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Sample records for autophagic components contribute

  1. Autophagic components contribute to hypersensitive cell death in Arabidopsis

    DEFF Research Database (Denmark)

    Hofius, Daniel; Schultz-Larsen, Torsten; Joensen, Jan

    2009-01-01

    Autophagy has been implicated as a prosurvival mechanism to restrict programmed cell death (PCD) associated with the pathogen-triggered hypersensitive response (HR) during plant innate immunity. This model is based on the observation that HR lesions spread in plants with reduced autophagy gene...... expression. Here, we examined receptor-mediated HR PCD responses in autophagy-deficient Arabidopsis knockout mutants (atg), and show that infection-induced lesions are contained in atg mutants. We also provide evidence that HR cell death initiated via Toll/Interleukin-1 (TIR)-type immune receptors through...... the defense regulator EDS1 is suppressed in atg mutants. Furthermore, we demonstrate that PCD triggered by coiled-coil (CC)-type immune receptors via NDR1 is either autophagy-independent or engages autophagic components with cathepsins and other unidentified cell death mediators. Thus, autophagic cell death...

  2. Transcriptional stimulation of rate-limiting components of the autophagic pathway improves plant fitness

    Czech Academy of Sciences Publication Activity Database

    Minina, E. A.; Moschou, P. N.; Vetukuri, R. R.; Sanchez-Vera, V.; Cardoso, C.; Liu, Q.; Elander, P. H.; Dalman, K.; Beganovic, M.; Lindberg Yilmaz, J.; Marmon, S.; Shabala, S.; Suarez, M.; Ljung, K.; Novák, Ondřej; Shabala, S.; Stymne, S.; Hofius, D.; Bozhkov, P. V.

    2018-01-01

    Roč. 69, č. 6 (2018), s. 1415-1432 ISSN 0022-0957 Institutional support: RVO:61389030 Keywords : Aging * ATG genes * Autophagy * Autophagy-related ubiquitin-like conjugation systems * Biomass * Oil content * Ratelimiting components of autophagic flux * Seed yield * Stress resistance * Transcriptional regulation Subject RIV: EB - Genetics ; Molecular Biology OBOR OECD: Genetics and heredity (medical genetics to be 3) Impact factor: 5.830, year: 2016

  3. Metabolic contribution of hepatic autophagic proteolysis: old wine in new bottles.

    Science.gov (United States)

    Ueno, Takashi; Ezaki, Junji; Kominami, Eiki

    2012-01-01

    Pioneering work on autophagy was achieved soon after the discovery of lysosomes more than 50 years ago. Due to its prominent lysosomal activity and technical ease of handling, the liver has been at the center of continuous and vigorous investigations into autophagy. Many important discoveries, including suppression by insulin and plasma amino acids and stimulation by glucagon, have been made through in vivo and in vitro studies using perfused liver and cultured hepatocytes. The long-term controversy about the origin and nature of the autophagosome membrane has finally led to the conclusion of "phagophore," through extensive molecular cell biological approaches enlightened by the discovery of autophagy-essential ATG genes. Furthermore, recent studies using liver-specific autophagy-deficient mice have thrown light on the unique role of a selective substrate of autophagy, p62. The stabilized p62 accumulating in autophagy-deficient liver manipulates Nrf2-dependent transcription activation through specific binding to Keap1, which results in the elevated gene expression involved in detoxification. This is the first example of the dysregulation of gene expression under autophagy deficiency. Thus, basal liver autophagy makes a large contribution to the maintenance of cell homeostasis and health. Meanwhile, precise comparisons of wild-type and liver-specific autophagy-deficient mice under starvation conditions have revealed that amino acids released by autophagic degradation can be metabolized to produce glucose via gluconeogenesis for the maintenance of blood glucose, and can also be excreted to the circulation to supply serum amino acids. These results strongly confirm that induced liver autophagy plays a pivotal role in metabolic compensation. This article is part of a Special Issue entitled: Proteolysis 50 years after the discovery of lysosome. Copyright © 2011 Elsevier B.V. All rights reserved.

  4. Depletion of the Third Complement Component Ameliorates Age-Dependent Oxidative Stress and Positively Modulates Autophagic Activity in Aged Retinas in a Mouse Model.

    Science.gov (United States)

    Rogińska, Dorota; Kawa, Miłosz P; Pius-Sadowska, Ewa; Lejkowska, Renata; Łuczkowska, Karolina; Wiszniewska, Barbara; Kaarniranta, Kai; Paterno, Jussi J; Schmidt, Christian A; Machaliński, Bogusław; Machalińska, Anna

    2017-01-01

    The aim of the study was to investigate the influence of complement component C3 global depletion on the biological structure and function of the aged retina. In vivo morphology (OCT), electrophysiological function (ERG), and the expression of selected oxidative stress-, apoptosis-, and autophagy-related proteins were assessed in retinas of 12-month-old C3-deficient and WT mice. Moreover, global gene expression in retinas was analyzed by RNA arrays. We found that the absence of active C3 was associated with (1) alleviation of the age-dependent decrease in retinal thickness and gradual deterioration of retinal bioelectrical function, (2) significantly higher levels of antioxidant enzymes (catalase and glutathione reductase) and the antiapoptotic survivin and Mcl-1/Bak dimer, (3) lower expression of the cellular oxidative stress marker-4HNE-and decreased activity of proapoptotic caspase-3, (4) ameliorated retinal autophagic activity with localization of ubiquitinated protein conjugates commonly along the retinal pigment epithelium (RPE) layer, and (5) significantly increased expression of several gene sets associated with maintenance of the physiological functions of the neural retina. Our findings shed light on mechanisms of age-related retinal alterations by identifying C3 as a potential therapeutic target for retinal aging.

  5. Depletion of the Third Complement Component Ameliorates Age-Dependent Oxidative Stress and Positively Modulates Autophagic Activity in Aged Retinas in a Mouse Model

    Directory of Open Access Journals (Sweden)

    Dorota Rogińska

    2017-01-01

    Full Text Available The aim of the study was to investigate the influence of complement component C3 global depletion on the biological structure and function of the aged retina. In vivo morphology (OCT, electrophysiological function (ERG, and the expression of selected oxidative stress-, apoptosis-, and autophagy-related proteins were assessed in retinas of 12-month-old C3-deficient and WT mice. Moreover, global gene expression in retinas was analyzed by RNA arrays. We found that the absence of active C3 was associated with (1 alleviation of the age-dependent decrease in retinal thickness and gradual deterioration of retinal bioelectrical function, (2 significantly higher levels of antioxidant enzymes (catalase and glutathione reductase and the antiapoptotic survivin and Mcl-1/Bak dimer, (3 lower expression of the cellular oxidative stress marker—4HNE—and decreased activity of proapoptotic caspase-3, (4 ameliorated retinal autophagic activity with localization of ubiquitinated protein conjugates commonly along the retinal pigment epithelium (RPE layer, and (5 significantly increased expression of several gene sets associated with maintenance of the physiological functions of the neural retina. Our findings shed light on mechanisms of age-related retinal alterations by identifying C3 as a potential therapeutic target for retinal aging.

  6. Lithium chloride contributes to blood-spinal cord barrier integrity and functional recovery from spinal cord injury by stimulating autophagic flux.

    Science.gov (United States)

    Tong, Minji; He, Zili; Lin, Xiaoxiao; Zhou, Yulong; Wang, Qingqing; Zheng, Zengming; Chen, Jian; Xu, Huazi; Tian, Naifeng

    2018-01-22

    Blood-spinal cord barrier (BSCB) disruption following spinal cord injury (SCI) significantly compromises functional neuronal recovery. Autophagy is a potential therapeutic target when seeking to protect the BSCB. We explored the effects of lithium chloride (LiCl) on BSCB permeability and autophagy-induced SCI both in a rat model of SCI and in endothelial cells subjected to oxygen-glucose deprivation. We evaluated BSCB status using the Evans Blue dye extravasation test and measurement of tight junction (TJ) protein levels; we also assessed functional locomotor recovery. We detected autophagy-associated proteins in vivo and in vitro using both Western blotting and immunofluorescence staining. We found that, in a rat model of SCI, LiCl attenuated the elevation in BSCB permeability, improved locomotor recovery, and inhibited the degradation of TJ proteins including occludin and claudin-5. LiCl significantly induced the extent of autophagic flux after SCI by increasing LC3-II and ATG-5 levels, and abolishing p62 accumulation. In addition, a combination of LiCl and the autophagy inhibitor chloroquine not only partially eliminated the BSCB-protective effect of LiCl, but also exacerbated TJ protein degradation both in vivo and in vitro. Together, these findings suggest that LiCl treatment alleviates BSCB disruption and promotes locomotor recovery after SCI, partly by stimulating autophagic flux. Copyright © 2017 Elsevier Inc. All rights reserved.

  7. Evidence for autophagic gridlock in aging and neurodegeneration.

    Science.gov (United States)

    Bakhoum, Mathieu F; Bakhoum, Christine Y; Ding, Zhixia; Carlton, Susan M; Campbell, Gerald A; Jackson, George R

    2014-07-01

    Autophagy is essential to neuronal homeostasis, and its impairment is implicated in the development of neurodegenerative pathology. However, the underlying mechanisms and consequences of this phenomenon remain a matter of conjecture. We show that misexpression of human tau in Drosophila induces accumulation of autophagic intermediates with a preponderance of large vacuoles, which we term giant autophagic bodies (GABs), which are reminiscent of dysfunctional autophagic entities. Lowering basal autophagy reduces GABs, whereas increasing autophagy decreases mature autolysosomes. Induction of autophagy is also associated with rescue of the tauopathy phenotype, suggesting that formation of GABs may be a compensatory mechanism rather than a trigger of neurodegeneration. Last, we show that the peculiar Biondi bodies observed in the choroid epithelium of both elderly and Alzheimer's disease human brains express immunoreactive markers similar to those of GABs. Collectively, these data indicate that autophagic gridlock contributes to the development of pathology in aging and neurodegeneration. Published by Mosby, Inc.

  8. Contribution of the GOCE gradiometer components to regional gravity solutions

    Science.gov (United States)

    Naeimi, Majid; Bouman, Johannes

    2017-05-01

    The contribution of the GOCE gravity gradients to regional gravity field solutions is investigated in this study. We employ radial basis functions to recover the gravity field on regional scales over Amazon and Himalayas as our test regions. In the first step, four individual solutions based on the more accurate gravity gradient components Txx, Tyy, Tzz and Txz are derived. The Tzz component gives better solution than the other single-component solutions despite the less accuracy of Tzz compared to Txx and Tyy. Furthermore, we determine five more solutions based on several selected combinations of the gravity gradient components including a combined solution using the four gradient components. The Tzz and Tyy components are shown to be the main contributors in all combined solutions whereas the Txz adds the least value to the regional gravity solutions. We also investigate the contribution of the regularization term. We show that the contribution of the regularization significantly decreases as more gravity gradients are included. For the solution using all gravity gradients, regularization term contributes to about 5 per cent of the total solution. Finally, we demonstrate that in our test areas, regional gravity modelling based on GOCE data provide more reliable gravity signal in medium wavelengths as compared to pre-GOCE global gravity field models such as the EGM2008.

  9. The determination of contribution of emotional intelligence and parenting styles components to predicts positive psychological components

    OpenAIRE

    hosein Ebrahimi moghadam; mahin Fekraty

    2015-01-01

    Background: Since the essential of positive psychological components, as compliment of deficiency oriented approaches, has begun in recent days,we decided to take into account this new branch of psychology which scientifically considers studying forces of human, as well as because of the importance of this branch of psychology, we also tried to search the contribution of emotional intelligence and parenting styles components to predict positive psychological components. Materials and Methods:...

  10. Autophagic regulation of smooth muscle cell biology

    Directory of Open Access Journals (Sweden)

    Joshua K. Salabei

    2015-04-01

    Full Text Available Autophagy regulates the metabolism, survival, and function of numerous cell types, including those comprising the cardiovascular system. In the vasculature, changes in autophagy have been documented in atherosclerotic and restenotic lesions and in hypertensive vessels. The biology of vascular smooth muscle cells appears particularly sensitive to changes in the autophagic program. Recent evidence indicates that stimuli or stressors evoked during the course of vascular disease can regulate autophagic activity, resulting in modulation of VSMC phenotype and viability. In particular, certain growth factors and cytokines, oxygen tension, and pharmacological drugs have been shown to trigger autophagy in smooth muscle cells. Importantly, each of these stimuli has a redox component, typically associated with changes in the abundance of reactive oxygen, nitrogen, or lipid species. Collective findings support the hypothesis that autophagy plays a critical role in vascular remodeling by regulating smooth muscle cell phenotype transitions and by influencing the cellular response to stress. In this graphical review, we summarize current knowledge on the role of autophagy in the biology of the smooth muscle cell in (pathophysiology.

  11. The determination of contribution of emotional intelligence and parenting styles components to predicts positive psychological components

    Directory of Open Access Journals (Sweden)

    hosein Ebrahimi moghadam

    2015-05-01

    Full Text Available Background: Since the essential of positive psychological components, as compliment of deficiency oriented approaches, has begun in recent days,we decided to take into account this new branch of psychology which scientifically considers studying forces of human, as well as because of the importance of this branch of psychology, we also tried to search the contribution of emotional intelligence and parenting styles components to predict positive psychological components. Materials and Methods:In this cross sectional study 200 psychological students of Azad university (Rudehen branch selected using cluster sampling method. Then they were estimated by Bradbery and Grivers emotional intelligence questionnaire , Bamrind parenting styles and Rajayi et al positive psychological components questionnaire. Research data was analyzed using descriptive statistics (mean and standard deviation, inferential statistics (multiple regression and Pierson correlation coefficient and SPSS software. Results:Among the components of emotional intelligence, the component of emotional self consciousness (β=0.464 had the greatest predictable , and reaction leadership showed no predictability in this research between parenting styles , authority parenting styles had positive significance relationship with positive psychological components. And no significant relationship was found between despot parenting styles and positive psychological components. Conclusion: Regarding the results of this research and importance of positive psychological components, it is suggested to treat the emotional intelligence from childhood and to learn it to parents and remind them the parenting way to decrease the satisfaction of individuals which leads to promotion of society mental health.

  12. Signalome-wide RNAi screen identifies GBA1 as a positive mediator of autophagic cell death

    Science.gov (United States)

    Dasari, Santosh K; Bialik, Shani; Levin-Zaidman, Smadar; Levin-Salomon, Vered; Merrill, Alfred H; Futerman, Anthony H; Kimchi, Adi

    2017-01-01

    Activating alternative cell death pathways, including autophagic cell death, is a promising direction to overcome the apoptosis resistance observed in various cancers. Yet, whether autophagy acts as a death mechanism by over consumption of intracellular components is still controversial and remains undefined at the ultrastructural and the mechanistic levels. Here we identified conditions under which resveratrol-treated A549 lung cancer cells die by a mechanism that fulfills the previous definition of autophagic cell death. The cells displayed a strong and sustained induction of autophagic flux, cell death was prevented by knocking down autophagic genes and death occurred in the absence of apoptotic or necroptotic pathway activation. Detailed ultrastructural characterization revealed additional critical events, including a continuous increase over time in the number of autophagic vacuoles, in particular autolysosomes, occupying most of the cytoplasm at terminal stages. This was followed by loss of organelles, disruption of intracellular membranes including the swelling of perinuclear space and, occasionally, a unique type of nuclear shedding. A signalome-wide shRNA-based viability screen was applied to identify positive mediators of this type of autophagic cell death. One top hit was GBA1, the Gaucher disease-associated gene, which encodes glucocerebrosidase, an enzyme that metabolizes glucosylceramide to ceramide and glucose. Interestingly, glucocerebrosidase expression levels and activity were elevated, concomitantly with increased intracellular ceramide levels, both of which correlated in time with the appearance of the unique death characteristics. Transfection with siGBA1 attenuated the increase in glucocerebrosidase activity and the intracellular ceramide levels. Most importantly, GBA1 knockdown prevented the strong increase in LC3 lipidation, and many of the ultrastructural changes characteristic of this type of autophagic cell death, including a significant

  13. Integrated steel components contribute to improvement of reliability of LWRs

    International Nuclear Information System (INIS)

    Anon.

    1985-01-01

    The technological development of steel products has been a major contribution to the present high capacity ratio of the nuclear power plants in Japan. That is the summary of such matters as the continuous effort to manufacture high quality products, the scaling-up of components aiming at the reduction of welded seams, the application of in-service inspection and the counter-measures to prevent defects in materials. Steel plates and pipes for nuclear plants must be processed under complete quality control from steel making to final inspection. Major steel makers exercise quality control in line with ASME Section 3, Nuclear power plant components. Many plants of the major steel makers have been granted Quality System Certificate (Materials), and/or authorized to use N stamps and/or NPT stamps by ASME. In addition, all the steel makers have developed their own QC activities. The nuclear fuel made in Japan has shown the extremely low failure rate due to the rigid quality assurance standards. The examples of the extra heavy steel plates used for reactor pressure vessels, the nuclear steel components with reduced welded seams, nuclear grade stainless steel, Alloy 600 and SCR-3 are explained. (Kako, I.)

  14. Characterization of Autophagic Responses in Drosophila melanogaster.

    Science.gov (United States)

    Xu, T; Kumar, S; Denton, D

    2017-01-01

    Drosophila is an excellent model system for studying autophagy during animal development due to the availability of genetic reagents and opportunity for in vivo cell biological analysis. The regulation and mechanism of autophagy are highly evolutionarily conserved and the role of autophagy has been characterized during various stages of Drosophila development as well as following starvation. Studies in Drosophila have revealed novel insights into the role of distinct components of the autophagy machinery. This chapter describes protocols for examining autophagy during Drosophila development. A crucial step in the induction of autophagy is the incorporation of Atg8a into the autophagosome. This can be measured as autophagic puncta using live fluorescent imaging, immunostaining, or immunoblot analysis of LC3/Atg8a processing. The level of autophagy can also be examined using other specific components of the autophagy pathway as markers detected by immunofluorescent imaging. Based on the distinct morphology of autophagy, it can also be examined by transmission electron microscopy. In addition, one of the advantages of using Drosophila as a model is the ability to undertake genetic analysis of individual components of the autophagy machinery. Current approaches that can be used to monitor autophagy, including the overall flux and individual steps in Drosophila melanogaster, will be discussed. © 2017 Elsevier Inc. All rights reserved.

  15. How to reduce the accumulation of autophagic vacuoles in NPC1-deficient neurons: a comparison of two pharmacological strategies.

    Science.gov (United States)

    Meske, Volker; Priesnitz, Timm; Albert, Frank; Ohm, Thomas Georg

    2015-02-01

    A disturbed autophagic pathway leads to chronically increased levels of autophagic vacuoles in Niemann Pick Type-C 1 (NPC1) deficient neurons. Since these accumulations potentially contribute to neuronal cell death associated with the disease, we investigated two pharmacological strategies which potentially reduce the number of autophagic structures under following aspects: efficiency, sustainability and effect on neuronal cell viability. The strategies comprised (i) an interruption of the autophagic flux by the class III PI3K inhibitor 3-methyladenine (3-MA) and (ii) an acceleration of the autophagic execution by 2-hydroxypropyl-β-cyclodextrin (pCD). Our data show that the inhibition of autophagy with 3-MA only initially reduced the number of autophagic vacuoles in cultured neurons. Prolonged treatments with the PI3K-inhibitor reversed this lowering effect. The re-increase in the number of autophagic vacuoles was combined with a defect in the integrity of lysosomes which endangered further survival of cells. The treatment with pCD evoked a slow but sustained reduction of autophagic structures and had no negative effects on neuronal survival.

  16. Understanding How Components of Organisations Contribute to Attacks

    DEFF Research Database (Denmark)

    Gu, Min; Aslanyan, Zaruhi; Probst, Christian W.

