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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. PRAS40 plays a pivotal role in protecting against stroke by linking the Akt and mTOR pathways.

    PubMed

    Xiong, Xiaoxing; Xie, Rong; Zhang, Hongfei; Gu, Lijuan; Xie, Weiying; Cheng, Michelle; Jian, Zhihong; Kovacina, Kristina; Zhao, Heng

    2014-06-01

    The proline-rich Akt substrate of 40kDa (PRAS40) protein is not only a substrate of the protein kinase Akt but also a component of the mTOR complex 1 (mTORC1), thus it links the Akt and the mTOR pathways. We investigated the potential protective role of PRAS40 in cerebral ischemia and its underlying mechanisms by using rats with lentiviral over-expression of PRAS40 and mice with PRAS40 gene knockout (PRAS40 KO). Our results show that gene transfer of PRAS40 reduced infarction size in rats by promoting phosphorylation of Akt, FKHR (FOXO1), PRAS40, and mTOR. In contrast, PRAS40 KO increased infarction size. Although the PRAS40 KO under normal condition did not alter baseline levels of phosphorylated proteins in the Akt and mTOR pathways, PRAS40 KO that underwent stroke exhibited reduced protein levels of p-S6K and p-S6 in the mTOR pathway but not p-Akt, or p-PTEN in the Akt pathway. Furthermore, co-immunoprecipitation suggests that there were less interactive effects between Akt and mTOR in the PRAS40 KO. In conclusion, PRAS40 appears to reduce brain injury by converting cell signaling from Akt to mTOR. Copyright © 2014. Published by Elsevier Inc.

  3. PRAS40 ACTS AS A NODAL REGULATOR OF HIGH GLUCOSE-INDUCED TORC1 ACTIVATION IN GLOMERULAR MESANGIAL CELL HYPERTROPHY

    PubMed Central

    Dey, Nirmalya; Ghosh-Choudhury, Nandini; Das, Falguni; Li, Xiaonan; Venkatesan, Balachandar; Barnes, Jeffrey L.; Kasinath, Balakuntalam S.; Choudhury, Goutam Ghosh

    2010-01-01

    Diabetic nephropathy manifests aberrant activation of TORC1, which senses key signals to modulate protein synthesis and renal hypertrophy. PRAS40 has recently been identified as a raptor-interacting protein and is a component and a constitutive inhibitor of TORC1. The mechanism by which high glucose stimulates TORC1 activity is not known. PRAS40 was identified in the mesangial cells in renal glomeruli and in tubulointerstitium of rat kidney. Streptozotocin-induced diabetic renal hypertrophy was associated with phosphorylation of PRAS40 in the cortex and glomeruli. In vitro, high glucose concentration increased PRAS40 phosphorylation in a PI 3 kinase- and Akt-dependent manner, resulting in dissociation of raptor-PRAS40 complex in mesangial cells. High glucose augmented the inactivating and activating phosphorylation of 4EBP-1 and S6 kinase, respectively with concomitant induction of protein synthesis and hypertrophy. Expression of TORC1-nonphosphorylatable mutant of 4EBP-1 and dominant negative S6 kinase significantly inhibited high glucose-induced protein synthesis and hypertrophy. PRAS40 knockdown mimicked the effect of high glucose on phosphorylation of 4EBP-1 and S6 kinase, protein synthesis and hypertrophy. To elucidate the role of PRAS40 phosphorylation, we used phosphorylation-deficient mutant of PRAS40, which in contrast to PRAS40 knockdown inhibited phosphorylation of 4EBP-1 and S6 kinase, leading to reduced mesangial cell hypertrophy. Thus our data identify high glucose-induced phosphorylation and inactivation of PRAS40 as a central node for mesangial cell hypertrophy in diabetic nephropathy. PMID:20629086

  4. 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 .

  5. Alcohol and PRAS40 Knockdown Decrease mTOR Activity and Protein Synthesis via AMPK Signaling and Changes in mTORC1 Interaction

    PubMed Central

    Hong-Brown, Ly Q.; Brown, C. Randell; Kazi, Abid A.; Huber, Danuta S.; Pruznak, Anne M.; Lang, Charles H.

    2013-01-01

    The mTORC1 protein kinase complex consists of mTOR, raptor, mLST8/GβL and PRAS40. Previously, we reported that mTOR plays an important role in regulating protein synthesis in response to alcohol (EtOH). However, the mechanisms by which EtOH regulates mTORC1 activity have not been established. Here, we investigated the effect of EtOH on the phosphorylation and interaction of components of mTORC1 in C2C12 myocytes. We also examined the specific role that PRAS40 plays in this process. Incubation of myocytes with EtOH (100 mM, 24 h) increased raptor and PRAS40 phosphorylation. Likewise, there were increased levels of the PRAS40 upstream regulators Akt and IRS-1. EtOH also caused changes in mTORC1 protein-protein interactions. EtOH enhanced the binding of raptor and PRAS40 with mTOR. These alterations occurred in concert with increased binding of 14-3-3 to raptor, while the PRAS40 and 14-3-3 interaction was not affected. The shRNA knockdown (KD) of PRAS40 decreased protein synthesis similarly to EtOH. PRAS40 KD increased raptor phosphorylation and its association with 14-3-3, while it decreased GβL-mTOR binding. The effects of EtOH and PRAS40 KD were mediated by AMPK. Both factors increased in vitro AMPK activity towards the substrate raptor. In addition, knockdown enhanced the activity of AMPK towards TSC2. Collectively, our results indicate that EtOH stabilizes the association of raptor, PRAS40 and GβL with mTOR, while likewise increasing the interaction of raptor with 14-3-3. These data suggest a possible mechanism for the inhibitory effects of EtOH on mTOR kinase activity and protein synthesis in myocytes. PMID:20127721

  6. Emory University: "LC-MS analysis of PRAS40 protein-protein interactions" | Office of Cancer Genomics

    Cancer.gov

    This study focuses on subcellular localization and interactome of nuclear PRAS40 in HeLa cells.  Read the abstract.  Experimental Approaches Read the detailed Experimental Approaches. If you cannot access the manuscript, or if you have additional questions, please email Andrei Ivanov.

  7. Incorporation of Markov reliability models for digital instrumentation and control systems into existing PRAs

    SciTech Connect

    Bucci, P.; Mangan, L. A.; Kirschenbaum, J.; Mandelli, D.; Aldemir, T.; Arndt, S. A.

    2006-07-01

    Markov models have the ability to capture the statistical dependence between failure events that can arise in the presence of complex dynamic interactions between components of digital instrumentation and control systems. One obstacle to the use of such models in an existing probabilistic risk assessment (PRA) is that most of the currently available PRA software is based on the static event-tree/fault-tree methodology which often cannot represent such interactions. We present an approach to the integration of Markov reliability models into existing PRAs by describing the Markov model of a digital steam generator feedwater level control system, how dynamic event trees (DETs) can be generated from the model, and how the DETs can be incorporated into an existing PRA with the SAPHIRE software. (authors)

  8. Uric acid priming in human monocytes is driven by the AKT-PRAS40 autophagy pathway.

    PubMed

    Crişan, Tania O; Cleophas, Maartje C P; Novakovic, Boris; Erler, Kathrin; van de Veerdonk, Frank L; Stunnenberg, Hendrik G; Netea, Mihai G; Dinarello, Charles A; Joosten, Leo A B

    2017-05-23

    Metabolic triggers are important inducers of the inflammatory processes in gout. Whereas the high serum urate levels observed in patients with gout predispose them to the formation of monosodium urate (MSU) crystals, soluble urate also primes for inflammatory signals in cells responding to gout-related stimuli, but also in other common metabolic diseases. In this study, we investigated the mechanisms through which uric acid selectively lowers human blood monocyte production of the natural inhibitor IL-1 receptor antagonist (IL-1Ra) and shifts production toward the highly inflammatory IL-1β. Monocytes from healthy volunteers were first primed with uric acid for 24 h and then subjected to stimulation with lipopolysaccharide (LPS) in the presence or absence of MSU. Transcriptomic analysis revealed broad inflammatory pathways associated with uric acid priming, with NF-κB and mammalian target of rapamycin (mTOR) signaling strongly increased. Functional validation did not identify NF-κB or AMP-activated protein kinase phosphorylation, but uric acid priming induced phosphorylation of AKT and proline-rich AKT substrate 40 kDa (PRAS 40), which in turn activated mTOR. Subsequently, Western blot for the autophagic structure LC3-I and LC3-II (microtubule-associated protein 1A/1B-light chain 3) fractions, as well as fluorescence microscopy of LC3-GFP-overexpressing HeLa cells, revealed lower autophagic activity in cells exposed to uric acid compared with control conditions. Interestingly, reactive oxygen species production was diminished by uric acid priming. Thus, the Akt-PRAS40 pathway is activated by uric acid, which inhibits autophagy and recapitulates the uric acid-induced proinflammatory cytokine phenotype.

  9. mTORC1 Coordinates Protein Synthesis and Immunoproteasome Formation via PRAS40 to Prevent Accumulation of Protein Stress.

    PubMed

    Yun, Young Sung; Kim, Kwan Hyun; Tschida, Barbara; Sachs, Zohar; Noble-Orcutt, Klara E; Moriarity, Branden S; Ai, Teng; Ding, Rui; Williams, Jessica; Chen, Liqiang; Largaespada, David; Kim, Do-Hyung

    2016-02-18

    Reduction of translational fidelity often occurs in cells with high rates of protein synthesis, generating defective ribosomal products. If not removed, such aberrant proteins can be a major source of cellular stress causing human diseases. Here, we demonstrate that mTORC1 promotes the formation of immunoproteasomes for efficient turnover of defective proteins and cell survival. mTORC1 sequesters precursors of immunoproteasome β subunits via PRAS40. When activated, mTORC1 phosphorylates PRAS40 to enhance protein synthesis and simultaneously to facilitate the assembly of the β subunits for forming immunoproteasomes. Consequently, the PRAS40 phosphorylations play crucial roles in clearing aberrant proteins that accumulate due to mTORC1 activation. Mutations of RAS, PTEN, and TSC1, which cause mTORC1 hyperactivation, enhance immunoproteasome formation in cells and tissues. Those mutations increase cellular dependence on immunoproteasomes for stress response and survival. These results define a mechanism by which mTORC1 couples elevated protein synthesis with immunoproteasome biogenesis to protect cells against protein stress. Copyright © 2016 Elsevier Inc. All rights reserved.

  10. Integron-containing IncU R plasmids pRAS1 and pAr-32 from the fish pathogen Aeromonas salmonicida.

    PubMed

    Sørum, Henning; L'Abée-Lund, Trine M; Solberg, Asta; Wold, Anette

    2003-04-01

    A 45-kb R plasmid, pRAS1, that confers resistance to tetracyclines, trimethoprim, and sulfonamides was isolated in 1989 from an atypical strain of the fish pathogen Aeromonas salmonicida. This plasmid could be transferred by conjugation to Escherichia coli with a high degree of efficiency (frequency, 0.48). The following year pRAS1 was isolated from A. salmonicida subsp. salmonicida in the same area. Incompatibility group U plasmid pRAS1 contained a drug resistance-determining region of 12 kb consisting of a class 1 integron similar to In4 of Tn1696 but with a dfrA16 gene cassette inserted. Close to IS6100 at the right end of Tn4 was a truncated Tn1721. Restriction enzyme analysis showed that R plasmid pAr-32, isolated from A. salmonicida in Japan in 1970, had the same backbone structure as pRAS1, while the drug resistance-determining region contained a complex class 1 integron with an aadA2 cassette; the chloramphenicol resistance gene catA2, as in In6 of pSa; and a duplicate of the 3' conserved segment of the integron.

  11. Automated quantitative multiplex immunofluorescence in situ imaging identifies phospho-S6 and phospho-PRAS40 as predictive protein biomarkers for prostate cancer lethality

    PubMed Central

    2014-01-01

    Background We have witnessed significant progress in gene-based approaches to cancer prognostication, promising early intervention for high-risk patients and avoidance of overtreatment for low-risk patients. However, there has been less advancement in protein-based approaches, even though perturbed protein levels and post-translational modifications are more directly linked with phenotype. Most current, gene expression-based platforms require tissue lysis resulting in loss of structural and molecular information, and hence are blind to tumor heterogeneity and morphological features. Results Here we report an automated, integrated multiplex immunofluorescence in situ imaging approach that quantitatively measures protein biomarker levels and activity states in defined intact tissue regions where the biomarkers of interest exert their phenotype. Using this approach, we confirm that four previously reported prognostic markers, PTEN, SMAD4, CCND1 and SPP1, can predict lethal outcome of human prostate cancer. Furthermore, we show that two PI3K pathway-regulated protein activities, pS6 (RPS6-phosphoserines 235/236) and pPRAS40 (AKT1S1-phosphothreonine 246), correlate with prostate cancer lethal outcome as well (individual marker hazard ratios of 2.04 and 2.03, respectively). Finally, we incorporate these 2 markers into a novel 5-marker protein signature, SMAD4, CCND1, SPP1, pS6, and pPRAS40, which is highly predictive for prostate cancer-specific death. The ability to substitute PTEN with phospho-markers demonstrates the potential of quantitative protein activity state measurements on intact tissue. Conclusions In summary, our approach can reproducibly and simultaneously quantify and assess multiple protein levels and functional activities on intact tissue specimens. We believe it is broadly applicable to not only cancer but other diseases, and propose that it should be well suited for prognostication at early stages of pathogenesis where key signaling protein levels and

  12. Impact of antibiotic treatments on the expression of the R plasmid tra genes and on the host innate immune activity during pRAS1 bearing Aeromonas hydrophila infection in zebrafish (Danio rerio)

    PubMed Central

    2012-01-01

    Background The transfer of R plasmids between bacteria has been well studied under laboratory conditions and the transfer frequency has been found to vary between plasmids and under various physical conditions. For the first time, we here study the expression of the selected plasmid mobility genes traD, virB11 and virD4 in the 45 kb IncU plasmid, pRAS1, conferring resistance to tetracycline, trimethoprim and sulphonamide, using an in vivo zebrafish infection- treatment model. Results Three days after oral infection of adult zebrafish with Aeromonas hydrophila harboring pRAS1, elevated expression of pro-inflammatory cytokine (TNF α, IL-1β and IL-8) and complement C3 genes in the intestine coincided with disease symptoms. Tetracycline, trimethoprim and an ineffective concentration of flumequine given 48 h prior to sampling, strongly increased expression of plasmid mobility genes, whereas an effective dosage of flumequine resulted in lower levels of mRNA copies of these genes relative to placebo treatment. Following effective treatment with flumequine, and ineffective treatments with a low concentration of flumequine, with trimethoprim or with sulphonamide, the intestinal expression of immune genes was strongly induced compared to placebo treated control fish. Conclusions Treatment of zebrafish infected with an antibiotic resistant (TcR, TmR, SuR) A. hydrophila with ineffective concentrations of flumequine or the ineffective antimicrobials tetracycline and trimethoprim strongly induced expression of genes mediating conjugative transfer of the R-plasmid pRAS1. Simultaneously, there was a strong induction of selected inflammatory and immune response genes, which was again evident in fish subjected to ineffective treatment protocols. Our findings point to the essential role of therapeutic practices in escalation or control of antibiotic resistance transfer, and suggest that antibiotic substances, even in sub-inhibitory concentrations, may stimulate innate defenses

  13. 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

  14. 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.

  15. Materials Data on PrAs (SG:225) by Materials Project

    SciTech Connect

    Kristin Persson

    2015-02-09

    Computed materials data using density functional theory calculations. These calculations determine the electronic structure of bulk materials by solving approximations to the Schrodinger equation. For more information, see https://materialsproject.org/docs/calculations

  16. Materials Data on PrAs (SG:123) by Materials Project

    SciTech Connect

    Kristin Persson

    2016-09-21

    Computed materials data using density functional theory calculations. These calculations determine the electronic structure of bulk materials by solving approximations to the Schrodinger equation. For more information, see https://materialsproject.org/docs/calculations

  17. Peer research assistantships and the ethics of reciprocity in community-based research.

    PubMed

    Greene, Saara

    2013-04-01

    A major component of community-based research (CBR) in the field of HIV is the Meaningful Involvement of People Living with HIV/AIDS (MIPA) through hiring, training, and supporting peer research assistants (PRAs). CBR researchers and PRAs have begun to dialogue about the successes and challenges associated with peer research assistantships as they attempt to address the range of ethical issues that impact the PRAs' experience at different stages throughout the research process. I discuss some of the ethical tensions related to the PRA/researcher relationship, the relationship of the PRA to the research itself, and suggestions for how to move forward in addressing these tensions.

  18. Overview of methodology used for NUREG-1150 risk analyses

    SciTech Connect

    Bergeron, E.D.; Breeding, R.J.; Helton, J.C.

    1988-01-01

    Five probabilistic risk assessment (PRAs) form the basis for the conclusions in the recent Nuclear Regulatory Commission's report ''Severe Accident Risks: An Assessment for Five US Nuclear Power Plants'' (NUREG-1150). Four of the five PRAs were conducted at Sandia National Laboratories (SNL); the fifth was conducted at Idaho National Engineering Laboratory and Brookhaven National Laboratory. The analysis methods used for the risk analyses were developed at SNL. This paper describes those methods and how they differ from methods used in other PRAs. 16 refs., 2 figs., 1 tab.

  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. Opportunities, ethical challenges, and lessons learned from working with peer research assistants in a multi-method HIV community-based research study in Ontario, Canada.

    PubMed

    Logie, Carmen; James, Llana; Tharao, Wangari; Loutfy, Mona R

    2012-10-01

    We discuss ethical challenges and opportunities experienced by peer research assistants (PRAs) in a multi-method HIV community-based research study in Ontario, Canada. We review lessons learned and best practices based on our experience conducting a qualitative investigation of research priorities with diverse women living with HIV (WLWH) and implementation of a cross-sectional survey with African, Caribbean, and Black WLWH. While some opportunities were similar across research phases for PRAs (e.g., skill building), distinct challenges emerged in qualitative and quantitative phases. For example, our training did not adequately prepare PRAs with focus group facilitation skills; at times, survey implementation became counseling sessions. Researchers should assess how best to support PRAs as part of multi-method research processes.

  1. The role of NUREG-1150 in accident management

    SciTech Connect

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

    1988-01-01

    The NUREG-1150 report is being prepared by the US Nuclear Regulatory Commission 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 provided a framework for evaluating accident management alternatives from a risk standpoint. This paper describes the accident management benefits that NUREG-1150 is providing.

  2. 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.

  3. 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.

  4. The mechanism of insulin-stimulated 4E-BP protein binding to mammalian target of rapamycin (mTOR) complex 1 and its contribution to mTOR complex 1 signaling.

    PubMed

    Rapley, Joseph; Oshiro, Noriko; Ortiz-Vega, Sara; Avruch, Joseph

    2011-11-04

    Insulin activation of mTOR complex 1 is accompanied by enhanced binding of substrates. We examined the mechanism and contribution of this enhancement to insulin activation of mTORC1 signaling in 293E and HeLa cells. In 293E, insulin increased the amount of mTORC1 retrieved by the transiently expressed nonphosphorylatable 4E-BP[5A] to an extent that varied inversely with the amount of PRAS40 bound to mTORC1. RNAi depletion of PRAS40 enhanced 4E-BP[5A] binding to ∼70% the extent of maximal insulin, and PRAS40 RNAi and insulin together did not increase 4E-BP[5A] binding beyond insulin alone, suggesting that removal of PRAS40 from mTORC1 is the predominant mechanism of an insulin-induced increase in substrate access. As regards the role of increased substrate access in mTORC1 signaling, RNAi depletion of PRAS40, although increasing 4E-BP[5A] binding, did not stimulate phosphorylation of endogenous mTORC1 substrates S6K1(Thr(389)) or 4E-BP (Thr(37)/Thr(46)), the latter already ∼70% of maximal in amino acid replete, serum-deprived 293E cells. In HeLa cells, insulin and PRAS40 RNAi also both enhanced the binding of 4E-BP[5A] to raptor but only insulin stimulated S6K1 and 4E-BP phosphorylation. Furthermore, Rheb overexpression in 293E activated mTORC1 signaling completely without causing PRAS40 release. In the presence of Rheb and insulin, PRAS40 release is abolished by Akt inhibition without diminishing mTORC1 signaling. In conclusion, dissociation of PRAS40 from mTORC1 and enhanced mTORC1 substrate binding results from Akt and mTORC1 activation and makes little or no contribution to mTORC1 signaling, which rather is determined by Rheb activation of mTOR catalytic activity, through mechanisms that remain to be fully elucidated.

  5. Rationale, design, and baseline data of a cross-national randomized trial on the effect of built shade in public parks for sun protection.

    PubMed

    Buller, David B; Dobbinson, Suzanne; English, Dallas R; Wakefield, Melanie; Buller, Mary Klein

    2017-04-01

    Environments can be structured to reduce solar ultraviolet radiation (UV) exposure to prevent skin cancer. A prospective randomized trial is being conducted to test whether introducing shade sails in passive recreation areas (PRAs) in public parks will increase use and decrease UV exposure in the shaded compared to unshaded PRAs. Shade effects will be compared between Melbourne, Australia and Denver, USA. The trial enrolled 145 public parks with PRAs suitable for shade construction and randomized parks to intervention or control in a 1:3 ratio. Use of PRAs and UV levels were recorded at each park by trained observers during 30-minute periods on four weekend days in each of two summers (pretest and posttest). Shade sails were constructed between the summers. Given low numbers of users at pretest, the outcome measure was modified to use of the PRA (use vs. no use) and unit of analysis to the individual observation. Observations (n=580) occurred on average 29days from the summer solstice and 55min from solar noon in warm weather (mean=26.2°C) with some cloud cover but only slight or no wind. Typically, PRAs had benches and picnic tables and were located near playgrounds. PRAs were in use during 13.3% of observations (mean=0.41 users). UV over 30-minutes at the PRA boundary (mean=3.2 standard erythemal dose [SED]) and center (mean=3.3 SED) was high. Shade for skin cancer prevention has been understudied. This study will address this gap by determining whether purpose-built shade structures promote greater use of shaded areas within public parks. Copyright © 2017 Elsevier Inc. All rights reserved.

  6. Reflections on the role of the pharmacy regulatory authority in enhancing quality related event reporting in community pharmacies.

    PubMed

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

    2014-01-01

    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. This study was aimed to gain a better understanding of the perceived roles of PRAs in enhancing QRE reporting and learning in community pharmacies, and identifying regulatory best practices to execute such roles. 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. 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. 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 help to mitigate this conflict

  7. 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

  8. 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.

  9. Engine Response to Distorted Inflow Conditions: Conference Proceedings of the Propulsion and Energetics Specialists’ Meeting (68th) Held in Munich, Germany on 8-9 September 1986.

