclear factor κB (IKK/NF-κB) pathways, which are potentially linked to induction of insulin resistance. Our second aim was to determine whether acute exercise that improved insulin-stimulated glucose uptake by muscles would attenuate activation of these pathways. We compared HFD-fed rats with rats fed a low-fat diet (LFD). Some animals from each diet group were sedentary and others were studied 3 h postexercise, when insulin-stimulated glucose uptake was increased. The results did not provide evidence that brief HFD activated either the mTORC1 (including phosphorylation of mTOR(Ser2448), TSC2(Ser939), p70S6K(Thr412), and RPS6(Ser235/236)) or the IKK/NF-κB (including abundance of IκBα or phosphorylation of NF-κB(Ser536), IKKα/β(Ser177/181), and IκB(Ser32)) pathway in insulin-resistant muscles. Exercise did not oppose the activation of either pathway, as evidenced by no attenuation of phosphorylation of key proteins in the IKK/NF-κB pathway (NF-κB(Ser536), IKKα/β(Ser177/181), and IκB(Ser32)), unaltered IκBα abundance, and no attenuation of phosphorylation of key proteins in the mTORC1 pathway (mTOR(Ser2448), TSC2(Ser939), and RPS6(Ser235/236)). Instead, exercise induced greater phosphorylation of 2 proteins of the mTORC1 pathway (PRAS40(Thr246) and p70S6K(Thr412)) in insulin-stimulated muscles, regardless of diet. Insulin resistance induced by a brief HFD was not attributable to greater activation of the mTORC1 or the IKK/NF-κB pathway in muscle, and exercise-induced improvement in insulin sensitivity was not attributable to attenuated activation of these pathways in muscle. PMID:25706655

  16. Testosterone regulation of Akt/mTORC1/FoxO3a signaling in skeletal muscle.

    PubMed

    White, James P; Gao, Song; Puppa, Melissa J; Sato, Shuichi; Welle, Stephen L; Carson, James A

    2013-01-30

    Low endogenous testosterone production, known as hypogonadism is commonly associated with conditions inducing muscle wasting. Akt signaling can control skeletal muscle mass through mTOR regulation of protein synthesis and FoxO regulation of protein degradation, and this pathway has been previously identified as a target of androgen signaling. However, the testosterone sensitivity of Akt/mTOR signaling requires further understanding in order to grasp the significance of varied testosterone levels seen with wasting disease on muscle protein turnover regulation. Therefore, the purpose of this study is to determine the effect of androgen availability on muscle Akt/mTORC1/FoxO3a regulation in skeletal muscle and cultured C(2)C(12) myotubes. C57BL/6 mice were either castrated for 42 days or castrated and treated with the nandrolone decanoate (ND) (6 mg/kg bw/wk). Testosterone loss (TL) significantly decreased volitional grip strength, body weight, and gastrocnemius (GAS) muscle mass, and ND reversed these changes. Related to muscle mass regulation, TL decreased muscle IGF-1 mRNA, the rate of myofibrillar protein synthesis, Akt phosphorylation, and the phosphorylation of Akt targets, GSK3β, PRAS40 and FoxO3a. TL induced expression of FoxO transcriptional targets, MuRF1, atrogin1 and REDD1. Muscle AMPK and raptor phosphorylation, mTOR inhibitors, were not altered by low testosterone. ND restored IGF-1 expression and Akt/mTORC1 signaling while repressing expression of FoxO transcriptional targets. Testosterone (T) sensitivity of Akt/mTORC1 signaling was examined in C(2)C(12) myotubes, and mTOR phosphorylation was induced independent of Akt activation at low T concentrations, while a higher T concentration was required to activate Akt signaling. Interestingly, low concentration T was sufficient to amplify myotube mTOR and Akt signaling after 24 h of T withdrawal, demonstrating the potential in cultured myotubes for a T initiated positive feedback mechanism to amplify Akt

  17. Research Resource: Identification of Novel Growth Hormone-Regulated Phosphorylation Sites by Quantitative Phosphoproteomics

    PubMed Central

    Ray, Bridgette N.; Kweon, Hye Kyong; Argetsinger, Lawrence S.; Fingar, Diane C.; Andrews, Philip C.