    2016-01-01

    components quickly results in a large quantity of interrelations, which are hard to grasp. In this work we present several approaches for visualising attributes of attacks such as likelihood of success, impact, and required time or skill level. The resulting visualisations provide a link between attacks...

  17. Components of Maternal Healthcare Delivery System Contributing to ...

    African Journals Online (AJOL)

    They included inadequate clinical workups and monitoring, missed and incorrect diagnoses, delayed or incorrect treatment, delayed referrals and transfers, patients not being stabilized before being referred and outright negligence. The SBA component should be investigated further. Interventions based on evidence from ...

  18. NOTE - Contribution of components of production on snap bean yield

    Directory of Open Access Journals (Sweden)

    Rogério Figueiredo Daher

    2012-09-01

    Full Text Available Aiming to estimate the path coefficients among morphological traits and effects of production components on the yield of grains and pods, thirty snap bean genotypes (27 lines and three commercial controls were evaluated in Bom Jesus of Itabapoana-RJ. The experiments were carried out in a randomized block design, with four replications, from May to June, in 2009 and 2010. Eight traits were evaluated and the number of pods per plant, associated with high genetic correlation, is the character with the most significant direct effect on productivity. There is a high rate of genotypic association between the yields of pods and grains, as well as direct effects of high magnitude and positive signal between them, indicating that the selection for increased pod yield allows increased grain yield.

  19. Herpes simplex virus type I induces an incomplete autophagic response in human neuroblastoma cells.

    Science.gov (United States)

    Santana, Soraya; Bullido, Maria Jesús; Recuero, Maria; Valdivieso, Fernando; Aldudo, Jesus

    2012-01-01

    Autophagy is a homeostatic process involved in the turnover or elimination of cytoplasmic components, damaged organelles, and protein aggregates via a lysosomal degradation mechanism. Autophagy also provides a mechanism of innate immunity, known as xenophagy, designed to protect cells from intracellular pathogens, but it may unfortunately be subverted to act as a pro-viral pathway facilitating the replication of certain viruses. Herpes simplex virus type I (HSV-1) is a neurotropic virus that remains latent in host neurons; it is the most common cause of sporadic viral encephalitis. Moreover, HSV-1 has been related to the pathogenesis of Alzheimer's disease. HSV-1 can modulate the autophagic process through a mechanism mediated by the viral protein ICP34.5. Here we report that HSV-1 induces a strong increase in GFP-LC3 and endogenous LC3 lipidation, and triggers the accumulation of intracellular autophagic compartments (mainly autophagosomes) without enhancing autophagic long-lived protein degradation in the late stages of infection. Autophagy inhibition mediated by ATG5 gene silencing had no effect on viral growth. The present results suggest that HSV-1 infection activates the host autophagic machinery and strongly controls the autophagic process, blocking the fusion of autophagosomes with lysosomes. These events might be important in the neurodegenerative process associated with HSV-1 infection.

  20. Increased autophagic response in a population of metastatic breast cancer cells

    Science.gov (United States)

    LI, YI; LIBBY, EMILY FALK; LEWIS, MONICA J.; LIU, JIANZHONG; SHACKA, JOHN J.; HURST, DOUGLAS R.

    2016-01-01

    Breast cancer cells are heterogeneous in their ability to invade and fully metastasize, and thus also in their capacity to survive the numerous stresses encountered throughout the multiple steps of the metastatic cascade. Considering the role of autophagy as a survival response to stress, the present study hypothesized that distinct populations of breast cancer cells may possess an altered autophagic capacity that influences their metastatic potential. It was observed that a metastatic breast cancer cell line, MDA-MB-231, that was sensitive to autophagic induction additionally possessed the ability to proliferate following nutrient deprivation. Furthermore, a selected subpopulation of these cells that survived multiple exposures to starvation conditions demonstrated a heightened response to autophagic induction compared to their parent cells. Although this subpopulation maintained a more grape-like pattern in three-dimensional culture compared to the extended spikes of the parent population, autophagic induction in this subpopulation elicited an invasive phenotype with extended spikes. Taken together, these results suggest that autophagic induction may contribute to the ability of distinct breast cancer cell populations to survive and invade. PMID:27347175

  1. Autophagic flux is highly active in early mitosis and differentially regulated throughout the cell cycle.

    Science.gov (United States)

    Li, Zhiyuan; Ji, Xinmiao; Wang, Dongmei; Liu, Juanjuan; Zhang, Xin

    2016-06-28

    Mitosis is a fast process that involves dramatic cellular remodeling and has a high energy demand. Whether autophagy is active or inactive during the early stages of mitosis in a naturally dividing cell is still debated. Here we aimed to use multiple assays to resolve this apparent discrepancy. Although the LC3 puncta number was reduced in mitosis, the four different cell lines we tested all have active autophagic flux in both interphase and mitosis. In addition, the autophagic flux was highly active in nocodazole-induced, double-thymidine synchronization released as well as naturally occurring mitosis in HeLa cells. Multiple autophagy proteins are upregulated in mitosis and the increased Beclin-1 level likely contributes to the active autophagic flux in early mitosis. It is interesting that although the autophagic flux is active throughout the cell cycle, early mitosis and S phase have relatively higher autophagic flux than G1 and late G2 phases, which might be helpful to degrade the damaged organelles and provide energy during S phase and mitosis.

  2. The contribution of aromatic components in Katsuobushi to preference formation and reinforcement effect.

    Science.gov (United States)

    Amitsuka, Takahiko; Okamura, Maya; Mukuta, Kei; Shiibashi, Hiroko; Haraguchi, Kenji; Saito, Tsukasa; Inoue, Kazuo; Fushiki, Tohru

    2017-08-01

    Katsuodashi, a dried bonito broth, is very basic and indispensable in Japanese cuisine and contains taste-exhibiting components and unique aroma. We previously reported that its unique aroma contributes to the preference and reinforcement effect associated with dried bonito. This study aims to elucidate the contribution of aromatic components in Katsuobushi to preference formation and reinforcement effect. Volatile components obtained from dried bonito were fractionated and the fractions were subjected to two-bottle choice test. The fractionation test suggested that the component responsible for the preference is not one but comprises multiple components. In the GC-MS analysis/reconstruction test, solution with aromatic flavor narrowed down to 125 compounds had preference, and also had reinforcement effect. Moreover, GC-MS-olfactometry analysis narrowed down the candidate components to 28 out of 125. Mice showed preference for the test solution with aromatic flavor reconstructed with 28 components but did not show reinforcement behavior.

  3. MnSOD upregulation induces autophagic programmed cell death in senescent keratinocytes.

    Directory of Open Access Journals (Sweden)

    Emeric Deruy

    Full Text Available Senescence is a state of growth arrest resulting mainly from telomere attrition and oxidative stress. It ultimately leads to cell death. We have previously shown that, in keratinocytes, senescence is induced by NF-kappaB activation, MnSOD upregulation and H(2O(2 overproduction. We have also shown that senescent keratinocytes do not die by apoptosis but as a result of high macroautophagic activity that targets the primary vital cell components. Here, we investigated the mechanisms that activate this autophagic cell death program. We show that corpses occurring at the senescence plateau display oxidatively-damaged mitochondria and nucleus that colocalize with autophagic vacuoles. The occurrence of such corpses was decreased by specifically reducing the H(2O(2 level with catalase, and, conversely, reproduced by overexpressing MnSOD or applying subtoxic doses of H(2O(2. This H(2O(2-induced cell death did occur through autophagy since it was accompanied by an accumulation of autophagic vesicles as evidenced by Lysotracker staining, LC3 vesiculation and transmission electron microscopy. Most importantly, it was partly abolished by 3-methyladenine, the specific inhibitor of autophagosome formation, and by anti-Atg5 siRNAs. Taken together these results suggest that autophagic cell death is activated in senescent keratinocytes because of the upregulation of MnSOD and the resulting accumulation of oxidative damages to nucleus and mitochondria.

  4. Autophagic clearance of bacterial pathogens: molecular recognition of intracellular microorganisms.

    Science.gov (United States)

    Pareja, Maria Eugenia Mansilla; Colombo, Maria I

    2013-01-01

    Autophagy is involved in several physiological and pathological processes. One of the key roles of the autophagic pathway is to participate in the first line of defense against the invasion of pathogens, as part of the innate immune response. Targeting of intracellular bacteria by the autophagic machinery, either in the cytoplasm or within vacuolar compartments, helps to control bacterial proliferation in the host cell, controlling also the spreading of the infection. In this review we will describe the means used by diverse bacterial pathogens to survive intracellularly and how they are recognized by the autophagic molecular machinery, as well as the mechanisms used to avoid autophagic clearance.

  5. The bifunctional autophagic flux by 2-deoxyglucose to control survival or growth of prostate cancer cells

    International Nuclear Information System (INIS)

    Jeon, Jeong Yong; Kim, Seung Won; Park, Ki Cheong; Yun, Mijin

    2015-01-01

    Recent reports using metabolism regulating drugs showed that nutrient deprivation was an efficient tool to suppress cancer progression. In addition, autophagy control is emerging to prevent cancer cell survival. Autophagy breaks down the unnecessary cytoplasmic components into anabolic units and energy sources, which are the most important sources for making the ATP that maintains homeostasis in cancer cell growth and survival. Therefore, the glucose analog 2-deoxyglucose (2DG) has been used as an anticancer reagent due to its inhibition of glycolysis. Prostate cancer cells (PC3) were treated with 2DG for 6 h or 48 h to analyze the changing of cell cycle and autophagic flux. Rapamycin and LC3B overexpressing vectors were administered to PC3 cells for autophagy induction and chloroquine and shBeclin1 plasmid were used to inhibit autophagy in PC3 cells to analyze PC3 cells growth and survival. The samples for western blotting were prepared in each culture condition to confirm the expression level of autophagy related and regulating proteins. We demonstrated that 2DG inhibits PC3 cells growth and had discriminating effects on autophagy regulation based on the different time period of 2DG treatment to control cell survival. Short-term treatment of 2DG induced autophagic flux, which increased microtubule associated protein 1 light chain 3B (LC3B) conversion rates and reduced p62 levels. However, 2DG induced autophagic flux is remarkably reduced over an extended time period of 2DG treatment for 48 h despite autophagy inducing internal signaling being maintained. The relationship between cell growth and autophagy was proved. Increased autophagic flux by rapamycin or LC3B overexpression powerfully reduced cell growth, while autophagy inhibition with shBeclin1 plasmid or chloroquine had no significant effect on regulating cell growth. Given these results, maintaining increased autophagic flux was more effective at inhibiting cancer cell progression than inhibition of

  6. How components of facial width to height ratio differently contribute to the perception of social traits

    Science.gov (United States)

    Lio, Guillaume; Gomez, Alice; Sirigu, Angela

    2017-01-01

    Facial width to height ratio (fWHR) is a morphological cue that correlates with sexual dimorphism and social traits. Currently, it is unclear how vertical and horizontal components of fWHR, distinctly capture faces’ social information. Using a new methodology, we orthogonally manipulated the upper facial height and the bizygomatic width to test their selective effect in the formation of impressions. Subjects (n = 90) saw pair of faces and had to select the face expressing better different social traits (trustworthiness, aggressiveness and femininity). We further investigated how sex and fWHR components interact in the formation of these judgements. Across experiments, changes along the vertical component better predicted participants' ratings rather than the horizontal component. Faces with smaller height were perceived as less trustworthy, less feminine and more aggressive. By dissociating fWHR and testing the contribution of its components independently, we obtained a powerful and discriminative measure of how facial morphology guides social judgements. PMID:28235081

  7. Monitoring Autophagic Responses in Caenorhabditis elegans.

    Science.gov (United States)

    Papandreou, M E; Tavernarakis, N

    2017-01-01

    Autophagy, from the Greek auto (self) and phagy (eating), is a self-degradative process critical for eukaryotic cell homeostasis. Its rapidly responsive, highly dynamic nature renders this process essential for adapting to and offsetting acute/harsh conditions such as starvation, organelle dysfunction, and deoxyribonucleic acid (DNA) damage. Autophagy involves an intricate network of interacting factors with multiple levels of control. Importantly, dysregulation of autophagy has been linked to numerous debilitating pathologies, including cancer and neurodegenerative conditions in humans. Methods to monitor and quantify autophagic activity reliably are essential both for studying the basic mechanisms of autophagy and for dissecting its involvement in disease. The nematode Caenorhabditis elegans is a particularly suitable model organism to effectively visualize and study autophagy, in vivo, in a physiological and pathological context due to its optical transparency, experimental malleability, and precise developmental and anatomical characterization. Here, we outline the main tools and approaches to monitor and measure autophagic responses in C. elegans. © 2017 Elsevier Inc. All rights reserved.

  8. How do different components of Effortful Control contribute to children's mathematics achievement?

    Science.gov (United States)

    Sánchez-Pérez, Noelia; Fuentes, Luis J; Pina, Violeta; López-López, Jose A; González-Salinas, Carmen

    2015-01-01

    This work sought to investigate the specific contribution of two different components of Effortful Control (EC) -attentional focusing (AF) and inhibitory control- to children's mathematics achievement. The sample was composed of 142 children aged 9-12 year-old. EC components were measured through the Temperament in Middle Childhood Questionnaire (TMCQ; parent's report); math achievement was measured via teacher's report and through the standard Woodcock-Johnson test. Additionally, the contribution of other cognitive and socio-emotional processes was taken into account. Our results showed that only AF significantly contributed to the variance of children's mathematics achievement; interestingly, mediational models showed that the relationship between effortful attentional self-regulation and mathematics achievement was mediated by academic peer popularity, as well as by intelligence and study skills. Results are discussed in the light of the current theories on the role of children's self-regulation abilities in the context of school.

  9. Time-independent and time-dependent contributions to the unavailability of standby safety system components

    International Nuclear Information System (INIS)

    Lofgren, E.V.; Uryasev, S.; Samanta, P.

    1997-01-01

    The unavailability of standby safety system components due to failures in nuclear power plants is considered to involve a time-independent and a time-dependent part. The former relates to the component's unavailability from demand stresses due to usage, and the latter represents the component's unavailability due to standby-time stresses related to the environment. In this paper, data from the nuclear plant reliability data system (NPRDS) were used to partition the component's unavailability into the contributions from standby-time stress (i.e., due to environmental factors) and demand stress (i.e., due to usage). Analyses are presented of motor-operated valves (MOVs), motor-driven pumps (MDPs), and turbine-driven pumps (TDPs). MOVs fail predominantly (approx. 78 %) from environmental factors (standby-time stress failures). MDPs fail slightly more frequently from demand stresses (approx. 63 %) than standby-time stresses, while TDPs fail predominantly from standby-time stresses (approx. 78 %). Such partitions of component unavailability have many uses in risk-informed and performance-based regulation relating to modifications to Technical Specification, in-service testing, precise determination of dominant accident sequences, and implementation of maintenance rules

  10. Application of energy derivative method to determine the structural components' contribution on the deceleration in crashes.

    Science.gov (United States)

    Nagasaka, Kei; Mizuno, Koji; Thomson, Robert

    2018-03-26

    For occupant protection, it is important to understand how a car's deceleration-time history in crashes can be designed using efficient of energy absorption by a car body's structure. In a previous paper, the authors proposed an energy derivative method to determine each structural component's contribution on the longitudinal deceleration of a car passenger compartment in crashes. In this study, this method was extended to two dimensions in order to analyze various crash test conditions. The contribution of each structure estimated from the energy derivative method was compared to that from a conventional finite element (FE) analysis method using cross-sectional forces. A two-dimensional energy derivative method was established. A simple FE model with a structural column connected to a rigid body was used to confirm the validity of this method and to compare with the result of cross-sectional forces determined using conventional analysis. Applying this method to a full-width frontal impact simulation of a car FE model, the contribution and the cross-sectional forces of the front rails were compared. In addition, this method was applied to a pedestrian headform FE simulation in order to determine the influence of the structural and inertia forces of the hood structures on the deceleration of the headform undergoing planar motion. In an oblique impact of the simple column and rigid body model, the sum of the contributions of each part agrees with the rigid body deceleration, which indicates the validity of two-dimensional energy derivative method. Using the energy derivative method, it was observed that each part of the column contributes to the deceleration of the rigid body by collapsing in the sequence from front to rear whereas the cross-section force at the rear of the column cannot detect the continuous collapse. In the full-width impact of a car, the contributions of the front rails estimated in the energy derivative method was smaller than that using the

  11. How do different components of Effortful Control contribute to children’s mathematics achievement?

    Science.gov (United States)

    Sánchez-Pérez, Noelia; Fuentes, Luis J.; Pina, Violeta; López-López, Jose A.; González-Salinas, Carmen

    2015-01-01

    This work sought to investigate the specific contribution of two different components of Effortful Control (EC) -attentional focusing (AF) and inhibitory control- to children’s mathematics achievement. The sample was composed of 142 children aged 9–12 year-old. EC components were measured through the Temperament in Middle Childhood Questionnaire (TMCQ; parent’s report); math achievement was measured via teacher’s report and through the standard Woodcock–Johnson test. Additionally, the contribution of other cognitive and socio-emotional processes was taken into account. Our results showed that only AF significantly contributed to the variance of children’s mathematics achievement; interestingly, mediational models showed that the relationship between effortful attentional self-regulation and mathematics achievement was mediated by academic peer popularity, as well as by intelligence and study skills. Results are discussed in the light of the current theories on the role of children’s self-regulation abilities in the context of school. PMID:26441758

  12. How do different components of Effortful Control contribute to children's mathematics achievement?

    Directory of Open Access Journals (Sweden)

    Noelia eSánchez-Pérez

    2015-09-01

    Full Text Available This work sought to investigate the specific contribution of two different components of Effortful Control -attentional focusing and inhibitory control- to children’s mathematics achievement. The sample was composed of 142 children aged 9 to 12 years old. Effortful Control components were measured through the Temperament in Middle Childhood Questionnaire (TMCQ; parent´s report; math achievement was measured via teacher’s report and through the standard Woodcock-Johnson test. Additionally, the contribution of other cognitive and socio-emotional processes was taken into account. Our results showed that only attentional focusing significantly contributed to the variance of children’s mathematics achievement; interestingly, mediational models showed that the relationship between effortful attentional self-regulation and mathematics achievement was mediated by academic peer popularity, as well as by intelligence and study skills. Results are discussed in the light of the current theories on the role of children’ self-regulation abilities in the context of school.

  13. Design Process Components and Perceived Product Quality : Can a Design Education Program Contribute to better Product Quality?

    NARCIS (Netherlands)

    Kok, B.N.E.

    2016-01-01

    In this PhD research the design process components that can contribute to a better perceived product quality are studied. First the design process components are determined. Secondly the effect of these components on the perceived quality is studied. This research is mainly based on design processes

  14. Deoxycholate, an Endogenous Cytotoxin/Geno toxin, Induces the Autophagic Stress-Survival Pathway: Implications for Colon Carcinogenesis

    International Nuclear Information System (INIS)

    Payne, C.M.; Skillicorn, C.C.; Holubec, H.; Bernstein, C.; Dvorak, K.; Bernstein, H.; Moyer, M.P.; Garewal, H.