    DTIC Science & Technology

    1987-03-01

    e3l. 041 CIRCUMFERENTIAL LOCATION (DEGREES) FIGURE 3b ARP1420 TOTAL PRESSURE DISTORTION ELEMENTS (2) RING RADIAL DISTORTION ELEMENTS ,( PrA ) - (PAV) i...d’alirsestation, Os fooctionnant pras de Is Liatte do d~crochage, A forte contrepresaton et A faihie d~bit, dana une zone o de faibies perturbations...et l’tcart flux-profiL (0 one consante engutaire pras ) en sortie d’aubagen. tine dernl~re relation sur L𔄀voiutios radile den lignen de courant A La

  10. Modified periodontal risk assessment score: long-term predictive value of treatment outcomes. A retrospective study.

    PubMed

    Leininger, Matthieu; Tenenbaum, Henri; Davideau, Jean-Luc

    2010-05-01

    The aim of this study was to evaluate the long-term clinical predictive value of the periodontal risk assessment diagram surface (PRAS) score and the influence of patient compliance on the treatment outcomes. Thirty subjects suffering from periodontitis were re-examined 6-12 years after the initial diagnosis and periodontal treatments. The baseline PRAS score was calculated from the initial clinical and radiograph records. Patients were then classified into a low-to-moderate (0-20) or a high-risk group (>20). Patients who did not attend any supportive periodontal therapy were classified into a non-compliant group. PRAS and compliance were correlated to the mean tooth loss (TL)/year and the mean variation in the number of periodontal pockets with a probing depth (PPD) >4 mm. TL was 0.11 for the low-to-moderate-risk group and 0.26 for the high-risk group (p<0.05); PPD number reduction was 2.57 and 2.17, respectively, and bleeding on probing reduction was 6.7% and 23.3%, respectively. Comparing the compliance groups, the PPD number reduction was 3.39 in the compliant group and 1.40 in the non-compliant group (p<0.05). This study showed the reliability of PRAS in evaluating long-term TL and patient susceptibility to periodontal disease. Our data confirmed the positive influence of patient compliance on periodontal treatment outcomes.

  11. 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.

  12. 76 FR 5218 - Advisory Committee on Reactor Safeguards

    Federal Register 2010, 2011, 2012, 2013, 2014

    2011-01-28

    ... COMMISSION Advisory Committee on Reactor Safeguards In accordance with the purposes of Sections 29 and 182b of the Atomic Energy Act (42 U.S.C. 2039, 2232b), the Advisory Committee on Reactor Safeguards (ACRS... Facilities and Probabilistic Risk Assessments (PRAs) for Reactors (Open)--The Committee will...

  13. Radiation-associated angiosarcoma in the setting of breast cancer mimicking radiation dermatitis: A diagnostic pitfall.

    PubMed

    Daniels, Brianne H; Ko, Jennifer S; Rowe, J Jordi; Downs-Kelly, Erinn; Billings, Steven D

    2017-05-01

    We have encountered cases of post-radiation angiosarcoma (PRAS) histologically mimicking radiation dermatitis. Cases of PRAS from institutional/consultation archives from 2006 to 2016 were reviewed. For inclusion, tumors had to have inapparent/subtle tumor at low magnification and scattered individual tumor cells resembling radiation fibroblasts. Prior ancillary studies were reviewed, with additional immunostains performed as needed. 10 cases met criteria. All occurred in women treated for breast cancer (mean age 71 years). All had similar findings: in particular, scattered single atypical cells with pleomorphic nuclei associated with microscopic hemorrhage. They also had narrow, slightly wavy "worm-like" vascular channels lined by atypical endothelial cells that lacked architectural complexity. Four cases showed focal areas of more conventional angiosarcoma. One case was an excision of a large mass that showed the "radiation dermatitis-like" pattern radiating out from the central mass. All were positive for vascular markers (CD31, CD34, and/or ERG) and MYC. MYC amplification was demonstrated by FISH in both cases tested. In 3 of 3 cases with available re-excision specimens, more obvious angiosarcoma was seen. PRAS can be very subtle and histologically mimic radiation dermatitis. Careful attention to histologic features and ancillary tests allow accurate diagnosis in subtle PRAS. © 2017 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.

  14. 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.

  15. 78 FR 14510 - Notice of Availability of New Guidelines for Pest Risk Assessments of Imported Fruits and Vegetables

    Federal Register 2010, 2011, 2012, 2013, 2014

    2013-03-06

    ... Assessments of Imported Fruits and Vegetables AGENCY: Animal and Plant Health Inspection Service, USDA. ACTION... health pest risk assessments for imported fruit and vegetable commodities. These new guidelines are...-initiated, qualitative pest risk assessments (PRAs) for imports of fruits and vegetables. A PRA is defined...

  16. The long-term outcome of treated sensitized patients who undergo heart transplantation.

    PubMed

    Kobashigawa, Jon A; Patel, Jignesh K; Kittleson, Michelle M; Kawano, Matt A; Kiyosaki, Krista K; Davis, Stephanie N; Moriguchi, Jaime D; Reed, Elaine F; Ardehali, Abbas A

    2011-01-01

    Sensitized patients prior to heart transplantation are reportedly at risk for hyperacute rejection and for poor outcome after heart transplantation. It is not known whether the reduction of circulating antibodies pre-transplant alters post-transplant outcome. Between July 1993 and July 2003, we reviewed 523 heart transplant patients of which 95 had pre-transplant panel reactive antibody (PRAs) >10%; 21/95 were treated pre-transplant for circulating antibodies. These 21 patients had PRAs > 10% (majority 50-100%) and were treated with combination therapy including plasmapheresis, intravenous gamma globulin and rituximab to reduce antibody counts. The 74 untreated patients with PRAs > 10% (untreated sensitized group) and those patients with PRAs < 10% (control group) were used for comparison. Routine post-transplant immunosuppression included triple-drug therapy. After desensitization therapy, circulating antibody levels pre-transplant decreased from a mean of 70.5 to 30.2%, which resulted in a negative prospective donor-specific crossmatch and successful heart transplantation. Compared to the untreated sensitized group and the control group, the treated sensitized group had similar five-yr survival (81.1% and 75.7% vs. 71.4%, respectively, p = 0.523) and freedom from cardiac allograft vasculopathy (74.3% and 72.7% vs. 76.2%, respectively, p = 0.850). Treatment of sensitized patients pre-transplant appears to result in acceptable long-term outcome after heart transplantation. © 2010 John Wiley & Sons A/S.

  17. The long-term outcome of treated sensitized patients who undergo heart transplantation

    PubMed Central

    Kobashigawa, Jon A.; Patel, Jignesh K.; Kittleson, Michelle M.; Kawano, Matt A.; Kiyosaki, Krista K.; Davis, Stephanie N.; Moriguchi, Jaime D.; Reed, Elaine F.; Ardehali, Abbas A.

    2013-01-01

    Background Sensitized patients prior to heart transplantation are reportedly at risk for hyperacute rejection and for poor outcome after heart transplantation. It is not known whether the reduction of circulating antibodies pre-transplant alters post-transplant outcome. Methods and Results Between July 1993 and July 2003, we reviewed 523 heart transplant patients of which 95 had pre-transplant panel reactive antibody (PRAs) >10%; 21/95 were treated pre-transplant for circulating antibodies. These 21 patients had PRAs > 10% (majority 50–100%) and were treated with combination therapy including plasmapheresis, intravenous gamma globulin and rituximab to reduce antibody counts. The 74 untreated patients with PRAs > 10% (untreated sensitized group) and those patients with PRAs < 10% (control group) were used for comparison. Routine post-transplant immunosuppression included triple-drug therapy. After desensitization therapy, circulating antibody levels pre-transplant decreased from a mean of 70.5 to 30.2%, which resulted in a negative prospective donor-specific crossmatch and successful heart transplantation. Compared to the untreated sensitized group and the control group, the treated sensitized group had similar five-yr survival (81.1% and 75.7% vs. 71.4%, respectively, p = 0.523) and freedom from cardiac allograft vasculopathy (74.3% and 72.7% vs. 76.2%, respectively, p = 0.850). Conclusion Treatment of sensitized patients pre-transplant appears to result in acceptable long-term outcome after heart transplantation. PMID:20973825

  18. 75 FR 22207 - Importation of Papayas From Colombia and Ecuador

    Federal Register 2010, 2011, 2012, 2013, 2014

    2010-04-28

    ... experience, along with our PRAs, our RMD, and our knowledge of the conditions in Colombia and Ecuador... must be halted until the rate of capture drops to an average of 7 or fewer Medflies per trap per week... papayas from that production area must be halted until the rate of capture drops to an average of 7 or...

  19. 32 CFR 1901.13 - Requirements as to identification of requester.

    Code of Federal Regulations, 2014 CFR

    2014-07-01

    ... for aliens. Only aliens lawfully admitted for permanent residence (PRAs) may file a request pursuant... required under paragraph (a) of this section, their Alien Registration Number and the date that status was... paragraph (a) or (b) of this section, evidence of such representation by submission of a certified copy...

  20. 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. © 2016 Society for Risk Analysis.

  1. 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.

  2. 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.

  3. Risk-significant functional dependencies in PWRs: Final report

    SciTech Connect

    Frank, M.V.; Fleming, K.N.

    1987-12-01

    This report was inspired by the informal observation that functional dependencies among plant systems, particularly those between frontline safety systems and support systems, are often major contributors to the risks calculated in completed PRAs. This study provides evidence that this is indeed the case and seeks to determine how the risk impact of functional dependencies can be reduced in future nuclear power plant designs. Our insights have been summarized by a set of nine design principles that are not new to the nuclear industry and, indeed, have generally been implemented. Their risk significance, however, may not have been fully appreciated in the design process because of the usual practice of not emphasizing the beyond-design basis accidents. It is in pointing out the dependencies that are important to risk that both PRAs and this study make a contribution. 1 fig., 6 tabs.

  4. Analysis of standby and demand stress failures modes. Methodology and applications to EDGs and MOVs

    SciTech Connect

    Lofgren, E.V.; Thaggard, M.

    1992-10-01

    This report describes work to develop and demonstrates methods for partitioning standby component failure modes into causes that fail the component while it is in standby, and when it changes state, during testing or from other demands. Failure of the component from standby stresses is modeled using a model that explicitly contains the length of the test interval. Failure of the component from demand stresses such as vibration, wind, etc., is modeled using the probability of failure on demand model. Misuse of these models in PRAS, could lead to PRAs that, give misleading results, or that are more useful for decision purposes. A method was developed and demonstrated to partition standby/demand stresses. The method was used on the work maintenance records from two Nuclear Power Plants (NPPs) to estimate reliability parameters for Motor Operated Valves And Emergency Diesel Generators (EDGs).

  5. Analysis of standby and demand stress failures modes

    SciTech Connect

    Lofgren, E.V.; Thaggard, M. )

    1992-10-01

    This report describes work to develop and demonstrates methods for partitioning standby component failure modes into causes that fail the component while it is in standby, and when it changes state, during testing or from other demands. Failure of the component from standby stresses is modeled using a model that explicitly contains the length of the test interval. Failure of the component from demand stresses such as vibration, wind, etc., is modeled using the probability of failure on demand model. Misuse of these models in PRAS, could lead to PRAs that, give misleading results, or that are more useful for decision purposes. A method was developed and demonstrated to partition standby/demand stresses. The method was used on the work maintenance records from two Nuclear Power Plants (NPPs) to estimate reliability parameters for Motor Operated Valves And Emergency Diesel Generators (EDGs).

  6. The perception of primary and secondary stress in English.

    PubMed

    Mattys, S L

    2000-02-01

    Most models of word recognition concerned with prosody are based on a distinction between strong syllables (containing a full vowel) and weak syllables (containing a schwa). In these models, the possibility that listeners take advantage of finer grained prosodic distinctions, such as primary versus secondary stress, is usually rejected on the grounds that these two categories are not discriminable from each other without lexical information or normalization of the speaker's voice. In the present experiment, subjects were presented with word fragments that differed only by their degree of stress--namely, primary or secondary stress (e.g.,/'prasI/vs./"prasI/). The task was to guess the origin of the fragment (e.g., "prosecutor" vs. "prosecution"). The results showed that guessing performance significantly exceeds the chance level, which indicates that making fine stress distinctions is possible without lexical information and with minimal speech normalization. This finding is discussed in the framework of prosody-based word recognition theories.

  7. 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.

  8. Scramjet Combustor Simulations Using Reduced Chemical Kinetics for Practical Fuels

    DTIC Science & Technology

    2003-12-01

    Stochastic Simulation of an HCCI Engine Using an Automatically Reduced Mechanism,� ICE, Vol. 37-2, 2001 Fall Technical Conference...Christopher J. Montgomery, and Wei Zhao Reaction Engineering International (REI) 77 West 200 South, Suite 210 Salt Lake City, UT 84101 Dean R...DOUGLAS L. DAVIS CAPT. BRIAN C. MCDONALD AFRL/PRAS, Project Engineer Branch Chief Propulsion Sciences Branch Propulsion

  9. Applications of Probabilistic Risk Assessment

    SciTech Connect

    Burns, K.J.; Chapman, J.R.; Follen, S.M.; O'Regan, P.J. )

    1991-05-01

    This report provides a summary of potential and actual applications of Probabilistic Risk Assessment (PRA) technology and insights. Individual applications are derived from the experiences of a number of US nuclear utilities. This report identifies numerous applications of PRA techniques beyond those typically associated with PRAs. In addition, believing that the future use of PRA techniques should not be limited to those of the past, areas of plant operations, maintenance, and financial resource allocation are discussed. 9 refs., 3 tabs.

  10. Taxonomic Workstation System User Guide

    DTIC Science & Technology

    1993-05-01

    any notes you may want to make about a record. 7he notes are "localized" to this template and will not show up on screan or paper printouts. - Wen done...files which then allow "one touch " access. Details are provided in Appendix I, ACSS= EXT 5 APP2ICATIaS PRAS. 52 Enterin N-B ENTERIMI NE ’TAN34CHI:ES

  11. 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?.…

  12. 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?.…

  13. DEGRADATION SUSCEPTIBILITY METRICS AS THE BASES FOR BAYESIAN RELIABILITY MODELS OF AGING PASSIVE COMPONENTS AND LONG-TERM REACTOR RISK

    SciTech Connect

    Unwin, Stephen D.; Lowry, Peter P.; Toyooka, Michael Y.; Ford, Benjamin E.

    2011-07-17

    Conventional probabilistic risk assessments (PRAs) are not well-suited to addressing long-term reactor operations. Since passive structures, systems and components are among those for which refurbishment or replacement can be least practical, they might be expected to contribute increasingly to risk in an aging plant. Yet, passives receive limited treatment in PRAs. Furthermore, PRAs produce only snapshots of risk based on the assumption of time-independent component failure rates. This assumption is unlikely to be valid in aging systems. The treatment of aging passive components in PRA does present challenges. First, service data required to quantify component reliability models are sparse, and this problem is exacerbated by the greater data demands of age-dependent reliability models. A compounding factor is that there can be numerous potential degradation mechanisms associated with the materials, design, and operating environment of a given component. This deepens the data problem since the risk-informed management of materials degradation and component aging will demand an understanding of the long-term risk significance of individual degradation mechanisms. In this paper we describe a Bayesian methodology that integrates the metrics of materials degradation susceptibility being developed under the Nuclear Regulatory Commission's Proactive Management of Materials of Degradation Program with available plant service data to estimate age-dependent passive component reliabilities. Integration of these models into conventional PRA will provide a basis for materials degradation management informed by the predicted long-term operational risk.

  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. A paramagnetic molecular voltmeter

    NASA Astrophysics Data System (ADS)

    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 p K shift of the reacted cysteine.

  16. 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

  17. Pim1 inhibition as a novel therapeutic strategy for Alzheimer's disease.

    PubMed

    Velazquez, Ramon; Shaw, Darren M; Caccamo, Antonella; Oddo, Salvatore

    2016-07-13

    Alzheimer's disease (AD) is the most prevalent neurodegenerative disorder worldwide. Clinically, AD is characterized by impairments of memory and cognitive functions. Accumulation of amyloid-β (Aβ) and neurofibrillary tangles are the prominent neuropathologies in patients with AD. Strong evidence indicates that an imbalance between production and degradation of key proteins contributes to the pathogenesis of AD. The mammalian target of rapamycin (mTOR) plays a key role in maintaining protein homeostasis as it regulates both protein synthesis and degradation. A key regulator of mTOR activity is the proline-rich AKT substrate 40 kDa (PRAS40), which directly binds to mTOR and reduces its activity. Notably, AD patients have elevated levels of phosphorylated PRAS40, which correlate with Aβ and tau pathologies as well as cognitive deficits. Physiologically, PRAS40 phosphorylation is regulated by Pim1, a protein kinase of the protoconcogene family. Here, we tested the effects of a selective Pim1 inhibitor (Pim1i), on spatial reference and working memory and AD-like pathology in 3xTg-AD mice. We have identified a Pim1i that crosses the blood brain barrier and reduces PRAS40 phosphorylation. Pim1i-treated 3xTg-AD mice performed significantly better than their vehicle treated counterparts as well as non-transgenic mice. Additionally, 3xTg-AD Pim1i-treated mice showed a reduction in soluble and insoluble Aβ40 and Aβ42 levels, as well as a 45.2 % reduction in Aβ42 plaques within the hippocampus. Furthermore, phosphorylated tau immunoreactivity was reduced in the hippocampus of Pim1i-treated 3xTg-AD mice by 38 %. Mechanistically, these changes were linked to a significant increase in proteasome activity. These results suggest that reductions in phosphorylated PRAS40 levels via Pim1 inhibition reduce Aβ and Tau pathology and rescue cognitive deficits by increasing proteasome function. Given that Pim1 inhibitors are already being tested in ongoing human clinical trials

  18. 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

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

    2016-01-01

    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. 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. 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. 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.

  19. RELIABILITY MODELS OF AGING PASSIVE COMPONENTS INFORMED BY MATERIALS DEGRADATION METRICS TO SUPPORT LONG-TERM REACTOR OPERATIONS

    SciTech Connect

    Unwin, Stephen D.; Lowry, Peter P.; Toyooka, Michael Y.

    2012-05-01

    Paper describes a methodology for the synthesis of nuclear power plant service data with expert-elicited materials degradation information to estimate the future failure rates of passive components. This method should be an important resource to long-term plant operations and reactor life extension. Conventional probabilistic risk assessments (PRAs) are not well suited to addressing long-term reactor operations. Since passive structures and components are among those for which replacement can be least practical, they might be expected to contribute increasingly to risk in an aging plant; yet, passives receive limited treatment in PRAs. Furthermore, PRAs produce only snapshots of risk based on the assumption of time-independent component failure rates. This assumption is unlikely to be valid in aging systems. The treatment of aging passive components in PRA presents challenges. Service data to quantify component reliability models are sparse, and this is exacerbated by the greater data demands of age-dependent reliability models. Another factor is that there can be numerous potential degradation mechanisms associated with the materials and operating environment of a given component. This deepens the data problem since risk-informed management of component aging will demand an understanding of the long-term risk significance of individual degradation mechanisms. In this paper we describe a Bayesian methodology that integrates metrics of materials degradation susceptibility with available plant service data to estimate age-dependent passive component reliabilities. Integration of these models into conventional PRA will provide a basis for materials degradation management informed by predicted long-term operational risk.

  20. Prasugrel in children with sickle cell disease: pharmacokinetic and pharmacodynamic data from an open-label, adaptive-design, dose-ranging study.

    PubMed

    Styles, Lori; Heiselman, Darell; Heath, Lori E; Moser, Brian A; Small, David S; Jakubowski, Joseph A; Zhou, Chunmei; Redding-Lallinger, Rupa; Heeney, Matthew M; Quinn, Charles T; Rana, Sohail R; Kanter, Julie; Winters, Kenneth J

    2015-01-01

    This phase 2 study was designed to characterize the relationship among prasugrel dose, prasugrel's active metabolite (Pras-AM), and platelet inhibition while evaluating safety in children with sickle cell disease. It was open-label, multicenter, adaptive design, dose ranging, and conducted in 2 parts. Part A: Patients received escalating single doses leading to corresponding increases in Pras-AM exposure and VerifyNow®P2Y12 (VN) platelet inhibition and decreases in VNP2Y12 reaction units and vasodilator-stimulated phosphoprotein platelet reactivity index. Part B: Patients were assigned daily doses (0.06, 0.08, and 0.12 mg/kg) based on VN pharmacodynamic measurements at the start of 2 dosing periods, each 14±4 days. Platelet inhibition was significantly higher at 0.12 mg/kg (56.3%±7.4%; least squares mean±SE) compared with 0.06 mg/kg (33.8%±7.4%) or 0.08 mg/kg (37.9%±5.6%). Patients receiving 0.12 mg/kg achieved ≥30% platelet inhibition; only 1 patient receiving 0.06 mg/kg exceeded 60% platelet inhibition. High interpatient variability in response to prasugrel and the small range of exposures precluded rigorous characterization of the relationship among dose, Pras-AM, and platelet inhibition. No hemorrhagic events occurred in Part A; 3 occurred in Part B, all mild and self-limited. Most children with sickle cell disease may achieve clinically relevant platelet inhibition with titration of daily-dose prasugrel.

  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. NUREG-1150 methodology overview

    SciTech Connect

    Jow, Hong-Nian

    1989-01-01

    The Nuclear Engineering Department of National Tsing Hua University organized a workshop on Severe Accident Management. The workshop was sponsored by Taiwan Power Company and was held at Taipei, Taiwan from July 31 to August 11, 1989. The topics covered in the workshop included the general in-vessel LWR severe accident phenomena, containment responses and performances under severe accident conditions, results of Level 1 PRAs of three Nuclear Power Plants at Taiwan, and also two lectures related to the NUREG-1150 report just published by US NRC. This presentation covers these two lectures.

  3. 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

  4. 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.

  5. 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.

  6. 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.

  7. 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.

  8. 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.

  9. 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.

  10. 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.

  11. 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.

  12. Neuroprotection of Sevoflurane Against Ischemia/Reperfusion-Induced Brain Injury Through Inhibiting JNK3/Caspase-3 by Enhancing Akt Signaling Pathway.

    PubMed

    Wen, Xiang-Ru; Fu, Yan-Yan; Liu, Hong-Zhi; Wu, Jian; Shao, Xiao-Ping; Zhang, Xun-Bao; Tang, Man; Shi, Yue; Ma, Kai; Zhang, Fang; Wang, Yi-Wen; Tang, Hui; Han, Dong; Zhang, Pu; Wang, Shu-Ling; Xu, Zhou; Song, Yuan-Jian

    2016-04-01

    In this study, we investigated the neuroprotective effect of sevoflurane against ischemic brain injury and its underlying molecular mechanisms. Transient global brain ischemia was induced by 4-vessel occlusion in adult male Sprague-Dawley rats. The rats were pretreated with sevoflurane alone or sevoflurane combined with LY294002/wortmannin (selective inhibitor of PI3K) before ischemia. Cresyl violet staining was used to examine the survival of hippocampal CA1 pyramidal neurons. Immunoblotting and immunoprecipitation were performed to measure the phosphorylation of Akt1, PRAS40, ASK1, and JNK3 and the expression of cleaved-caspase-3. The results demonstrated that a moderate dose of sevoflurane inhalation of 2% for 2 h had significant neuroprotective effects against ischemia/reperfusion induced hippocampal neuron death. Sevoflurane significantly increased Akt and PRAS40 phosphorylation and decreased the phosphorylation of ASK1 at 6 h after reperfusion and the phosphorylation of JNK3 at 3 days after reperfusion following 15 min of transient global brain ischemia. Conversely, LY294002 and wortmannin significantly inhibited the effects of sevoflurane. Taken together, the results suggest that sevoflurane could suppress ischemic brain injury by downregulating the activation of the ASK1/JNK3 cascade via increasing the phosphorylation of Akt1 during ischemia/reperfusion.

  13. Molecular markers of cancer in cartilaginous fish: immunocytochemical study of PCNA, p-53, myc and ras expression in neoplastic and hyperplastic tissues from free ranging blue sharks, Prionace glauca (L.).