    2012-01-01

    GH and GH receptors are expressed throughout life, and GH elicits a diverse range of responses, including growth and altered metabolism. It is therefore important to understand the full spectrum of GH signaling pathways and cellular responses. We applied mass spectrometry-based phosphoproteomics combined with stable isotope labeling with amino acids in cell culture to identify proteins rapidly phosphorylated in response to GH in 3T3-F442A preadipocytes. We identified 132 phosphosites in 95 proteins that exhibited rapid (5 or 15 min) GH-dependent statistically significant increases in phosphorylation by more than or equal to 50% and 96 phosphosites in 46 proteins that were down-regulated by GH by more than or equal to 30%. Several of the GH-stimulated phosphorylation sites were known (e.g. regulatory Thr/Tyr in Erks 1 and 2, Tyr in signal transducers and activators of transcription (Stat) 5a and 5b, Ser939 in tuberous sclerosis protein (TSC) 2 or tuberin). The remaining 126 GH-stimulated sites were not previously associated with GH. Kyoto Encyclopedia of Genes and Genomes pathway analysis of GH-stimulated sites indicated enrichment in proteins associated with the insulin and mammalian target of rapamycin (mTOR) pathways, regulation of the actin cytoskeleton, and focal adhesions. Akt/protein kinase A consensus sites (RXRXXS/T) were the most commonly phosphorylated consensus sites. Immunoblotting confirmed GH-stimulated phosphorylation of all seven novel GH-dependent sites tested [regulatory sites in proline-rich Akt substrate, 40 kDA (PRAS40), regulatory associated protein of mTOR, ATP-citrate lyase, Na+/H+ exchanger-1, N-myc downstream regulated gene 1, and Shc]). The immunoblot results suggest that many, if not most, of the GH-stimulated phosphosites identified in this large-scale quantitative phosphoproteomics analysis, including sites in multiple proteins in the Akt/ mTOR complex 1 pathway, are phosphorylated in response to GH. Their identification significantly

  18. Developing and evaluating distributions for probabilistic human exposure assessments

    SciTech Connect

    Maddalena, Randy L.; McKone, Thomas E.

    2002-08-01

    This report describes research carried out at the Lawrence Berkeley National Laboratory (LBNL) to assist the U. S. Environmental Protection Agency (EPA) in developing a consistent yet flexible approach for evaluating the inputs to probabilistic risk assessments. The U.S. EPA Office of Emergency and Remedial Response (OERR) recently released Volume 3 Part A of Risk Assessment Guidance for Superfund (RAGS), as an update to the existing two-volume set of RAGS. The update provides policy and technical guidance on performing probabilistic risk assessment (PRA). Consequently, EPA risk managers and decision-makers need to review and evaluate the adequacy of PRAs for supporting regulatory decisions. A critical part of evaluating a PRA is the problem of evaluating or judging the adequacy of input distributions PRA. Although the overarching theme of this report is the need to improve the ease and consistency of the regulatory review process, the specific objectives are presented in two parts. The objective of Part 1 is to develop a consistent yet flexible process for evaluating distributions in a PRA by identifying the critical attributes of an exposure factor distribution and discussing how these attributes relate to the task-specific adequacy of the input. This objective is carried out with emphasis on the perspective of a risk manager or decision-maker. The proposed evaluation procedure provides consistency to the review process without a loss of flexibility. As a result, the approach described in Part 1 provides an opportunity to apply a single review framework for all EPA regions and yet provide the regional risk manager with the flexibility to deal with site- and case-specific issues in the PRA process. However, as the number of inputs to a PRA increases, so does the complexity of the process for calculating, communicating and managing risk. As a result, there is increasing effort required of both the risk professionals performing the analysis and the risk manager

  19. Infrastructure of Baltic Region Transmission System: Analysis of Technical and Economic Factors of its Development

    NASA Astrophysics Data System (ADS)

    Obushevs, A.; Oleinikova, I.; Mutule, A.

    2014-08-01

    The operational conditions of new networks dictate new requirements for the transmission planning, which would include the electricity market figures and a sizable involvement of renewable generation. This paper focuses on the transmission expansion planning techniques based on the calculations of optimal power flows and on the concept of development planning and sustainability. A description is given for the mathematical model of calculations and analysis of transmission system. The results have shown that the Baltic transmission system infrastructure can successfully be analyzed based on the proposed methodology and developed mathematical model Baltijas valstu (Latvijas, Lietuvas un Igaunijas) energosistēmas ir cieši saistītas vēsturiski, un to darbība nav iespējama bez savstarpējas sadarbības attīstības un darba režīmu jautājumos. Ekonomisko attiecību īstenošanu enerģētikas sektorā paātrināja elektroenerģijas tirgus attīstība. Baltijas valstu enerģētikas politika ir integrēta ES enerģētikas stratēģijas sastāvdaļa, nosakot trīs galvenos mērķus: enerģētikas nozares konkurētspēja, ilgtspējīga attīstība un drošība. Visas trīs Baltijas energosistēmas veica lielu darba apjomu iekārtu modernizācijā un standartu saskaņošanā, kuras ir saskaņā ar Eiropas Savienības prasībām, kā arī par tirgus attiecību un tehnoloģiju standartu ieviešanu, lai nodrošinātu energoapgādes drošību un elektroenerģijas pieejamību patērētājiem Tomēr, ņemot vērā strauji mainīgos ārējos apstākļus, it īpaši ģeopolitiskos faktorus, Baltijas valstu enerģētikas politika būtu jāizskata ar mērķi novērtēt, kā šie faktori ietekmē energosistēmas ilgtspējīgu attīstību kopumā. No iepriekš minētā izriet, ka nepieciešama jauna nacionāla enerģētikas stratēģija, kura stiprinātu efektīvu ekonomisko un sociālo pamatu ilgtspējīgu attīstību Baltijas valstu nacionālā ekonomikā. Šī darba m