    2009-01-01

    We report that deoxycholate (DOC), a hydrophobic bile acid associated with a high-fat diet, activates the autophagic pathway in non-cancer colon epithelial cells (NCM-460), and that this activation contributes to cell survival. The DOC-induced increase in autophagy was documented by an increase in autophagic vacuoles (detected using transmission electron microscopy, increased levels of LC3-I and LC3-II (western blotting), an increase in acidic vesicles (fluorescence spectroscopy of monodansylcadaverine and lyso tracker red probes), and increased expression of the autophagic protein, beclin-1 (immunohistochemistry/western blotting). The DOC-induced increase in beclin-1 expression was ROS-dependent. Rapa mycin (activator of autophagy) pre-treatment of NCM-460 cells significantly (P<.05) decreased, and 3-MA (inhibitor of autophagy) significantly (P<.05) increased the cell loss caused by DOC treatment, alone. Rapa mycin pre-treatment of the apoptosis-resistant colon cancer cell line, HCT-116RC (developed in our laboratory), resulted in a significant decrease in DOC-induced cell death. Bafilomycin A1 and hydroxychloroquine (inhibitors of the autophagic process) increased the DOC-induced percentage of apoptotic cells in HCT-116RC cells. It was concluded that the activation of autophagy by DOC has important implications for colon carcinogenesis and for the treatment of colon cancer in conjunction with commonly used chemotherapeutic agents.

  15. Serratia marcescens Is Able to Survive and Proliferate in Autophagic-Like Vacuoles inside Non-Phagocytic Cells

    Science.gov (United States)

    Colombo, María Isabel; García Véscovi, Eleonora

    2011-01-01

    Serratia marcescens is an opportunistic human pathogen that represents a growing problem for public health, particularly in hospitalized or immunocompromised patients. However, little is known about factors and mechanisms that contribute to S. marcescens pathogenesis within its host. In this work, we explore the invasion process of this opportunistic pathogen to epithelial cells. We demonstrate that once internalized, Serratia is able not only to persist but also to multiply inside a large membrane-bound compartment. This structure displays autophagic-like features, acquiring LC3 and Rab7, markers described to be recruited throughout the progression of antibacterial autophagy. The majority of the autophagic-like vacuoles in which Serratia resides and proliferates are non-acidic and have no degradative properties, indicating that the bacteria are capable to either delay or prevent fusion with lysosomal compartments, altering the expected progression of autophagosome maturation. In addition, our results demonstrate that Serratia triggers a non-canonical autophagic process before internalization. These findings reveal that S. marcescens is able to manipulate the autophagic traffic, generating a suitable niche for survival and proliferation inside the host cell. PMID:21901159

  16. Discrete contributions of elastic fiber components to arterial development and mechanical compliance.

    Science.gov (United States)

    Carta, Luca; Wagenseil, Jessica E; Knutsen, Russell H; Mariko, Boubacar; Faury, Gilles; Davis, Elaine C; Starcher, Barry; Mecham, Robert P; Ramirez, Francesco

    2009-12-01

    Even though elastin and fibrillin-1 are the major structural components of elastic fibers, mutations in elastin and fibrillin-1 lead to narrowing of large arteries in supravalvular aortic stenosis and dilation of the ascending aorta in Marfan syndrome, respectively. A genetic approach was therefore used here to distinguish the differential contributions of elastin and fibrillin-1 to arterial development and compliance. Key parameters of cardiovascular function were compared among adult mice haploinsufficient for elastin (Eln(+/-)), fibrillin-1 (Fbn1(+/-)), or both proteins (dHet). Physiological and morphological comparisons correlate elastin haploinsufficiency with increased blood pressure and vessel length and tortuosity in dHet mice, and fibrillin-1 haploinsufficiency with increased aortic diameter in the same mutant animals. Mechanical tests confirm that elastin and fibrillin-1 impart elastic recoil and tensile strength to the aortic wall, respectively. Additional ex vivo analyses demonstrate additive and overlapping contributions of elastin and fibrillin-1 to the material properties of vascular tissues. Lastly, light and electron microscopy evidence implicates fibrillin-1 in the hypertension-promoted remodeling of the elastin-deficient aorta. These results demonstrate that elastin and fibrillin-1 have both differential and complementary roles in arterial wall formation and function, and advance our knowledge of the structural determinants of vascular physiology and disease.

  17. Autophagic dysfunction in a lysosomal storage disorder due to impaired proteolysis.

    Science.gov (United States)

    Elrick, Matthew J; Lieberman, Andrew P

    2013-02-01

    Alterations in macroautophagy (hereafter referred to as "autophagy") are a common feature of lysosomal storage disorders, and have been hypothesized to play a major role in the pathogenesis of these diseases. We have recently reported multiple defects in autophagy contributing to the lysosomal storage disorder Niemann-Pick type C (NPC). These include increased formation of autophagosomes, slowed turnover of autophagosomes secondary to impaired lysosomal proteolysis, and delivery of stored lipids to the lysosome via autophagy. The study summarized here describes novel methods for the interrogation of individual stages of the autophagic pathway, and suggests mechanisms by which lipid storage may result in broader lysosomal dysfunction.

  18. The Two-Component System ChtRS Contributes to Chlorhexidine Tolerance in Enterococcus faecium.

    Science.gov (United States)

    Guzmán Prieto, Ana M; Wijngaarden, Jessica; Braat, Johanna C; Rogers, Malbert R C; Majoor, Eline; Brouwer, Ellen C; Zhang, Xinglin; Bayjanov, Jumamurat R; Bonten, Marc J M; Willems, Rob J L; van Schaik, Willem

    2017-05-01

    Enterococcus faecium is one of the primary causes of nosocomial infections. Disinfectants are commonly used to prevent infections with multidrug-resistant E. faecium in hospitals. Worryingly, E. faecium strains that exhibit tolerance to disinfectants have already been described. We aimed to identify and characterize E. faecium genes that contribute to tolerance to the disinfectant chlorhexidine (CHX). We used a transposon mutant library, constructed in a multidrug-resistant E. faecium bloodstream isolate, to perform a genome-wide screen to identify genetic determinants involved in tolerance to CHX. We identified a putative two-component system (2CS), composed of a putative sensor histidine kinase (ChtS) and a cognate DNA-binding response regulator (ChtR), which contributed to CHX tolerance in E. faecium Targeted chtR and chtS deletion mutants exhibited compromised growth in the presence of CHX. Growth of the chtR and chtS mutants was also affected in the presence of the antibiotic bacitracin. The CHX- and bacitracin-tolerant phenotype of E. faecium E1162 was linked to a unique, nonsynonymous single nucleotide polymorphism in chtR Transmission electron microscopy showed that upon challenge with CHX, the Δ chtR and Δ chtS mutants failed to divide properly and formed long chains. Normal growth and cell morphology were restored when the mutations were complemented in trans Morphological abnormalities were also observed upon exposure of the Δ chtR and Δ chtS mutants to bacitracin. The tolerance to both chlorhexidine and bacitracin provided by ChtRS in E. faecium highlights the overlap between responses to disinfectants and antibiotics and the potential for the development of cross-tolerance for these classes of antimicrobials. Copyright © 2017 American Society for Microbiology.

  19. Age-related disruption of autophagy in dermal fibroblasts modulates extracellular matrix components

    International Nuclear Information System (INIS)

    Tashiro, Kanae; Shishido, Mayumi; Fujimoto, Keiko; Hirota, Yuko; Yo, Kazuyuki; Gomi, Takamasa; Tanaka, Yoshitaka

    2014-01-01

    Highlights: •Autophagosomes accumulate in aged dermal fibroblasts. •Autophagic degradation is impaired in aged dermal fibroblasts. •Autophagy disruption affects extracellular matrix components in dermal fibroblasts. -- Abstract: Autophagy is an intracellular degradative system that is believed to be involved in the aging process. The contribution of autophagy to age-related changes in the human skin is unclear. In this study, we examined the relationship between autophagy and skin aging. Transmission electron microscopy and immunofluorescence microscopy analyses of skin tissue and cultured dermal fibroblasts derived from women of different ages revealed an increase in the number of nascent double-membrane autophagosomes with age. Western blot analysis showed that the amount of LC3-II, a form associated with autophagic vacuolar membranes, was significantly increased in aged dermal fibroblasts compared with that in young dermal fibroblasts. Aged dermal fibroblasts were minimally affected by inhibition of autophagic activity. Although lipofuscin autofluorescence was elevated in aged dermal fibroblasts, the expression of Beclin-1 and Atg5—genes essential for autophagosome formation—was similar between young and aged dermal fibroblasts, suggesting that the increase of autophagosomes in aged dermal fibroblasts was due to impaired autophagic flux rather than an increase in autophagosome formation. Treatment of young dermal fibroblasts with lysosomal protease inhibitors, which mimic the condition of aged dermal fibroblasts with reduced autophagic activity, altered the fibroblast content of type I procollagen, hyaluronan and elastin, and caused a breakdown of collagen fibrils. Collectively, these findings suggest that the autophagy pathway is impaired in aged dermal fibroblasts, which leads to deterioration of dermal integrity and skin fragility

  20. Conditioned place preference for social interaction in rats: contribution of sensory components

    Directory of Open Access Journals (Sweden)

    Kai eKummer

    2011-11-01

    Full Text Available A main challenge in the therapy of drug dependent individuals is to help them reactivate interest in non-drug-associated activities. We previously developed a rat experimental model based on the conditioned place preference (CPP paradigm in which only four 15-min episodes of social interaction with a gender- and weight-matched male Sprague Dawley rat (i reversed CPP from cocaine to social interaction despite continuing cocaine training and (ii prevented the reinstatement of cocaine CPP. In the present study, we investigated which of the sensory modalities of the composite stimulus 'social interaction' contributes most to the rats’ preference for it. If touch was limited by steel bars spaced at a distance of 2 cm and running across the whole length of a partitioning, CPP was still acquired, albeit to a lesser degree. If both rats were placed on the same side of a partitioning, rats did not develop CPP for social interaction. Thus, decreasing the available area for social interaction from 750 to 375 cm² prevented the acquisition of CPP to social interaction despite the fact that animals could touch each other more intensely than through the bars of the partitioning. When touch was fully restricted by a glass screen dividing the conditioning chambers, and the only sensory modalities left were visual and olfactory cues, place preference shifted to place aversion. Overall, our findings indicate that the major rewarding sensory component of the composite stimulus 'social interaction' is touch (tactition.

  1. Differential contribution of hippocampal subfields to components of associative taste learning.

    Science.gov (United States)

    Chinnakkaruppan, Adaikkan; Wintzer, Marie E; McHugh, Thomas J; Rosenblum, Kobi

    2014-08-13

    The ability to associate the consumption of a taste with its positive or negative consequences is fundamental to survival and influences the behavior of species ranging from invertebrate to human. As a result, for both research and clinical reasons, there has been a great effort to understand the neuronal circuits, as well as the cellular and molecular mechanisms, underlying taste learning. From a neuroanatomical perspective, the contributions of the cortex and amygdala are well documented; however, the literature is riddled with conflicting results regarding the role of the hippocampus in different facets of taste learning. Here, we use conditional genetics in mice to block NMDA receptor-dependent plasticity individually in each of the three major hippocampal subfields, CA1, CA3, and the dentate gyrus, via deletion of the NR1 subunit. Across the CA1, CA3, and dentate gyrus NR1 knock-out lines, we uncover a pattern of differential deficits that establish the dispensability of hippocampal plasticity in incidental taste learning, the requirement of CA1 plasticity for associative taste learning, and a specific requirement for plasticity in the dentate gyrus when there is a long temporal gap between the taste and its outcome. Together, these data establish that the hippocampus is involved in associative taste learning and suggest an episodic component to this type of memory. Copyright © 2014 the authors 0270-6474/14/3411007-09$15.00/0.

  2. Routine Western blot to check autophagic flux : Cautions and recommendations

    NARCIS (Netherlands)

    Gomez-Sanchez, Ruben; Pizarro-Estrella, Elisa; Yakhine-Diop, Sokhna M. S.; Rodriguez-Arribas, Mario; Bravo-San Pedro, Jose M.; Fuentes, Jose M.; Gonzalez-Polo, Rosa A.

    2015-01-01

    At present, the analysis of autophagic flux by Western blotting (WB), which measures two of the most important markers of autophagy, i.e., microtubule-associated protein 1 light chain 3 (LC3) and p62, is widely accepted in the scientific community. In this study, we addressed the possible

  3. Research program Integrity of Components (FKS). A substantial contribution to component safety; Forschungsvorhaben Komponentensicherheit (FKS). Ein wesentlicher Beitrag zur Komponentensicherheit

    Energy Technology Data Exchange (ETDEWEB)

    Kussmaul, K.; Roos, E.; Foehl, J.

    1998-11-01

    The main objectives pursued are: (a) verify the quality of reactor pressure vessels in existing LWR-type reactors, and (b) quantify the safety margin using both specified and non-specified materials and welds. On the basis of knowledge obtained through earlier programmes, the research project was to examine in particular deviations from the specified materials properties, for more exact quantification of the safety margin before RPV failure. There are three major factors influencing the component performance until failure, which are aggregate material fatigue, flaws, loading conditions, and the research work was to focus on the materials properties. An item of main interest was to assess the impact of long service life on the materials properties, assuming particularly unfavourable boundary conditions for materials properties and operational loads. (orig./CB) [Deutsch] Die Hauptziele des Forschungsvorhabens Komponentensicherheit waren (a) die Qualitaet bestehender Reaktordruckbehaelter von Leichtwasserreaktoren zu verifizieren, und (b) den Sicherheitsabstand zu quantifizieren unter Verwendung von Werkstoffen und Schweissverbindungen, die innerhalb und ausserhalb der Spezifikation liegen. Gestuetzt auf Erkenntnisse aus frueheren Programmen sollten zur quantitativen Erfassung des Sicherheitsabstandes gegen Versagen des RDB`s insbesondere auch Abweichungen vom spezifikationsgemaessen Werkstoffzustand betrachtet werden. Von den drei Haupteinflussgroessen Werkstoffzustand, Fehlerzustand, Beanspruchungszustand, die das Versagensverhalten bestimmen, lag der Schwerpunkt des FKS auf der Untersuchung des Werkstoffeinflusses. Insbesondere sollte geprueft werden, wie sich der Langzeitbetrieb auf die Aenderung der Werkstoffeigenschaften auswirkt, wenn besonders unguenstige Randbedingungen von Werkstoffzustand und Betriebsbedingungen zugrunde gelegt werden. (orig./MM)

  4. Left dorsal speech stream components and their contribution to phonological processing.

    Science.gov (United States)

    Murakami, Takenobu; Kell, Christian A; Restle, Julia; Ugawa, Yoshikazu; Ziemann, Ulf

    2015-01-28

    Models propose an auditory-motor mapping via a left-hemispheric dorsal speech-processing stream, yet its detailed contributions to speech perception and production are unclear. Using fMRI-navigated repetitive transcranial magnetic stimulation (rTMS), we virtually lesioned left dorsal stream components in healthy human subjects and probed the consequences on speech-related facilitation of articulatory motor cortex (M1) excitability, as indexed by increases in motor-evoked potential (MEP) amplitude of a lip muscle, and on speech processing performance in phonological tests. Speech-related MEP facilitation was disrupted by rTMS of the posterior superior temporal sulcus (pSTS), the sylvian parieto-temporal region (SPT), and by double-knock-out but not individual lesioning of pars opercularis of the inferior frontal gyrus (pIFG) and the dorsal premotor cortex (dPMC), and not by rTMS of the ventral speech-processing stream or an occipital control site. RTMS of the dorsal stream but not of the ventral stream or the occipital control site caused deficits specifically in the processing of fast transients of the acoustic speech signal. Performance of syllable and pseudoword repetition correlated with speech-related MEP facilitation, and this relation was abolished with rTMS of pSTS, SPT, and pIFG. Findings provide direct evidence that auditory-motor mapping in the left dorsal stream causes reliable and specific speech-related MEP facilitation in left articulatory M1. The left dorsal stream targets the articulatory M1 through pSTS and SPT constituting essential posterior input regions and parallel via frontal pathways through pIFG and dPMC. Finally, engagement of the left dorsal stream is necessary for processing of fast transients in the auditory signal. Copyright © 2015 the authors 0270-6474/15/351411-12$15.00/0.

  5. Safety and reliability of pressure components with special emphasis on the contribution of component and large specimen testing to structural integrity assessment methodology. Vol. 1 and 2

    International Nuclear Information System (INIS)

    1987-01-01

    The 51 papers of the 13. MPA-seminar contribute to structural integrity assessment methodology with special emphasis on the component and large specimen testing. 8 of the papers deal with fracture mechanics, 6 papers with dynamic loading, 13 papers with nondestructive testing, 2 papers with radiation embrittlement, 5 papers with pipe failure, 4 papers with components, 2 papers with thermal shock loading, 5 papers with the high temperature behaviour, 4 papers with the integrity of vessels and 3 papers with the integrity of welded joints. Especially also the fracture behaviour of steel material is verificated. All papers are separately indexed and analysed for the database. (DG) [de

  6. Differential contribution of specific working memory components to mathematics achievement in 2nd and 3rd graders

    OpenAIRE

    Meyer, M.L.; Salimpoor, V.N.; Wu, S.S.; Geary, D.C.; Menon, V.

    2010-01-01

    The contribution of the three core components of working memory (WM) to the development of mathematical skills in young children is poorly understood. The relation between specific WM components and Numerical Operations, which emphasize computation and fact retrieval, and Mathematical Reasoning, which emphasizes verbal problem solving abilities in 48 2nd and 50 3rd graders was assessed using standardized WM and mathematical achievement measures. For 2nd graders, the central executive and phon...

  7. Pb isotope evidence for contributions from different Iceland mantle components to Palaeogene East Greenland flood basalts

    DEFF Research Database (Denmark)

    Peate, David; Stecher, Ole

    2003-01-01

    to the most radiogenic values found in recent Icelandic basalts. Furthermore, the main volume of lavas in East Greenland is displaced away from the NAEM towards this radiogenic Pb component. Thus, this ‘Iceland radiogenic Pb end-member’ component was a significant contributor to the break-up-related magmatism...

  8. Understanding Oral Reading Fluency among Adults with Low Literacy: Dominance Analysis of Contributing Component Skills

    Science.gov (United States)

    Mellard, Daryl F.; Anthony, Jason L.; Woods, Kari L.

    2012-01-01

    This study extends the literature on the component skills involved in oral reading fluency. Dominance analysis was applied to assess the relative importance of seven reading-related component skills in the prediction of the oral reading fluency of 272 adult literacy learners. The best predictors of oral reading fluency when text difficulty was…

  9. Akebia saponin PA induces autophagic and apoptotic cell death in AGS human gastric cancer cells.

    Science.gov (United States)

    Xu, Mei-Ying; Lee, Dong Hwa; Joo, Eun Ji; Son, Kun Ho; Kim, Yeong Shik

    2013-09-01

    In this study, we investigated the anticancer mechanism of akebia saponin PA (AS), a natural product isolated from Dipsacus asperoides in human gastric cancer cell lines. It was shown that AS-induced cell death is caused by autophagy and apoptosis in AGS cells. The apoptosis-inducing effect of AS was characterized by annexin V/propidium (PI) staining, increase of sub-G1 phase and caspase-3 activation, while the autophagy-inducing effect was indicated by the formation of cytoplasmic vacuoles and microtubule-associated protein 1 light chain-3 II (LC3-II) conversion. The autophagy inhibitor bafilomycin A1 (BaF1) decreased AS-induced cell death and caspase-3 activation, but caspase-3 inhibitor Ac-DEVD-CHO did not affect LC3-II accumulation or AS-induced cell viability, suggesting that AS induces autophagic cell death and autophagy contributes to caspase-3-dependent apoptosis. Furthermore, AS activated p38/c-Jun N-terminal kinase (JNK), which could be inhibited by BaF1, and caspase-3 activation was attenuated by both SB202190 and SP600125, indicating that AS-induced autophagy promotes mitogen-activated protein kinases (MAPKs)-mediated apoptosis. Taken together, these results demonstrate that AS induces autophagic and apoptotic cell death and autophagy plays the main role in akebia saponin PA-induced cell death. Copyright © 2013 Elsevier Ltd. All rights reserved.