    PubMed

    Borucinska, J D; Schmidt, B; Tolisano, J; Woodward, D

    2008-02-01

    Archival formalin-fixed tissues from wild-caught adult blue sharks, Prionace glauca (L.), were used for immunocytochemical detection of proliferating cell nuclear antigen (PCNA), two oncoproteins from the oncogenes c-myc and pan-ras, and a protein product from the tumour suppressor gene p-53. All sharks were caught during summer months between 2000 and 2006 by recreational fishermen off the USA coast in the northwestern Atlantic. The sharks were necropsied on landing and selected organ samples were collected into elasmobranch formalin and processed for paraffin embedding and light microscopy. Paraffin-embedded sections from collected tissue were both stained with haematoxylin and eosin and processed by immunocytochemical techniques using antibodies raised against the PCNA, p-ras, c-myc and p-53 proteins. The lesions examined in this study included two well differentiated adenomatous gastric polyps, a testicular capsular mesothelioma, a gingival fibropapilloma with elements of ameloblastoma, three liver tumours, two pericardial fibropapillomas and six cases of proliferative serositis (pericarditis and peritonitis). Normal and hyperplastic tissues from blue sharks, and human neoplastic tissues served as negative and positive controls, respectively. We detected upregulation of PCNA in many neoplastic, one dysplastic and in some hyperplastic lesions, and positive p-ras and c-myc signals in some of the neoplastic lesions. None of the examined tissues showed positive p-53 signalling. This is the first literature report on immunocytochemical detection of molecular markers of cancer in sharks and in fish of the class Chondrichthyes.

  14. Guidelines for condensed documentation of a probabilistic risk assessment. Final report

    SciTech Connect

    Dewailly, J.

    1999-01-01

    A desire to ``codify`` practices for the preparation and use of Probabilistic Risk Assessments (PRAs) is emerging in France. EDF has set itself the objective of developing PRAs that are representative of each nuclear power plant series in operation, that will produce standard results (core damage frequency, ranking of risk components, etc.), that meet the requirements of applications, and that use common tools. As PRA applications develop, it becomes even more important to ensure a consistent documentation of the PRA models for the application at hand. An important issue here is the turnover of engineers at utilities. As engineers move in and out of the utility or even the PRA group, the memory of the hidden assumptions in the PRA models must be captured reliably. That is, it must be captured in a framework that allows easy retrieval by staff who may never have participated in the original development. Condensed documentation of the main strategic choices and technical assumptions greatly facilitates the appropriation of PRA models and their use for applications. The purpose of this report is to outline four sections of the PRA condensed documentation (Sequence Development, System Analysis, Component Reliability data, Initiating Events). Each section is illustrated in its companion appendix.

  15. 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.

  16. 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.

  17. 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.

  18. 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.

  19. 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

  20. 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

  1. 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

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

    PubMed Central

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

    2016-01-01

    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

  3. Concurrent resistance and aerobic exercise stimulates both myofibrillar and mitochondrial protein synthesis in sedentary middle-aged men.

    PubMed

    Donges, Cheyne E; Burd, Nicholas A; Duffield, Rob; Smith, Greg C; West, Daniel W D; Short, Michael J; Mackenzie, Richard; Plank, Lindsay D; Shepherd, Peter R; Phillips, Stuart M; Edge, Johann A

    2012-06-01

    We determined myofibrillar and mitochondrial protein fractional synthesis rates (FSR), intramuscular signaling protein phosphorylation, and mRNA expression responses after isolated bouts of resistance exercise (RE), aerobic exercise (AE), or in combination [termed concurrent exercise (CE)] in sedentary middle-aged men. Eight subjects (age = 53.3 ± 1.8 yr; body mass index = 29.4 ± 1.4 kg·m(2)) randomly completed 8 × 8 leg extension repetitions at 70% of one repetition-maximum, 40 min of cycling at 55% peak aerobic power output (AE), or (consecutively) 50% of the RE and AE trials (CE). Biopsies were obtained (during a primed, constant infusion of l-[ring-(13)C(6)]phenylalanine) while fasted, and at 1 and 4 h following postexercise ingestion of 20 g of protein. All trials increased mitochondrial FSR above fasted rates (RE = 1.3-fold; AE = 1.5; CE = 1.4; P < 0.05), although only CE (2.2) and RE (1.8) increased myofibrillar FSR (P < 0.05). At 1 h postexercise, phosphorylation of Akt on Ser(473) (CE = 7.7; RE = 4.6) and Thr(308) (CE = 4.4; RE = 2.9), and PRAS40 on Thr(246) (CE = 3.8; AE = 2.5) increased (P < 0.05), with CE greater than AE for Akt Ser(473)-Thr(308) and greater than RE for PRAS40 (P < 0.05). Despite increased phosphorylation of Akt-PRAS40, phosphorylation of mammalian target of rapamycin (Ser(2448)) remained unchanged (P > 0.05), while rpS6 (Ser(235/236)) increased only in RE (10.4) (P < 0.05). CE and AE both resulted in increased peroxisome proliferator receptor-γ coactivator 1-α (PGC1α) expression at 1 h (CE = 2.9; AE = 2.8; P < 0.05) and 4 h (CE = 2.6; AE = 2.4) and PGC1β expression at 4 h (CE = 2.1; AE = 2.6; P < 0.05). These data suggest that CE-induced acute stimulation of myofibrillar and mitochondrial FSR, protein signaling, and mRNA expression are equivalent to either isolate mode (RE or AE). These results occurred without an interference effect on muscle protein subfractional synthesis rates, protein signaling, or mRNA expression.

  4. Alga-PrAS (Algal Protein Annotation Suite): A Database of Comprehensive Annotation in Algal Proteomes

    PubMed Central

    Kurotani, Atsushi; Yamada, Yutaka

    2017-01-01

    Algae are smaller organisms than land plants and offer clear advantages in research over terrestrial species in terms of rapid production, short generation time and varied commercial applications. Thus, studies investigating the practical development of effective algal production are important and will improve our understanding of both aquatic and terrestrial plants. In this study we estimated multiple physicochemical and secondary structural properties of protein sequences, the predicted presence of post-translational modification (PTM) sites, and subcellular localization using a total of 510,123 protein sequences from the proteomes of 31 algal and three plant species. Algal species were broadly selected from green and red algae, glaucophytes, oomycetes, diatoms and other microalgal groups. The results were deposited in the Algal Protein Annotation Suite database (Alga-PrAS; http://alga-pras.riken.jp/), which can be freely accessed online. PMID:28069893

  5. 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.

  6. 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.

  7. The risk management implications of NUREG--1150 methods and results

    SciTech Connect

    Camp, A.L.; Maloney, K.J.; Sype, T.T. )

    1989-09-01

    This report describes the potential uses of NUREG-1150 and similar Probabilistic Risk Assessments (PRAs) in NRC and industry risk management programs. NUREG-1150 uses state-of-the-art PRA techniques to estimate the risk from five nuclear power plants. The methods and results produced in NUREG-1150 provide a framework within which current risk management strategies can be evaluated, and future risk management programs can be developed and assessed. While the development of plant-specific risk management strategies is beyond the scope of this document, examples of the use of the NUREG-1150 framework for identifying and evaluating risk management options are presented. All phases of risk management from prevention of initiating events though reduction of offsite consequences are discussed, with particular attention given to the early phase of accidents. 14 refs., 9 figs., 28 tabs.

  8. 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.

  9. 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.

  10. Alga-PrAS (Algal Protein Annotation Suite): A Database of Comprehensive Annotation in Algal Proteomes.

    PubMed

    Kurotani, Atsushi; Yamada, Yutaka; Sakurai, Tetsuya

    2017-01-01

    Algae are smaller organisms than land plants and offer clear advantages in research over terrestrial species in terms of rapid production, short generation time and varied commercial applications. Thus, studies investigating the practical development of effective algal production are important and will improve our understanding of both aquatic and terrestrial plants. In this study we estimated multiple physicochemical and secondary structural properties of protein sequences, the predicted presence of post-translational modification (PTM) sites, and subcellular localization using a total of 510,123 protein sequences from the proteomes of 31 algal and three plant species. Algal species were broadly selected from green and red algae, glaucophytes, oomycetes, diatoms and other microalgal groups. The results were deposited in the Algal Protein Annotation Suite database (Alga-PrAS; http://alga-pras.riken.jp/), which can be freely accessed online. © The Author 2017. Published by Oxford University Press on behalf of Japanese Society of Plant Physiologists.

  11. 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.

  12. 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)

  13. Response of structures to energetic events for the Savannah River Site production reactors probabilistic risk assessment

    SciTech Connect

    Santa Cruz, S.M.; Smith, D.C.; Yau, W.F.

    1992-10-01

    The response of structures to energetic events postulated to arise in a probabilistic risk assessment (PRA) of a Savannah River Site (SRS) production reactor is addressed. Energetic events that arise in PRAs can damage structures and therefore have a significant influence on subsequent accident progression. Consequently, the structural response is important to the calculated risk of operating a plant. Difficulties are encountered, however, in the analysis of structural response of components to energetic loadings. First, the analysis of energetic events often does not provide well-defined static or dynamic loads acting on the structures. Secondly, risk assessments, by their nature, address a wide range of events that are not necessarily precisely defined. This paper describes an approach taken to develop the structural analysis required to support the PRA of the SRS production reactor, that overcomes these difficulties.

  14. Response of structures to energetic events for the Savannah River Site production reactors probabilistic risk assessment

    SciTech Connect

    Santa Cruz, S.M.; Smith, D.C. ); Yau, W.F. )

    1992-01-01

    The response of structures to energetic events postulated to arise in a probabilistic risk assessment (PRA) of a Savannah River Site (SRS) production reactor is addressed. Energetic events that arise in PRAs can damage structures and therefore have a significant influence on subsequent accident progression. Consequently, the structural response is important to the calculated risk of operating a plant. Difficulties are encountered, however, in the analysis of structural response of components to energetic loadings. First, the analysis of energetic events often does not provide well-defined static or dynamic loads acting on the structures. Secondly, risk assessments, by their nature, address a wide range of events that are not necessarily precisely defined. This paper describes an approach taken to develop the structural analysis required to support the PRA of the SRS production reactor, that overcomes these difficulties.

  15. 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.

  16. 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.

  17. 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

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

    SciTech Connect

    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

    2016-06-15

    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.

  19. 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.

  20. 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.

  1. Incorporation of Melcor source term predictions into probabilistic risk assessments

    SciTech Connect

    Summers, R.M.; Helton, J.C.; Leigh, C.D.

    1989-01-01

    The MELCOR code has been developed as an advanced computational tool for performing primary source term analyses that will incorporate current phenomenological understanding into probabilistic risk assessments (PRAs). Although MELCOR is reasonably fast running, it is not feasible to perform a MELCOR calculation for each of the thousands of sets of conditions requiring a source term estimate in an integrated PRA. Therefore, the RELTRAC code is being developed to generate secondary source term estimates for use directly in a PRA for the LaSalle nuclear power plant by appropriately manipulating results from calculations by a primary source term code such as MELCOR. This paper describes the MELCOR and RELTRAC models and the manner in which MELCOR calculations are used to provide input to the RELTRAC model. 26 refs., 2 figs., 1 tab.

  2. 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.

  3. 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.

  4. Personal Retirement Accounts and Saving†

    PubMed Central

    Aguila, Emma

    2017-01-01

    Aging populations are leading countries worldwide to social security reforms. Many countries are moving from pay-as-you-go to personal retirement account (PRA) systems because of their financial sustainability and positive impact on private savings. PRA systems boost private savings at a macro level by converting a government liability into financial wealth managed by private fund managers. However, at a micro level, changes in retirement wealth affect individuals' saving and consumption patterns through their working lives. Retirement wealth increased for lower-income workers after Mexico introduced PRAs, crowding out saving, increasing consumption, and offsetting some of the PRA effect on private savings. (JEL D14, E21, H55, J26, O16) PMID:28286607

  5. Evaluation of the current disease severity scores in paediatric FMF: is it necessary to develop a new one?

    PubMed

    Kalkan, Gokhan; Demirkaya, Erkan; Acikel, Cengiz Han; Polat, Adem; Peru, Harun; Karaoglu, Abdulbaki; Sari, Erkan; Dursun, Ismail; Gok, Faysal; Ozen, Seza

    2012-04-01

    Modified adult disease severity scoring systems are being used for childhood FMF. We aim to test the clinical consistency of two common severity scoring systems and to evaluate the correlation of scores with the type of FMF mutations in paediatric FMF patients since certain mutations are prone to severe disease. Two hundred and fifty-eight children with FMF were cross-sectionally studied. Assessment of the disease severity was performed by using the modified scoring systems of Mor et al. and Pras et al. Genetic analysis was performed using PCR and restriction endonuclease digestion methods for the presence of 15 FMF gene mutations. FMF mutations were grouped into three based on well-known genotypic-phenotypic associations. Correlation between the mutation groups and the severity scoring systems was assessed. The consistency of the severity scoring systems was evaluated. The results of two scoring systems were not statistically consistent with each other (κ = 0.171). This inconsistency persisted even in a more homogeneous subgroup of patients with only homozygote mutations of M694V, M680I and M694I (κ = 0.125). There was no correlation between the mutation groups and either of the scoring systems (P = 0.002, r = 0,196 for scoring systems of Mor et al.; P = 0.009, r = 0.162 for Pras et al.). The inconsistency of the two scoring systems and lack of correlation between the scoring systems and mutation groups raises concerns about the reliability of these scoring systems in children. There is a need to develop a scoring system in children based on a prospective registry.

  6. High glucose enhances microRNA-26a to activate mTORC1 for mesangial cell hypertrophy and matrix protein expression

    PubMed Central

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

    2015-01-01

    High glucose milieu inhibits PTEN expression to activate Akt kinase and induces glomerular mesangial cell hypertrophy and matrix protein expression in diabetic nephropathy. Specific mechanism by which high glucose inhibits PTEN expression is not clear. We found that high glucose increased the expression of the microRNA-26a (miR-26a) in mesangial cells. Using a sensor plasmid with 3’UTR-driven luciferase, we showed PTEN as a target of miR-26a in response to high glucose. Overexpression of miR-26a reduced the PTEN protein levels resulting in increased Akt kinase activity similar to high glucose treatment. In contrast, anti-miR-26a reversed high glucose-induced suppression of PTEN with concomitant inhibition of Akt kinase activity. Akt-mediated phosphorylation of tuberin and PRAS40 regulates mTORC1, which is necessary for mesangial cell hypertrophy and matrix protein expression. Inhibition of high glucose-induced miR-26a blocked phosphorylation of tuberin and PRAS40, which lead to suppression of phosphorylation of S6 kinase and 4EBP-1, two substrates of mTORC1. Furthermore, we show that expression of miR-26a induced mesangial cell hypertrophy and increased fibronectin and collagen I (α2) expression similar to that observed with the cells incubated with high glucose. Anti-miR-26a inhibited these phenomena in response to high glucose. Together our results provide the first evidence for the involvement of miR-26a in high glucose-induced mesangial cell hypertrophy and matrix protein expression. These data indicate the potential therapeutic utility of anti-miR-26a for the complications of diabetic kidney disease. PMID:25797045

  7. Genetic Regulation of Fate Decisions in Therapeutic T Cells to Enhance Tumor Protection and Memory Formation.

    PubMed

    Veliça, Pedro; Zech, Mathias; Henson, Sian; Holler, Angelika; Manzo, Teresa; Pike, Rebecca; Santos E Sousa, Pedro; Zhang, Lei; Heinz, Niels; Schiedlmeier, Bernhard; Pule, Martin; Stauss, Hans; Chakraverty, Ronjon

    2015-07-01

    A key challenge in the field of T-cell immunotherapy for cancer is creating a suitable platform for promoting differentiation of effector cells while at the same time enabling self-renewal needed for long-term memory. Although transfer of less differentiated memory T cells increases efficacy through greater expansion and persistence in vivo, the capacity of such cells to sustain effector functions within immunosuppressive tumor microenvironments may still be limiting. We have therefore directly compared the impact of effector versus memory differentiation of therapeutic T cells in tumor-bearing mice by introducing molecular switches that regulate cell fate decisions via mTOR. Ectopic expression of RAS homolog enriched in brain (RHEB) increased mTORC1 signaling, promoted a switch to aerobic glycolysis, and increased expansion of effector T cells. By rapidly infiltrating tumors, RHEB-transduced T cells significantly reduced the emergence of immunoedited escape variants. In contrast, expression of proline-rich Akt substrate of 40 kDa (PRAS40) inhibited mTORC1, promoted quiescence, and blocked tumor infiltration. Fate mapping studies following transient expression of PRAS40 demonstrated that mTORC1(low) T cells made no contribution to initial tumor control but instead survived to become memory cells proficient in generating recall immunity. Our data support the design of translational strategies for generating heterogeneous T-cell immunity against cancer, with the appropriate balance between promoting effector differentiation and self-renewal. Unlike pharmacologic inhibitors, the genetic approach described here allows for upregulation as well as inhibition of the mTORC1 pathway and is highly selective for the therapeutic T cells without affecting systemic mTORC1 functions. ©2015 American Association for Cancer Research.

  8. 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.

  9. 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.

  10. Knowledge, Attitudes and Practices Related to African Swine Fever Within Smallholder Pig Production in Northern Uganda.

    PubMed

    Chenais, E; Boqvist, S; Sternberg-Lewerin, S; Emanuelson, U; Ouma, E; Dione, M; Aliro, T; Crafoord, F; Masembe, C; Ståhl, K

    2017-02-01

    Uganda is a low-income country with the largest pig population in East Africa. Pig keeping has a large potential, commercially and as a tool for poverty reduction, but African swine fever (ASF) is a major hurdle for development of the sector. The objective of this study was to evaluate knowledge, attitudes and practices related to ASF in the smallholder pig production value chain in northern Uganda. The study included three separate series of participatory rural appraisals (PRA), comprising purposively selected farmers and other actors in the pig production value chain. In the PRAs, various participatory epidemiology tools were used. A total of 49 PRAs and 574 participants, representing 64 different villages, were included. The results indicate that participants were well aware of the clinical signs of ASF, routes for disease spread and measures for disease control. However, awareness of the control measures did not guarantee their implementation. A majority of middlemen and butchers acknowledged having sold live pigs, carcasses or pork they believed infected with ASF. Outbreaks of ASF had a strong negative impact on participants' socio-economic status with loss of revenue and reversal into more severe poverty. In conclusion, lack of knowledge is not what is driving the continuous circulation of ASF virus in this setting. To control ASF and reduce its impact, initiatives that stimulate changes in management are needed. Because the behaviour of all actors in the value chain is largely influenced by the deep rural poverty in the region, this needs to be combined with efforts to reduce rural poverty.

  11. 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

  12. 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.

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

    PubMed Central

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

    2016-01-01

    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

  14. 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

  15. Photosynthetic picoeukaryote community structure in the South East Pacific Ocean encompassing the most oligotrophic waters on Earth.

    PubMed

    Lepère, Cécile; Vaulot, Daniel; Scanlan, David J

    2009-12-01

    Photosynthetic picoeukaryotes (PPEs), comprising organisms < 3 mum in size, are important primary producers in marine food webs and include representatives from all known algal lineages. Little is known, however, regarding the composition and distribution of PPE communities, particularly at large spatial scales, or in relation to the underlying biotic and abiotic factors that influence this structure. Here, we analysed PPE community structure along a transect in the South East Pacific Ocean (BIOSOPE cruise) that encompassed a large trophic gradient, including hyper-oligotrophic waters in the South Pacific Gyre (SPG), considered to be some of the 'clearest' natural waters on Earth. Using dot blot hybridizations with 16S rRNA oligonucleotide probes, we established that the PPE community was dominated by members of the classes Prymnesiophyceae and Chrysophyceae throughout the transect. Moreover, clone library construction followed by phylogenetic analysis of sequenced clones revealed several novel 16S rRNA gene lineages, including new clades of prymnesiophytes (designated Prym 16S-III) and prasinophytes (Pras 16S-VIII). Pras 16S-VIII was found at all five stations at which clone libraries were constructed, representing a range of trophic conditions, including the South Pacific Gyre, suggesting members of this clade have a broad distribution in this part of the South East Pacific at least. In contrast, Prym 16S-III sequences were largely restricted to oligotrophic stations of the SPG. Subsequent multivariate statistical analyses showed that, within the measured factors, chemical and biological factors seem to influence PPE community structure more than physical parameters. However, more than 50% of the variation in distribution of PPE classes remained unexplained.

  16. Establishing the Canadian HIV Women's Sexual and Reproductive Health Cohort Study (CHIWOS): Operationalizing Community-based Research in a Large National Quantitative Study.

    PubMed

    Loutfy, Mona; Greene, Saara; Kennedy, V Logan; Lewis, Johanna; Thomas-Pavanel, Jamie; Conway, Tracey; de Pokomandy, Alexandra; O'Brien, Nadia; Carter, Allison; Tharao, Wangari; Nicholson, Valerie; Beaver, Kerrigan; Dubuc, Danièle; Gahagan, Jacqueline; Proulx-Boucher, Karène; Hogg, Robert S; Kaida, Angela

    2016-08-19

    Community-based research has gained increasing recognition in health research over the last two decades. Such participatory research approaches are lauded for their ability to anchor research in lived experiences, ensuring cultural appropriateness, accessing local knowledge, reaching marginalized communities, building capacity, and facilitating research-to-action. While having these positive attributes, the community-based health research literature is predominantly composed of small projects, using qualitative methods, and set within geographically limited communities. Its use in larger health studies, including clinical trials and cohorts, is limited. We present the Canadian HIV Women's Sexual and Reproductive Health Cohort Study (CHIWOS), a large-scale, multi-site, national, longitudinal quantitative study that has operationalized community-based research in all steps of the research process. Successes, challenges and further considerations are offered. Through the integration of community-based research principles, we have been successful in: facilitating a two-year long formative phase for this study; developing a novel survey instrument with national involvement; training 39 Peer Research Associates (PRAs); offering ongoing comprehensive support to PRAs; and engaging in an ongoing iterative community-based research process. Our community-based research approach within CHIWOS demanded that we be cognizant of challenges managing a large national team, inherent power imbalances and challenges with communication, compensation and volunteering considerations, and extensive delays in institutional processes. It is important to consider the iterative nature of community-based research and to work through tensions that emerge given the diverse perspectives of numerous team members. Community-based research, as an approach to large-scale quantitative health research projects, is an increasingly viable methodological option. Community-based research has several

  17. Preclinical pharmacology of AZD5363, an inhibitor of AKT: pharmacodynamics, antitumor activity, and correlation of monotherapy activity with genetic background.