  20. An ecodesign method for reducing the effects of hazardous substances in the product lifecycle

    NASA Astrophysics Data System (ADS)

    Simanovska, J.; Valters, K.; Bažbauers, G.; Luttropp, C.

    2012-10-01

    ārtējo vidi novēršanu. Tāpēc radīta jauna, daļēji kvantitatīva ekodizaina metode, apvienojot produktu izstrādes prasības ar zinātniskā ķīmiskā riska novērtēšanas principiem, kas piedāvā bīstamo īpašību prioritizēšanu, izmantojot Globāli harmonizētās sistēmas ķīmisko vielu klasifikācijas kodus, kā arī iedarbības un materiālu efektivitātes aspektu prioritizēšanu. Metode tika aprobēta, demonstrējot tās izmantošanu. Metode ļauj produkta izstrādātājam identificēt pārmaiņu nepieciešamību, izstrādāt ekodizaina priekšlikumus, izvērtēt alternatīvas, un palīdz uzlabot saziņu par materiālu īpašībām un ietekmi uz vidi un cilvēka veselību izejvielu un produktu piegādes ķēdē.

  1. Fragility Analysis Methodology for Degraded Structures and Passive Components in Nuclear Power Plants - Illustrated using a Condensate Storage Tank

    SciTech Connect

    Nie, J.; Braverman, J.; Hofmayer, C.; Choun, Y.; Kim, M.; Choi, I.

    2010-06-30

    The Korea Atomic Energy Research Institute (KAERI) is conducting a five-year research project to develop a realistic seismic risk evaluation system which includes the consideration of aging of structures and components in nuclear power plants (NPPs). The KAERI research project includes three specific areas that are essential to seismic probabilistic risk assessment (PRA): (1) probabilistic seismic hazard analysis, (2) seismic fragility analysis including the effects of aging, and (3) a plant seismic risk analysis. Since 2007, Brookhaven National Laboratory (BNL) has entered into a collaboration agreement with KAERI to support its development of seismic capability evaluation technology for degraded structures and components. The collaborative research effort is intended to continue over a five year period. The goal of this collaboration endeavor is to assist KAERI to develop seismic fragility analysis methods that consider the potential effects of age-related degradation of structures, systems, and components (SSCs). The research results of this multi-year collaboration will be utilized as input to seismic PRAs. In the Year 1 scope of work, BNL collected and reviewed degradation occurrences in US NPPs and identified important aging characteristics needed for the seismic capability evaluations. This information is presented in the Annual Report for the Year 1 Task, identified as BNL Report-81741-2008 and also designated as KAERI/RR-2931/2008. The report presents results of the statistical and trending analysis of this data and compares the results to prior aging studies. In addition, the report provides a description of U.S. current regulatory requirements, regulatory guidance documents, generic communications, industry standards and guidance, and past research related to aging degradation of SSCs. In the Year 2 scope of work, BNL carried out a research effort to identify and assess degradation models for the long-term behavior of dominant materials that are

  2. IMPLEMENTING THE NFPA 805 PROCESS: Observations of a Technical Reviewer

    SciTech Connect

    Short, Steven M.; Coles, Garill A.; Bohlander, Karl L.; Layton, Robert F.; Ivans, William J.; dePeralta, Fleurdeliza A.; Lowry, Peter P.

    2015-04-26

    submittals, PNNL is in a position to observe the array of implementation tactics taken in these submittals, and observe different ways licensees are making the NFPA 805 process work. For example, we see differences in how fire areas are being transitioned, the kinds of plant modifications being implemented, the changes being made to plant procedures, the number and types of recovery actions being credited, and the kinds and extent of detailed modeling being performed in support of the Fire PRAs. As a caveat, we note that it is probably too early to comment on the overall success or limitations of the NFPA 805 process or provide lessons learned for the future. Furthermore, it is not our intention to endorse any particular approach taken in a submittal over another or to critique the industry or the regulator. Rather our goal in this paper is to summarize a set of interesting and useful differences across submittals that may provide context for further future discussions about what we (i.e., reviewers, industry, and regulators) have learned in being part of the NFPA process; and how to best use that information to inform future NFPA 805 activities or other risk-informed endeavors.