  10. A computer-assisted transfusion management system and changed transfusion practices contribute to appropriate management of blood components.

    Science.gov (United States)

    Ohsaka, Akimichi; Abe, Katsumi; Ohsawa, Toshiya; Miyake, Noriko; Sugita, Shio; Tojima, Ikuko

    2008-08-01

    ABO-incompatible blood transfusions attributable to inadequate identification (ID) of the patient or the blood unit are among the most serious of transfusion hazards. It has been unclear whether a computer-assisted transfusion management system connected to a bar code ID system could contribute to the appropriate management of blood components, as well as to the prevention of mistransfusions. A transfusion management system has been developed that links the hospital information system, a bar code patient-blood unit ID system, and an automated device for pretransfusion testing. The guidelines for issuing blood components from the transfusion service were also changed. The appropriateness of blood management was evaluated by monitoring the time to initiate transfusion after issuing a blood unit from the transfusion service (time after issuing [TAI]) and by calculating the number of units issued and subsequently returned, as well as the rate of date-expired red cell (RBC) components. From July 2002 to December 2006, a total of 49,974 blood components were transfused without a single mistransfusion. The monitoring of TAI and the notice to use the issued blood immediately had the effect of shortening TAI in the inpatient ward. The number of issued and subsequently returned RBC components, as well as the rate of date-expired RBC components, decreased significantly after the introduction of the system. A computer-assisted transfusion management system and changing transfusion practices appear useful in preventing mistransfusions and in contributing to the appropriate management of blood components.

  11. Autophagic machinery activated by dengue virus enhances virus replication

    International Nuclear Information System (INIS)

    Lee, Y.-R.; Lei, H.-Y.; Liu, M.-T.; Wang, J.-R.; Chen, S.-H.; Jiang-Shieh, Y.-F.; Lin, Y.-S.; Yeh, T.-M.; Liu, C.-C.; Liu, H.-S.

    2008-01-01

    Autophagy is a cellular response against stresses which include the infection of viruses and bacteria. We unravel that Dengue virus-2 (DV2) can trigger autophagic process in various infected cell lines demonstrated by GFP-LC3 dot formation and increased LC3-II formation. Autophagosome formation was also observed under the transmission electron microscope. DV2-induced autophagy further enhances the titers of extracellular and intracellular viruses indicating that autophagy can promote viral replication in the infected cells. Moreover, our data show that ATG5 protein is required to execute DV2-induced autophagy. All together, we are the first to demonstrate that DV can activate autophagic machinery that is favorable for viral replication

  12. Autophagic degradation of dBruce controls DNA fragmentation in nurse cells during late Drosophila melanogaster oogenesis

    Science.gov (United States)

    Shravage, Bhupendra V.; Sagona, Antonia P.; Lamark, Trond; Bjørkøy, Geir; Johansen, Terje; Rusten, Tor Erik; Brech, Andreas; Baehrecke, Eric H.

    2010-01-01

    Autophagy is an evolutionarily conserved pathway responsible for degradation of cytoplasmic material via the lysosome. Although autophagy has been reported to contribute to cell death, the underlying mechanisms remain largely unknown. In this study, we show that autophagy controls DNA fragmentation during late oogenesis in Drosophila melanogaster. Inhibition of autophagy by genetically removing the function of the autophagy genes atg1, atg13, and vps34 resulted in late stage egg chambers that contained persisting nurse cell nuclei without fragmented DNA and attenuation of caspase-3 cleavage. The Drosophila inhibitor of apoptosis (IAP) dBruce was found to colocalize with the autophagic marker GFP-Atg8a and accumulated in autophagy mutants. Nurse cells lacking Atg1 or Vps34 in addition to dBruce contained persisting nurse cell nuclei with fragmented DNA. This indicates that autophagic degradation of dBruce controls DNA fragmentation in nurse cells. Our results reveal autophagic degradation of an IAP as a novel mechanism of triggering cell death and thereby provide a mechanistic link between autophagy and cell death. PMID:20713604

  13. Comparison of the relative contributions of intra-abdominal and liver fat to components of the metabolic syndrome

    DEFF Research Database (Denmark)

    Kotronen, Anna; Yki-Järvinen, Hannele; Sevastianova, Ksenia

    2011-01-01

    Abdominally obese individuals with the metabolic syndrome often have excess fat deposition both intra-abdominally (IA) and in the liver, but the relative contribution of these two deposits to variation in components of the metabolic syndrome remains unclear. We determined the mutually independent...... were correlated (r = 0.65, P density lipoprotein (HDL) cholesterol, plasma glucose, insulin and liver enzyme concentrations, and hepatic...

  14. Analysis of near-field components of a plasmonic optical antenna and their contribution to quantum dot infrared photodetector enhancement.

    Science.gov (United States)

    Gu, Guiru; Vaillancourt, Jarrod; Lu, Xuejun

    2014-10-20

    In this paper, we analyze near-field vector components of a metallic circular disk array (MCDA) plasmonic optical antenna and their contribution to quantum dot infrared photodetector (QDIP) enhancement. The near-field vector components of the MCDA optical antenna and their distribution in the QD active region are simulated. The near-field overlap integral with the QD active region is calculated at different wavelengths and compared with the QDIP enhancement spectrum. The x-component (E(x)) of the near-field vector shows a larger intensity overlap integral and stronger correlation with the QDIP enhancement than E(z) and thus is determined to be the major near-field component to the QDIP enhancement.

  15. Studies on the mechanisms of autophagy: maturation of the autophagic vacuole

    OpenAIRE

    1990-01-01

    Data presented in the accompanying paper suggests nascent autophagic vacuoles are formed from RER (Dunn, W. A. 1990. J. Cell Biol. 110:1923- 1933). In the present report, the maturation of newly formed or nascent autophagic vacuoles into degradative vacuoles was examined using morphological and biochemical methods combined with immunological probes. Within 15 min of formation, autophagic vacuoles acquired acid hydrolases and lysosomal membrane proteins, thus becoming degradative vacuoles. A p...

  16. What component of executive functions contributes to normal and impaired reading comprehension in young adults?

    Science.gov (United States)

    Georgiou, George K; Das, J P

    2016-01-01

    The purpose of this study was two-fold: (a) to examine what component of executive functions (EF) - planning and working memory - predicts reading comprehension in young adults (Study 1), and (b) to examine if less skilled comprehenders experience deficits in the EF components (Study 2). In Study 1, we assessed 178 university students (120 females; mean age=21.82 years) on planning (Planned Connections, Planned Codes, and Planned Patterns), working memory (Listening Span, Digit Span Backward, and Digit Memory), and reading comprehension (Nelson-Denny Reading Test). The results of structural equation modeling indicated that only planning was a significant predictor of reading comprehension. In Study 2, we assessed 30 university students with a specific reading comprehension deficit (19 females; mean age=23.01 years) and 30 controls (18 females; mean age=22.77 years) on planning (Planned Connections and Crack the Code) and working memory (Listening Span and Digit Span Backward). The results showed that less skilled comprehenders performed significantly poorer than controls only in planning. Taken together, the findings of both studies suggest that planning is the preeminent component of EF that is driving its relationship with reading comprehension in young adults. Copyright © 2015 Elsevier Ltd. All rights reserved.

  17. Sensory profile and contribution of major components of aroma in dry red wine quality

    Directory of Open Access Journals (Sweden)

    Luisa Costa de Oliveira

    2012-11-01

    Full Text Available This study aimed to determine the sensory profile and main volatile compounds of a set of commercial wines from two major wine regions in Brazil. A total of 28 descriptors were selected by quantitative descriptive analysis, and “red”, “violet”, “pungent aroma”, “vinegary aroma” and “softness” were the most important descriptors in sample discrimination (p<=0.05. 42 volatile aroma compounds were considered relevant for the evaluation of red wine samples. Several acetates and esters that contribute to the pleasant aroma in wines were found in the samples, but other undesirable compounds were also identified: acetic acid and octanoic acid may have contributed to the vinegary and sulphur odors perceived by a trained team.

  18. YAP enhances autophagic flux to promote breast cancer cell survival in response to nutrient deprivation.

    Directory of Open Access Journals (Sweden)

    Qinghe Song

    Full Text Available The Yes-associated protein (YAP, a transcriptional coactivator inactivated by the Hippo tumor suppressor pathway, functions as an oncoprotein in a variety of cancers. However, its contribution to breast cancer remains controversial. This study investigated the role of YAP in breast cancer cells under nutrient deprivation (ND. Here, we show that YAP knockdown sensitized MCF7 breast cancer cells to nutrient deprivation-induced apoptosis. Furthermore, in response to ND, YAP increased the autolysosome degradation, thereby enhancing the cellular autophagic flux in breast cancer cells. Of note, autophagy is crucial for YAP to protect MCF7 cells from apoptosis under ND conditions. In addition, the TEA domain (TEAD family of growth-promoting transcription factors was indispensable for YAP-mediated regulation of autophagy. Collectively, our data reveal a role for YAP in promoting breast cancer cell survival upon ND stress and uncover an unappreciated function of YAP/TEAD in the regulation of autophagy.

  19. The contribution of inflammasome components on macrophage response to surface nanotopography and chemistry

    Science.gov (United States)

    Christo, Susan; Bachhuka, Akash; Diener, Kerrilyn R.; Vasilev, Krasimir; Hayball, John D.

    2016-05-01

    Implantable devices have become an established part of medical practice. However, often a negative inflammatory host response can impede the integration and functionality of the device. In this paper, we interrogate the role of surface nanotopography and chemistry on the potential molecular role of the inflammasome in controlling macrophage responses. To achieve this goal we engineered model substrata having precisely controlled nanotopography of predetermined height and tailored outermost surface chemistry. Bone marrow derived macrophages (BMDM) were harvested from genetically engineered mice deficient in the inflammasome components ASC, NLRP3 and AIM2. These cells were then cultured on these nanoengineered substrata and assessed for their capacity to attach and express pro-inflammatory cytokines. Our data provide evidence that the inflammasome components ASC, NLRP3 and AIM2 play a role in regulating macrophage adhesion and activation in response to surface nanotopography and chemistry. The findings of this paper are important for understanding the inflammatory consequences caused by biomaterials and pave the way to the rational design of future implantable devices having controlled and predictable inflammatory outcomes.

  20. RNA is an integral component of chromatin that contributes to its structural organization.

    Directory of Open Access Journals (Sweden)

    Antonio Rodríguez-Campos

    Full Text Available Chromatin structure is influenced by multiples factors, such as pH, temperature, nature and concentration of counterions, post-translational modifications of histones and binding of structural non-histone proteins. RNA is also known to contribute to the regulation of chromatin structure as chromatin-induced gene silencing was shown to depend on the RNAi machinery in S. pombe, plants and Drosophila. Moreover, both in Drosophila and mammals, dosage compensation requires the contribution of specific non-coding RNAs. However, whether RNA itself plays a direct structural role in chromatin is not known. Here, we report results that indicate a general structural role for RNA in eukaryotic chromatin. RNA is found associated to purified chromatin prepared from chicken liver, or cultured Drosophila S2 cells, and treatment with RNase A alters the structural properties of chromatin. Our results indicate that chromatin-associated RNAs, which account for 2%-5% of total chromatin-associated nucleic acids, are polyA(- and show a size similar to that of the DNA contained in the corresponding chromatin fragments. Chromatin-associated RNA(s are not likely to correspond to nascent transcripts as they are also found bound to chromatin when cells are treated with alpha-amanitin. After treatment with RNase A, chromatin fragments of molecular weight >3.000 bp of DNA showed reduced sedimentation through sucrose gradients and increased sensitivity to micrococcal nuclease digestion. This structural transition, which is observed both at euchromatic and heterochromatic regions, proceeds without loss of histone H1 or any significant change in core-histone composition and integrity.

  1. Complement component 5 contributes to poor disease outcome in humans and mice with pneumococcal meningitis

    Science.gov (United States)

    Woehrl, Bianca; Brouwer, Matthijs C.; Murr, Carmen; Heckenberg, Sebastiaan G.B.; Baas, Frank; Pfister, Hans W.; Zwinderman, Aeilko H.; Morgan, B. Paul; Barnum, Scott R.; van der Ende, Arie; Koedel, Uwe; van de Beek, Diederik

    2011-01-01

    Pneumococcal meningitis is the most common and severe form of bacterial meningitis. Fatality rates are substantial, and long-term sequelae develop in about half of survivors. Disease outcome has been related to the severity of the proinflammatory response in the subarachnoid space. The complement system, which mediates key inflammatory processes, has been implicated as a modulator of pneumococcal meningitis disease severity in animal studies. Additionally, SNPs in genes encoding complement pathway proteins have been linked to susceptibility to pneumococcal infection, although no associations with disease severity or outcome have been established. Here, we have performed a robust prospective nationwide genetic association study in patients with bacterial meningitis and found that a common nonsynonymous complement component 5 (C5) SNP (rs17611) is associated with unfavorable disease outcome. C5 fragment levels in cerebrospinal fluid (CSF) of patients with bacterial meningitis correlated with several clinical indicators of poor prognosis. Consistent with these human data, C5a receptor–deficient mice with pneumococcal meningitis had lower CSF wbc counts and decreased brain damage compared with WT mice. Adjuvant treatment with C5-specific monoclonal antibodies prevented death in all mice with pneumococcal meningitis. Thus, our results suggest C5-specific monoclonal antibodies could be a promising new antiinflammatory adjuvant therapy for pneumococcal meningitis. PMID:21926466

  2. Working memory contributions to reading comprehension components in middle childhood children.

    Science.gov (United States)

    Chrysochoou, Elisavet; Bablekou, Zoe; Tsigilis, Nikolaos

    2011-01-01

    This study examined working memory contributions to reading comprehension subskills in Greek children (mean age 9 years, 1 month). The phonological loop of the Baddeley and Hitch working memory model was assessed with 3 recall tasks (words, nonwords, and digits) and a word list matching task. The central executive (CE) was assessed with 3 tasks (listening, counting, and backward digit recall). Participants were also given a receptive vocabulary task, a reading fluency task, and written stories accompanied by comprehension questions. Canonical correlation analyses showed that the comprehension variables were related to the CE rather than the phonological loop measures. CE functions were more strongly associated with elaborative inference generation (involving significant offline processing) and comprehension control (involving metacognitive monitoring). Smaller yet significant associations were observed between the CE and the necessary inference and literal comprehension measures, whereas a moderate relationship was found in the case of the simile comprehension variable. Among the CE variables, listening recall demonstrated the highest loading on the canonical function, followed by moderate yet significant counting and backward digit recall loadings. Vocabulary was found to fully mediate several associations between working memory and comprehension measures; however, the relationship between listening recall and elaborative inferences was partly mediated. Reading fluency and, on several occasions, Greek vocabulary knowledge did not mediate the relationships between CE measures and comprehension skills assessed. This study demonstrates the usefulness of CE measures for identifying young children's possible difficulties in carrying out specific reading comprehension processes.

  3. Cement blocks with EVA waste for extensive modular green roof: contribution of the components for thermal insulation

    Directory of Open Access Journals (Sweden)

    A. B. DE MELO

    Full Text Available Abstract Green roofs can contribute in many ways to the quality of the environment, being known for reducing the heat transfer to the interior of the buildings. Amongst the available techniques for the execution of this type of covering, the use of light cement blocks which are compatible with the system of extensive modular green roofs is proposed. For the light cement blocks, produced with EVA aggregates (waste from the footwear industry, an additional contribution in the capacity of thermal insulation of the proposed green roof is expected. In the present article, the demonstration of such contribution is intended through measurements carried out in prototypes in hot and humid climates. After characterizing the capacity of thermal insulation of the proposed green roof, with different types of conventional covering as a reference, an additional contribution of the component used in this green roof was identified by making comparisons with measurements collected from another green roof, executed with cement blocks without the presence of the EVA aggregates. In the experiments, external and internal surface temperatures were measured in each of the prototypes' coverings, as well as the air temperatures in the internal and external environments. From the analysis of the data for a typical summer day, it was possible to prove that the proposed green roof presented the lowest temperature ranges, considering the internal air and surface temperatures. The presence of the EVA aggregates in the proposed blocks contributed to the decrease of the internal temperatures.

  4. Components of Complex Non-crystalline Mineralogy Contribute Differently to Soil Carbon Storage and Turnover

    Science.gov (United States)

    Crow, S. E.; Lazaro, M.; Heckman, K. A.; Lawrence, C. R.; Giardina, C. P.; Litton, C. M.

    2016-12-01

    Mineral-control on soil carbon (C) storage is well established, including the overarching role of poorly- or non-crystalline minerals (P-NCM) in C accumulation and stabilization. However, variations within the P-NCM may explain observed patterns in C concentration and turnover within the established relationships and project future C balance. In volcanic ash-derived soils from undisturbed forest along a 5°C mean annual temperature (MAT) gradient on the windward slopes of Mauna Kea on the Island of Hawaii, we observed variations in forms of P-NCM and crystalline iron (Fe)-oxides that better explained C storage and turnover than MAT directly. The organo-complexed Al contributed to higher than average C concentration and lower relative age. Selective dissolution of various Fe and aluminum (Al) phases further indicated that metal-humus complexes were of intermediate mean residence time compared to the light fraction and other mineral phases. These data suggest that C associated with the organo-Al complexation continuously accretes, but may be left vulnerable to microbial activity. Conversely, transition of P-NCM to crystalline Fe-oxides formed concretions that protected and stabilized the older soil C occluded within. In a batch sorption experiment, high concentrations of P-NCM increased sorption of dissolved organic C and the degree of organo-Al complexation was positively related to preferential sorption of aromatics. Although high concentrations of P-NCM decreased the labile C respired, a high index of organo-Al complexation decreased the apparent temperature sensitivity during incubation. The observed combination of high concentrations of P-NCM, high organo-Al complexation index, and protection within concretions of crystalline Fe-oxides that collectively results in extraordinary C storage also likely protects against loss under future, short-term increases in temperature.

  5. Listeria phospholipases subvert host autophagic defenses by stalling pre-autophagosomal structures

    Science.gov (United States)

    Tattoli, Ivan; Sorbara, Matthew T; Yang, Chloe; Tooze, Sharon A; Philpott, Dana J; Girardin, Stephen E

    2013-01-01

    Listeria can escape host autophagy defense pathways through mechanisms that remain poorly understood. We show here that in epithelial cells, Listeriolysin (LLO)-dependent cytosolic escape of Listeria triggered a transient amino-acid starvation host response characterized by GCN2 phosphorylation, ATF3 induction and mTOR inhibition, the latter favouring a pro-autophagic cellular environment. Surprisingly, rapid recovery of mTOR signalling was neither sufficient nor necessary for Listeria avoidance of autophagic targeting. Instead, we observed that Listeria phospholipases PlcA and PlcB reduced autophagic flux and phosphatidylinositol 3-phosphate (PI3P) levels, causing pre-autophagosomal structure stalling and preventing efficient targeting of cytosolic bacteria. In co-infection experiments, wild-type Listeria protected PlcA/B-deficient bacteria from autophagy-mediated clearance. Thus, our results uncover a critical role for Listeria phospholipases C in the inhibition of autophagic flux, favouring bacterial escape from host autophagic defense. PMID:24162724

  6. Do different components of terrestrial sources contribute to the riverine suspended load?

    Science.gov (United States)

    Voss, B. M.; Peucker-Ehrenbrink, B.; Eglinton, T. I.; Galy, V.