    PubMed

    Davies, Barry R; Greenwood, Hannah; Dudley, Phillippa; Crafter, Claire; Yu, De-Hua; Zhang, Jingchuan; Li, Jing; Gao, Beirong; Ji, Qunsheng; Maynard, Juliana; Ricketts, Sally-Ann; Cross, Darren; Cosulich, Sabina; Chresta, Christine C; Page, Ken; Yates, James; Lane, Clare; Watson, Rebecca; Luke, Richard; Ogilvie, Donald; Pass, Martin

    2012-04-01

    AKT is a key node in the most frequently deregulated signaling network in human cancer. AZD5363, a novel pyrrolopyrimidine-derived compound, inhibited all AKT isoforms with a potency of 10 nmol/L or less and inhibited phosphorylation of AKT substrates in cells with a potency of approximately 0.3 to 0.8 μmol/L. AZD5363 monotherapy inhibited the proliferation of 41 of 182 solid and hematologic tumor cell lines with a potency of 3 μmol/L or less. Cell lines derived from breast cancers showed the highest frequency of sensitivity. There was a significant relationship between the presence of PIK3CA and/or PTEN mutations and sensitivity to AZD5363 and between RAS mutations and resistance. Oral dosing of AZD5363 to nude mice caused dose- and time-dependent reduction of PRAS40, GSK3β, and S6 phosphorylation in BT474c xenografts (PRAS40 phosphorylation EC(50) ~ 0.1 μmol/L total plasma exposure), reversible increases in blood glucose concentrations, and dose-dependent decreases in 2[18F]fluoro-2-deoxy-D-glucose ((18)F-FDG) uptake in U87-MG xenografts. Chronic oral dosing of AZD5363 caused dose-dependent growth inhibition of xenografts derived from various tumor types, including HER2(+) breast cancer models that are resistant to trastuzumab. AZD5363 also significantly enhanced the antitumor activity of docetaxel, lapatinib, and trastuzumab in breast cancer xenografts. It is concluded that AZD5363 is a potent inhibitor of AKT with pharmacodynamic activity in vivo, has potential to treat a range of solid and hematologic tumors as monotherapy or a combinatorial agent, and has potential for personalized medicine based on the genetic status of PIK3CA, PTEN, and RAS. AZD5363 is currently in phase I clinical trials.

  18. 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.

  19. 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

  20. mTOR activity in AIDS-related diffuse large B-cell lymphoma

    PubMed Central

    Diaz-Perez, Julio A.; Preziosi, Michael; King, Charles C.; Jones, George A.; Jain, Sonia; Sun, Xiaoying; Reid, Erin G.; VandenBerg, Scott; Wang, Huan-You

    2017-01-01

    Background Patients infected with HIV have a significantly increased risk of developing non–Hodgkin lymphomas despite the widespread use of HAART. To investigate mTOR pathway activity in acquired immunodeficiency syndrome (AIDS) related diffuse large B-cell lymphoma AR-DLBCL, we used immunohistochemistry to examine the presence of the phosphorylated 70 ribosomal S6 protein-kinase (p70S6K), an extensively studied effector of mTOR Complex 1 (mTORC1) and the phosphorylated phosphatase and tensin homolog (pPTEN), a negative regulator of mTORC1 pathway. Materials and methods We evaluated tissue samples from 126 patients with AR-DLBCL. Among them, 98 samples were from tissue microarrays (TMAs) supplied by the Aids and Cancer Specimen Resource (ACSR), the remaining 28 samples were from cases diagnosed and treated at the University of California, San Diego (UCSD). The presence of p70S6K was evaluated with two antibodies directed against the combined epitopes Ser235/236 and Ser240/244, respectively; and additional monoclonal anti-bodies were used to identify pPTEN and phosphorylated proline-rich Akt substrate of 40kDa (pPRAS40). The degree of intensity and percentage of cells positive for p70S6K and pPTEN were assessed in all the samples. In addition, a subgroup of 28 patients from UCSD was studied to assess the presence of pPRAS40, an insulin-regulated activator of the mTORC1. The expression of each of these markers was correlated with clinical and histopathologic features. Results The majority of the patients evaluated were males (88%); only two cases (1.6%) were older than 65 years of age. We found high levels of both p70S6K-paired epitopes studied, 48% positivity against Ser235/236 (44% in ACSR and 64% in UCSD group), and 86% positivity against Ser240/244 (82% in ACSR and 100% in UCSD group). We observed more positive cells and stronger intensity with epitope Ser240/244 in comparison to Ser235/236 (p<0.0001). The degree of intensity and percentage of cells positive

  1. 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

  2. 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

  3. Tobacco Smoke-Induced Hepatic Injury with Steatosis, Inflammation, and Impairments in Insulin and Insulin-Like Growth Factor Signaling

    PubMed Central

    de la Monte, Suzanne M.; Tong, M; Agarwal, AR; Cadenas, E

    2016-01-01

    Background Alcoholic liver disease (ALD) is associated with impairments in hepatic insulin and insulin-like growth factor (IGF) signaling through cell growth, survival, and metabolic pathways. Since not all heavy drinkers develop ALD, co-factors may be important. Epidemiologic data indicate that most heavy drinkers smoke tobacco and experimental data revealed that low-level nitrosamine exposures, including those from tobacco, can cause steatohepatitis with hepatic insulin/IGF resistance and exacerbate ALD. We hypothesize that cigarette smoke (CS) exposures also cause liver injury with impaired hepatic insulin/IGF signaling, and thereby contribute to ALD. Methods Adult male A/J mice were exposed to air for 8 weeks (A8), CS for 4 (CS4) or 8 (CS8) weeks, or CS for 8 weeks with 2 weeks recovery (CS8+R). Results CS exposures caused progressive liver injury with disruption of the normal hepatic chord architecture, lobular inflammation, apoptosis or necrosis, micro-steatosis, sinusoidal dilatation, and nuclear pleomorphism. Histopathological liver injury scores increased significantly from A8 to CS4 and then further to CS8 (P<0.0001). The mean histological grade was also higher in CS8+R relative to A8 (P<0.0001) but lower than in CS4, reflecting partial resolution of injury by CS withdrawal. CS exposures impaired insulin and IGF-1 signaling through IRS-1, Akt, GSK-3β, and PRAS40. Livers from CS8+R mice had normalized or elevated levels of insulin receptor, pYpY-Insulin-R, 312S-IRS-1, 473S-Akt, S9-GSK-3β, and pT246-PRAS40 relative to A8, CS4, or CS8, reflecting partial recovery. Conclusion CS-mediated liver injury and steatohepatitis with impairments in insulin/IGF signalling are reminiscent of the findings in ALD. Therefore, CS exposures (either first or second-hand) may serve as a co-factor in ALD. The persistence of several abnormalities following CS exposure cessation suggests that some aspects of CS-mediated hepatic metabolic dysfunction are not readily reversible

  4. Bariatric Surgery in Morbidly Obese Insulin Resistant Humans Normalises Insulin Signalling but Not Insulin-Stimulated Glucose Disposal

    PubMed Central

    de Berker, David A. R.; May, Margaret T.; Hers, Ingeborg; Dayan, Colin M.; Andrews, Robert C.; Tavaré, Jeremy M.

    2015-01-01

    Aims Weight-loss after bariatric surgery improves insulin sensitivity, but the underlying molecular mechanism is not clear. To ascertain the effect of bariatric surgery on insulin signalling, we examined glucose disposal and Akt activation in morbidly obese volunteers before and after Roux-en-Y gastric bypass surgery (RYGB), and compared this to lean volunteers. Materials and Methods The hyperinsulinaemic euglycaemic clamp, at five infusion rates, was used to determine glucose disposal rates (GDR) in eight morbidly obese (body mass index, BMI=47.3±2.2 kg/m2) patients, before and after RYGB, and in eight lean volunteers (BMI=20.7±0.7 kg/m2). Biopsies of brachioradialis muscle, taken at fasting and insulin concentrations that induced half-maximal (GDR50) and maximal (GDR100) GDR in each subject, were used to examine the phosphorylation of Akt-Thr308, Akt-473, and pras40, in vivo biomarkers for Akt activity. Results Pre-operatively, insulin-stimulated GDR was lower in the obese compared to the lean individuals (P<0.001). Weight-loss of 29.9±4 kg after surgery significantly improved GDR50 (P=0.004) but not GDR100 (P=0.3). These subjects still remained significantly more insulin resistant than the lean individuals (p<0.001). Weight loss increased insulin-stimulated skeletal muscle Akt-Thr308 and Akt-Ser473 phosphorylation, P=0.02 and P=0.03 respectively (MANCOVA), and Akt activity towards the substrate PRAS40 (P=0.003, MANCOVA), and in contrast to GDR, were fully normalised after the surgery (obese vs lean, P=0.6, P=0.35, P=0.46, respectively). Conclusions Our data show that although Akt activity substantially improved after surgery, it did not lead to a full restoration of insulin-stimulated glucose disposal. This suggests that a major defect downstream of, or parallel to, Akt signalling remains after significant weight-loss. PMID:25876175

  5. TGFβ-Stimulated MicroRNA-21 Utilizes PTEN to Orchestrate AKT/mTORC1 Signaling for Mesangial Cell Hypertrophy and Matrix Expansion

    PubMed Central

    Dey, Nirmalya; Ghosh-Choudhury, Nandini; Kasinath, Balakuntalam S.; Choudhury, Goutam Ghosh

    2012-01-01

    Transforming growth factor-β (TGFβ) promotes glomerular hypertrophy and matrix expansion, leading to glomerulosclerosis. MicroRNAs are well suited to promote fibrosis because they can repress gene expression, which negatively regulate the fibrotic process. Recent cellular and animal studies have revealed enhanced expression of microRNA, miR-21, in renal cells in response to TGFβ. Specific miR-21 targets downstream of TGFβ receptor activation that control cell hypertrophy and matrix protein expression have not been studied. Using 3′UTR-driven luciferase reporter, we identified the tumor suppressor protein PTEN as a target of TGFβ-stimulated miR-21 in glomerular mesangial cells. Expression of miR-21 Sponge, which quenches endogenous miR-21 levels, reversed TGFβ-induced suppression of PTEN. Additionally, miR-21 Sponge inhibited TGFβ-stimulated phosphorylation of Akt kinase, resulting in attenuation of phosphorylation of its substrate GSK3β. Tuberin and PRAS40, two other Akt substrates, and endogenous inhibitors of mTORC1, regulate mesangial cell hypertrophy. Neutralization of endogenous miR-21 abrogated TGFβ-stimulated phosphorylation of tuberin and PRAS40, leading to inhibition of phosphorylation of S6 kinase, mTOR and 4EBP-1. Moreover, downregulation of miR-21 significantly suppressed TGFβ-induced protein synthesis and hypertrophy, which were reversed by siRNA-targeted inhibition of PTEN expression. Similarly, expression of constitutively active Akt kinase reversed the miR-21 Sponge-mediated inhibition of TGFβ-induced protein synthesis and hypertrophy. Furthermore, expression of constitutively active mTORC1 prevented the miR-21 Sponge-induced suppression of mesangial cell protein synthesis and hypertrophy by TGFβ. Finally, we show that miR-21 Sponge inhibited TGFβ-stimulated fibronectin and collagen expression. Suppression of PTEN expression and expression of both constitutively active Akt kinase and mTORC1 independently reversed this miR-21-mediated

  6. Montelukast Induces Apoptosis-Inducing Factor-Mediated Cell Death of Lung Cancer Cells

    PubMed Central

    Chang, Wei-An; Tsai, Pei-Hsun; Wu, Cheng-Ying; Ho, Ya-Wen; Yen, Meng-Chi; Lin, Yi-Shiuan; Kuo, Po-Lin; Hsu, Ya-Ling

    2017-01-01

    Developing novel chemo-prevention techniques and advancing treatment are key elements to beating lung cancer, the most common cause of cancer mortality worldwide. Our previous cohort study showed that cysteinyl leukotriene receptor antagonists, mainly montelukast, decreased the lung cancer risk in asthma patients. In the current study, we conducted in vivo and in vitro experiments to demonstrate the inhibiting effect of montelukast on lung cancer and to investigate the underlying mechanisms. Using Lewis lung carcinoma-bearing mice, we showed that feeding montelukast significantly delayed the tumor growth in mice (p < 0.0001). Montelukast inhibited cell proliferation and colony formation and induced the cell death of lung cancer cells. Further investigation showed the down-regulation of B-cell lymphoma 2 (Bcl-2), up-regulation of Bcl-2 homologous antagonist/killer (Bak), and nuclear translocation of apoptosis-inducing factor (AIF) in montelukast-treated lung cancer cells. Montelukast also markedly decreased the phosphorylation of several proteins, such as with no lysine 1 (WNK1), protein kinase B (Akt), extracellular signal-regulated kinase 1/2 (Erk1/2), MAPK/Erk kinase (MEK), and proline-rich Akt substrate of 40-kDa (PRAS40), which might contribute to cell death. In conclusion, montelukast induced lung cancer cell death via the nuclear translocation of AIF. This study confirmed the chemo-preventive effect of montelukast shown in our previous cohort study. The utility of montelukast in cancer prevention and treatment thus deserves further studies. PMID:28672809

  7. 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.

  8. A role for Raptor phosphorylation in the mechanical activation of mTOR signaling.

    PubMed

    Frey, John W; Jacobs, Brittany L; Goodman, Craig A; Hornberger, Troy A

    2014-02-01

    The activation of mTOR signaling is necessary for mechanically-induced changes in skeletal muscle mass, but the mechanisms that regulate the mechanical activation of mTOR signaling remain poorly defined. In this study, we set out to determine if changes in the phosphorylation of Raptor contribute to the mechanical activation of mTOR. To accomplish this goal, mouse skeletal muscles were subjected to mechanical stimulation via a bout of eccentric contractions (EC). Using mass spectrometry and Western blot analysis, we found that ECs induced an increase in Raptor S696, T706, and S863 phosphorylation, and this effect was not inhibited by rapamycin. This observation suggested that changes in Raptor phosphorylation might be an upstream event in the pathway through which mechanical stimuli activate mTOR. To test this, we employed a phospho-defective mutant of Raptor (S696A/T706A/S863A) and found that the EC-induced activation of mTOR signaling was significantly blunted in muscles expressing this mutant. Furthermore, mutation of the three phosphorylation sites altered the interactions of Raptor with PRAS40 and p70(S6k), and it also prevented the EC-induced dissociation of Raptor from p70(S6k). Combined, these results suggest that changes in the phosphorylation of Raptor play an important role in the pathway through which mechanical stimuli activate mTOR signaling.

  9. Approaches to uncertainty analysis in probabilistic risk assessment

    SciTech Connect

    Bohn, M.P.; Wheeler, T.A.; Parry, G.W.

    1988-01-01

    An integral part of any probabilistic risk assessment (PRA) is the performance of an uncertainty analysis to quantify the uncertainty in the point estimates of the risk measures considered. While a variety of classical methods of uncertainty analysis exist, application of these methods and developing new techniques consistent with existing PRA data bases and the need for expert (subjective) input has been an area of considerable interest since the pioneering Reactor Safety Study (WASH-1400) in 1975. This report presents the results of a critical review of existing methods for performing uncertainty analyses for PRAs, with special emphasis on identifying data base limitations on the various methods. Both classical and Baysian approaches have been examined. This work was funded by the US Nuclear Regulatory Commission in support of its ongoing full-scope PRA of the LaSalle nuclear power station. Thus in addition to the review, this report contains recommendations for a suitable uncertainty analysis methodology for the LaSalle PRA.

  10. 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.

  11. Localization and trafficking of an isoform of the AtPRA1 family to the Golgi apparatus depend on both N- and C-terminal sequence motifs.

    PubMed

    Jung, Chan Jin; Lee, Myoung Hui; Min, Myung Ki; Hwang, Inhwan

    2011-02-01

    Prenylated Rab acceptors (PRAs) bind to prenylated Rab proteins and possibly aid in targeting Rabs to their respective compartments. In Arabidopsis, 19 isoforms of PRA1 have been identified and, depending upon the isoforms, they localize to the endoplasmic reticulum (ER), Golgi apparatus and endosomes. Here, we investigated the localization and trafficking of AtPRA1.B6, an isoform of the Arabidopsis PRA1 family. In colocalization experiments with various organellar markers, AtPRA1.B6 tagged with hemagglutinin (HA) at the N-terminus localized to the Golgi apparatus in protoplasts and transgenic plants. The valine residue at the C-terminal end and an EEE motif in the C-terminal cytoplasmic domain were critical for anterograde trafficking from the ER to the Golgi apparatus. The N-terminal region contained a sequence motif for retention of AtPRA1.B6 at the Golgi apparatus. In addition, anterograde trafficking of AtPRA1.B6 from the ER to the Golgi apparatus was highly sensitive to the HA:AtPRA1.B6 level. The region that contains the sequence motif for Golgi retention also conferred the abundance-dependent trafficking inhibition. On the basis of these results, we propose that AtPRA1.B6 localizes to the Golgi apparatus and its ER-to-Golgi trafficking and localization to the Golgi apparatus are regulated by multiple sequence motifs in both the C- and N-terminal cytoplasmic domains.

  12. Equipment qualification (EQ): Risk scoping study

    SciTech Connect

    Bustard, L.D.; Clark, J.; Medford, G.T.; Kolaczkowski, A.M.

    1989-01-01

    The objective of the EQ--Risk Scoping Study was to use probabilistic risk assessment (PRA) techniques (1) to assess the impact of electrical equipment environmental qualification or lack thereof on reactor risk and its uncertainties, and (2) to identify any analyses or testing that may be necessary to reduce the risk or its uncertainties stemming from lack of qualification of equipment important to safety. To achieve these objectives, PRA techniques and insights were employed to identify equipment that must function in accident-induced harsh environments and whose failure would be risk significant. Several components from the resultant list were then selected for more detailed analyses. Accident scenarios and environments, which PRAs suggest are risk significant, were determined for each selected equipment operation. For these accident conditions, both equipment qualification research and test experiences were examined to determine whether equipment accident reliability might differ substantially from the reliability values based on normal operation conditions employed in past PRA analyses. Note, accident reliability information is generally unavailable. Where significant differences were considered probable, parametric risk achievement analyses were used to assess the potential risk impact of the equipment failures. In addition, those equipment qualification practices and outstanding research issues that potentially could impact the accident equipment reliability were noted. This information, when combined with perspectives regarding potential equipment risk impact, provided a basis for assessing the potential risk importance of various EQ practices and issues. Additional discussion regarding the study's approach, conclusions, and recommendations is provided. 54 refs., 9 figs., 33 tabs.

  13. 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.

  14. 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.

  15. Human factors issues in qualitative and quantitative safety analyses

    SciTech Connect

    Hahn, H.A.

    1993-10-01

    Humans are a critical and integral part of any operational system, be it a nuclear reactor, a facility for assembly or disassembling hazardous components, or a transportation network. In our concern over the safety of these systems, we often focus our attention on the hardware engineering components of such systems. However, experience has repeatedly demonstrated that it is often the human component that is the primary determinant of overall system safety. Both the nuclear reactor accidents at Chernobyl and Three Mile Island and shipping disasters such as the Exxon Valdez and the Herald of Free Enterprise accidents are attributable to human error. Concern over human contributions to system safety prompts us to include reviews of human factors issues in our safety analyses. In the conduct of Probabilistic Risk Assessments (PRAs), human factors issues are addressed using a quantitative method called Human Reliability Analysis (HRA). HRAs typically begin with the identification of potential sources of human error in accident sequences of interest. Human error analysis often employs plant and/or procedures walk-downs in which the analyst considers the ``goodness`` of procedures, training, and human-machine interfaces concerning their potential contribution to human error. Interviews with expert task performers may also be conducted. In the application of HRA, once candidate sources of human error have been identified, error probabilities are developed.

  16. 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

    2014-01-01

    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.

  17. Progesterone receptor A stability is mediated by glycogen synthase kinase-3β in the Brca1-deficient mammary gland.

    PubMed

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

    2013-09-06

    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-A(S390A) 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.

  18. Advanced Nuclear Technology. Using Technology for Small Modular Reactor Staff Optimization, Improved Effectiveness, and Cost Containment, 3002007071

    SciTech Connect

    Loflin, Leonard

    2016-03-21

    Through this grant, the U.S. Department of Energy (DOE) will review several functional areas within a nuclear power plant, including fire protection, operations and operations support, refueling, training, procurement, maintenance, site engineering, and others. Several functional areas need to be examined since there appears to be no single staffing area or approach that alone has the potential for significant staff optimization at new nuclear power plants. Several of the functional areas will require a review of technology options such as automation, remote monitoring, fleet wide monitoring, new and specialized instrumentation, human factors engineering, risk informed analysis and PRAs, component and system condition monitoring and reporting, just in time training, electronic and automated procedures, electronic tools for configuration management and license and design basis information, etc., that may be applied to support optimization. Additionally, the project will require a review key regulatory issues that affect staffing and could be optimized with additional technology input. Opportunities to further optimize staffing levels and staffing functions by selection of design attributes of physical systems and structures need also be identified. A goal of this project is to develop a prioritized assessment of the functional areas, and R&D actions needed for those functional areas, to provide the best optimization

  19. 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.

  20. 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. Copyright © 2016 Elsevier B.V. All rights reserved.

  1. 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

  2. Phosphoproteomics Reveals Resveratrol-Dependent Inhibition of Akt/mTORC1/S6K1 Signaling

    PubMed Central

    2015-01-01

    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

  3. 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).

  4. 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."

  5. 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.

  6. 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.

  7. Evaluation of Three Devices for the Isolation of the Stromal Vascular Fraction from Adipose Tissue and for ASC Culture: A Comparative Study

    PubMed Central

    Pratta, Anne-Sophie; Abbassi, Nacira; Fabre, Hugo; Rodriguez, Fanny; Debard, Cyrille; Adobati, Jacqueline; Boucher, Fabien; Mallein-Gerin, Frédéric; Auxenfans, Céline; Damour, Odile; Mojallal, Ali

    2017-01-01

    Adipose-derived stem/stromal cells (ASCs) reside in the stromal vascular fraction (SVF) of adipose tissue (AT) and can be easily isolated. However, extraction of the SVF from lipoaspirate is a critical step in generating ASC, and semiautomated devices have been developed to enhance the efficacy and reproducibility of the outcomes and to decrease manipulation and contamination. In this study, we compared the reference method used in our lab for SVF isolation from lipoaspirate, with three medical devices: GID SVF-1™, Puregraft™, and Stem.pras®. Cell yield and their viability were evaluated as well as their phenotype with flow cytometry. Further on, we determined their proliferative potential using population doublings (PD), PD time (PDT), and clonogenicity assay (CFU-F). Finally, we checked their genetic stability using RT-qPCR for TERT mRNA assay and karyotyping as well as their multilineage potential including adipogenic, chondrogenic, and osteogenic differentiation. Our results demonstrate that all the devices allow the production of SVF cells with consistent yield and viability, in less time than the reference method. Expanded cells from the four methods showed no significant differences in terms of phenotype, proliferation capabilities, differentiation abilities, and genetic stability. PMID:28321259

  8. Passive ALWR requirements to prevent containment failure. Advanced Reactor Severe Accident Program

    SciTech Connect

    Additon, S.L.; Blanchard, D.P.; Leaver, D.E.; Persinko, D. |

    1991-12-01

    The purpose of this report is to document a systematic evaluation of the Passive Advanced Light Water Reactor (ALWR) design requirements which address severe accident mitigation. This evaluation was performed concurrent with completion of the ALWR Requirements Document to assure the adequacy of these mitigation requirements. The passive plant approach to containment integrity assurance reflects an expansion of the approach established earlier for evolutionary ALWRs. The report identifies containment challenges that might occur coincident with or result from a core damage event, compiles the set of passive ALWR design requirements which addresses each challenge, and evaluates each set of requirements on an integrated basis to confirm that the requirements provide substantial assurance that coincident core damage and containment failure are precluded. Based on past PRAs, a review of pertinent safety functions, severe accident analyses, current regulatory requirements, and reviews by ALWR design personnel, twenty-three (23) potential containment challenges were identified. The report concludes that the relevant ALWR requirements severe to limit the likelihood and magnitude of the challenges, and to assure the capability of the containment to accommodate all challenges which remain potentially risk-significant.