  3. Methods and strategies for future reactor safety goals

    NASA Astrophysics Data System (ADS)

    Arndt, Steven Andrew

    There have been significant discussions over the past few years by the United States Nuclear Regulatory Commission (NRC), the Advisory Committee on Reactor Safeguards (ACRS), and others as to the adequacy of the NRC safety goals for use with the next generation of nuclear power reactors to be built in the United States. The NRC, in its safety goals policy statement, has provided general qualitative safety goals and basic quantitative health objectives (QHOs) for nuclear reactors in the United States. Risk metrics such as core damage frequency (CDF) and large early release frequency (LERF) have been used as surrogates for the QHOs. In its review of the new plant licensing policy the ACRS has looked at the safety goals, as has the NRC. A number of issues have been raised including what the Commission had in mind when it drafted the safety goals and QHOs, how risk from multiple reactors at a site should be combined for evaluation, how the combination of a new and old reactor at the same site should be evaluated, what the criteria for evaluating new reactors should be, and whether new reactors should be required to be safer than current generation reactors. As part of the development and application of the NRC safety goal policy statement the Commissioners laid out the expectations for the safety of a nuclear power plant but did not address the risk associated with current multi-unit sites, potential modular reactor sites, and hybrid sites that could contain current generation reactors, new passive reactors, and/or modular reactors. The NRC safety goals and the QHOs refer to a "nuclear power plant," but do not discuss whether a "plant" refers to only a single unit or all of the units on a site. There has been much discussion on this issue recently due to the development of modular reactors. Additionally, the risk of multiple reactor accidents on the same site has been largely ignored in the probabilistic risk assessments (PRAs) done to date, and in most risk

  4. Power Generation Investment Planning in a Modern Power System With High Share of Renewables

    NASA Astrophysics Data System (ADS)

    Oleinikova, I.; Ruksans, O.; Turcik, M.

    2014-04-01

    enerācijas tehnoloģijas izmaksu novērtēšana; - elektrostaciju ģenerācijas īstermiņa un ilgtermiņa izmaksu novērtēšana; - elektrostaciju ģenerācijas investīciju un vadības izmaksu novērtēšana; - dažādu ģenerācijas tehnoloģiju izmaksu skaitliskie aprēķini un analīze. Īpaša uzmanība veltīta investīciju plānošanai elektroenerģijas ražošanas nozarē liberalizēta tirgus apstākļos; tika izanalizēti efektīvie instrumenti, izmaksu metodes un ekonomiskās efektivitātes novērtēšanas nozīme dažāda tipa ģenerējošām jaudām un tās atbilstība mūsdienu elektroapgādes sistēmas prasībām

  5. Greenhouse Gas Emission Reduction Due to Improvement of Biodegradable Waste Management System

    NASA Astrophysics Data System (ADS)

    Bendere, R.; Teibe, I.; Arina, D.; Lapsa, J.

    2014-12-01

    ārdāmo atkritumu apsaimniekošanas statistikas datu novērtējums atbilstoši likumdošanas prasībām. Izmantojot matemātisko modelēšanas programmu WAMPS, analizēti trīs dažādi bioloģisko noārdāmo atkritumu apsaimniekošanas scenāriji, kuriem veikts vides ietekmes novērtējums, kas izteikts klimata pārmaiņu potenciālā - tonnas CO2 ekv. Darbā secināts, ka lielākais siltumnīcefektu (SEG) avots atkritumu apsaimniekošanas ir atkritumu poligoni (Bāzes scenārijs), ko galvenokārt ietekmē CH4 rašanās, organiskajiem atkritumiem sadaloties anaerobos apstākļos. Būtisku pozitīvo efektu SEG emisiju samazināšanā dod atkritumu pārstrāde otrreizējās izejvielās un sadedzināšana cementa ražotnē, kas ļauj samazināt dabīgo izejmateriālu un fosilo enerģijas resursu patēriņu. Attīstot pārtikas atkritumu pārstrādi biogāzē, lietderīgi veidot alternatīvās vai izmantot esošās sistēmas, kas nodrošina iegūtās enerģijas un digestāta patēriņu, t.i lauksaimniecība, transports vai komunālie pakalpojumi. Lai no zaļajiem dārza atkritumiem iegūtu augstvērtīgu kompostu, valstī jārada tam nepieciešami likumdošanas un ekonomiskie instrumenti, kas veicina komposta tirgus attīstību.