    2012-04-01

    Establishing the relationship between source (bedrock, soil, floodplain sediments, vegetation) and mobilized materials (bedload and suspended load) within a river drainage network is critical to understanding the fate of particulate matter exported to the coastal ocean. First, linking material carried in river channels to its terrestrial sources aides in predicting the reactivity of organic matter associated with mineral particles and understanding which portions of a watershed contribute substantially to organic carbon fluxes and transformations in these systems. Second, identifying terrestrial reservoirs of future riverine suspended material can enhance our ability to comprehensively characterize the chemical and physical nature of fluvial sediments. We present a study of sedimentological and bulk organic carbon properties of sediments from across the Fraser River watershed in southwestern British Columbia, Canada. Bulk samples and size fractions from surface soils and riverbank sediments, as well as vegetation, are analyzed for metrics including carbon and nitrogen content, 13C and 14C composition, and specific surface area. These are compared with measurements of riverine suspended sediments and size fractions of sediments deposited in the Fraser estuary. The correspondence of suspended sediment properties with different portions of soil, alluvial, and vegetation pools from different sites suggests a complex link between source materials and exported material. Such variability may stem from the heterogeneous nature of soil types, hillslope morphology, and runoff regimes in different portions of the drainage basin; settling/resuspension processes during river transit; and/or modification of particle structure and organic matter between mobilization of terrestrial material and arrival at distant downstream sites. The preferential loss/preservation of different size fractions within mineral source materials highlights the unequal importance of different mineral

  7. Group-contribution+ (GC+) based estimation of properties of pure components: Improved property estimation and uncertainty analysis

    DEFF Research Database (Denmark)

    Hukkerikar, Amol; Sarup, Bent; Ten Kate, Antoon

    2012-01-01

    , Hansen solubility parameters, Hildebrand solubility parameter, octanol/water partition coefficient, acentric factor, and liquid molar volume at 298 K. Important issues related to property modeling such as reliability and predictive capability of the property prediction models, and thermodynamic......The aim of this work is to present revised and improved model parameters for group-contribution+ (GC+) models (combined group-contribution (GC) method and atom connectivity index (CI) method) employed for the estimation of pure component properties, together with covariance matrices to quantify...... uncertainties in the estimated property values. For this purpose, a systematic methodology for property modeling and uncertainty analysis of GC models and CI models using maximum-likelihood estimation theory is developed. For parameter estimation, large data-sets of experimentally measured property values...

  8. Contributions of biarticular myogenic components to the limitation of the range of motion after immobilization of rat knee joint

    Science.gov (United States)

    2014-01-01

    Background Muscle atrophy caused by immobilization in the shortened position is characterized by a decrease in the size or cross-sectional area (CSA) of myofibers and decreased muscle length. Few studies have addressed the relationship between limitation of the range of motion (ROM) and the changes in CSA specifically in biarticular muscles after atrophy because of immobilization. We aimed to determine the contribution of 2 distinct muscle groups, the biarticular muscles of the post thigh (PT) and those of the post leg (PL), to the limitation of ROM as well as changes in the myofiber CSAs after joint immobilization surgery. Methods Male Wistar rats (n = 40) were randomly divided into experimental and control groups. In the experimental group, the left knee was surgically immobilized by external fixation for 1, 2, 4, 8, or 16 weeks (n = 5 each) and sham surgery was performed on the right knee. The rats in the control groups (n = 3 per time point) did not undergo surgery. After the indicated immobilization periods, myotomy of the PT or PL biarticular muscles was performed and the ROM was measured. The hamstrings and gastrocnemius muscles from the animals operated for 1 or 16 weeks were subjected to morphological analysis. Results In immobilized knees, the relative contribution of the PT biarticular myogenic components to the total restriction reached 80% throughout the first 4 weeks and decreased thereafter. The relative contribution of the PL biarticular myogenic components remained contracture did not significantly change during the experimental period. However, the ratio of hamstrings CSAs to the sham side was larger than the ratio of medial gastrocnemius CSAs to the sham side after complete atrophy because of immobilization. PMID:25001065

  9. Associations of depression and seasonality with morning-evening preference: Comparison of contributions of its morning and evening components.

    Science.gov (United States)

    Putilov, Arcady A

    2018-04-01

    Despite predominance of positive findings on associations of morning-evening preference with seasonality and depression, it remains to be clarified whether morning and evening components of this preference equally contribute to these associations and whether these associations persist after accounting for confounding variables. Data on retrospectively reported seasonal changes in well-being, mood, and behaviors were collected from 2398 residents of West Siberia, South and North Yakutia, Chukotka, Alaska, and Turkmenistan. Other self-reports included mental and physical health, sleep duration, and adaptabilities of the sleep-wake cycle. Depression was found to be linked to morning rather than evening component of morning-evening preference, i.e., morning lateness. Morning lateness was also linked to retrospectively reported degree of seasonal changes rather than to severity of problems associated with such changes. Variation in morning-evening preference explained not more than 2% and 4% of the total variation in depression and seasonality, respectively. The associations became even weaker but remained significant after accounting for other differences between respondents, such as their gender, age, physical health, and adaptability of their sleep-wake cycle. These results have practical relevance for understanding of the roles playing by morning earliness and insensitivity to seasonal changes in the environment to protection against different mood disorders. Copyright © 2017 Elsevier B.V. All rights reserved.

  10. A novel acridine derivative, LS-1-10 inhibits autophagic degradation and triggers apoptosis in colon cancer cells.

    Science.gov (United States)

    Fu, Wan; Li, Xue; Lu, Xiaopeng; Zhang, Luyao; Li, Ran; Zhang, Nan; Liu, Shan; Yang, Xin; Wang, Yue; Zhao, Ying; Meng, Xiangbao; Zhu, Wei-Guo

    2017-10-05

    Autophagy promotes cancer cell survival and drug resistance by degrading harmful cellular components and maintaining cellular energy levels. Disruption of autophagy may be a promising approach to sensitize cancer cells to anticancer drugs. The combination of autophagic inhibitors, such as chloroquine (CQ) and lucanthone with conventional cancer therapeutics has been investigated in clinical trials, but adverse drug-drug interactions are a high possibility. Here we designed and synthesized a novel, small-molecule library based on an acridine skeleton and the CQ structure with various modifications and substitutions and screened the compounds for effective autophagy inhibition. We found that 9-chloro-2-(3-(dimethylamino)propyl)pyrrolo[2,3,4-kl]acridin-1(2H)-one (LS-1-10) was the most effective from our library at inhibiting autophagic-mediated degradation and could decrease the viability of multiple colon cancer cells. In addition, LS-1-10 induced DNA damage and caspase 8-mediated apoptosis. Overall, this small molecule was more efficient at reducing the viability of cancer cells than other conventional chemotherapeutic agents, such as CQ and amsacrine. The anticancer and autophagy-inhibiting activities of LS-1-10 were confirmed in vivo in a xenograft mouse model. Collectively, this study has identified a new and efficient single compound with both autophagy-inhibiting and anticancer activity, which may provide a novel approach for cancer therapy.

  11. Fetoscopic laser coagulation of intertwin anastomoses reduces discordant placental autophagic activities in discordant twin growth

    Directory of Open Access Journals (Sweden)

    Yao-Lung Chang

    2015-10-01

    Conclusion: The discordance of placenta autophagic activity in the monochorionic twin with sIUGR was reduced after laser coagulation of the intertwin anastomoses, which may result from the effect of correction of the discordant intertwin placenta perfusion.

  12. Studies on the mechanisms of autophagy: formation of the autophagic vacuole

    OpenAIRE

    1990-01-01

    Autophagic vacuoles form within 15 min of perfusing a liver with amino acid-depleted medium. These vacuoles are bound by a "smooth" double membrane and do not contain acid phosphatase activity. In an attempt to identify the membrane source of these vacuoles, I have used morphological techniques combined with immunological probes to localize specific membrane antigens to the limiting membranes of newly formed or nascent autophagic vacuoles. Antibodies to three integral membrane proteins of the...

  13. Absolute continuity of autophage measures on finite-dimensional vector spaces

    International Nuclear Information System (INIS)

    Raja, C.R.E.

    2002-06-01

    We consider a class of measures called autophage which was introduced and studied by Szekely for measures on the real line. We show that the autophage measures on finite-dimensional vector spaces over real or Q p are infinitely divisible without idempotent factors and are absolutely continuous with bounded continuous density. We also show that certain semistable measures on such vector spaces are absolutely continuous. (author)

  14. Targeting physical activity and nutrition interventions towards mothers with young children: a review on components that contribute to attendance and effectiveness

    NARCIS (Netherlands)

    Hartman, Marieke A.; Hosper, Karen; Stronks, Karien

    2011-01-01

    To gain insight into intervention components targeted specifically to mothers of young children that may contribute to attendance and effectiveness on physical activity and healthy eating. Systematic literature searches were performed using MEDLINE, Embase and cited references. Articles were

  15. Contribution to the understanding of how principal component analysis-derived dietary patterns emerge from habitual data on food consumption.

    Science.gov (United States)

    Schwedhelm, Carolina; Iqbal, Khalid; Knüppel, Sven; Schwingshackl, Lukas; Boeing, Heiner

    2018-02-01

    Principal component analysis (PCA) is a widely used exploratory method in epidemiology to derive dietary patterns from habitual diet. Such dietary patterns seem to originate from intakes on multiple days and eating occasions. Therefore, analyzing food intake of study populations with different levels of food consumption can provide additional insights as to how habitual dietary patterns are formed. We analyzed the food intake data of German adults in terms of the relations among food groups from three 24-h dietary recalls (24hDRs) on the habitual, single-day, and main-meal levels, and investigated the contribution of each level to the formation of PCA-derived habitual dietary patterns. Three 24hDRs were collected in 2010-2012 from 816 adults for an European Prospective Investigation into Cancer and Nutrition (EPIC)-Potsdam subcohort study. We identified PCA-derived habitual dietary patterns and compared cross-sectional food consumption data in terms of correlation (Spearman), consistency (intraclass correlation coefficient), and frequency of consumption across all days and main meals. Contribution to the formation of the dietary patterns was obtained through Spearman correlation of the dietary pattern scores. Among the meals, breakfast appeared to be the most consistent eating occasion within individuals. Dinner showed the strongest correlations with "Prudent" (Spearman correlation = 0.60), "Western" (Spearman correlation = 0.59), and "Traditional" (Spearman correlation = 0.60) dietary patterns identified on the habitual level, and lunch showed the strongest correlations with the "Cereals and legumes" (Spearman correlation = 0.60) habitual dietary pattern. Higher meal consistency was related to lower contributions to the formation of PCA-derived habitual dietary patterns. Absolute amounts of food consumption did not strongly conform to the habitual dietary patterns by meals, suggesting that these patterns are formed by complex combinations of variable food

  16. The contribution of three components of nutrition knowledge to socio-economic differences in food purchasing choices.

    Science.gov (United States)

    McKinnon, Loretta; Giskes, Katrina; Turrell, Gavin

    2014-08-01

    To assess socio-economic differences in three components of nutrition knowledge, i.e. knowledge of (i) the relationship between diet and disease, (ii) the nutrient content of foods and (iii) dietary guideline recommendations; furthermore, to determine if socio-economic differences in nutrition knowledge contribute to inequalities in food purchasing choices. The cross-sectional study considered household food purchasing, nutrition knowledge, socio-economic and demographic information. Household food purchasing choices were summarised by three indices, based on self-reported purchasing of sixteen groceries, nineteen fruits and twenty-one vegetables. Socio-economic position (SEP) was measured by household income and education. Associations between SEP, nutrition knowledge and food purchasing were examined using general linear models adjusted for age, gender, household type and household size. Brisbane, Australia in 2000. Main household food shoppers (n 1003, response rate 66·4 %), located in fifty small areas (Census Collectors Districts). Shoppers in households of low SEP made food purchasing choices that were less consistent with dietary guideline recommendations: they were more likely to purchase grocery foods comparatively higher in salt, sugar and fat, and lower in fibre, and they purchased a narrower range of fruits and vegetables. Those of higher SEP had greater nutrition knowledge and this factor attenuated most associations between SEP and food purchasing choices. Among nutrition knowledge factors, knowledge of the relationship between diet and disease made the greatest and most consistent contribution to explaining socio-economic differences in food purchasing. Addressing inequalities in nutrition knowledge is likely to reduce socio-economic differences in compliance with dietary guidelines. Improving knowledge of the relationship between diet and disease appears to be a particularly relevant focus for health promotion aimed to reduce socio

  17. Mathematics Anxiety and Statistics Anxiety. Shared but Also Unshared Components and Antagonistic Contributions to Performance in Statistics

    Directory of Open Access Journals (Sweden)

    Manuela Paechter

    2017-07-01

    the structural equation model and, therefore, contributed indirectly and negatively to performance. Furthermore, it had a direct negative impact on performance (probably via increased tension and worry in the exam. The results of the study speak for shared but also unique components of statistics anxiety and mathematics anxiety. They are also important for instruction and give recommendations to learners as well as to instructors.

  18. Mathematics Anxiety and Statistics Anxiety. Shared but Also Unshared Components and Antagonistic Contributions to Performance in Statistics

    Science.gov (United States)

    Paechter, Manuela; Macher, Daniel; Martskvishvili, Khatuna; Wimmer, Sigrid; Papousek, Ilona

    2017-01-01

    equation model and, therefore, contributed indirectly and negatively to performance. Furthermore, it had a direct negative impact on performance (probably via increased tension and worry in the exam). The results of the study speak for shared but also unique components of statistics anxiety and mathematics anxiety. They are also important for instruction and give recommendations to learners as well as to instructors. PMID:28790938

  19. Mathematics Anxiety and Statistics Anxiety. Shared but Also Unshared Components and Antagonistic Contributions to Performance in Statistics.

    Science.gov (United States)

    Paechter, Manuela; Macher, Daniel; Martskvishvili, Khatuna; Wimmer, Sigrid; Papousek, Ilona

    2017-01-01

    equation model and, therefore, contributed indirectly and negatively to performance. Furthermore, it had a direct negative impact on performance (probably via increased tension and worry in the exam). The results of the study speak for shared but also unique components of statistics anxiety and mathematics anxiety. They are also important for instruction and give recommendations to learners as well as to instructors.

  20. TGFB1 is secreted through an unconventional pathway dependent on the autophagic machinery and cytoskeletal regulators.

    Science.gov (United States)

    Nüchel, Julian; Ghatak, Sushmita; Zuk, Alexandra V; Illerhaus, Anja; Mörgelin, Matthias; Schönborn, Katrin; Blumbach, Katrin; Wickström, Sara A; Krieg, Thomas; Sengle, Gerhard; Plomann, Markus; Eckes, Beate

    2018-03-11

    TGFB1 (transforming growth factor beta 1) is a potent cytokine playing a driving role in development, fibrosis and cancer. It is synthesized as prodomain-growth factor complex that requires tethering to LTBP (latent transforming growth factor beta binding protein) for efficient secretion into the extracellular space. Upon release, this large latent complex is sequestered by anchorage to extracellular matrix (ECM) networks, from which the mature growth factor needs to be activated in order to reach its receptors and initiate signaling. Here, we uncovered a novel intracellular secretion pathway by which the latent TGFB1 complex reaches the plasma membrane and is released from fibroblasts, the key effector cells during tissue repair, fibrosis and in the tumor stroma. We show that secretion of latent TGFB1, but not of other selected cytokines or of bulk cargo, is regulated by fibroblast-ECM communication through ILK (integrin linked kinase) that restricts RHOA activity by interacting with ARHGAP26/GRAF1. Latent TGFB1 interacts with GORASP2/GRASP55 and is detected inside MAP1LC3-positive autophagosomal intermediates that are secreted by a RAB8A-dependent pathway. Interestingly, TGFB1 secretion is fully abrogated in human and murine fibroblasts and macrophages that lack key components of the autophagic machinery. Our data demonstrate an unconventional secretion mode of TGFB1 adding another level of control of its bioavailability and activity in order to effectively orchestrate cellular programs prone to dysregulation as seen in fibrosis and cancer.

  1. Evaluation of the Cytotoxic and Autophagic Effects of Atorvastatin on Mcf-7 Breast Cancer Cells.

    Science.gov (United States)

    Martinez, Tuğba Alarcon; Zeybek, Naciye Dilara; Müftüoğlu, Sevda

    2018-02-27

    Recently, cytotoxic effects of statins on breast cancer cells have been reported. However, the mechanism of anti-proliferative effects is currently unknown. Autophagy is a non-apoptotic programmed cell death, which is characterized by degradation of cytoplasmic components and with a role in cancer pathogenesis. To investigate the anti-proliferative effects of atorvastatin was on MCF-7 human breast adenocarcinoma cells in aspect of autophagy and apoptosis. Cell culture study. Cell viability was analyzed using WST-1 cell proliferation assay. Apoptosis was determined by TUNEL method, whereas autophagy was assessed by Beclin-1 and LC3B immunofluorescence staining. Ultrastructural analysis of cells was performed by electron microscopy. Atorvastatin reduced MCF-7 cell proliferation in a dose- and time-dependent manner inducing TUNEL, Beclin-1, and LC3B positive cells. Moreover, ultrastructural analysis showed apoptotic, autophagic and necrotic morphological changes in treatment groups. Statistically significant increase in apoptotic index was detected with increased concentrations of atorvastatin at 24h and 48h (p<0.05). The anti-proliferative effects of atorvastatin on breast cancer cells is mediated by induction of apoptosis and autophagy which shows statins as a potential treatment option for breast cancer.

  2. Method to assess component contribution to toxicity of complex mixtures: Assessment of puberty acquisition in rats exposed to disinfection byproducts.

    Science.gov (United States)

    Parvez, Shahid; Rice, Glenn E; Teuschler, Linda K; Simmons, Jane Ellen; Speth, Thomas F; Richardson, Susan D; Miltner, Richard J; Hunter, E Sidney; Pressman, Jonathan G; Strader, Lillian F; Klinefelter, Gary R; Goldman, Jerome M; Narotsky, Michael G

    2017-08-01

    A method based on regression modeling was developed to discern the contribution of component chemicals to the toxicity of highly complex, environmentally realistic mixtures of disinfection byproducts (DBPs). Chemical disinfection of drinking water forms DBP mixtures. Because of concerns about possible reproductive and developmental toxicity, a whole mixture (WM) of DBPs produced by chlorination of a water concentrate was administered as drinking water to Sprague-Dawley (S-D) rats in a multigenerational study. Age of puberty acquisition, i.e., preputial separation (PPS) and vaginal opening (VO), was examined in male and female offspring, respectively. When compared to controls, a slight, but statistically significant delay in puberty acquisition was observed in females but not in males. WM-induced differences in the age at puberty acquisition were compared to those reported in S-D rats administered either a defined mixture (DM) of nine regulated DBPs or individual DBPs. Regression models were developed using individual animal data on age at PPS or VO from the DM study. Puberty acquisition data reported in the WM and individual DBP studies were then compared with the DM models. The delay in puberty acquisition observed in the WM-treated female rats could not be distinguished from delays predicted by the DM regression model, suggesting that the nine regulated DBPs in the DM might account for much of the delay observed in the WM. This method is applicable to mixtures of other types of chemicals and other endpoints. Copyright © 2017. Published by Elsevier B.V.

  3. Autophagonizer, a novel synthetic small molecule, induces autophagic cell death

    Energy Technology Data Exchange (ETDEWEB)

    Choi, In-Kwon; Cho, Yoon Sun; Jung, Hye Jin [Chemical Genomics Laboratory, Department of Biotechnology, Translational Research Center for Protein Function Control, College of Life Science and Biotechnology, Yonsei University, Seoul 120-749 (Korea, Republic of); Kwon, Ho Jeong, E-mail: kwonhj@yonsei.ac.kr [Chemical Genomics Laboratory, Department of Biotechnology, Translational Research Center for Protein Function Control, College of Life Science and Biotechnology, Yonsei University, Seoul 120-749 (Korea, Republic of)

    2010-03-19

    Autophagy is an apoptosis-independent mechanism of cell death that protects the cell from environmental imbalances and infection by pathogens. We identified a novel small molecule, 2-(3-Benzyl-4-oxo-3,4,5,6,7,8-hexahydro-benzo[4,5]thieno[2,3-d] pyrimidin-2-ylsulfanylmethyl)-oxazole-4-carboxylic acid (2-pyrrolidin-1-yl-ethyl)-amide (referred as autophagonizer), using high-content cell-based screening and the autophagosome marker EGFP-LC3. Autophagonizer inhibited growth and induced cell death in the human tumor cell lines MCF7, HeLa, HCT116, A549, AGS, and HT1080 via a caspase-independent pathway. Conversion of cytosolic LC3-I to autophagosome-associated LC3-II was greatly enhanced by autophagonizer treatment. Transmission electron microscopy and acridine orange staining revealed increased autophagy in the cytoplasm of autophagonizer-treated cells. In conclusion, autophagonizer is a novel autophagy inducer with unique structure, which induces autophagic cell death in the human tumor cell lines.