  9. Passive ALWR requirements to prevent containment failure. [Advanced light water reactors

    SciTech Connect

    Additon, S.L.; Blanchard, D.P.; Leaver, D.E.; Persinko, D. TENERA, L.P., Bethesda, MD )

    1991-12-01

    The purpose of this report is to document a systematic evaluation of the Passive Advanced Light Water Reactor (ALWR) design requirements which address severe accident mitigation. This evaluation was performed concurrent with completion of the ALWR Requirements Document to assure the adequacy of these mitigation requirements. The passive plant approach to containment integrity assurance reflects an expansion of the approach established earlier for evolutionary ALWRs. The report identifies containment challenges that might occur coincident with or result from a core damage event, compiles the set of passive ALWR design requirements which addresses each challenge, and evaluates each set of requirements on an integrated basis to confirm that the requirements provide substantial assurance that coincident core damage and containment failure are precluded. Based on past PRAs, a review of pertinent safety functions, severe accident analyses, current regulatory requirements, and reviews by ALWR design personnel, twenty-three (23) potential containment challenges were identified. The report concludes that the relevant ALWR requirements severe to limit the likelihood and magnitude of the challenges, and to assure the capability of the containment to accommodate all challenges which remain potentially risk-significant.

  10. Review and development of common nomenclature for naming and labeling schemes for probabilistic risk assessment

    SciTech Connect

    Trusty, A.D.; Mackowiak, D.P. )

    1992-08-01

    This report describes the review and development of common nomenclature for naming and labeling schemes for probabilistic risk assessments (PRAS) conducted by the Idaho National Engineering Laboratory (INEL). Based on the review, the INEL recommends using an existing basic event labeling scheme and existing naming schemes for systems, component types, and component failure modes. The review showed no adequate accident sequence labeling schemes currently exist. Therefore, the INEL developed a scheme that would meet the review requirements of not exceeding 16 characters and being highly descriptive of the accident sequence involved. As parts of the developed accident sequence labeling scheme, the INEL also developed transient and loss-of-coolant accident initiating event codes, a sequence naming scheme, and accident type codes. Applications of the accident sequence labeling scheme are presented along with tables to allow changes from other schemes to the recommended naming schemes. The review and development were conducted to provide the Nuclear Regulatory Commission with the means to coordinate and integrate their internal activities through a common nomenclature for their many data bases.

  11. 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.

  12. A Statistical Testing Approach for Quantifying Software Reliability; Application to an Example System

    SciTech Connect

    Chu, Tsong-Lun; Varuttamaseni, Athi; Baek, Joo-Seok

    2016-11-01

    The U.S. Nuclear Regulatory Commission (NRC) encourages the use of probabilistic risk assessment (PRA) technology in all regulatory matters, to the extent supported by the state-of-the-art in PRA methods and data. Although much has been accomplished in the area of risk-informed regulation, risk assessment for digital systems has not been fully developed. The NRC established a plan for research on digital systems to identify and develop methods, analytical tools, and regulatory guidance for (1) including models of digital systems in the PRAs of nuclear power plants (NPPs), and (2) incorporating digital systems in the NRC's risk-informed licensing and oversight activities. Under NRC's sponsorship, Brookhaven National Laboratory (BNL) explored approaches for addressing the failures of digital instrumentation and control (I and C) systems in the current NPP PRA framework. Specific areas investigated included PRA modeling digital hardware, development of a philosophical basis for defining software failure, and identification of desirable attributes of quantitative software reliability methods. Based on the earlier research, statistical testing is considered a promising method for quantifying software reliability. This paper describes a statistical software testing approach for quantifying software reliability and applies it to the loop-operating control system (LOCS) of an experimental loop of the Advanced Test Reactor (ATR) at Idaho National Laboratory (INL).

  13. Interaction of PDK1 with Phosphoinositides Is Essential for Neuronal Differentiation but Dispensable for Neuronal Survival

    PubMed Central

    Zurashvili, Tinatin; Cordón-Barris, Lluís; Ruiz-Babot, Gerard; Zhou, Xiangyu; Lizcano, Jose M.; Gómez, Nestor; Giménez-Llort, Lydia

    2013-01-01

    3-Phosphoinositide-dependent protein kinase 1 (PDK1) operates in cells in response to phosphoinositide 3-kinase activation and phosphatidylinositol-3,4,5-trisphosphate [PtdIns(3,4,5)P3] production by activating a number of AGC kinases, including protein kinase B (PKB)/Akt. Both PDK1 and PKB contain pleckstrin homology (PH) domains that interact with the PtdIns(3,4,5)P3 second messenger. Disrupting the interaction of the PDK1 PH domain with phosphoinositides by expressing the PDK1 K465E knock-in mutation resulted in mice with reduced PKB activation. We explored the physiological consequences of this biochemical lesion in the central nervous system. The PDK1 knock-in mice displayed a reduced brain size due to a reduction in neuronal cell size rather than cell number. Reduced BDNF-induced phosphorylation of PKB at Thr308, the PDK1 site, was observed in the mutant neurons, which was not rate limiting for the phosphorylation of those PKB substrates governing neuronal survival and apoptosis, such as FOXO1 or glycogen synthase kinase 3 (GSK3). Accordingly, the integrity of the PDK1 PH domain was not essential to support the survival of different embryonic neuronal populations analyzed. In contrast, PKB-mediated phosphorylation of PRAS40 and TSC2, allowing optimal mTORC1 activation and brain-specific kinase (BRSK) protein synthesis, was markedly reduced in the mutant mice, leading to impaired neuronal growth and differentiation. PMID:23275438

  14. Evaluation of 2-deoxy-2-[18F]fluoro-D-glucose- and 3'-deoxy-3'-[18F]fluorothymidine-positron emission tomography as biomarkers of therapy response in platinum-resistant ovarian cancer.

    PubMed

    Perumal, Meg; Stronach, Euan A; Gabra, Hani; Aboagye, Eric O

    2012-12-01

    We evaluated whether 2-deoxy-2-[(18)F]fluoro-D-glucose ([(18)F]FDG) and 3'-deoxy-3'-[(18)F]fluorothymidine ([(18)F]FLT) positron emission tomography (PET) could be used as imaging biomarkers of platinum resensitization in ovarian cancer. Paired platinum-sensitive and platinum-resistant ovarian cancer cells from the same patient, PEO1 and PEO4, grown as tumor xenografts in nude mice, were assessed by PET. The AKT inhibitor, API-2, resensitized platinum-resistant PEO4 tumors to cisplatin, leading to a markedly lower Ki67 labeling index (p ≤ 0.006, n = 6 per group). [(18)F]FDG-PET and [(18)F]FLT-PET imaging variables were lower after combination treatment compared with vehicle treatment (p ≤ 0.006, n = 6 per group). No changes were seen with either drug alone. PRAS40 phosphorylation status was a sensitive biochemical marker of pathway inhibition, whereas reductions thymidine kinase 1 expression defined the [(18)F]FLT response. Therapeutic inhibition of AKT activation in acquired platinum-resistant disease can be imaged noninvasively by [(18)F]FDG-PET and [(18)F]FLT-PET warranting further assessment.

  15. 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.

  16. A Role for Raptor Phosphorylation in the Mechanical Activation of mTOR Signaling

    PubMed Central

    Frey, John W.; Jacobs, Brittany L.; Goodman, Craig A.; Hornberger, Troy A.

    2013-01-01

    The activation of mTOR signaling is necessary for mechanically-induced changes in skeletal muscle mass, but the mechanisms that regulate the mechanical activation of mTOR signaling remain poorly defined. In this study, we set out to determine if changes in the phosphorylation of Raptor contribute to the mechanical activation of mTOR. To accomplish this goal, mouse skeletal muscles were subjected to mechanical stimulation via a bout of eccentric contractions (EC). Using mass spectrometry and Western blot analysis, we found that ECs induced an increase in Raptor S696, T706, and S863 phosphorylation, and this effect was not inhibited by rapamycin. This observation suggested that changes in Raptor phosphorylation might be an upstream event in the pathway through which mechanical stimuli activate mTOR. To test this, we employed a phospho-defective mutant of Raptor (S696A/T706A/S863A) and found that the EC-induced activation of mTOR signaling was significantly blunted in muscles expressing this mutant. Furthermore, mutation of the three phosphorylation sites altered the interactions of Raptor with PRAS40 and p70S6k, and it also prevented the EC-induced dissociation of Raptor from p70S6k. Combined, these results suggest that changes in the phosphorylation of Raptor play an important role in the pathway through which mechanical stimuli activate mTOR signaling. PMID:24239769

  17. Interaction of PDK1 with phosphoinositides is essential for neuronal differentiation but dispensable for neuronal survival.

    PubMed

    Zurashvili, Tinatin; Cordón-Barris, Lluís; Ruiz-Babot, Gerard; Zhou, Xiangyu; Lizcano, Jose M; Gómez, Nestor; Giménez-Llort, Lydia; Bayascas, Jose R

    2013-03-01

    3-Phosphoinositide-dependent protein kinase 1 (PDK1) operates in cells in response to phosphoinositide 3-kinase activation and phosphatidylinositol-3,4,5-trisphosphate [PtdIns(3,4,5)P(3)] production by activating a number of AGC kinases, including protein kinase B (PKB)/Akt. Both PDK1 and PKB contain pleckstrin homology (PH) domains that interact with the PtdIns(3,4,5)P(3) second messenger. Disrupting the interaction of the PDK1 PH domain with phosphoinositides by expressing the PDK1 K465E knock-in mutation resulted in mice with reduced PKB activation. We explored the physiological consequences of this biochemical lesion in the central nervous system. The PDK1 knock-in mice displayed a reduced brain size due to a reduction in neuronal cell size rather than cell number. Reduced BDNF-induced phosphorylation of PKB at Thr308, the PDK1 site, was observed in the mutant neurons, which was not rate limiting for the phosphorylation of those PKB substrates governing neuronal survival and apoptosis, such as FOXO1 or glycogen synthase kinase 3 (GSK3). Accordingly, the integrity of the PDK1 PH domain was not essential to support the survival of different embryonic neuronal populations analyzed. In contrast, PKB-mediated phosphorylation of PRAS40 and TSC2, allowing optimal mTORC1 activation and brain-specific kinase (BRSK) protein synthesis, was markedly reduced in the mutant mice, leading to impaired neuronal growth and differentiation.

  18. 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. © The Author (2015). Published by Oxford University Press on behalf of Journal of Molecular Cell Biology, IBCB, SIBS, CAS. All rights reserved.

  19. 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.

  20. 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.

  1. 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].

  2. Quantification of operator actions during ATWS following MSIV closure

    SciTech Connect

    Luckas, W.J. Jr.; O'Brien, J.N.; Perline, R.K.; Spettell, C.M.

    1986-01-01

    Brookhaven National Laboratory (BNL) assisted the Accident Sequence Evaluation Program (ASEP) by performing a Human Reliability Analysis (HRA) of the operations crew tasks during the Anticipated Transient Without Scram (ATWS) accident sequence with Main Steam Isolation Valve (MSIV) closure at the Peach Bottom Atomic Power Station, Unit 2. A detailed task analysis was performed based on consideration of staffing, team interaction, and control room layout at Peach Bottom. ATWS scenarios developed by Oak Ridge National Laboratory (ORNL) and Idaho National Engineering Laboratory (INEL) were reviewed. Discussions were held with thermal-hydrodynamic/core neutronics engineers at BNL to determine the success criterion for tasks. Five major operator tasks were identified. After reviewing a computerized data base of human error probabilities (HEPs) from 19 probabilistic risk assessments (PRAs) for tasks similar to those above to establish the historic range of HEPs for such errors, consensus opinion and structured expert judgment was used to quantify each of these tasks at each branch point in the event tree within that range.

  3. Evaluation of Three Devices for the Isolation of the Stromal Vascular Fraction from Adipose Tissue and for ASC Culture: A Comparative Study.

    PubMed

    Rodriguez, Jonathan; Pratta, Anne-Sophie; Abbassi, Nacira; Fabre, Hugo; Rodriguez, Fanny; Debard, Cyrille; Adobati, Jacqueline; Boucher, Fabien; Mallein-Gerin, Frédéric; Auxenfans, Céline; Damour, Odile; Mojallal, Ali

    2017-01-01

    Adipose-derived stem/stromal cells (ASCs) reside in the stromal vascular fraction (SVF) of adipose tissue (AT) and can be easily isolated. However, extraction of the SVF from lipoaspirate is a critical step in generating ASC, and semiautomated devices have been developed to enhance the efficacy and reproducibility of the outcomes and to decrease manipulation and contamination. In this study, we compared the reference method used in our lab for SVF isolation from lipoaspirate, with three medical devices: GID SVF-1™, Puregraft™, and Stem.pras®. Cell yield and their viability were evaluated as well as their phenotype with flow cytometry. Further on, we determined their proliferative potential using population doublings (PD), PD time (PDT), and clonogenicity assay (CFU-F). Finally, we checked their genetic stability using RT-qPCR for TERT mRNA assay and karyotyping as well as their multilineage potential including adipogenic, chondrogenic, and osteogenic differentiation. Our results demonstrate that all the devices allow the production of SVF cells with consistent yield and viability, in less time than the reference method. Expanded cells from the four methods showed no significant differences in terms of phenotype, proliferation capabilities, differentiation abilities, and genetic stability.

  4. Value-impact assessment for resolution of generic safety issue 143 - availability of HVAC and chilled water systems

    SciTech Connect

    Daling, P.M.; Marler, J.E.; Vo, T.V.

    1995-02-01

    The Pacific Northwest Laboratory (PNL), under contract to the U.S. Nuclear Regulatory Commission (NRC), has conducted an assessment of the values (benefits) and impacts (costs) associated with potential resolutions to Generic Issue 143, {open_quotes}Availability of Heating, Ventilation, and Air Conditioning (HVAC) and Chilled Water Systems.{close_quotes} This assessment was conducted to identify vulnerabilities related to failure of HVAC, chilled water and room cooling systems and develop estimates of the core damage frequencies and public risks associated with failures of these systems. This information was used to develop proposed resolution strategies to this generic issue and perform a value/impact assessment to determine their cost-effectiveness. Probabilistic risk assessments (PRAs) for four representative plants from the basis for the core damage frequency and public risk calculations. Internally-initiated core damage sequences as well as external events were considered. Three proposed resolution strategies were developed for this safety issue and it was determined that all three were not cost-effective. Additional evaluations were performed to develop {open_quotes}generic{close_quotes} insights on potential design-related vulnerabilities and potential high-frequency accident sequences that involve failures of HVAC/room cooling functions.

  5. 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

    2014-12-05

    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.

  6. 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.

  7. 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.

  8. A first-principle study of the structural, elastic, lattice dynamical and thermodynamic properties of PrX (X=P, As)

    NASA Astrophysics Data System (ADS)

    Kocak, B.; Ciftci, Y. O.; Colakoglu, K.; Deligoz, E.

    2012-02-01

    The structural, phase transition, elastic, lattice dynamic and thermodynamic properties of rare-earth compounds PrP and PrAs with NaCl (B1), CsCl (B2), ZB (B3), WC (B h) and CuAu (L1 0) structures are investigated using the first principles calculations within the generalized gradient approximation (GGA). For the total-energy calculation, we have used the projected augmented plane-wave (PAW) implementation of the Vienna Ab-initio Simulation Package (VASP). Specifically, some basic physical parameters, e.g. lattice constants, bulk modulus, elastic constants, shear modulus, Young's modulus and Poison's ratio, are predicted. The obtained equilibrium structure parameters are in excellent agreement with the experimental and theoretical data. The temperature and pressure variations of the volume, bulk modulus, thermal expansion coefficient, heat capacity and Debye temperature are calculated in wide pressure and temperature ranges. The phonon dispersion curves and corresponding one-phonon density of states (DOS) for both compounds are also computed in the NaCl (B1) structure.

  9. Targeting protein kinase-b3 (akt3) signaling in melanoma.

    PubMed

    Madhunapantula, SubbaRao V; Robertson, Gavin P

    2017-03-01

    Deregulated Akt activity leading to apoptosis inhibition, enhanced proliferation and drug resistance has been shown to be responsible for 35-70% of advanced metastatic melanomas. Of the three isoforms, the majority of melanomas have elevated Akt3 expression and activity. Hence, potent inhibitors targeting Akt are urgently required, which is possible only if (a) the factors responsible for the failure of Akt inhibitors in clinical trials is known; and (b) the information pertaining to synergistically acting targeted therapeutics is available. Areas covered: This review provides a brief introduction of the PI3K-Akt signaling pathway and its role in melanoma development. In addition, the functional role of key Akt pathway members such as PRAS40, GSK3 kinases, WEE1 kinase in melanoma development are discussed together with strategies to modulate these targets. Efficacy and safety of Akt inhibitors is also discussed. Finally, the mechanism(s) through which Akt leads to drug resistance is discussed in this expert opinion review. Expert opinion: Even though Akt play key roles in melanoma tumor progression, cell survival and drug resistance, many gaps still exist that require further understanding of Akt functions, especially in the (a) metastatic spread; (b) circulating melanoma cells survival; and (c) melanoma stem cells growth.

  10. The Akt signaling pathway

    PubMed Central

    Madhunapantula, SubbaRao V; Mosca, Paul J

    2011-01-01

    Studies using cultured melanoma cells and patient tumor biopsies have demonstrated deregulated PI3 kinase-Akt3 pathway activity in ∼70% of melanomas. Furthermore, targeting Akt3 and downstream PRAS40 has been shown to inhibit melanoma tumor development in mice. Although these preclinical studies and several other reports using small interfering RNAs and pharmacological agents targeting key members of this pathway have been shown to retard melanoma development, analysis of early Phase I and Phase II clinical trials using pharmacological agents to target this pathway demonstrate the need for (1) selection of patients whose tumors have PI3 kinase-Akt pathway deregulation, (2) further optimization of therapeutic agents for increased potency and reduced toxicity, (3) the identification of additional targets in the same pathway or in other signaling cascades that synergistically inhibit the growth and progression of melanoma, and (4) better methods for targeted delivery of pharmaceutical agents inhibiting this pathway. In this review we discuss key potential targets in PI3K-Akt3 signaling, the status of pharmacological agents targeting these proteins, drugs under clinical development, and strategies to improve the efficacy of therapeutic agents targeting this pathway. PMID:22157148

  11. 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.

  12. 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.

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

    PubMed

    McMullen, David C; Hallenbeck, John M

    2010-08-01

    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 (Thr(308) and Ser(473)) 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.

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

    PubMed

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

    2016-02-24

    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.

  15. 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

  16. 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.

  17. 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

  18. The flavones apigenin and luteolin induce FOXO1 translocation but inhibit gluconeogenic and lipogenic gene expression in human cells.

    PubMed

    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.

  19. 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.

  20. Pulsatile delivery of a leucine supplement during long-term continuous enteral feeding enhances lean growth in term neonatal pigs.

    PubMed

    Boutry, Claire; El-Kadi, Samer W; Suryawan, Agus; Steinhoff-Wagner, Julia; Stoll, Barbara; Orellana, Renán A; Nguyen, Hanh V; Kimball, Scot R; Fiorotto, Marta L; Davis, Teresa A

    2016-04-15

    Neonatal pigs are used as a model to study and optimize the clinical treatment of infants who are unable to maintain oral feeding. Using this model, we have shown previously that pulsatile administration of leucine during continuous feeding over 24 h via orogastric tube enhanced protein synthesis in skeletal muscle compared with continuous feeding alone. To determine the long-term effects of leucine pulses, neonatal piglets (n = 11-12/group) were continuously fed formula via orogastric tube for 21 days, with an additional parenteral infusion of either leucine (CON + LEU; 800 μmol·kg(-1)·h(-1)) or alanine (CON + ALA) for 1 h every 4 h. The results show that body and muscle weights and lean gain were ∼25% greater, and fat gain was 48% lower in CON + LEU than CON + ALA; weights of other tissues were unaffected by treatment. Fractional protein synthesis rates in longissimus dorsi, gastrocnemius, and soleus muscles were ∼30% higher in CON + LEU compared with CON + ALA and were associated with decreased Deptor abundance and increased mTORC1, mTORC2, 4E-BP1, and S6K1 phosphorylation, SNAT2 abundance, and association of eIF4E with eIF4G and RagC with mTOR. There were no treatment effects on PKB, eIF2α, eEF2, or PRAS40 phosphorylation, Rheb, SLC38A9, v-ATPase, LAMTOR1, LAMTOR2, RagA, RagC, and LAT1 abundance, the proportion of polysomes to nonpolysomes, or the proportion of mRNAs encoding rpS4 or rpS8 associated with polysomes. Our results demonstrate that pulsatile delivery of a leucine supplement during 21 days of continuous enteral feeding enhances lean growth by stimulating the mTORC1-dependent translation initiation pathway, leading to protein synthesis in skeletal muscle of neonates.

  1. Traditional livestock breeding practices of men and women Somali pastoralists: trait preferences and selection of breeding animals.

    PubMed

    Marshall, K; Mtimet, N; Wanyoike, F; Ndiwa, N; Ghebremariam, H; Mugunieri, L; Costagli, R

    2016-12-01

    Somalia, one of the world's poorest countries, has livestock as the mainstay of the economy, with an estimated 65% of the population engaged in the livestock sector. This paper presents a gendered study on the traditional livestock breeding practices of Somali pastoralists for camels, cattle, sheep and goats, with a focus on documenting livestock traits of importance, the criteria used to select male breeding animals and the criteria used to cull female breeding animals. Data for the study were obtained by performing participatory rural appraisals (PRAs) with separate male and female pastoral groups from 20 settlements of the Tog-Dheer region of Somaliland (in north-western Somalia). In total, more than 500 pastoralists were involved. In terms of livestock ownership, goats were the most common species kept (97% of all households), followed by sheep (64%), camels (37%) and cattle (9%), with considerable herd size variation across households. Traits of key importance to the pastoralists varied by species and gender of the PRA group, but included adaptedness to harsh environmental conditions, high market value/high meat production and high milk production. The pastoralists practised sensible criteria for the selection of male breeding animals for all species, capturing aspects of productivity (milk yield, reproduction), adaptedness (good hardiness) and marketability (body size and conformation). Similarly, they practised sensible criteria for culling of female breeding animals, with females removed from the herd primarily for poor performance, but also to meet the livelihood needs of the family. Differences in the selection and culling criteria were noted by species, as well as gender of the pastoralists. On the whole, there was strong alignment between the livestock selection criteria used by the Somali pastoralists, their reasons for keeping livestock and the market requirements. This is not surprising given the intimate and long-standing relationship between Somali

  2. Disrupting the key circadian regulator CLOCK leads to age-dependent cardiovascular disease.

    PubMed

    Alibhai, Faisal J; LaMarre, Jonathan; Reitz, Cristine J; Tsimakouridze, Elena V; Kroetsch, Jeffrey T; Bolz, Steffen-Sebastian; Shulman, Alex; Steinberg, Samantha; Burris, Thomas P; Oudit, Gavin Y; Martino, Tami A

    2017-04-01

    The circadian mechanism underlies daily rhythms in cardiovascular physiology and rhythm disruption is a major risk factor for heart disease and worse outcomes. However, the role of circadian rhythms is generally clinically unappreciated. Clock is a core component of the circadian mechanism and here we examine the role of Clock as a vital determinant of cardiac physiology and pathophysiology in aging. Clock(Δ19/Δ19) mice develop age-dependent increases in heart weight, hypertrophy, dilation, impaired contractility, and reduced myogenic responsiveness. Young Clock(Δ19/Δ19) hearts express dysregulated mRNAs and miRNAs in the PTEN-AKT signal pathways important for cardiac hypertrophy. We found a rhythm in the Pten gene and PTEN protein in WT hearts; rhythmic oscillations are lost in Clock(Δ19/Δ19) hearts. Changes in PTEN are associated with reduced AKT activation and changes in downstream mediators GSK-3β, PRAS40, and S6K1. Cardiomyocyte cultures confirm that Clock regulates the AKT signalling pathways crucial for cardiac hypertrophy. In old Clock(Δ19/Δ19) mice cardiac AKT, GSK3β, S6K1 phosphorylation are increased, consistent with the development of age-dependent cardiac hypertrophy. Lastly, we show that pharmacological modulation of the circadian mechanism with the REV-ERB agonist SR9009 reduces AKT activation and heart weight in old WT mice. Furthermore, SR9009 attenuates cardiac hypertrophy in mice subjected to transverse aortic constriction (TAC), supporting that the circadian mechanism plays an important role in regulating cardiac growth. These findings demonstrate a crucial role for Clock in growth and renewal; disrupting Clock leads to age-dependent cardiomyopathy. Pharmacological targeting of the circadian mechanism provides a new opportunity for treating heart disease.

  3. Soluble bone-derived osteopontin promotes migration and stem-like behavior of breast cancer cells

    PubMed Central

    Pio, Graciella M.; Xia, Ying; Piaseczny, Matthew M.; Chu, Jenny E.

    2017-01-01

    Breast cancer is a leading cause of cancer death in women, with the majority of these deaths caused by metastasis to distant organs. The most common site of breast cancer metastasis is the bone, which has been shown to provide a rich microenvironment that supports the migration and growth of breast cancer cells. Additionally, growing evidence suggests that breast cancer cells that do successfully metastasize have a stem-like phenotype including high activity of aldehyde dehydrogenase (ALDH) and/or a CD44+CD24- phenotype. In the current study, we tested the hypothesis that these ALDHhiCD44+CD24- breast cancer cells interact with factors in the bone secondary organ microenvironment to facilitate metastasis. Specifically, we focused on bone-derived osteopontin and its ability to promote the migration and stem-like phenotype of breast cancer cells. Our results indicate that bone-derived osteopontin promotes the migration, tumorsphere-forming ability and colony-forming ability of whole population and ALDHhiCD44+CD24- breast cancer cells in bone marrow-conditioned media (an ex vivo representation of the bone microenvironment) (p≤0.05). We also demonstrate that CD44 and RGD-dependent cell surface integrins facilitate this functional response to bone-derived osteopontin (p≤0.05), potentially through activation of WNK-1 and PRAS40-related pathways. Our findings suggest that soluble bone-derived osteopontin enhances the ability of breast cancer cells to migrate to the bone and maintain a stem-like phenotype within the bone microenvironment, and this may contribute to the establishment and growth of bone metastases. PMID:28498874

  4. Disruption of REDD1 gene ameliorates sepsis-induced decrease in mTORC1 signaling but has divergent effects on proteolytic signaling in skeletal muscle.

    PubMed

    Steiner, Jennifer L; Crowell, Kristen T; Kimball, Scot R; Lang, Charles H

    2015-12-15

    Sepsis-induced skeletal muscle atrophy and weakness are due in part to decreased mTORC1-mediated protein synthesis and increased proteolysis via the autophagy-lysosomal system and ubiquitin-proteasome pathway. The REDD1 (regulated in development and DNA damage-1) protein is increased in sepsis and can negatively regulate mTORC1 activity. However, the contribution of REDD1 to the sepsis-induced change in muscle protein synthesis and degradation has not been determined. Sepsis was produced by cecal ligation and puncture in female REDD1(-/-) or wild-type (WT) mice, and end points were assessed 24 h later in gastrocnemius; time-matched, pair-fed controls of each genotype were included. Sepsis increased REDD1 protein 300% in WT mice, whereas REDD1 was absent in REDD1(-/-) muscle. Sepsis decreased protein synthesis and phosphorylation of downstream targets of mTORC1 (S6K1 Thr(389), rpS6 Ser(240/244), 4E-BP1 Ser(65)) in WT but not REDD1(-/-) mice. However, Akt and PRAS40 phosphorylation was suppressed in both sham and septic muscle from REDD1(-/-) mice despite unaltered PDK1, PP2A, or TSC2 expression. Sepsis increased autophagy as indicated by decreased ULK1 Ser(757) phosphorylation and p62 abundance and increased LC3B-II/I in WT mice, whereas these changes were absent in septic REDD1(-/-) mice. Conversely, REDD1 deletion did not prevent the sepsis-induced decrease in IGF-I mRNA or the concomitant increase in IL-6, TNFα, MuRF1, and atrogin1 mRNA expression. Lastly, 5-day survival in a separate set of septic mice did not differ between WT and REDD1(-/-) mice. These data highlight the central role of REDD1 in regulating both protein synthesis and autophagy in skeletal muscle during sepsis. Copyright © 2015 the American Physiological Society.

  5. Apoptosis-inducing Effect of a Palladium(II) Complex-[PdCl(terpy)](sac).2H2O] on Ehrlich Ascites Carcinoma (EAC) in Mice.

    PubMed

    Ikitimur-Armutak, Elif I; Ulukaya, Engin; Gurel-Gurevin, Ebru; Yaylim, Ilhan; Isbilen-Basok, Banu; Sennazli, Gulbin; Yuzbasioglu-Ozturk, Gulay; Sonmez, Kivilcim; Celik, Faruk; Kucukhuseyin, Ozlem; Korkmaz, Gurbet; Yilmaz, Veysel T; Zeybek, Sakir Umit

    2016-01-01

    New compounds for cancer treatment are needed due to persistenly unsatisfactory management of cancer. [PdCl(terpy)](sac)·2H2O] (sac=saccharinate, and terpy=2,2':6',2"-terpyridine) is a compound synthesized for this purpose. We investigated its anti-proliferative and pro-apoptotic effects on Ehrlich Ascites Carcinoma (EAC) in vivo. 42 Balb-c female mice were subcutaneously (s.c.) injected with EAC cells (1st day) and then randomly divided into 5 groups: control (0.9% NaCl), complex (2 mg/kg), complex (3 mg/kg) cisplatin (4 mg/kg) and paclitaxel (12.5 mg/kg). On the 5th and 12th day animals were drug administrated. At 14th day, animals were sacrificed. Expression of cell death and/or cell cycle-related markers (Bcl-2, Bax, active caspase-3, p53, PCNA) and apoptosis were investigated immunohisto-chemically. Survival-related markers (Akt, GSK-3β, IGF-1R, IR, IRS-1, p70S6K, PRAS40) were evaluated by luminex analysis. Expression of p53, PCNA, Bcl-2 was found decreased (p<0.001) and that of active caspase-3, Bax, and apoptotic cells was found increased (p<0.001) in all groups. The survival-related markers did not show any statistical difference in complex groups. The Pd(II)-complex seems to have a strong anticancer activity on EAC by inducing apoptosis via both suppression of proliferation and activation of apoptosis in vivo, similar to the effects of cisplatin and paclitaxel. Copyright © 2016 International Institute of Anticancer Research (Dr. John G. Delinassios), All rights reserved.

  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. PDK1 selectively phosphorylates Thr(308) on Akt and contributes to human platelet functional responses

    PubMed Central

    Dangelmaier, Carol; Manne, Bhanu Kanth; Liverani, Elizabetta; Jin, Jianguo; Bray, Paul; Kunapuli, Satya P.

    2014-01-01

    Summary 3-phosphoinositide-dependent protein kinase 1 (PDK1), a member of the protein A,G and C (AGC) family of proteins, is a Ser/Thr protein kinase that can phosphorylate and activate other protein kinases from the AGC family, including Akt at Thr308, all of which play important roles in mediating cellular responses. The functional role of PDK1 or the importance of phosphorylation of Akt on Thr308 for its activity has not been investigated in human platelets. In this study, we tested two pharmacological inhibitors of PDK1, BX795 and BX912, to assess the role of Thr308 phosphorylation on Akt. PAR4-induced phosphorylation of Akt onThr308 was inhibited by BX795 without affecting phosphorylation of Akt on Ser473. The lack of Thr308 phosphorylation on Akt also led to the inhibition of PAR4-induced phosphorylation of two downstream substrates of Akt, viz. GSK3β and PRAS40. In vitro kinase activity of Akt was completely abolished if Thr308 on Akt was not phosphorylated. BX795 caused inhibition of 2-MeSADP-induced or collagen-induced aggregation, ATP secretion and thromboxane generation. Primary aggregation induced by 2-MeSADP was also inhibited in the presence of BX795. PDK1 inhibition also resulted in reduced clot retraction indicating its role in outside-in signalling. These results demonstrate that PDK1 selectively phosphorylates Thr308 on Akt thereby regulating its activity and plays a positive regulatory role in platelet physiological responses. PMID:24352480

  8. Moderate alcohol consumption does not impair overload-induced muscle hypertrophy and protein synthesis

    PubMed Central

    Steiner, Jennifer L; Gordon, Bradley S; Lang, Charles H

    2015-01-01

    Chronic alcohol consumption leads to muscle weakness and atrophy in part by suppressing protein synthesis and mTORC1-mediated signaling. However, it is unknown whether moderate alcohol consumption also prevents overload-induced muscle growth and related anabolic signaling. Hypertrophy of the plantaris muscle was induced by removal of a section of the gastrocnemius and soleus muscles from one leg of C57BL/6 adult male mice while the contralateral leg remained intact as the sham control. A nutritionally complete alcohol-containing liquid diet (EtOH) or isocaloric, alcohol-free liquid diet (Con) was provided for 14 days post-surgery. EtOH intake was increased progressively (day 1–5) before being maintained at ∽20 g/day/kg BW. The plantaris muscle from the sham and OL leg was removed after 14 days at which time there was no difference in body weight between Con and EtOH-fed mice. OL increased muscle weight (90%) and protein synthesis (125%) in both Con and EtOH mice. The overload-induced increase in mTOR (Ser2448), 4E-BP1 (Thr37/46), S6K1 (Thr389), rpS6 (Ser240/244), and eEF2 (Thr56) were comparable in muscle from Con and EtOH mice. Modulation of signaling upstream of mTORC1 including REDD1 protein expression, Akt (Thr308), PRAS40 (Thr246), and ERK (Thr202/Tyr204) also did not differ between Con and EtOH mice. Markers of autophagy (ULK1, p62, and LC3) suggested inhibition of autophagy with overload and activation with alcohol feeding. These data show that moderate alcohol consumption does not impair muscle growth, and therefore imply that resistance exercise may be an effective therapeutic modality for alcoholic-related muscle disease. PMID:25780086

  9. Anti-diabetic activity of aerial parts of Sarcopoterium spinosum.

    PubMed

    Elyasiyan, Uriel; Nudel, Adi; Skalka, Nir; Rozenberg, Konstantin; Drori, Elyashiv; Oppenheimer, Rachela; Kerem, Zohar; Rosenzweig, Tovit

    2017-07-06

    Sarcopoterium spinosum (S. spinosum) is used by Bedouin medicinal practitioners for the treatment of diabetes. While the anti-diabetic activity of S. spinosum root extract was validated in previous studies, the activity of aerial parts of the same plants has not been elucidated yet. The aim of this study was to clarify the glucose lowering properties of the aerial parts of the shrub. Anti-diabetic properties were evaluated by measuring the activity of carbohydrate digesting enzymes, glucose uptake into 3 T3-L1 adipocytes, and insulin secretion. Insulin signaling cascade was followed in L6 myotubes using Western blot and PathScan analysis. Activity of α-amylase and α-glucosidase was inhibited by extracts of all S. spinosum organs. Basal and glucose-induced insulin secretion was measured in Min6 cells and found to be enhanced as well. Glucose uptake was induced by all S. spinosum extracts, with roots found to be the most effective and fruits the least. The effect of S. spinosum on Akt phosphorylation was minor compared to insulin effect. However, GSK3β and PRAS40, which are downstream elements of the insulin cascade, were found to be highly phosphorylated by S. spinosum extracts. Inhibition of PI3K and Akt, but not AMPK and ERK, abrogated the induction of glucose uptake by the aerial parts of the shrub. The aerial organs of S. spinosum have anti-diabetic properties and may be used as a basis for the development of dietary supplements or to identify new agents for the treatment of type 2 diabetes.

  10. 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.

  11. 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.

  12. 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.

  13. 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

    2014-12-12

    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.

  14. 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.

  15. Benzyl Isothiocyanate potentiates p53 signaling and antitumor effects against breast cancer through activation of p53-LKB1 and p73-LKB1 axes

    PubMed Central

    Xie, Bei; Nagalingam, Arumugam; Kuppusamy, Panjamurthy; Muniraj, Nethaji; Langford, Peter; Győrffy, Balázs; Saxena, Neeraj K.; Sharma, Dipali

    2017-01-01

    Functional reactivation of p53 pathway, although arduous, can potentially provide a broad-based strategy for cancer therapy owing to frequent p53 inactivation in human cancer. Using a phosphoprotein-screening array, we found that Benzyl Isothiocynate, (BITC) increases p53 phosphorylation in breast cancer cells and reveal an important role of ERK and PRAS40/MDM2 in BITC-mediated p53 activation. We show that BITC rescues and activates p53-signaling network and inhibits growth of p53-mutant cells. Mechanistically, BITC induces p73 expression in p53-mutant cells, disrupts the interaction of p73 and mutant-p53, thereby releasing p73 from sequestration and allowing it to be transcriptionally active. Furthermore, BITC-induced p53 and p73 axes converge on tumor-suppressor LKB1 which is transcriptionally upregulated by p53 and p73 in p53-wild-type and p53-mutant cells respectively; and in a feed-forward mechanism, LKB1 tethers with p53 and p73 to get recruited to p53-responsive promoters. Analyses of BITC-treated xenografts using LKB1-null cells corroborate in vitro mechanistic findings and establish LKB1 as the key node whereby BITC potentiates as well as rescues p53-pathway in p53-wild-type as well as p53-mutant cells. These data provide first in vitro and in vivo evidence of the integral role of previously unrecognized crosstalk between BITC, p53/LKB1 and p73/LKB1 axes in breast tumor growth-inhibition. PMID:28071670

  16. The metabolic waste ammonium regulates mTORC2 and mTORC1 signaling

    PubMed Central

    Merhi, Ahmad; Delrée, Paul; Marini, Anna Maria

    2017-01-01

    Two structurally and functionally distinct mammalian TOR complexes control cell growth and metabolism in physiological and pathological contexts including cancer. Upregulated glutaminolysis is part of the metabolic reprogramming occurring in cancer, providing fuels for growth but also liberating ammonium, a potent neurotoxic waste product. Here, we identify ammonium as a novel dose-dependent signal mediating rapid mTORC2 activation and further regulating mTORC1. We show that ammonium induces rapid RICTOR-dependent phosphorylation of AKT-S473, a process requiring the PI3K pathway and further involving the Src-family kinase YES1, the FAK kinase and the ITGβ1 integrin. Release of calcium from the endoplasmic reticulum store triggers rapid mTORC2 activation, similar to ammonium-induced activation, the latter being conversely prevented by calcium chelation.Moreover, in analogy to growth factors, ammonium triggers the AKT-dependent phosphoinhibition of the TSC complex and of PRAS40, two negative regulators of mTORC1. Consistent with mTORC1 stimulation, ammonium induces the inhibitory phosphorylation of 4EBP1, a negative regulator of protein biogenesis. Ammonium however dually impacts on the phosphorylation of p70S6K1 triggering a transient AKT-independent decrease in the phosphorylation of this second mTORC1 readout. Finally, we reveal ammonium as a dose-dependent stimulator of proliferation. This study underscores an mTORC2 and mTORC1 response to the so-called ammonium waste. PMID:28303961

  17. Effects of an oral allosteric AKT inhibitor (MK-2206) on human nasopharyngeal cancer in vitro and in vivo

    PubMed Central

    Zhao, Yuan-Yuan; Tian, Ying; Zhang, Jing; Xu, Fei; Yang, Yun-Peng; Huang, Yan; Zhao, Hong-Yun; Zhang, Jian-Wei; Xue, Cong; Lam, Michael H; Yan, Li; Hu, Zhi-Huang; Dinglin, Xiao-Xiao; Zhang, Li

    2014-01-01

    Aim Protein kinase B (AKT) signaling frequently is deregulated in human cancers and plays an important role in nasopharyngeal carcinoma (NPC). This preclinical study investigated the effect of MK-2206, a potent allosteric AKT inhibitor, on human NPC cells in vitro and in vivo. Methods The effect of MK-2206 on the growth and proliferation of CNE-1, CNE-2, HONE-1, and SUNE-1 cells was assessed by Cell Counting Kit 8 and colony formation assay. Flow cytometry was performed to analyze cell cycle and apoptosis. The effects of MK-2206 on the AKT pathway were analyzed by Western blotting. Autophagy induction was evaluated via electron microscopy and Western blot. To test the effects of MK-2206 in vivo, CNE-2 cells were subcutaneously implanted into nude mice. Tumor-bearing mice were treated orally with MK-2206 or placebo. Tumors were harvested for immunohistochemical analysis. Results In vitro, MK-2206 inhibited the four NPC cell line growths and reduced the sizes of the colonies in a dose-dependent manner. At 72 and 96 hours, the half maximal inhibitory concentration (IC50) values of MK-2206 in CNE-1, CNE-2, and HONE-1 cell lines were 3–5 μM, whereas in SUNE-1, IC50 was less than 1 μM, and MK-2206 induced cell cycle arrest at the G1 phase. However, our study found no evidence of apoptosis. MK-2206 induced autophagy in NPC cells, as evidenced by electron microscopy and Western blot, and inhibited the growth of tumors that were subcutaneously implanted in mice. Inhibition of downstream phosphorylation through the PRAS40 and S6 pathways seems to be the main mechanism for the MK-2206-induced growth inhibition. Conclusion Our preclinical study suggests that MK-2206’s antiproliferative effect may be useful for NPC treatment; however, strategies for reinforcing this effect are needed to maximize clinical benefit. PMID:25336925

  18. Seismic Fragility Analysis of a Condensate Storage Tank with Age-Related Degradations

    SciTech Connect

    Nie, J.; Braverman, J.; Hofmayer, C; Choun, Y-S; Kim, MK; Choi, I-K

    2011-04-01

    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. This report describes the research effort performed by BNL for the Year 4 scope of work. This report was developed as an update to the Year 3 report by incorporating a major supplement to the Year 3 fragility analysis. In the Year 4 research scope, an additional study was carried out to consider an additional degradation scenario, in which the three basic degradation scenarios, i.e., degraded tank shell, degraded anchor bolts, and cracked anchorage concrete, are combined in a non-perfect correlation manner. A representative operational water level is used for this effort. Building on the same CDFM procedure implemented for the Year 3 Tasks, a simulation method was applied using optimum Latin Hypercube samples to characterize the deterioration behavior of the fragility capacity as a function of age-related degradations. The results are summarized in Section 5

  19. AKT1 E17K in Colorectal Carcinoma Is Associated with BRAF V600E but Not MSI-H Status: A Clinicopathologic Comparison to PIK3CA Helical and Kinase Domain Mutants

    PubMed Central

    Hechtman, Jaclyn F.; Sadowska, Justyna; Huse, Jason T.; Borsu, Laetitia; Yaeger, Rona; Shia, Jinru; Vakiani, Efsevia; Ladanyi, Marc; Arcila, Maria E.

    2016-01-01

    The PI3K/AKT/mTOR pathway is activated through multiple mechanisms in colorectal carcinoma. Here, the clinicopathologic and molecular features of AKT1 E17K–mutated colorectal carcinoma in comparison with PIK3CA-mutated colorectal carcinoma are described in detail. Interestingly, in comparison with PIK3CA mutants, AKT1 E17K was significantly associated with mucinous morphology and concurrent BRAF V600E mutation. Among PIK3CA mutants, exon 21 mutations were significantly associated with BRAF V600E mutation, MSI-H status, and poor differentiation, while exon 10 mutations were associated with KRAS/NRAS mutations. Three of four AKT1 mutants with data from both primary and metastatic lesions had concordant AKT1 mutation status in both. Both AKT1-and PIK3CA-mutant colorectal carcinoma demonstrated frequent loss of PTEN expression (38% and 34%, respectively) and similar rates of p-PRAS 40 expression (63% and 50%, respectively). Both patients with AKT1 E17K alone had primary resistance to cetuximab, whereas 7 of 8 patients with PIK3CA mutation alone experienced tumor shrinkage or stability with anti-EGFR therapy. These results demonstrate that AKT1 E17K mutation in advanced colorectal carcinoma is associated with mucinous morphology, PIK3CA wild-type status, and concurrent RAS/RAF mutations with similar pattern to PIK3CA exon 21 mutants. Thus, AKT1 E17K mutations contribute to primary resistance to cetuximab and serve as an actionable alteration. PMID:25714871

  20. 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.

  1. Role of AKT/mTORC1 pathway in pancreatic β-cell proliferation.

    PubMed

    Balcazar Morales, Norman; Aguilar de Plata, Cecilia

    2012-07-01

    Growth factors, insulin signaling and nutrients are important regulators of β-cell mass and function. The events linking these signals to regulation of β-cell mass are not completely understood. Recent findings indicate that mTOR pathway integrates signals from growth factors and nutrients with transcription, translation, cell size, cytoskeleton remodeling and mitochondrial metabolism. mTOR is a part of two distinct complexes; mTORC1 and mTORC2. The mammalian TORC1 is sensitive to rapamycin and contains Raptor, deptor, PRAS40 and the G protein β-subunit-like protein (GβL). mTORC1 activates key regulators of protein translation; ribosomal S6 kinase (S6K) and eukaryote initiation factor 4E-binding protein 1. This review summarizes current findings about the role of AKT/mTORC1 signaling in regulation of pancreatic β cell mass and proliferation. mTORC1 is a major regulator of β-cell cycle progression by modulation of cyclins D2, D3 and cdk4/cyclin D activity. These studies uncovered key novel pathways controlling cell cycle progression in β-cells in vivo. This information can be used to develop alternative approaches to expand β-cell mass in vivo and in vitro without the risk of oncogenic transformation. The acquisition of such knowledge is critical for the design of improved therapeutic strategies for the treatment and cure of diabetes as well as to understand the effects of mTOR inhibitors in β-cell function.

  2. 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.

  3. Does breast-feeding affect severity of familial Mediterranean fever?

    PubMed

    Makay, Balahan; Unsal, Erbil

    2009-12-01

    Familial Mediterranean fever (FMF) is the most common inherited autoinflammatory disease, which is caused by an inborn error in innate immune system. It was shown that disease severity of patients of the same ethnic origin differed according to different country of residence, suggesting an influence of environment on phenotype of FMF. Different microbial milieus of the countries were accused. Breast-feeding has an important role on innate immunity and protects the infant from infections. The aim of this study is to investigate whether being breast-fed and duration of breast-feeding has an impact on disease severity of FMF. The mothers of patients were asked to fill a questionnaire about the feeding type in infancy. Mode of delivery, gestational age, and age at onset of FMF symptoms were also asked. The disease severity score of each patient was calculated according to the scoring system suggested by Pras et al. (Am J Med Genet 75:216-219, 1998). MEFV mutations were noted. The mothers of 81 FMF patients completed the questionnaire. Fifteen patients (18.5%) had mild, 49 (60.5%) had moderate, and 17 (21%) had severe disease. All the patients except four were breast-fed for some period. The duration of breast-feeding was similar between three severity groups. Time to introduce cow's milk and complementary foods also did not differ between groups. Longer duration of breast-feeding did not delay the onset of FMF symptoms. Mode of delivery and gestational age had no effect on disease severity. Patients homozygous for M694V had higher severity scores. This preliminary study suggests that breast-feeding is not an exogenous factor having an influence on phenotype of FMF. M694V genotype seems to cause more severe disease.