  4. Dicrocoelium dendriticum induces autophagic vacuoles accumulation in human hepatocarcinoma cells.

    Science.gov (United States)

    Pepe, P; Castellano, M; Alfano, S; Della Pepa, M E; Tirino, V; Piemonte, M; Desiderio, V; Zappavigna, S; Galdiero, M; Caraglia, M; Cringoli, G; Rinaldi, L; Galdiero, M

    2015-09-15

    The relationship between Dicrocoelium dendriticum and cancer has been poorly investigated so far, but a large amount of findings suggest that other trematodes can favour cancer in both animals and humans. In this study, the effects of D. dendriticum on cell proliferation, cell death mechanisms and oxidative stress induction were evaluated in hepatocellular carcinoma (HCC) cell lines (HepG2 and HuH7). Results showed that short time exposure to low concentrations of somatic antigens from D. dendriticum caused slight proliferation in both HepG2 and HuH7 cells while high concentrations and long exposure time to extracts from D. dendriticum caused a significant growth inhibition. This effect was, however, not paralleled by apoptosis but it occurred with an about 40% increase of the formation of autophagic vacuoles. In the same experimental conditions, a strong oxidative stress was recorded with an about 100% increase of the intracellular O(2-). These data suggest the occurrence of an escape anti-apoptotic mechanism in HCC cells. In conclusion, these results suggest a role for D. dendriticum in the chronic oxidative stress and in the regulation of transformation processes in HCC warranting additional investigations in this specific area of research. Copyright © 2015 Elsevier B.V. All rights reserved.

  5. Effects of Epigallocatechin-3-Gallate on Autophagic Lipolysis in Adipocytes

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    Sang-Nam Kim

    2017-06-01

    Full Text Available Previous studies demonstrated effects of green tea on weight loss; however, green tea-induced modulation of adipocyte function is not fully understood. Here, we investigated effects of the major green tea phytochemical, epigallocatechin-3-gallate (EGCG on triglyceride contents, lipolysis, mitochondrial function, and autophagy, in adipocytes differentiated from C3H10T1/2 cells and immortalized pre-adipocytes in vitro. EGCG reduced the triglycerol content significantly in adipocytes by 25%, comparable to the nutrient starvation state. EGCG did not affect protein kinase A signaling or brown adipocyte marker expression in adipocytes; however, EGCG increased autophagy, as measured by autophagy flux analysis and immunoblot analysis of LC3B, ATG7, and Beclin1. EGCG treatment reduced mitochondrial membrane potential by 56.8% and intracellular ATP levels by 49.1% compared to controls. Although mammalian target of rapamycin signaling was not upregulated by EGCG treatment, EGCG treatment induced AMP-activated protein kinase phosphorylation, indicating an energy-depleted state. In addition, EGCG increased the association between RAB7 and lipid droplets, suggesting that lipophagy was activated. Finally, knockdown of Rab7 attenuated the EGCG-dependent reduction in lipid contents. Collectively, these results indicated that EGCG upregulated autophagic lipolysis in adipocytes, supporting the therapeutic potential of EGCG as a caloric restriction mimetic to prevent obesity and obesity-related metabolic diseases.

  6. Bortezomib induces autophagic death in proliferating human endothelial cells

    Energy Technology Data Exchange (ETDEWEB)

    Belloni, Daniela; Veschini, Lorenzo [Myeloma Unit, Department of Oncology, IRCCS H San Raffaele, Milan (Italy); Foglieni, Chiara [Department of Cardiology, IRCCS H San Raffaele, Milan (Italy); Dell' Antonio, Giacomo [Department of Pathology, IRCCS H San Raffaele, Milan (Italy); Caligaris-Cappio, Federico [Myeloma Unit, Department of Oncology, IRCCS H San Raffaele, Milan (Italy); Universita Vita-Salute IRCCS H San Raffaele, Milan (Italy); Ferrarini, Marina [Myeloma Unit, Department of Oncology, IRCCS H San Raffaele, Milan (Italy); Ferrero, Elisabetta, E-mail: elisabetta.ferrero@hsr.it [Myeloma Unit, Department of Oncology, IRCCS H San Raffaele, Milan (Italy)

    2010-04-01

    The proteasome inhibitor Bortezomib has been approved for the treatment of relapsed/refractory multiple myeloma (MM), thanks to its ability to induce MM cell apoptosis. Moreover, Bortezomib has antiangiogenic properties. We report that endothelial cells (EC) exposed to Bortezomib undergo death to an extent that depends strictly on their activation state. Indeed, while quiescent EC are resistant to Bortezomib, the drug results maximally toxic in EC switched toward angiogenesis with FGF, and exerts a moderate effect on subconfluent HUVEC. Moreover, EC activation state deeply influences the death pathway elicited by Bortezomib: after treatment, angiogenesis-triggered EC display typical features of apoptosis. Conversely, death of subconfluent EC is preceded by ROS generation and signs typical of autophagy, including intense cytoplasmic vacuolization with evidence of autophagosomes at electron microscopy, and conversion of the cytosolic MAP LC3 I form toward the autophagosome-associated LC3 II form. Treatment with the specific autophagy inhibitor 3-MA prevents both LC3 I/LC3 II conversion and HUVEC cell death. Finally, early removal of Bortezomib is accompanied by the recovery of cell shape and viability. These findings strongly suggest that Bortezomib induces either apoptosis or autophagy in EC; interfering with the autophagic response may potentiate the antiangiogenic effect of the drug.

  7. Routine Western blot to check autophagic flux: cautions and recommendations.

    Science.gov (United States)

    Gómez-Sánchez, Rubén; Pizarro-Estrella, Elisa; Yakhine-Diop, Sokhna M S; Rodríguez-Arribas, Mario; Bravo-San Pedro, José M; Fuentes, José M; González-Polo, Rosa A

    2015-05-15

    At present, the analysis of autophagic flux by Western blotting (WB), which measures two of the most important markers of autophagy, i.e., microtubule-associated protein 1 light chain 3 (LC3) and p62, is widely accepted in the scientific community. In this study, we addressed the possible disadvantages and limitations that this method presents for a correct interpretation of the results according to the lysis buffer used for extracting proteins. Here, we tested the LC3 and p62 protein levels by WB in four cell models (mouse embryonic and human fibroblasts (MEFs and HFs, respectively), N27 rat mesencephalic dopaminergic neurons and SH-SY5Y human neuroblastoma cells). The cells were exposed to the autophagy inhibitor bafilomycin A1 (Baf. A1) in combination (or not) with nutrient deprivation to induce autophagy, and they were lysed by using four different buffers (nonyl phenoxypolyethoxylethanol (NP-40), radioimmunoprecipitation assay (RIPA), Triton X-100, and sample buffer (SB) 1×). Based on our observations, we want to highlight that this technique is not always appropriate for analyzing and monitoring autophagy. In this report, we show conflicting data that hinder the correct interpretation of the results, especially in relation to p62 protein levels, at least in the models studied in this work. Copyright © 2015 Elsevier Inc. All rights reserved.

  8. Clozapine Induces Autophagic Cell Death in Non-Small Cell Lung Cancer Cells

    Directory of Open Access Journals (Sweden)

    Yu-Chun Yin

    2015-02-01

    Full Text Available Background/Aims: Previous studies have shown that patients with schizophrenia have a lower incidence of cancer than the general population, and several antipsychotics have been demonstrated to have cytotoxic effects on cancer cells. However, the mechanisms underlying these results remain unclear. The present study aimed to investigate the effect of clozapine, which is often used to treat patients with refractory schizophrenia, on the growth of non-small cell lung carcinoma cell lines and to examine whether autophagy contributes to its effects. Methods: A549 and H1299 cells were treated with clozapine, and cell cytotoxicity, cell cycle and autophagy were then assessed. The autophagy inhibitor bafilomycin A1 and siRNA-targeted Atg7 were used to determine the role of autophagy in the effect of clozapine. Results: Clozapine inhibited A549 and H1299 proliferation and increased p21 and p27 expression levels, leading to cell cycle arrest. Clozapine also induced a high level of autophagy, but not apoptosis, in both cell lines, and the growth inhibitory effect of clozapine was blunted by treatment with the autophagy inhibitor bafilomycin A1 or with an siRNA targeting atg7. Conclusions: Clozapine inhibits cell proliferation by inducing autophagic cell death in two non-small cell lung carcinoma cell lines. These findings may provide insights into the relationship between clozapine use and the lower incidence of lung cancer among patients with schizophrenia.

  9. Proposal of a calculation method to determine the structural components' contribution on the deceleration of a passenger compartment based on the energy-derivative method.

    Science.gov (United States)

    Nagasaka, Kei; Mizuno, Koji; Ito, Daisuke; Saida, Naoya

    2017-05-29

    In car crashes, the passenger compartment deceleration significantly influences the occupant loading. Hence, it is important to consider how each structural component deforms in order to control the passenger compartment deceleration. In frontal impact tests, the passenger compartment deceleration depends on the energy absorption property of the front structures. However, at this point in time there are few papers describing the components' quantitative contributions on the passenger compartment deceleration. Generally, the cross-sectional force is used to examine each component's contribution to passenger compartment deceleration. However, it is difficult to determine each component's contribution based on the cross-sectional forces, especially within segments of the individual members itself such as the front rails, because the force is transmitted continuously and the cross-sectional forces remain the same through the component. The deceleration of a particle can be determined from the derivative of the kinetic energy. Using this energy-derivative method, the contribution of each component on the passenger compartment deceleration can be determined. Using finite element (FE) car models, this method was applied for full-width and offset impact tests. This method was also applied to evaluate the deceleration of the powertrain. The finite impulse response (FIR) coefficient of the vehicle deceleration (input) and the driver chest deceleration (output) was calculated from Japan New Car Assessment Program (JNCAP) tests. These were applied to the component's contribution on the vehicle deceleration in FE analysis, and the component's contribution to the deceleration of the driver's chest was determined. The sum of the contribution of each component coincides with the passenger compartment deceleration in all types of impacts; therefore, the validity of this method was confirmed. In the full-width impact, the contribution of the crush box was large in the initial phases

  10. Fusobacterium nucleatum-Induced Impairment of Autophagic Flux Enhances the Expression of Proinflammatory Cytokines via ROS in Caco-2 Cells.

    Directory of Open Access Journals (Sweden)

    Bin Tang

    Full Text Available Fusobacterium nucleatum (F. nucleatum plays a critical role in gastrointestinal inflammation. However, the exact mechanism by which F. nucleatum contributes to inflammation is unclear. In the present study, it was revealed that F. nucleatum could induce the production of proinflammatory cytokines (IL-8, IL-1β and TNF-α and reactive oxygen species (ROS in Caco-2 colorectal adenocarcinoma cells. Furthermore, ROS scavengers (NAC or Tiron could decrease the production of proinflammatory cytokines during F. nucleatum infection. In addition, we observed that autophagy is impaired in Caco-2 cells after F. nucleatum infection. The production of proinflammatory cytokines and ROS induced by F. nucleatum was enhanced with either autophagy pharmacologic inhibitors (3-methyladenine, bafilomycin A1 or RNA interference in essential autophagy genes (ATG5 or ATG12 in Caco-2 cells. Taken together, these results indicate that F. nucleatum-induced impairment of autophagic flux enhances the expression of proinflammatory cytokines via ROS in Caco-2 Cells.

  11. Fusobacterium nucleatum-Induced Impairment of Autophagic Flux Enhances the Expression of Proinflammatory Cytokines via ROS in Caco-2 Cells.

    Science.gov (United States)

    Tang, Bin; Wang, Kun; Jia, Yin-Ping; Zhu, Pan; Fang, Yao; Zhang, Zhu-Jun; Mao, Xu-Hu; Li, Qian; Zeng, Dong-Zhu

    2016-01-01

    Fusobacterium nucleatum (F. nucleatum) plays a critical role in gastrointestinal inflammation. However, the exact mechanism by which F. nucleatum contributes to inflammation is unclear. In the present study, it was revealed that F. nucleatum could induce the production of proinflammatory cytokines (IL-8, IL-1β and TNF-α) and reactive oxygen species (ROS) in Caco-2 colorectal) adenocarcinoma cells. Furthermore, ROS scavengers (NAC or Tiron) could decrease the production of proinflammatory cytokines during F. nucleatum infection. In addition, we observed that autophagy is impaired in Caco-2 cells after F. nucleatum infection. The production of proinflammatory cytokines and ROS induced by F. nucleatum was enhanced with either autophagy pharmacologic inhibitors (3-methyladenine, bafilomycin A1) or RNA interference in essential autophagy genes (ATG5 or ATG12) in Caco-2 cells. Taken together, these results indicate that F. nucleatum-induced impairment of autophagic flux enhances the expression of proinflammatory cytokines via ROS in Caco-2 Cells.

  12. The natural product peiminine represses colorectal carcinoma tumor growth by inducing autophagic cell death

    Energy Technology Data Exchange (ETDEWEB)

    Lyu, Qing [School of Life Sciences, Tsinghua University, Beijing, 100084 (China); Key Lab in Healthy Science and Technology, Division of Life Science, Graduate School at Shenzhen, Tsinghua University, Shenzhen, 518055 (China); Tou, Fangfang [Jiangxi Provincial Key Lab of Oncology Translation Medicine, Jiangxi Cancer Hospital, Nanchang, 330029 (China); Su, Hong; Wu, Xiaoyong [First Affiliated Hospital, Guiyang College of Traditional Chinese Medicine, Guiyang, 550002 (China); Chen, Xinyi [Department of Hematology and Oncology, Beijing University of Chinese Medicine, Beijing, 100029 (China); Zheng, Zhi, E-mail: zheng_sheva@hotmail.com [Jiangxi Provincial Key Lab of Oncology Translation Medicine, Jiangxi Cancer Hospital, Nanchang, 330029 (China)

    2015-06-19

    Autophagy is evolutionarily conservative in eukaryotic cells that engulf cellular long-lived proteins and organelles, and it degrades the contents through fusion with lysosomes, via which the cell acquires recycled building blocks for the synthesis of new molecules. In this study, we revealed that peiminine induces cell death and enhances autophagic flux in colorectal carcinoma HCT-116 cells. We determined that peiminine enhances the autophagic flux by repressing the phosphorylation of mTOR through inhibiting upstream signals. Knocking down ATG5 greatly reduced the peiminine-induced cell death in wild-type HCT-116 cells, while treating Bax/Bak-deficient cells with peiminine resulted in significant cell death. In summary, our discoveries demonstrated that peiminine represses colorectal carcinoma cell proliferation and cell growth by inducing autophagic cell death. - Highlights: • Peiminine induces autophagy and upregulates autophagic flux. • Peiminine represses colorectal carcinoma tumor growth. • Peiminine induces autophagic cell death. • Peiminine represses mTOR phosphorylation by influencing PI3K/Akt and AMPK pathway.

  13. 'How can I halt thee?' The puzzles involved in autophagic inhibition.

    Science.gov (United States)

    Vinod, V; Padmakrishnan, C J; Vijayan, Bejoy; Gopala, Srinivas

    2014-04-01

    The strategy for interpreting the role of autophagy on the basis of evidence obtained through autophagic inhibition sounds logical, but is beset with practical constraints. The knock down of autophagy-related (ATG) gene(s) or blockage of class III PI3-Kinase are the most common approaches for inhibiting autophagy. However, during stressful conditions, autophagy may operate in synchrony with other processes such as apoptosis; autophagy-related genes, unlike what their name implies, exert their regulation on apoptosis as well. Knocking down such genes not only blocks autophagy but also renders apoptosis defective, making the interpretation of autophagic roles unreliable. Similarly, class III PI3-Kinase aids in initiating autophagy but it is not a quintessential autophagic regulator. Class III PI3-Kinase also has a role in regulating almost all membrane transport in cells. Blocking it not only inhibits autophagy, but also hampers all the membrane trades, including endosomal transport. The pharmacological inhibitors used to block autophagy by blocking class III PI3-Kinase further compound these limitations with their off-target effects. Knowing the limitations involved in blocking a target or using an autophagy-blocking tool is a prerequisite for designing the experiments meant for analyzing autophagic functions. This review attempts to provide a detailed overview about the practical constraints involved in using autophagic inhibition as a strategy to understand autophagy. Copyright © 2014 Elsevier Ltd. All rights reserved.

  14. Anti-osteoclastogenesis of Mineral Trioxide Aggregate through Inhibition of the Autophagic Pathway.

    Science.gov (United States)

    Cheng, Xue; Zhu, Lingxin; Zhang, Jie; Yu, Jingjing; Liu, Shan; Lv, Fengyuan; Lin, Ying; Liu, Guojing; Peng, Bin

    2017-05-01

    Mineral trioxide aggregate (MTA) regulates bone remodeling, particularly osteoclast differentiation. However, intracellular mechanisms underlying the anti-osteoclastogenesis of MTA remain unclear. This study aimed to evaluate the potential alterations of autophagic pathway during anti-osteoclastogenic effects by MTA in vitro and investigate their underlying mechanisms. Osteoclast precursors were treated with MTA extracts containing the receptor activator of nuclear factor-kappa B ligand (RANKL). Rapamycin was used to activate autophagy. RANKL-induced osteoclast differentiation was stained with tartrate-resistant acid phosphatase. Several specific autophagy features in osteoclast precursors were measured by using immunofluorescence, monodansylcadaverine, and transmission electron microscope. Autophagy-related proteins were investigated via Western blot analysis. The mRNA expression involved in autophagic and osteoclastic activities was detected with quantitative real-time polymerase chain reaction. MTA extracts inhibited osteoclast differentiation via preventing the fusion of osteoclast precursors without cytotoxicity. MTA extracts interrupted RANKL-induced acidic vesicular organelle formation and autophagic vacuole appearance in osteoclast precursors. Moreover, autophagic genes and proteins stimulated with RANKL diminished with MTA extracts. Notably, autophagy activation through rapamycin promoted multinucleated osteoclasts formation and increased osteoclastic genes expression, which almost reversed MTA-mediated anti-osteoclastogenic effects. MTA inhibited osteoclastogenesis for bone repair through attenuating the autophagic pathway. Copyright © 2017 American Association of Endodontists. Published by Elsevier Inc. All rights reserved.

  15. The natural product peiminine represses colorectal carcinoma tumor growth by inducing autophagic cell death

    International Nuclear Information System (INIS)

    Lyu, Qing; Tou, Fangfang; Su, Hong; Wu, Xiaoyong; Chen, Xinyi; Zheng, Zhi

    2015-01-01

    Autophagy is evolutionarily conservative in eukaryotic cells that engulf cellular long-lived proteins and organelles, and it degrades the contents through fusion with lysosomes, via which the cell acquires recycled building blocks for the synthesis of new molecules. In this study, we revealed that peiminine induces cell death and enhances autophagic flux in colorectal carcinoma HCT-116 cells. We determined that peiminine enhances the autophagic flux by repressing the phosphorylation of mTOR through inhibiting upstream signals. Knocking down ATG5 greatly reduced the peiminine-induced cell death in wild-type HCT-116 cells, while treating Bax/Bak-deficient cells with peiminine resulted in significant cell death. In summary, our discoveries demonstrated that peiminine represses colorectal carcinoma cell proliferation and cell growth by inducing autophagic cell death. - Highlights: • Peiminine induces autophagy and upregulates autophagic flux. • Peiminine represses colorectal carcinoma tumor growth. • Peiminine induces autophagic cell death. • Peiminine represses mTOR phosphorylation by influencing PI3K/Akt and AMPK pathway

  16. Aggressive human neuroblastomas show a massive increase in the numbers of autophagic vacuoles and damaged mitochondria.