  4. 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

  5. REDD1 deletion prevents dexamethasone-induced skeletal muscle atrophy.

    PubMed

    Britto, Florian A; Begue, Gwenaelle; Rossano, Bernadette; Docquier, Aurélie; Vernus, Barbara; Sar, Chamroeun; Ferry, Arnaud; Bonnieu, Anne; Ollendorff, Vincent; Favier, François B

    2014-12-01

    REDD1 (regulated in development and DNA damage response 1) has been proposed to inhibit the mechanistic target of rapamycin complex 1 (mTORC1) during in vitro hypoxia. REDD1 expression is low under basal conditions but is highly increased in response to several catabolic stresses, like hypoxia and glucocorticoids. However, REDD1 function seems to be tissue and stress dependent, and its role in skeletal muscle in vivo has been poorly characterized. Here, we investigated the effect of REDD1 deletion on skeletal muscle mass, protein synthesis, proteolysis, and mTORC1 signaling pathway under basal conditions and after glucocorticoid administration. Whereas skeletal muscle mass and typology were unchanged between wild-type (WT) and REDD1-null mice, oral gavage with dexamethasone (DEX) for 7 days reduced tibialis anterior and gastrocnemius muscle weights as well as tibialis anterior fiber size only in WT. Similarly, REDD1 deletion prevented the inhibition of protein synthesis and mTORC1 activity (assessed by S6, 4E-BP1, and ULK1 phosphorylation) observed in gastrocnemius muscle of WT mice following single DEX administration for 5 h. However, our results suggest that REDD1-mediated inhibition of mTORC1 in skeletal muscle is not related to the modulation of the binding between TSC2 and 14-3-3. In contrast, our data highlight a new mechanism involved in mTORC1 inhibition linking REDD1, Akt, and PRAS40. Altogether, these results demonstrated in vivo that REDD1 is required for glucocorticoid-induced inhibition of protein synthesis via mTORC1 downregulation. Inhibition of REDD1 may thus be a strategy to limit muscle loss in glucocorticoid-mediated atrophy. Copyright © 2014 the American Physiological Society.

  6. Efficacy of AKT Inhibitor ARQ 092 Compared with Sorafenib in a Cirrhotic Rat Model with Hepatocellular Carcinoma.

    PubMed

    Roth, Gaël S; Macek Jilkova, Zuzana; Zeybek Kuyucu, Ayca; Kurma, Keerthi; Ahmad Pour, Séyédéh Tayébéh; Abbadessa, Giovanni; Yu, Yi; Busser, Benoit; Marche, Patrice N; Leroy, Vincent; Decaens, Thomas

    2017-10-01

    Hepatocellular carcinoma (HCC) is the second most common cause of cancer-related mortality worldwide. The AKT pathway has been found activated in 50% of HCC cases, making it a promising target. Therefore, we assess efficacy of the allosteric AKT inhibitor ARQ 092 compared with untreated control and standard treatment, sorafenib, in vitro and in vivo ARQ 092 blocked phosphorylation of AKT in vitro and strongly inhibited cell growth with significantly higher potency than sorafenib. Similarly, apoptosis and cell migration were strongly reduced by ARQ 092 in vitro To mimic human advanced HCC, we used a diethylnitrosamine-induced cirrhotic rat model with fully developed HCC. MRI analyses showed that ARQ 092 significantly reduced overall tumor size. Furthermore, number of tumors was decreased by ARQ 092, which was associated with increased apoptosis and decreased proliferation. Tumor contrast enhancement was significantly decreased in the ARQ 092 group. Moreover, on tumor tissue sections, we observed a vascular normalization and a significant decrease in fibrosis in the surrounding liver of animals treated with ARQ 092. Finally, pAKT/AKT levels in ARQ 092-treated tumors were reduced, followed by downregulation of actors of AKT downstream signaling pathway: pmTOR, pPRAS40, pPLCγ1, and pS6K1. In conclusion, we demonstrated that ARQ 092 blocks AKT phosphorylation in vitro and in vivo In the HCC-rat model, ARQ 092 was well tolerated, showed antifibrotic effect, and had stronger antitumor effect than sorafenib. Our results confirm the importance of targeting AKT in HCC. Mol Cancer Ther; 16(10); 2157-65. ©2017 AACR. ©2017 American Association for Cancer Research.

  7. Erythropoietin and mTOR: A “One-Two Punch” for Aging-Related Disorders Accompanied by Enhanced Life Expectancy

    PubMed Central

    Maiese, Kenneth

    2016-01-01

    Life expectancy continues to increase throughout the world, but is accompanied by a rise in the incidence of non-communicable diseases. As a result, the benefits of an increased lifespan can be limited by aging-related disorders that necessitate new directives for the development of effective and safe treatment modalities. With this objective, the mechanistic target of rapamycin (mTOR), a 289-kDa serine/threonine protein, and its related pathways of mTOR Complex 1 (mTORC1), mTOR Complex 2 (mTORC2), proline rich Akt substrate 40 kDa (PRAS40), AMP activated protein kinase (AMPK), Wnt signaling, and silent mating type information regulation 2 homolog 1 (Saccharomyces cerevisiae) (SIRT1), have generated significant excitement for furthering novel therapies applicable to multiple systems of the body. Yet, the biological and clinical outcome of these pathways can be complex especially with oversight of cell death mechanisms that involve apoptosis and autophagy. Growth factors, and in particular erythropoietin (EPO), are one avenue under consideration to implement control over cell death pathways since EPO can offer potential treatment for multiple disease entities and is intimately dependent upon mTOR signaling. In experimental and clinical studies, EPO appears to have significant efficacy in treating several disorders including those involving the developing brain. However, in mature populations that are affected by aging-related disorders, the direction for the use of EPO to treat clinical disease is less clear that may be dependent upon a number of factors including the understanding of mTOR signaling. Continued focus upon the regulatory elements that control EPO and mTOR signaling could generate critical insights for targeting a broad range of clinical maladies. PMID:27488211

  8. An Arabidopsis Prenylated Rab Acceptor 1 Isoform, AtPRA1.B6, Displays Differential Inhibitory Effects on Anterograde Trafficking of Proteins at the Endoplasmic Reticulum1[W][OA

    PubMed Central

    Lee, Myoung Hui; Jung, Chanjin; Lee, Junho; Kim, Soo Youn; Lee, Yongjik; Hwang, Inhwan

    2011-01-01

    Prenylated Rab acceptors (PRAs), members of the Ypt-interacting protein family of small membrane proteins, are thought to aid the targeting of prenylated Rabs to their respective endomembrane compartments. In plants, the Arabidopsis (Arabidopsis thaliana) PRA1 family contains 19 members that display varying degrees of sequence homology to animal PRA1 and localize to the endoplasmic reticulum (ER) and/or endosomes. However, the exact role of these proteins remains to be fully characterized. In this study, the effect of AtPRA1.B6, a member of the AtPRA1 family, on the anterograde trafficking of proteins targeted to various endomembrane compartments was investigated. High levels of AtPRA1.B6 resulted in differential inhibition of coat protein complex II vesicle-mediated anterograde trafficking. The trafficking of the vacuolar proteins sporamin:GFP (for green fluorescent protein) and AALP:GFP, the secretory protein invertase:GFP, and the plasma membrane proteins PMP:GFP and H+-ATPase:GFP was inhibited in a dose-dependent manner, while the trafficking of the Golgi-localized proteins ST:GFP and KAM1(ΔC):mRFP was not affected. Conversely, in RNA interference plants displaying lower levels of AtPRA1.B6 transcripts, the trafficking efficiency of sporamin:GFP and AALP:GFP to the vacuole was increased. Localization and N-glycan pattern analyses of cargo proteins revealed that AtPRA1.B6-mediated inhibition of anterograde trafficking occurs at the ER. In addition, AtPRA1.B6 levels were controlled by cellular processes, including 26S proteasome-mediated proteolysis. Based on these results, we propose that AtPRA1.B6 is a negative regulator of coat protein complex II vesicle-mediated anterograde trafficking for a subset of proteins at the ER. PMID:21828250

  9. Evaluation of cochlear functions in children with Familial Mediterranean Fever.

    PubMed

    Lordoglu, Begüm; Acar, Baran; Yazilitas, Fatma; Ozlu, Sare Gulfem; Senel, Saliha

    2016-08-01

    To evaluate cochlear functions in patients with Familial Mediterranean Fever in relation to the disease severity score and treatment duration. 50 patients (4-18 years) who had been followed-up with the diagnosis of FMF and regularly receiving appropriate colchicine treatment and 39 healthy controls were included in the study. All the patients and controls were evaluated by audiologic evaluation, including high-frequency pure-tone audiometry and distortion product otoacoustic emission tests (DPOAE). The disease severity was determined by scoring system developed by Pras et al. Fifty patients (52% female, 48% male; mean age12.2 ± 4.1 years) and 39 controls (58.9% female, 41.1% male, mean age 11.1 ± 3.4 years) were enrolled the study. The pure tone average of FMF patients was significantly higher than that of the control group at 500, 4000, and 8000 Hz frequencies. The patients' DPOAE signal values at 6 kHz, 8 kHz frequencies and SNR values at 8 kHz were significantly higher than control group. The patients' audiometry and DPOAE results were compared with the disease severity scores. Pure tone average was significantly higher in severe and moderate patient groups compared to the mild patient group at 2000 Hz frequency. DPOAE signal values showed statistically significant differences between the patient severity scores at 1.4 and 2.8 kHz frequencies. The mean colchicine treatment duration was found to be 5.1 ± 3.7 years. There were significant differences at 250 and 500 Hz frequencies when patients' audiometry results were compared with the treatment periods. FMF affects cochlear functions particularly at high frequencies. Copyright © 2016 Elsevier Ireland Ltd. All rights reserved.

  10. The clinical utility of two renin mass methods to detect primary hyperaldosteronism compared with renin activity.

    PubMed

    Wedatilake, Yehani N; Scanlon, Mike J; Barnes, Sophie C

    2011-05-01

    Primary hyperaldosteronism (PHA) is characterized by a raised plasma aldosterone concentration (PAC) with suppressed plasma renin activity (PRA). We evaluated two renin mass methods for PHA detection compared with the PAC:PRA ratio. Samples from patients attending a specialist hypertensive clinic were analysed by Liaison automated chemiluminescent immunoassay and Diagnostic Systems Laboratories (DSL) immunoradiometric assay (IRMA) for renin mass; I(-125) radioimmunoassay of angiotensin I generated from endogenous angiotensinogen for PRA; Siemens Coat-a-count radioimmunoassay for PAC. Subjects included those on β-blockers which suppress renin, causing an equivalent biochemical picture to PHA. Aldosterone/renin ratios (ARR) were calculated for PRA, DSL and Liaison methods. The first 100 subjects were used to identify cut-off ratios ensuring maximum specificity at 100% sensitivity for PHA detection. This cut-off was retested in a subsequent population (n = 43). A Liaison renin of 5 ng/L separated PRAs of ≤0.5 from ≥0.6 pmol/mL/h. The DSL method had greater scatter. In population 1 (18 PHA), cut-off ratios of >118 pmol/ng (Liaison) and >60 pmol/ng (DSL) gave specificities of 58.5% and 61%, respectively, with 100% sensitivity. If criteria for PHA included PAC ≥350 pmol/L and excluded β-blocked subjects, specificity increased to 95.1% and 90% for Liaison and DSL, respectively. In population 2 (6 PHA), specificities for Liaison and DSL ARRs were 86.4% and 78.3%. Using the ratio with PAC and β-blocker criteria, specificities for Liaison and DSL were 97.3% and 86.5%, respectively. The Liaison ARR used with PAC and β-blocker criteria provided an automatable alternative to identify the same patients as the PAC:PRA ratio.

  11. Analysis of the results of the Midland PRA

    SciTech Connect

    Bozoki, G.; Teichmann, T.

    1986-01-01

    This paper presents the results of a limited review of the Midland PRA (MPRA), aimed at facilitating regulatory analyses and at providing insights into safety related plant failures. In particular, stress was laid on the root causes of accident sequences, particularly their failure modes, viz., hardware, human, maintenance, test, and repair. Because this information was difficult to extract in this detailed and sophisticated PRA (and in certain others) a special algorithm was developed to display the leading sequences contributing to core damage and/or to public risk in terms of the above generic failure modes. This was done in a hierarchical fashion to allow tracing the important accident sequences to the systems failures. The weighted core damage frequency (CDF) values of the sequences considered then provided a (quantitative) ranked importance listing of these failure modes, led by hardware failures (in 78%) and human factors (in 37%), etc. Multiple maintenance situations (reflecting on test and maintenance specifications) were also evaluated, but played only a small role (less than or equal to3%). Similar tabulations were also made of the (weighted) importance of the support systems (such as the electric power system, the component cooling water systems, etc.) and of the role of the major systems/functions (e.g., high pressure injection, etc.) contributions to these accident sequences. Finally, the role of certain particular operational and plant features (e.g., loss of offsite power initiators, RCP seal failure, bunkering, etc.) were briefly examined. The methods displayed seem applicable to an important class of extant and projected PRAs.

  12. 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.

  13. RhoA modulates signaling through the mechanistic target of rapamycin complex 1 (mTORC1) in mammalian cells

    PubMed Central

    Gordon, Bradley S.; Kazi, Abid A.; Coleman, Catherine S.; Dennis, Michael D.; Chau, Vincent; Jefferson, Leonard S.; Kimball, Scot R.

    2014-01-01

    The mechanistic target of rapamycin (mTOR) in complex 1 (mTORC1) pathway integrates signals generated by hormones and nutrients to control cell growth and metabolism. The activation state of mTORC1 is regulated by a variety of GTPases including Rheb and Rags. Recently, Rho1, the yeast ortholog of RhoA, was shown to interact directly with TORC1 and repress its activation state in yeast. Thus, the purpose of the present study was to test the hypothesis that the RhoA GTPase modulates signaling through mTORC1 in mammalian cells. In support of this hypothesis, exogenous overexpression of either wild type or constitutively active (ca)RhoA repressed mTORC1 signaling as assessed by phosphorylation of p70S6K1 (Thr389), 4E-BP1 (Ser65) and ULK1 (Ser757). Additionally, RhoA·GTP repressed phosphorylation of mTORC1-associatedmTOR (Ser2481). The RhoA·GTP mediated repression of mTORC1 signaling occurred independent of insulin or leucine induced stimulation. In contrast to the action of Rho1 in yeast, no evidence was found to support a direct interaction of RhoA·GTP with mTORC1. Instead, expression of caRheb, but not caRags, was able to rescue the RhoA·GTP mediated repression of mTORC1 suggesting RhoA functions upstream of Rheb to repress mTORC1 activity. Consistent with this suggestion, RhoA·GTP repressed phosphorylation of TSC2 (Ser939), PRAS40 (Thr246), Akt (Ser473), and mTORC2-associated mTOR (Ser2481). Overall, the results support a model in which RhoA·GTP represses mTORC1 signaling upstream of Akt and mTORC2. PMID:24316235

  14. Fisetin induces autophagic cell death through suppression of mTOR signaling pathway in prostate cancer cells

    PubMed Central

    Suh, Yewseok; Afaq, Farrukh; Khan, Naghma; Johnson, Jeremy J.; Khusro, Fatima H.; Mukhtar, Hasan

    2010-01-01

    The mammalian target of rapamycin (mTOR) kinase is an important component of PTEN/PI3K/Akt signaling pathway, which is frequently deregulated in prostate cancer (CaP). Recent studies suggest that targeting PTEN/PI3K/Akt and mTOR signaling pathway could be an effective strategy for the treatment of hormone refractory CaP. Here, we show that the treatment of androgen-independent and PTEN-negative human CaP PC3 cells with fisetin, a dietary flavonoid, resulted in inhibition of mTOR kinase signaling pathway. Treatment of cells with fisetin inhibited mTOR activity and downregulated Raptor, Rictor, PRAS40 and GβL that resulted in loss of mTOR complexes (mTORC)1/2 formation. Fisetin also activated the mTOR repressor TSC2 through inhibition of Akt and activation of AMPK. Fisetin-mediated inhibition of mTOR resulted in hypophosphorylation of 4EBP1 and suppression of Cap-dependent translation. We also found that fisetin treatment leads to induction of autophagic-programmed cell death rather than cytoprotective autophagy as shown by small interfering RNA Beclin1-knockdown and autophagy inhibitor. Taken together, we provide evidence that fisetin functions as a dual inhibitor of mTORC1/2 signaling leading to inhibition of Cap-dependent translation and induction of autophagic cell death in PC3 cells. These results suggest that fisetin could be a useful chemotherapeutic agent in treatment of hormone refractory CaP. PMID:20530556

  15. DUAL INHIBITION OF PI3K/AKT AND mTOR SIGNALING IN HUMAN NON-SMALL CELL LUNG CANCER CELLS BY A DIETARY FLAVONOID FISETIN

    PubMed Central

    Khan, Naghma; Afaq, Farrukh; Khusro, Fatima H.; Adhami, Vaqar Mustafa; Suh, Yewseok; Mukhtar, Hasan

    2011-01-01

    Lung cancer is one of the most commonly occurring malignancies. It has been reported that mTOR is phosphorylated in lung cancer and its activation was more frequent in tumors with over-expression of PI3K/Akt. Therefore, dual inhibitors of PI3K/Akt and mTOR signaling could be valuable agents for treating lung cancer. In the present study, we show that fisetin, a dietary tetrahydroxyflavone inhibits cell-growth with the concomitant suppression of PI3K/Akt and mTOR signaling in human non-small cell lung cancer (NSCLC) cells. Using autodock 4, we found that fisetin physically interacts with the mTOR complex at two sites. Fisetin treatment was also found to reduce the formation of A549 cell colonies in a dose-dependent manner. Treatment of cells with fisetin caused decrease in the protein expression of PI3K (p85 and p110), inhibition of phosphorylation of Akt, mTOR, p70S6K1, eIF-4E and 4E-BP1. Fisetin-treated cells also exhibited dose-dependent inhibition of the constituents of mTOR signaling complex like Rictor, Raptor, GβL and PRAS40. There was increase in the phosphorylation of AMPKα and decrease in the phosphorylation of TSC2 on treatment of cells with fisetin. We also found that treatment of cells with mTOR inhibitor rapamycin and mTOR-siRNA caused decrease in phosphorylation of mTOR and its target proteins which were further downregulated on treatment with fisetin, suggesting that these effects are mediated in part, through mTOR signaling. Our results show that fisetin suppressed PI3K/Akt and mTOR signaling in NSCLC cells and thus, could be developed as a chemotherapeutic agent against human lung cancer. PMID:21618507

  16. The action characterization matrix: A link between HERA (Human Events Reference for ATHEANA) and ATHEANA (a technique for human error analysis)

    SciTech Connect

    Hahn, H.A.

    1997-12-22

    The Technique for Human Error Analysis (ATHEANA) is a newly developed human reliability analysis (HRA) methodology that aims to facilitate better representation and integration of human performance into probabilistic risk assessment (PRA) modeling and quantification by analyzing risk-significant operating experience in the context of existing behavior science models. The fundamental premise of ATHEANA is that error-forcing contexts (EFCs), which refer to combinations of equipment/material conditions and performance shaping factors (PSFs), set up or create the conditions under which unsafe actions (UAs) can occur. ATHEANA is being developed in the context of nuclear power plant (NPP) PRAs, and much of the language used to describe the method and provide examples of its application are specific to that industry. Because ATHEANA relies heavily on the analysis of operational events that have already occurred as a mechanism for generating creative thinking about possible EFCs, a database, called the Human Events Reference for ATHEANA (HERA), has been developed to support the methodology. Los Alamos National Laboratory`s (LANL) Human Factors Group has recently joined the ATHEANA project team; LANL is responsible for further developing the database structure and for analyzing additional exemplar operational events for entry into the database. The Action Characterization Matrix (ACM) is conceived as a bridge between the HERA database structure and ATHEANA. Specifically, the ACM allows each unsafe action or human failure event to be characterized according to its representation along each of six different dimensions: system status, initiator status, unsafe action mechanism, information processing stage, equipment/material conditions, and performance shaping factors. This report describes the development of the ACM and provides details on the structure and content of its dimensions.

  17. 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

  18. 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

  19. Quality of life in adult patients with Familial Mediterranean fever living in Germany or Turkey compared to healthy subjects: a study evaluating the effect of disease severity and country of residence.

    PubMed

    Giese, Arnd; Kurucay, Mustafa; Kilic, Levent; Örnek, Ahmet; Şendur, Süleyman Nahit; Lainka, Elke; Henning, Bernhard Ferdinand

    2013-07-01

    We assessed quality of life (QOL) and disease activity in patients with Familial Mediterranean fever (FMF) of Turkish ancestry living in Germany or Turkey and conducted a correlation with FMF disease activity. 40 FMF patients in Turkey (TR), 40 FMF patients in Germany (G) and 40 healthy controls in Germany (C) were included. QOL was evaluated with the short form of the World Health Organisation Quality of Life scale (WHOQOL-BREF). FMF disease activity was examined with the Pras score. Mean age was TR 30.5 ± 10.6, G 35.2 ± 10.2, C 34.6 ± 10.7. Of the 120 participants, 77 were female. FMF patients in TR and G had a significantly decreased QOL physical health domain compared to controls (TR 59.7 ± 18.8, G 60.4 ± 19.4, C 76.5 ± 14.6). Turkish FMF patients had a lower QOL environment domain compared to controls (TR 62.3 ± 17.5, G 69.7 ± 16.5, C 72.3 ± 13.5). In the other QOL domains, no significant differences were found. The differences in QOL were robust to a regression analysis. No significant correlation between QOL and FMF disease activity was found. German FMF patients had longer duration of disease, younger age at onset and longer delay from disease onset to colchicine treatment. A total of 5 of 40 German FMF patients were not taking colchicine (TR:0). Erythrocyte sedimentation rate was lowest in TR with significant difference between TR and G as well as G and C (TR 13.2 ± 10.3, G 27.8 ± 19.4, C 16.3 ± 12.8 mm/h). C-reactive protein did not differ between TR and G. FMF has an important impact on QOL physical health domain. No correlation between FMF disease activity and the WHOQOL-BREF could be found.

  20. MANAGEMENT OF ALLOSENSITIZED CARDIAC TRANSPLANT CANDIDATES

    PubMed Central

    Velez, Mauricio; Johnson, Maryl R.

    2009-01-01

    expansion. Its pathophysiology is unclear, but may involve chronic complement-mediated endothelial injury. Sirolimus and everolimus can delay the progression of CAV. In some non-sensitized cardiac transplant recipients, the de novo formation of anti-HLA antibodies after transplantation may increase the likelihood of adverse clinical outcomes. Serial post-transplant PRAs may be advisable in patients at high risk of de novo allosensitization. PMID:19778695

  1. Challenges to Seismic Hazard Analysis of Critical Infrastructures

    NASA Astrophysics Data System (ADS)

    Klügel, J.

    2005-12-01

    Based on the background of the review of a large scale probabilistic seismic hazard analysis (PSHA) performed in Switzerland for the sites of Swiss nuclear power plants- the PEGASOS project (2000-2004) - challenges to seismic hazard analysis of critical infrastructures from the perspective of a professional safety analyst are discussed. The PEGASOS study was performed to provide a meaningful input for the update of the plant specific PRAs (Probabilistic Risk Assessment) of Swiss nuclear power plants. Earlier experience had shown that the results of these studies to a large extend are driven by the results of the seismic hazard analysis. The PEGASOS-study was performed in full compliance with the procedures developed by the Senior Seismic Hazard Analysis Committee (SSHAC) of U.S.A (SSHAC, 1997) developed for the treatment of uncertainties by the use of a structured expert elicitation process. The preliminary results derived from the project did show an unexpected amount of uncertainty and were regarded as not suitable for direct application. A detailed review of the SSHAC-methodology revealed a number of critical issues with respect to the treatment of uncertainties and the mathematical models applied, which will be presented in the paper. The most important issued to be discussed are: * The ambiguous solution of PSHA-logic trees * The inadequate mathematical treatment of the results of expert elicitations based on the assumption of bias free expert estimates * The problems associated with the "think model" of the separation of epistemic and aleatory uncertainties * The consequences of the ergodic assumption used to justify the transfer of attenuation equations of other regions to the region of interest. Based on these observations methodological questions with respect to the development of a risk-consistent design basis for new nuclear power plants as required by the U.S. NRC RG 1.165 will be evaluated. As an principal alternative for the development of a

  2. [Platelet-rich plasma: updating of extraction devices].

    PubMed

    Moreno, Raquel; Gaspar Carreño, Marisa; Alonso Herreros, Jose María; Romero Garrido, Jose Antonio; López-Sánchez, Piedad

    2016-09-01

    Objetivo: Describir los dispositivos para la obtención de Plasma Rico en Plaquetas (PRP) mediante la revisión de los productos existentes en España, teniendo en consideración las aportaciones de la Agencia Española de Medicamentos y Productos Sanitarios (AEMPS) y los grupos de trabajo de Productos Sanitarios (GPS), Farmacotecnia y Hemoderivados de la Sociedad Española de Farmacia Hospitalaria (SEFH). Método: Se realizaron tres búsquedas independientes sobre dispositivos de fraccionamiento de plasma. Se contactó con los proveedores y se estableció una reunión con cada uno de ellos. Se revisaron las características de cada dispositivo mediante una demostración del proceso de fraccionamiento virtual y se elaboró una tabla de comparación de kits. Los dispositivos se clasificaron como Técnica cerrada y Técnica abierta de acuerdo al informe del comité técnico de inspección de la AEMPS. Resultados: Se localizaron diez dispositivos: ACP®; Angel®, Cascade®, Endoret®, GPS®, Magellan®, Minos®, Ortho-pras®, Smart-prepr® y Tricell®, pudiendo conocer de forma detallada el funcionamiento en siete de ellos. Sin embargo, de Cascade ®, Magellan® y Smart-prepr® no se consiguió información suficiente. Conclusión: La revisión permitió conocer los principales dispositivos de extracción de PRP disponibles con marcado CE y sus características diferenciales; sin embargo, para garantizar la calidad del producto final es crucial poner atención en el propio proceso de extracción y administración del PRP. El Servicio de Farmacia debe implicarse en su selección por la estrecha relación que mantiene con la calidad del medicamento elaborado. El trabajo conjunto con la AEMPS permitirá definir de forma más específica el proceso correcto de elaboración.

  3. IL-24 Inhibits Lung Cancer Cell Migration and Invasion by Disrupting The SDF-1/CXCR4 Signaling Axis

    PubMed Central

    Panneerselvam, Janani; Jin, Jiankang; Shanker, Manish; Lauderdale, Jason; Bates, Jonathan; Wang, Qi; Zhao, Yan D.; Archibald, Stephen J.; Hubin, Timothy J.; Ramesh, Rajagopal

    2015-01-01

    Background The stromal cell derived factor (SDF)-1/chemokine receptor (CXCR)-4 signaling pathway plays a key role in lung cancer metastasis and is molecular target for therapy. In the present study we investigated whether interleukin (IL)-24 can inhibit the SDF-1/CXCR4 axis and suppress lung cancer cell migration and invasion in vitro. Further, the efficacy of IL-24 in combination with CXCR4 antagonists was investigated. Methods Human H1299, A549, H460 and HCC827 lung cancer cell lines were used in the present study. The H1299 lung cancer cell line was stably transfected with doxycycline-inducible plasmid expression vector carrying the human IL-24 cDNA and used in the present study to determine the inhibitory effects of IL-24 on SDF-1/CXCR4 axis. H1299 and A549 cell lines were used in transient transfection studies. The inhibitory effects of IL-24 on SDF1/CXCR4 and its downstream targets were analyzed by quantitative RT-PCR, western blot, luciferase reporter assay, flow cytometry and immunocytochemistry. Functional studies included cell migration and invasion assays. Principal Findings Endogenous CXCR4 protein expression levels varied among the four human lung cancer cell lines. Doxycycline-induced IL-24 expression in the H1299-IL24 cell line resulted in reduced CXCR4 mRNA and protein expression. IL-24 post-transcriptionally regulated CXCR4 mRNA expression by decreasing the half-life of CXCR4 mRNA (>40%). Functional studies showed IL-24 inhibited tumor cell migration and invasion concomitant with reduction in CXCR4 and its downstream targets (pAKTS473, pmTORS2448, pPRAS40T246 and HIF-1α). Additionally, IL-24 inhibited tumor cell migration both in the presence and absence of the CXCR4 agonist, SDF-1. Finally, IL-24 when combined with CXCR4 inhibitors (AMD3100, SJA5) or with CXCR4 siRNA demonstrated enhanced inhibitory activity on tumor cell migration. Conclusions IL-24 disrupts the SDF-1/CXCR4 signaling pathway and inhibits lung tumor cell migration and invasion

  4. Branched-Chain Amino Acid Ingestion Stimulates Muscle Myofibrillar Protein Synthesis following Resistance Exercise in Humans.

    PubMed

    Jackman, Sarah R; Witard, Oliver C; Philp, Andrew; Wallis, Gareth A; Baar, Keith; Tipton, Kevin D

    2017-01-01

    The ingestion of intact protein or essential amino acids (EAA) stimulates mechanistic target of rapamycin complex-1 (mTORC1) signaling and muscle protein synthesis (MPS) following resistance exercise. The purpose of this study was to investigate the response of myofibrillar-MPS to ingestion of branched-chain amino acids (BCAAs) only (i.e., without concurrent ingestion of other EAA, intact protein, or other macronutrients) following resistance exercise in humans. Ten young (20.1 ± 1.3 years), resistance-trained men completed two trials, ingesting either 5.6 g BCAA or a placebo (PLA) drink immediately after resistance exercise. Myofibrillar-MPS was measured during exercise recovery with a primed, constant infusion of L-[ring(13)C6] phenylalanine and collection of muscle biopsies pre and 4 h-post drink ingestion. Blood samples were collected at time-points before and after drink ingestion. Western blotting was used to measure the phosphorylation status of mTORC1 signaling proteins in biopsies collected pre, 1-, and 4 h-post drink. The percentage increase from baseline in plasma leucine (300 ± 96%), isoleucine (300 ± 88%), and valine (144 ± 59%) concentrations peaked 0.5 h-post drink in BCAA. A greater phosphorylation status of S6K1(Thr389) (P = 0.017) and PRAS40 (P = 0.037) was observed in BCAA than PLA at 1 h-post drink ingestion. Myofibrillar-MPS was 22% higher (P = 0.012) in BCAA (0.110 ± 0.009%/h) than PLA (0.090 ± 0.006%/h). Phenylalanine Ra was ~6% lower in BCAA (18.00 ± 4.31 μmol·kgBM(-1)) than PLA (21.75 ± 4.89 μmol·kgBM(-1); P = 0.028) after drink ingestion. We conclude that ingesting BCAAs alone increases the post-exercise stimulation of myofibrillar-MPS and phosphorylation status mTORC1 signaling.

  5. Branched-Chain Amino Acid Ingestion Stimulates Muscle Myofibrillar Protein Synthesis following Resistance Exercise in Humans

    PubMed Central

    Jackman, Sarah R.; Witard, Oliver C.; Philp, Andrew; Wallis, Gareth A.; Baar, Keith; Tipton, Kevin D.

    2017-01-01

    The ingestion of intact protein or essential amino acids (EAA) stimulates mechanistic target of rapamycin complex-1 (mTORC1) signaling and muscle protein synthesis (MPS) following resistance exercise. The purpose of this study was to investigate the response of myofibrillar-MPS to ingestion of branched-chain amino acids (BCAAs) only (i.e., without concurrent ingestion of other EAA, intact protein, or other macronutrients) following resistance exercise in humans. Ten young (20.1 ± 1.3 years), resistance-trained men completed two trials, ingesting either 5.6 g BCAA or a placebo (PLA) drink immediately after resistance exercise. Myofibrillar-MPS was measured during exercise recovery with a primed, constant infusion of L-[ring13C6] phenylalanine and collection of muscle biopsies pre and 4 h-post drink ingestion. Blood samples were collected at time-points before and after drink ingestion. Western blotting was used to measure the phosphorylation status of mTORC1 signaling proteins in biopsies collected pre, 1-, and 4 h-post drink. The percentage increase from baseline in plasma leucine (300 ± 96%), isoleucine (300 ± 88%), and valine (144 ± 59%) concentrations peaked 0.5 h-post drink in BCAA. A greater phosphorylation status of S6K1Thr389 (P = 0.017) and PRAS40 (P = 0.037) was observed in BCAA than PLA at 1 h-post drink ingestion. Myofibrillar-MPS was 22% higher (P = 0.012) in BCAA (0.110 ± 0.009%/h) than PLA (0.090 ± 0.006%/h). Phenylalanine Ra was ~6% lower in BCAA (18.00 ± 4.31 μmol·kgBM−1) than PLA (21.75 ± 4.89 μmol·kgBM−1; P = 0.028) after drink ingestion. We conclude that ingesting BCAAs alone increases the post-exercise stimulation of myofibrillar-MPS and phosphorylation status mTORC1 signaling. PMID:28638350

  6. 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.

  7. 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

  8. Constructing Dynamic Event Trees from Markov Models

    SciTech Connect

    Paolo Bucci; Jason Kirschenbaum; Tunc Aldemir; Curtis Smith; Ted Wood

    2006-05-01

    In the probabilistic risk assessment (PRA) of process plants, Markov models can be used to model accurately the complex dynamic interactions between plant physical process variables (e.g., temperature, pressure, etc.) and the instrumentation and control system that monitors and manages the process. One limitation of this approach that has prevented its use in nuclear power plant PRAs is the difficulty of integrating the results of a Markov analysis into an existing PRA. In this paper, we explore a new approach to the generation of failure scenarios and their compilation into dynamic event trees from a Markov model of the system. These event trees can be integrated into an existing PRA using software tools such as SAPHIRE. To implement our approach, we first construct a discrete-time Markov chain modeling the system of interest by: a) partitioning the process variable state space into magnitude intervals (cells), b) using analytical equations or a system simulator to determine the transition probabilities between the cells through the cell-to-cell mapping technique, and, c) using given failure/repair data for all the components of interest. The Markov transition matrix thus generated can be thought of as a process model describing the stochastic dynamic behavior of the finite-state system. We can therefore search the state space starting from a set of initial states to explore all possible paths to failure (scenarios) with associated probabilities. We can also construct event trees of arbitrary depth by tracing paths from a chosen initiating event and recording the following events while keeping track of the probabilities associated with each branch in the tree. As an example of our approach, we use the simple level control system often used as benchmark in the literature with one process variable (liquid level in a tank), and three control units: a drain unit and two supply units. Each unit includes a separate level sensor to observe the liquid level in the tank

  9. In vivo efficacy of the AKT inhibitor ARQ 092 in Noonan Syndrome with multiple lentigines-associated hypertrophic cardiomyopathy

    PubMed Central

    Abbadessa, Giovanni; Yu, Yi; Schwartz, Brian

    2017-01-01

    Noonan Syndrome with Multiple Lentigines (NSML, formerly LEOPARD syndrome) is an autosomal dominant "RASopathy" disorder manifesting in congenital heart disease. Most cases of NSML are caused by catalytically inactivating mutations in the protein tyrosine phosphatase (PTP), non-receptor type 11 (PTPN11), encoding the SH2 domain-containing PTP-2 (SHP2) protein. We previously generated knock-in mice harboring the PTPN11 mutation Y279C, one of the most common NSML alleles; these now-termed SHP2Y279C/+ mice recapitulate the human disorder and develop hypertrophic cardiomyopathy (HCM) by 12 weeks of age. Functionally, heart and/or cardiomyocyte lysates from SHP2Y279C/+ mice exhibit increased basal and agonist-induced AKT and mTOR activities. Here, we sought to determine whether we could reverse the hypertrophy in SHP2Y279C/+ mice using ARQ 092, an oral and selective allosteric AKT inhibitor currently in clinical trials for patients with PI3K/AKT-driven tumors or Proteus syndrome. We obtained echocardiographs of SHP2Y279C/+ and wildtype (SHP2+/+) littermates, either in the presence or absence of ARQ 092 at 12, 14, and 16 weeks of age. While SHP2Y279C/+ mice developed significant left ventricular hypertrophy by 12 weeks, as indicated by decreased chamber dimension and increased posterior wall thickness, treatment of SHP2Y279C/+ mice with ARQ 092 normalized the hypertrophy in as early as 2 weeks following treatment, with hearts comparable in size to those in wildtype (SHP2+/+) mice. In addition, we observed an increase in fractional shortening (FS%) in SHP2Y279C/+ mice, an effect of increased compensatory hypertrophy, which was not apparent in SHP2Y279C/+ mice treated with ARQ 092, suggesting functional improvement of HCM upon treatment with the AKT inhibitor. Finally, we found that ARQ 092 specifically inhibited AKT activity, as well as its downstream effectors, PRAS and S6RP in NSML mice. Taken together, these data suggest ARQ 092 may be a promising novel therapy for

  10. In vivo efficacy of the AKT inhibitor ARQ 092 in Noonan Syndrome with multiple lentigines-associated hypertrophic cardiomyopathy.

    PubMed

    Wang, Jianxun; Chandrasekhar, Vasanth; Abbadessa, Giovanni; Yu, Yi; Schwartz, Brian; Kontaridis, Maria I

    2017-01-01

    Noonan Syndrome with Multiple Lentigines (NSML, formerly LEOPARD syndrome) is an autosomal dominant "RASopathy" disorder manifesting in congenital heart disease. Most cases of NSML are caused by catalytically inactivating mutations in the protein tyrosine phosphatase (PTP), non-receptor type 11 (PTPN11), encoding the SH2 domain-containing PTP-2 (SHP2) protein. We previously generated knock-in mice harboring the PTPN11 mutation Y279C, one of the most common NSML alleles; these now-termed SHP2Y279C/+ mice recapitulate the human disorder and develop hypertrophic cardiomyopathy (HCM) by 12 weeks of age. Functionally, heart and/or cardiomyocyte lysates from SHP2Y279C/+ mice exhibit increased basal and agonist-induced AKT and mTOR activities. Here, we sought to determine whether we could reverse the hypertrophy in SHP2Y279C/+ mice using ARQ 092, an oral and selective allosteric AKT inhibitor currently in clinical trials for patients with PI3K/AKT-driven tumors or Proteus syndrome. We obtained echocardiographs of SHP2Y279C/+ and wildtype (SHP2+/+) littermates, either in the presence or absence of ARQ 092 at 12, 14, and 16 weeks of age. While SHP2Y279C/+ mice developed significant left ventricular hypertrophy by 12 weeks, as indicated by decreased chamber dimension and increased posterior wall thickness, treatment of SHP2Y279C/+ mice with ARQ 092 normalized the hypertrophy in as early as 2 weeks following treatment, with hearts comparable in size to those in wildtype (SHP2+/+) mice. In addition, we observed an increase in fractional shortening (FS%) in SHP2Y279C/+ mice, an effect of increased compensatory hypertrophy, which was not apparent in SHP2Y279C/+ mice treated with ARQ 092, suggesting functional improvement of HCM upon treatment with the AKT inhibitor. Finally, we found that ARQ 092 specifically inhibited AKT activity, as well as its downstream effectors, PRAS and S6RP in NSML mice. Taken together, these data suggest ARQ 092 may be a promising novel therapy for

  11. X-ray study with synchrotron radiation of cerium and praseodymium monopnictides with the NaCl-type structure at high pressures

    NASA Astrophysics Data System (ADS)

    Shirotani, Ichimin; Hayashi, Junichi; Yamanashi, Keigo; Hirano, Kouji; Adachi, Takafumi; Ishimatsu, Naoki; Shimomura, Osamu; Kikegawa, Takumi

    2003-06-01

    By use of synchrotron radiation, powder X-ray diffraction studies for cerium and praseodymium monopnictides [CeX and PrX (X=P, As, Sb and Bi)] with the NaCl-type structure have been carried out up to 40 GPa at room temperature. We have investigated in detail the pressure ( P) vs. cell volume ( V) relationship for CeP, CeAs and CeSb. The phase transition from the NaCl-type (B1) to the CsCl-type (B2) structure is observed at around 25 GPa for CeP and 21 GPa for CeAs. The transition pressures of both compounds are about 6 GPa higher than the results previously reported. Sevan et al. have predicted that a second isostructural B2-B2 transition for CeSb occurs at around 25.2 GPa with a volume collapse of 4%. However, we cannot find the volume collapse for CeSb at least up to 35 GPa. First-order phase transitions with the crystallographic change for PrX (X=P, As and Sb) are found at 26 GPa for PrP, 27 GPa for PrAs, 13 GPa for PrSb. The structure of the high-pressure phase of these compounds is tetragonal (distorted CsCl-type, P4/mmm). For PrBi, anomalous behavior in the X-ray diffraction pattern is observed around 4 GPa. This may be due to a pressure-induced intermediate phase. The structural phase transition in PrBi occurs at about 14 GPa. The high-pressure phases of PrBi consists of coexisting of tetragonal (distorted CsCl-type, P4/mmm) and cubic (CsCl-type, Pm3m) modifications at about 14 GPa. The bulk modulus of CeX and PrX (X=P, As, Sb and Bi) is obtained from the P- V curve fitted by the Birch equation of state. The relationship between bulk modulus and cell volume for these compounds is studied.

  12. 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

  13. Cardiosphere conditioned media influence the plasticity of human mediastinal adipose tissue-derived mesenchymal stem cells.

    PubMed

    Siciliano, Camilla; Chimenti, Isotta; Ibrahim, Mohsen; Napoletano, Chiara; Mangino, Giorgio; Scafetta, Gaia; Zoccai, Giuseppe Biondi; Rendina, Erino Angelo; Calogero, Antonella; Frati, Giacomo; De Falco, Elena

    2015-01-01

    Nowadays, cardiac regenerative medicine is facing many limitations because of the complexity to find the most suitable stem cell source and to understand the regenerative mechanisms involved. Mesenchymal stem cells (MSCs) have shown great regenerative potential due to their intrinsic properties and ability to restore cardiac functionality, directly by transdifferentiation and indirectly by paracrine effects. Yet, how MSCs could respond to definite cardiac-committing microenvironments, such as that created by resident cardiac progenitor cells in the form of cardiospheres (CSs), has never been addressed. Recently, a putative MSC pool has been described in the mediastinal fat (hmADMSCs), but both its biology and function remain hitherto unexplored. Accordingly, we investigated the potential of hmADMSCs to be committed toward a cardiovascular lineage after preconditioning with CS-conditioned media (CCM). Results indicated that CCM affects cell proliferation. Gene expression levels of multiple cardiovascular and stemness markers (MHC, KDR, Nkx2.5, Thy-1, c-kit, SMA) are significantly modulated, and the percentage of hmADMSCs preconditioned with CCM and positive for Nkx2.5, MHC, and KDR is significantly higher relative to FBS and explant-derived cell conditioned media (EDCM, the unselected stage before CS formation). Growth factor-specific and survival signaling pathways (i.e., Erk1/2, Akt, p38, mTOR, p53) present in CCM are all equally regulated. Nonetheless, earlier BAD phosphorylation (Ser112) occurs associated with the CS microenvironment (and to a lesser extent to EDCM), whereas faster phosphorylation of PRAS40 in FBS, and of Akt (Ser473) in EDCM and 5-azacytidine occurs compared to CCM. For the first time, we demonstrated that the MSC pool held in the mediastinal fat is adequately plastic to partially differentiate in vitro toward a cardiac-like lineage. Besides, we have provided novel evidence of the potent inductive niche-like microenvironment that the CS

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

    PubMed Central

    Thomas, Gregory W.; Rael, Leonard T.; Gersch, Elizabeth D.; Rubinstein, Pablo; Brody, Edward

    2015-01-01

    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. Significance This study describes the effect of a biologic currently under development for the treatment of osteoarthritis to induce both

  16. 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.

  17. 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

  18. Autocrine IGF-I/insulin receptor axis compensates for inhibition of AKT in ER-positive breast cancer cells with resistance to estrogen deprivation

    PubMed Central

    2013-01-01

    Introduction Estrogen receptor α-positive (ER+) breast cancers adapt to hormone deprivation and acquire resistance to antiestrogen therapies. Upon acquisition of hormone independence, ER+ breast cancer cells increase their dependence on the phosphatidylinositol-3 kinase (PI3K)/AKT pathway. We examined the effects of AKT inhibition and its compensatory upregulation of insulin-like growth factor (IGF)-I/InsR signaling in ER+ breast cancer cells with acquired resistance to estrogen deprivation. Methods Inhibition of AKT using the catalytic inhibitor AZD5363 was examined in four ER+ breast cancer cell lines resistant to long-term estrogen deprivation (LTED) by western blotting and proliferation assays. Feedback upregulation and activation of receptor tyrosine kinases (RTKs) was examined by western blotting, real-time qPCR, ELISAs, membrane localization of AKT PH-GFP by immunofluorescence and phospho-RTK arrays. For studies in vivo, athymic mice with MCF-7 xenografts were treated with AZD5363 and fulvestrant with either the ATP-competitive IGF-IR/InsR inhibitor AZD9362 or the fibroblast growth factor receptor (FGFR) inhibitor AZD4547. Results Treatment with AZD5363 reduced phosphorylation of the AKT/mTOR substrates PRAS40, GSK3α/β and S6K while inducing hyperphosphorylation of AKT at T308 and S473. Inhibition of AKT with AZD5363 suppressed growth of three of four ER+ LTED lines and prevented emergence of hormone-independent MCF-7, ZR75-1 and MDA-361 cells. AZD5363 suppressed growth of MCF-7 xenografts in ovariectomized mice and a patient-derived luminal B xenograft unresponsive to tamoxifen or fulvestrant. Combined treatment with AZD5363 and fulvestrant suppressed MCF-7 xenograft growth better than either drug alone. Inhibition of AKT with AZD5363 resulted in upregulation and activation of RTKs, including IGF-IR and InsR, upregulation of FoxO3a and ERα mRNAs as well as FoxO- and ER-dependent transcription of IGF-I and IGF-II ligands. Inhibition of IGF-IR/InsR or PI3

  19. 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

  20. 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

  1. 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.

  2. 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

  3. 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.

  4. 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