    Science.gov (United States)

    Samardzija, Gordana; Stevovic, Tamara Kravic; Djuricic, Slavisa; Djokic, Dragomir; Djurisic, Marina; Ciric, Darko; Martinovic, Tamara; Bumbasirevic, Vladimir; Vujic, Dragana

    2016-01-01

    Autophagy is activated in cancer cells in response to multiple stresses and has been demonstrated to promote tumor cell survival and drug resistance in neuroblastoma (NB). This study was conducted to analyze the ultrastructural features of peripheral neuroblastic tumors (pNTs) and identify the relation of the types of NTs, the proliferation rate, and MYCN gene amplification with a number of autophagic vacuoles. Our results indicate that aggressive human NBs show a massive increase in the number of autophagic vacuoles associated with proliferation rate and that alteration of the mitochondria might be an important factor for the induction of autophagy in NTs.

  17. Lung autophagic response following exposure of mice to whole body irradiation, with and without amifostine

    International Nuclear Information System (INIS)

    Zois, Christos E.; Giatromanolaki, Alexandra; Kainulainen, Heikki; Botaitis, Sotirios; Torvinen, Sira; Simopoulos, Constantinos; Kortsaris, Alexandros; Sivridis, Efthimios; Koukourakis, Michael I.

    2011-01-01

    Research highlights: → We investigated the effect 6 Gy of WBI on the autophagic machinery of normal mouse lung. → Irradiation induces dysfunction of the autophagic machinery in normal lung, characterized by decreased transcription of the LC3A/Beclin-1 mRNA and accumulation of the LC3A, and p62 proteins. → The membrane bound LC3A-II protein levels increased in the cytosolic fraction (not in the pellet), contrasting the patterns noted after starvation-induced autophagy. → Administration of amifostine, reversed all the LC3A and p62 findings, suggesting protection of the normal autophagic function. -- Abstract: Purpose: The effect of ionizing irradiation on the autophagic response of normal tissues is largely unexplored. Abnormal autophagic function may interfere the protein quality control leading to cell degeneration and dysfunction. This study investigates its effect on the autophagic machinery of normal mouse lung. Methods and materials: Mice were exposed to 6 Gy of whole body γ-radiation and sacrificed at various time points. The expression of MAP1LC3A/LC3A/Atg8, beclin-1, p62/sequestosome-1 and of the Bnip3 proteins was analyzed. Results: Following irradiation, the LC3A-I and LC3A-II protein levels increased significantly at 72 h and 7 days. Strikingly, LC3A-II protein was increased (5.6-fold at 7 days; p < 0.001) only in the cytosolic fraction, but remained unchanged in the membrane fraction. The p62 protein, was significantly increased in both supernatant and pellet fraction (p < 0.001), suggesting an autophagosome turnover deregulation. These findings contrast the patterns of starvation-induced autophagy up-regulation. Beclin-1 levels remained unchanged. The Bnip3 protein was significantly increased at 8 h, but it sharply decreased at 72 h (p < 0.05). Administration of amifostine (200 mg/kg), 30 min before irradiation, reversed all the LC3A and p62 findings on blots, suggesting restoration of the normal autophagic function. The LC3A and Beclin1 m

  18. Conessine Interferes with Oxidative Stress-Induced C2C12 Myoblast Cell Death through Inhibition of Autophagic Flux.

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    Hyunju Kim

    Full Text Available Conessine, a steroidal alkaloid isolated from Holarrhena floribunda, has anti-malarial activity and interacts with the histamine H3 receptor. However, the cellular effects of conessine are poorly understood. Accordingly, we evaluated the involvement of conessine in the regulation of autophagy. We searched natural compounds that modulate autophagy, and conessine was identified as an inhibitor of autophagic flux. Conessine treatment induced the formation of autophagosomes, and p62, an autophagic adapter, accumulated in the autophagosomes. Reactive oxygen species such as hydrogen peroxide (H2O2 result in muscle cell death by inducing excessive autophagic flux. Treatment with conessine inhibited H2O2-induced autophagic flux in C2C12 myoblast cells and also interfered with cell death. Our results indicate that conessine has the potential effect to inhibit muscle cell death by interfering with autophagic flux.

  19. Cigarette smoke extract induces prolonged endoplasmic reticulum stress and autophagic cell death in human umbilical vein endothelial cells.

    Science.gov (United States)

    Csordas, Adam; Kreutmayer, Simone; Ploner, Christian; Braun, Peter R; Karlas, Alexander; Backovic, Aleksandar; Wick, Georg; Bernhard, David

    2011-10-01

    Consumption of cigarette smoke (CS) is a well-known risk factor for early atherosclerosis; yet, the underlying mechanisms of smoking-associated atherosclerosis are poorly understood. Based on the previous results indicating that CS-induced endothelial cell death neither shows typical features of apoptosis nor of necrosis, we investigated the role of autophagy in CS extract (CSE)-induced cell death of human umbilical vein endothelial cells (HUVECs). Here, we demonstrate that overexpression of the classical apoptosis inhibitor BCL-XL had no protective effect on CSE-induced cell death, whereas the autophagy inhibitor 3-methyladenin and an shRNAi-mediated knockdown of the autophagy mediator ATG5 significantly delayed cell death. Our results indicate that CSE induces an excess accumulation of misfolded proteins in the endoplasmic reticulum (ER) and consequently the onset of the unfolded protein response. We provide evidence that the ER-resident kinase PERK is a major transducer of ER stress leading to phosphorylation of eIF2α and attenuation of protein synthesis. Finally, we show that prolonged ER stress in cells subjected to CS is followed by activation of an autophagic programme. CSE-induced autophagy is characterized by an increase in LC3 II/I ratio and activation ATG12. The autophagic signalling pathway via energy depletion and consequent activation AMP-activated protein kinase could be excluded. Our results confirm and extend previous findings reporting on the induction of autophagy by CSE in the lung. We show that protein damage caused by CSE activates autophagy, ultimately resulting in necrotic death of HUVECs. Via this mechanism, cigarette smoking may contribute to the deterioration of vascular endothelial function and the initiation of atherosclerosis.

  20. A Founder Mutation in VPS11 Causes an Autosomal Recessive Leukoencephalopathy Linked to Autophagic Defects.

    Directory of Open Access Journals (Sweden)

    Jinglan Zhang

    2016-04-01

    Full Text Available Genetic leukoencephalopathies (gLEs are a group of heterogeneous disorders with white matter abnormalities affecting the central nervous system (CNS. The causative mutation in ~50% of gLEs is unknown. Using whole exome sequencing (WES, we identified homozygosity for a missense variant, VPS11: c.2536T>G (p.C846G, as the genetic cause of a leukoencephalopathy syndrome in five individuals from three unrelated Ashkenazi Jewish (AJ families. All five patients exhibited highly concordant disease progression characterized by infantile onset leukoencephalopathy with brain white matter abnormalities, severe motor impairment, cortical blindness, intellectual disability, and seizures. The carrier frequency of the VPS11: c.2536T>G variant is 1:250 in the AJ population (n = 2,026. VPS11 protein is a core component of HOPS (homotypic fusion and protein sorting and CORVET (class C core vacuole/endosome tethering protein complexes involved in membrane trafficking and fusion of the lysosomes and endosomes. The cysteine 846 resides in an evolutionarily conserved cysteine-rich RING-H2 domain in carboxyl terminal regions of VPS11 proteins. Our data shows that the C846G mutation causes aberrant ubiquitination and accelerated turnover of VPS11 protein as well as compromised VPS11-VPS18 complex assembly, suggesting a loss of function in the mutant protein. Reduced VPS11 expression leads to an impaired autophagic activity in human cells. Importantly, zebrafish harboring a vps11 mutation with truncated RING-H2 domain demonstrated a significant reduction in CNS myelination following extensive neuronal death in the hindbrain and midbrain. Thus, our study reveals a defect in VPS11 as the underlying etiology for an autosomal recessive leukoencephalopathy disorder associated with a dysfunctional autophagy-lysosome trafficking pathway.

  1. Cement blocks with EVA waste for extensive modular green roof: contribution of the components for thermal insulation

    OpenAIRE

    MELO, A. B. DE; MENDONÇA, T. N. M.

    2017-01-01

    Abstract Green roofs can contribute in many ways to the quality of the environment, being known for reducing the heat transfer to the interior of the buildings. Amongst the available techniques for the execution of this type of covering, the use of light cement blocks which are compatible with the system of extensive modular green roofs is proposed. For the light cement blocks, produced with EVA aggregates (waste from the footwear industry), an additional contribution in the capacity of therm...

  2. Intense pseudotransport of a cationic drug mediated by vacuolar ATPase: Procainamide-induced autophagic cell vacuolization

    International Nuclear Information System (INIS)

    Morissette, Guillaume; Lodge, Robert; Marceau, Francois

    2008-01-01

    Cationic drugs frequently exhibit large apparent volumes of distribution, consistent with various forms of cellular sequestration. The contributions of organelles and metabolic processes that may mimic drug transport were defined in human vascular smooth muscle cells. We hypothesized that procainamide-induced vacuolar cytopathology is driven by intense pseudotransport mediated by the vacuolar (V)-ATPase and pursued the characterization of vesicular trafficking alterations in this model. Large amounts of procainamide were taken up by intact cells (maximal in 2 h, reversible upon washout, apparent K M 4.69 mM; fluorometric determination of cell-associated drug). Procainamide uptake was extensively prevented or reversed by pharmacological inhibition of the V-ATPase with bafilomycin A1 or FR 167356, decreased at low extracellular pH and preceded vacuolar cell morphology. However, the uptake of procainamide was unaffected by mitochondrial poisons that reduced the uptake of rhodamine 6G. Large vacuoles induced by millimolar procainamide were labeled with the late endosome/lysosome markers Rab7 and CD63 and the autophagy effector LC3; their osmotic formation (but not procainamide uptake) was reduced by extracellular mannitol and parallel to LC3 II formation. Procainamide-induced vacuolization is associated with defective endocytosis of fluorophore-labeled bovine serum albumin, but not with induction of the unfolded protein response. The contents of a vacuole subset slowly (≥ 24 h) become positive for Nile red staining (phospholipidosis-like response). V-ATPase-driven ion trapping is a form of intense cation pseudotransport that concerns the uncharged form of the drugs, and is associated with a vacuolar, autophagic and evolutive cytopathology and profound effects on vesicular trafficking

  3. Scoping calculation for components of the cow-milk dose pathway for evaluating the dose contribution from iodine-131

    International Nuclear Information System (INIS)

    Ikenberry, T.A.; Napier, B.A.

    1992-12-01

    A series of scoping calculations have been undertaken to evaluate The absolute and relative contribution of different exposure pathways to doses that may have been received by individuals living in the vicinity of the Hanford site. This scoping calculation (Calculation 001) examined the contributions of the various exposure pathways associated with environmental transport and accumulation of iodine-131 in the pasture-cow-milk pathway. Addressed in this calculation were the contributions to thyroid dose of infants and adult from (1) the ingestion by dairy cattle of various feedstuffs (pasturage, silage, alfalfa hay, and grass hay) in four different feeding regimes; (2) ingestion of soil by dairy cattle; (3) ingestion of stared feed on which airborne iodine-131 had been deposited; and (4) inhalation of airborne iodine-131 by dairy cows

  4. IsaB Inhibits Autophagic Flux to Promote Host Transmission of Methicillin-Resistant Staphylococcus aureus.

    Science.gov (United States)

    Liu, Pei-Feng; Cheng, Jin-Shiung; Sy, Cheng-Len; Huang, Wei-Chun; Yang, Hsiu-Chen; Gallo, Richard L; Huang, Chun-Ming; Shu, Chih-Wen

    2015-11-01

    Methicillin-resistant Staphylococcus aureus (MRSA) has emerged as a major nosocomial pathogen that is widespread in both health-care facilities and in the community at large, as a result of direct host-to-host transmission. Several virulence factors are associated with pathogen transmission to naive hosts. Immunodominant surface antigen B (IsaB) is a virulence factor that helps Staphylococcus aureus to evade the host defense system. However, the mechanism of IsaB on host transmissibility remains unclear. We found that IsaB expression was elevated in transmissible MRSA. Wild-type isaB strains inhibited autophagic flux to promote bacterial survival and elicit inflammation in THP-1 cells and mouse skin. MRSA isolates with increased IsaB expression showed decreased autophagic flux, and the MRSA isolate with the lowest IsaB expression showed increased autophagic flux. In addition, recombinant IsaB rescued the virulence of the isaB deletion strain and increased the group A streptococcus (GAS) virulence in vivo. Together, these results reveal that IsaB diminishes autophagic flux, thereby allowing MRSA to evade host degradation. These findings suggest that IsaB is a suitable target for preventing or treating MRSA infection.

  5. Autophagic clearance of proteasomes in yeast requires the conserved sorting nexin Snx4.

    Science.gov (United States)

    Nemec, Antonia A; Howell, Lauren A; Peterson, Anna K; Murray, Matthew A; Tomko, Robert J

    2017-12-29

    Turnover of the 26S proteasome by autophagy is an evolutionarily conserved process that governs cellular proteolytic capacity and eliminates inactive particles. In most organisms, proteasomes are located in both the nucleus and cytoplasm. However, the specific autophagy routes for nuclear and cytoplasmic proteasomes are unclear. Here, we investigate the spatial control of autophagic proteasome turnover in budding yeast ( Saccharomyces cerevisiae ). We found that nitrogen starvation-induced proteasome autophagy is independent of known nucleophagy pathways but is compromised when nuclear protein export is blocked. Furthermore, via pharmacological tethering of proteasomes to chromatin or the plasma membrane, we provide evidence that nuclear proteasomes at least partially disassemble before autophagic turnover, whereas cytoplasmic proteasomes remain largely intact. A targeted screen of autophagy genes identified a requirement for the conserved sorting nexin Snx4 in the autophagic turnover of proteasomes and several other large multisubunit complexes. We demonstrate that Snx4 cooperates with sorting nexins Snx41 and Snx42 to mediate proteasome turnover and is required for the formation of cytoplasmic proteasome puncta that accumulate when autophagosome formation is blocked. Together, our results support distinct mechanistic paths in the turnover of nuclear versus cytoplasmic proteasomes and point to a critical role for Snx4 in cytoplasmic agglomeration of proteasomes en route to autophagic destruction. © 2017 by The American Society for Biochemistry and Molecular Biology, Inc.

  6. Analysis of autophagic flux in response to sulforaphane in metastatic prostate cancer cells

    Science.gov (United States)

    Watson, Gregory W; Wickramasekara, Samanthi; Fang, Yufeng; Palomera-Sanchez, Zoraya; Maier, Claudia S; Williams, David E; Dashwood, Roderick H; Perez, Viviana I; Ho, Emily

    2015-01-01

    Scope The phytochemical sulforaphane has been shown to decrease prostate cancer metastases in a genetic mouse model of prostate carcinogenesis, though the mechanism of action is not fully known. Sulforaphane has been reported to stimulate autophagy, and modulation of autophagy has been proposed to influence sulforaphane cytotoxicity; however, no conclusions about autophagy can be drawn without assessing autophagic flux, which has not been characterized in prostate cancer cells following sulforaphane treatment. Methods and Results We conducted an investigation to assess the impact of sulforaphane on autophagic flux in two metastatic prostate cancer cell lines at a concentration shown to decrease metastasis in vivo. Autophagic flux was assessed by multiple autophagy related proteins and substrates. We found that sulforaphane can stimulate autophagic flux and cell death only at high concentrations, above what has been observed in vivo. Conclusion These results suggest that sulforaphane does not directly stimulate autophagy or cell death in metastatic prostate cancer cells under physiologically relevant conditions, but instead supports the involvement of in vivo factors as important effectors of sulforaphane- mediated prostate cancer suppression. PMID:26108801

  7. ATP Release from Dying Autophagic Cells and Their Phagocytosis Are Crucial for Inflammasome Activation in Macrophages

    Science.gov (United States)

    Ayna, Gizem; Krysko, Dmitri V.; Kaczmarek, Agnieszka; Petrovski, Goran; Vandenabeele, Peter; Fésüs, László

    2012-01-01

    Pathogen-activated and damage-associated molecular patterns activate the inflammasome in macrophages. We report that mouse macrophages release IL-1β while co-incubated with pro-B (Ba/F3) cells dying, as a result of IL-3 withdrawal, by apoptosis with autophagy, but not when they are co-incubated with living, apoptotic, necrotic or necrostatin-1 treated cells. NALP3-deficient macrophages display reduced IL-1β secretion, which is also inhibited in macrophages deficient in caspase-1 or pre-treated with its inhibitor. This finding demonstrates that the inflammasome is activated during phagocytosis of dying autophagic cells. We show that activation of NALP3 depends on phagocytosis of dying cells, ATP release through pannexin-1 channels of dying autophagic cells, P2X7 purinergic receptor activation, and on consequent potassium efflux. Dying autophagic Ba/F3 cells injected intraperitoneally in mice recruit neutrophils and thereby induce acute inflammation. These findings demonstrate that NALP3 performs key upstream functions in inflammasome activation in mouse macrophages engulfing dying autophagic cells, and that these functions lead to pro-inflammatory responses. PMID:22768222

  8. Autophagic effects of Hibiscus sabdariffa leaf polyphenols and epicatechin gallate (ECG) against oxidized LDL-induced injury of human endothelial cells.

    Science.gov (United States)

    Chen, Jing-Hsien; Lee, Ming-Shih; Wang, Chi-Ping; Hsu, Cheng-Chin; Lin, Hui-Hsuan

    2017-08-01

    Oxidized low-density lipoprotein (ox-LDL) contributes to the pathogenesis of atherosclerosis by promoting vascular endothelial cell injury. Hibiscus sabdariffa leaf polyphenols (HLP), rich in flavonoids, have been shown to possess antioxidant and antiatherosclerotic activities. In this study, we examined the protective role of HLP and its main compound (-)-epicatechin gallate (ECG) in human umbilical vein endothelial cells (HUVECs) exposed to ox-LDL in vitro. In a model of ox-LDL-impaired HUVECs, assessments of cell viability, cytotoxicity, cell proliferation, apoptosis, and autophagy were detected. To highlight the mechanisms of the antiapoptotic effects of HLP and ECG, the expressions of molecular proteins were measured by Western blotting, real-time PCR, and so on. HLP or ECG improved the survival of HUVECs from ox-LDL-induced viability loss. In addition, HLP or ECG showed potential in reducing ox-LDL-dependent apoptosis. Next, the ox-LDL-induced formation of acidic vesicular organelles and upregulation of the autophagy-related genes were increased by HLP or ECG. The HLP-triggered autophagic flux was further confirmed by increasing the LC3-II level under the pretreatment of an autophagy inhibitor chloroquine. Molecular data indicated the autophagic effect of HLP or ECG might be mediated via class III PI3K/Beclin-1 and PTEN/class I PI3K/Akt cascade signaling, as demonstrated by the usage of a class III PI3K inhibitor 3-methyladenine (3-MA) and a PTEN inhibitor SF1670. Our data imply that ECG-enriched HLP upregulates the autophagic pathway, which in turn led to reduce ox-LDL-induced HUVECs injury and apoptosis and provide a new mechanism for its antiatherosclerotic activity.

  9. Reactor pressure vessel and reactor coolant circuit cast duplex stainless steel components contribution of the expertise for life management studies

    International Nuclear Information System (INIS)

    Bezdikian, Georges

    2006-09-01

    The life management of French Nuclear Power Plants is a major stake from an economic and a technical point of view considering the aging management assessment of the key components of the plant. The actual life evaluation is the result of prediction of life assessment from important program of expertise for the 3-loop PWR and 4-loop PWR plants in operation. To optimize the strategic policy in order to achieve the best possible performance and to prepare the technical and economical choice and decision, the paper presents the association of life management strategy and the program of expertise considering: - the identification of degradation for different components and prediction criteria proposed; - the large database from cast reactor coolant and component removed from nuclear power plants and expertise studies to confirm the prediction; - the life evaluation of RPV with radiation surveillance program based on the expertise of irradiation capsules, it is particularly shown how the expertise is in the center of the strategic choice. The French utility has organized the life management of nuclear plant as a function of several programs of expertise of knowledge on the long term experience feedback and the maintenance program for life. This paper shows updated on RPV and reactor coolant equipment activities engaged by utility on: - periodic maintenance and volume of expertise; - Alternative maintenance actions; - Large volume of expertise and how are managed these results to predict the aging management. (author)

  10. Study of the contribution of the different components of atmospheric cosmic radiation in dose received by the aircraft crew

    International Nuclear Information System (INIS)

    Pereira, Marlon A.; Prado, Adriane C.M.; Federico, Claudio A.; Goncalez, Odair L.

    2014-01-01

    The crews and aircraft passengers are exposed to atmospheric cosmic radiation. The flow of this radiation is modulated by the solar cycle and space weather, varying with the geomagnetic latitude and altitude. This paper presents a study of the contributions of radiation in total ambient dose equivalent of the crews depending on flight altitude up to 20 km, during maximum and minimum solar and in equatorial and polar regions. The results of calculations of the particle flows generated by the EXPACS and QARM codes are used. The particles evaluated that contributing significantly in the ambient dose equivalent are neutrons, protons, electrons, positrons, alphas, photons, muons and charged pions. This review allows us to characterize the origin of the dose received by crews and also support a project of a dosimetric system suitable for this ionizing radiation field in aircraft and on the ground

  11. Contributions of Soil Moisture and Vegetation Components to Polarized Emission Based on the Soil Moisture Active Passive (SMAP) Mission Measurements

    Science.gov (United States)

    Zhao, T.; Talebi, S.; Li, S.; Entekhabi, D.; Lu, H.; Shi, J.; Akbar, R.; Wang, Z.; Weng, H.; Mccoll, K. A.

    2016-12-01

    The Soil Moisture Active Passive (SMAP) is an Earth satellite mission providing polarized L-band brightness temperature measurements with 6AM and 6PM equatorial crossing times. The brightness temperature measurements over land respond to land and water mixing across the landscape. Over land the soil dielectric constant and the vegetation structure and biomass cause variations in brightness temperature. The physical temperature of the landscape components and their emissivity determine the polarized brightness temperature. During the morning crossing when the physical temperature of the components are nearly equal, the difference of the polarizations normalized by the sum is independent of physical temperature. In this study, we use the Polarization Ratio (PR) as a measurement of surface emission because it does not depend on physical temperature and potentially is also a signature of soil moisture and vegetation. To decompose the PR signal into vegetation and soil components, SMAP Level 2 radiometer-only soil moisture products at 36-km are directly used. Radar observations are used as a measurement of vegetation, including cross-polarized backscattering coefficients and the Radar Vegetation Index (RVI). Regressions between these satellite observations are conducted. The regression coefficients are used to estimate percentage variance explained. Results show there is a positive correlation between PR and soil moisture and an inverse correlation exists between PR and the cross polarization of radar signal or RVI that corresponds to vegetation. In light to moderate vegetation regions, there is a substantial explained-variance between PR and soil moisture. But in dense vegetation the correlation is weak because the vegetation causes depolarization and reduces the dynamic range of the PR.

  12. Herpes simplex virus type I induces the accumulation of intracellular β-amyloid in autophagic compartments and the inhibition of the non-amyloidogenic pathway in human neuroblastoma cells.

    Science.gov (United States)

    Santana, Soraya; Recuero, Maria; Bullido, Maria Jesús; Valdivieso, Fernando; Aldudo, Jesus

    2012-02-01

    Mounting evidence suggests that herpes simplex virus type 1 (HSV-1) is involved in the pathogenesis of Alzheimer's disease (AD). Epidemiological analyses have shown that HSV-1 is a risk factor for AD in people with at least 1 type 4 allele of the apolipoprotein E gene. Recent studies have also suggested that HSV-1 contributes to the appearance of the biochemical anomalies characteristic of AD brains. In addition, autophagic activity appears to be reduced with aging, and the final stages of autophagy in neurodegenerative process appear to be impaired. The present work reports that HSV-1 provokes the strong intracellular accumulation of both the main species of β-amyloid (Aβ) in the autophagic compartments and that it is associated with a marked inhibition of Aβ secretion. Autophagosomes containing Aβ failed to fuse with lysosomes in HSV-1-infected cells, indicating the impaired degradation of Aβ localized in the autophagic vesicles. In addition, HSV-1 infection was associated with the inhibition of the nonamyloidogenic pathway of amyloid precursor protein (APP) processing without significantly affecting the activity of the secretases involved in the amyloidogenic pathway. Taken together, these data suggest that HSV-1 infection modulates autophagy and amyloid precursor protein processing, contributing to the accumulation of Aβ characteristic of AD. Copyright © 2012 Elsevier Inc. All rights reserved.

  13. Estimation of Properties of Pure Components Using Improved Group-Contribution+ (GC+) Based Models and Uncertainty Analysis

    DEFF Research Database (Denmark)

    Hukkerikar, Amol; Sarup, Bent; Abildskov, Jens

    the estimated property values using the GC+ approach, but also the uncertainties in the estimated property values. This feature allows one to evaluate the effects of these uncertainties on the product-process design calculations thereby contributing to better-informed and reliable engineering solutions....... prediction method, an engineer needs to know the uncertainties in the estimated property values obtained from that method. With this information, the engineer can then perform better- informed design calculations by taking into account these uncertainties. Hence, given the importance of reliable estimation...... of properties and uncertainties in the property estimates in the engineering calculations, this work aims to revise and improve GC+ method based estimation of properties as well as to estimate the confidence intervals of estimated property values. To this end, a systematic methodology for property modeling...

  14. Identification of novel autophagic Radix Polygalae fraction by cell membrane chromatography and UHPLC-(Q)TOF-MS for degradation of neurodegenerative disease proteins.

    Science.gov (United States)

    Wu, An-Guo; Wong, Vincent Kam-Wai; Zeng, Wu; Liu, Liang; Law, Betty Yuen-Kwan

    2015-11-24

    With its traditional use in relieving insomnia and anxiety, our previous study has identified onjisaponin B from Radix Polygalae (RP), as a novel autophagic enhancer with potential neuroprotective effects. In current study, we have further identified a novel active fraction from RP, contains 17 major triterpenoid saponins including the onjisaponin B, by the combinational use of cell membrane chromatography (CMC) and ultra-performance liquid chromatography coupled to (quadrupole) time-of-flight mass spectrometry {UHPLC-(Q)TOF-MS}. By exhibiting more potent autophagic effect in cells, the active fraction enhances the clearance of mutant huntingtin, and reduces protein level and aggregation of α-synuclein in a higher extent when compared with onjisaponin B. Here, we have reported for the first time the new application of cell-based CMC and UHPLC-(Q)TOF-MS analysis in identifying new autophagy inducers with neuroprotective effects from Chinese medicinal herb. This result has provided novel insights into the possible pharmacological actions of the active components present in the newly identified active fraction of RP, which may help to improve the efficacy of the traditional way of prescribing RP, and also provide new standard for the quality control of decoction of RP or its medicinal products in the future.

  15. The Contribution of Beverages to Intakes of Energy and MyPlate Components by Current, Former, and Never Smokers in the United States.

    Science.gov (United States)

    Zizza, Claire A; Sebastian, Rhonda S; Wilkinson Enns, Cecilia; ISIK, Zeynep; Goldman, Joseph D; Moshfegh, Alanna J

    2015-12-01

    Although beverage intake patterns have been shown to differ by smoking status, it is unknown whether the contributions of beverages to intakes of energy and MyPlate components also differ. The purpose of this study was to compare beverage intakes and contributions of energy and MyPlate components by source (food alone, beverages alone, and food and beverages together) in diets of adult current, former, and never smokers. Dietary data from 4,823 men and 4,672 women aged ≥20 years who participated in What We Eat in America, National Health and Nutrition Examination Survey 2005-2008, were analyzed. Beverage intake and the contributions to energy and MyPlate components by beverages. Regression analyses identified differences in intake among groups. Current smokers consumed more total beverages, coffee, and sugar-sweetened beverages than never and former smokers (Pbeverages than never and former smokers, whereas female current and former smokers both consumed more alcoholic beverages than never smokers. Current smokers obtained more energy from beverages than their nonsmoking counterparts, although total energy intake did not differ. Intakes of added sugars, alcohol, and empty calories were higher for current than never smokers, and differences were accounted for by current smokers' beverage choices. This study adds to the body of research on smoking and dietary behavior by showing that not only do smokers consume a higher volume of beverages, but they also have a higher intake of energy provided by beverages, mainly empty calories from added sugars and alcohol. Our findings highlight the importance of assessing beverages' contribution to the total diet. Recognizing the common co-occurrence of smoking and specific beverage choices can help target health promotion and disease prevention efforts for this subpopulation. Copyright © 2015 Academy of Nutrition and Dietetics. Published by Elsevier Inc. All rights reserved.

  16. Comparative study of the contribution of various PWR spacer grid components to hydrodynamic and wall pressure characteristics

    International Nuclear Information System (INIS)

    Bhattacharjee, Saptarshi; Ricciardi, Guillaume; Viazzo, Stéphane

    2017-01-01

    Highlights: • Complex geometry inside a PWR fuel assembly is simulated using simplified 3D models. • Structured meshes are generated as far as possible. • Fluctuating hydrodynamic and wall pressure field are analyzed using LES. • Comparative studies between square spacer grid, circular spacer grid and mixing vanes are presented. • Simulations are compared with experimental data. - Abstract: Flow-induced vibrations in a pressurized water reactor (PWR) core can cause fretting wear in fuel rods. These vibrations can compromise safety of a nuclear reactor. So, it is necessary to know the random fluctuating forces acting on the rods which cause these vibrations. In this paper, simplified 3D models like square spacer grid, circular spacer grid and symmetric mixing vanes have been used inside an annular pipe. Hydrodynamic and wall pressure characteristics are evaluated using large eddy simulations (LES). Structured meshes are generated as far as possible. Simulations are compared with an experiment. Results show that the grid and vanes have a combined effect: grid accelerates the flow whereas the vanes contribute to the swirl structures. Spectral analysis of the simulations illustrate vortex shedding phenomenon in the wake of spacer grids. This initial study opens up interesting perspectives towards improving the modeling strategy and understanding the complex phenomenon inside a PWR core.

  17. Comparative study of the contribution of various PWR spacer grid components to hydrodynamic and wall pressure characteristics

    Energy Technology Data Exchange (ETDEWEB)

    Bhattacharjee, Saptarshi, E-mail: saptarshi.bhattacharjee@outlook.com [Alternative Energies and Atomic Energy Commission (CEA) – Cadarache, DEN/DTN/STCP/LHC, 13108 Saint Paul lez Durance Cedex (France); Laboratoire de Mécanique, Modélisation et Procédés Propres (M2P2), UMR7340 CNRS, Aix-Marseille Université, Centrale Marseille, 13451 Marseille Cedex (France); Ricciardi, Guillaume [Alternative Energies and Atomic Energy Commission (CEA) – Cadarache, DEN/DTN/STCP/LHC, 13108 Saint Paul lez Durance Cedex (France); Viazzo, Stéphane [Laboratoire de Mécanique, Modélisation et Procédés Propres (M2P2), UMR7340 CNRS, Aix-Marseille Université, Centrale Marseille, 13451 Marseille Cedex (France)

    2017-06-15

    Highlights: • Complex geometry inside a PWR fuel assembly is simulated using simplified 3D models. • Structured meshes are generated as far as possible. • Fluctuating hydrodynamic and wall pressure field are analyzed using LES. • Comparative studies between square spacer grid, circular spacer grid and mixing vanes are presented. • Simulations are compared with experimental data. - Abstract: Flow-induced vibrations in a pressurized water reactor (PWR) core can cause fretting wear in fuel rods. These vibrations can compromise safety of a nuclear reactor. So, it is necessary to know the random fluctuating forces acting on the rods which cause these vibrations. In this paper, simplified 3D models like square spacer grid, circular spacer grid and symmetric mixing vanes have been used inside an annular pipe. Hydrodynamic and wall pressure characteristics are evaluated using large eddy simulations (LES). Structured meshes are generated as far as possible. Simulations are compared with an experiment. Results show that the grid and vanes have a combined effect: grid accelerates the flow whereas the vanes contribute to the swirl structures. Spectral analysis of the simulations illustrate vortex shedding phenomenon in the wake of spacer grids. This initial study opens up interesting perspectives towards improving the modeling strategy and understanding the complex phenomenon inside a PWR core.

  18. Doxorubicin resistance mediated by cytoplasmic macrophage colony-stimulating factor is associated with switch from apoptosis to autophagic cell death in MCF-7 breast cancer cells

    Science.gov (United States)

    Zhang, Mengxia; Zhang, Hailiang; Tang, Fan; Wang, Yuhua; Mo, Zhongcheng; Lei, Xiaoyong

    2016-01-01

    Macrophage colony-stimulating factor is a vital factor in maintaining the biological function of monocyte–macrophage lineage. It is expressed in many tumor tissues and cancer cells. Recent findings indicate that macrophage colony-stimulating factor might contribute to chemoresistance, but the precise mechanisms are unclear. This study was to explore the effect of macrophage colony-stimulating factor on doxorubicin resistance in MCF-7 breast cancer cells and the possible mechanism. In the study, the human breast cancer cells, MCF-7, were transfected with macrophage colony-stimulating factor. We document that cytoplasmic macrophage colony-stimulating factor induces doxorubicin resistance and inhibits apoptosis in MCF-7 cells. Further studies demonstrated that cytoplasmic macrophage colony-stimulating factor-mediated apoptosis inhibition was dependent on the activation of PI3K/Akt/Survivin pathway. More importantly, we found that macrophage colony-stimulating factor-induced autophagic cell death in doxorubicin-treated MCF-7 cells. Taken together, we show for the first time that macrophage colony-stimulating factor-induced doxorubicin resistance is associated with the changes in cell death response with defective apoptosis and promotion of autophagic cell death. PMID:27439542

  19. Live cell X-ray imaging of autophagic vacuoles formation and chromatin dynamics in fission yeast.

    Science.gov (United States)

    Strelnikova, Natalja; Sauter, Nora; Guizar-Sicairos, Manuel; Göllner, Michael; Diaz, Ana; Delivani, Petrina; Chacón, Mariola; Tolić, Iva M; Zaburdaev, Vasily; Pfohl, Thomas

    2017-10-23

    Seeing physiological processes at the nanoscale in living organisms without labeling is an ultimate goal in life sciences. Using X-ray ptychography, we explored in situ the dynamics of unstained, living fission yeast Schizosaccharomyces pombe cells in natural, aqueous environment at the nanoscale. In contrast to previous X-ray imaging studies on biological matter, in this work the eukaryotic cells were alive even after several ptychographic X-ray scans, which allowed us to visualize the chromatin motion as well as the autophagic cell death induced by the ionizing radiation. The accumulated radiation of the sequential scans allowed for the determination of a characteristic dose of autophagic vacuole formation and the lethal dose for fission yeast. The presented results demonstrate a practical method that opens another way of looking at living biological specimens and processes in a time-resolved label-free setting.

  20. Normal autophagic activity in macrophages from mice lacking Gαi3, AGS3, or RGS19.

    Directory of Open Access Journals (Sweden)

    Ali Vural

    Full Text Available In macrophages autophagy assists antigen presentation, affects cytokine release, and promotes intracellular pathogen elimination. In some cells autophagy is modulated by a signaling pathway that employs Gαi3, Activator of G-protein Signaling-3 (AGS3/GPSM1, and Regulator of G-protein Signaling 19 (RGS19. As macrophages express each of these proteins, we tested their importance in regulating macrophage autophagy. We assessed LC3 processing and the formation of LC3 puncta in bone marrow derived macrophages prepared from wild type, Gnai3(-/-, Gpsm1(-/-, or Rgs19(-/- mice following amino acid starvation or Nigericin treatment. In addition, we evaluated rapamycin-induced autophagic proteolysis rates by long-lived protein degradation assays and anti-autophagic action after rapamycin induction in wild type, Gnai3(-/-, and Gpsm1(-/- macrophages. In similar assays we compared macrophages treated or not with pertussis toxin, an inhibitor of GPCR (G-protein couple receptor triggered Gαi nucleotide exchange. Despite previous findings, the level of basal autophagy, autophagic induction, autophagic flux, autophagic degradation and the anti-autophagic action in macrophages that lacked Gαi3, AGS3, or RGS19; or had been treated with pertussis toxin, were similar to controls. These results indicate that while Gαi signaling may impact autophagy in some cell types it does not in macrophages.

  1. Death by over-eating: The Gaucher disease associated gene GBA1, identified in a screen for mediators of autophagic cell death, is necessary for developmental cell death in Drosophila midgut

    Science.gov (United States)

    Schejter, Eyal; Bialik, Shani; Levin-Zaidman, Smadar; Kimchi, Adi

    2017-01-01

    ABSTRACT Autophagy is critical for homeostasis and cell survival during stress, but can also lead to cell death, a little understood process that has been shown to contribute to developmental cell death in lower model organisms, and to human cancer cell death. We recently reported1 on our thorough molecular and morphologic characterization of an autophagic cell death system involving resveratrol treatment of lung carcinoma cells. To gain mechanistic insight into this death program, we performed a signalome-wide RNAi screen for genes whose functions are necessary for resveratrol-induced death. The screen identified GBA1, the gene encoding the lysosomal enzyme glucocerebrosidase, as an important mediator of autophagic cell death. Here we further show the physiological relevance of GBA1 to developmental cell death in midgut regression during Drosophila metamorphosis. We observed a delay in midgut cell death in two independent Gba1a RNAi lines, indicating the critical importance of Gba1a for midgut development. Interestingly, loss-of-function GBA1 mutations lead to Gaucher Disease and are a significant risk factor for Parkinson Disease, which have been associated with defective autophagy. Thus GBA1 is a conserved element critical for maintaining proper levels of autophagy, with high levels leading to autophagic cell death. PMID:28933588

  2. Autophagic vacuoles in cardiomyocytes of dilated cardiomyopathy with initially decompensated heart failure predict improved prognosis.

    Science.gov (United States)

    Saito, Tsunenori; Asai, Kuniya; Sato, Shigeru; Hayashi, Meiso; Adachi, Akiko; Sasaki, Yoshihiro; Takano, Hitoshi; Mizuno, Kyoichi; Shimizu, Wataru

    2016-01-01

    Autophagy is a process of bulk protein degradation and organelle turnover, and is a current therapeutic target in several diseases. The present study aimed to clarify the significance of myocardial autophagy of patients with dilated cardiomyopathy (DCM). Left ventricular endomyocardial biopsy was performed in 250 consecutive patients with DCM (54.9±13.9 years; male, 79%), initially presenting with decompensated heart failure (HF). The association of these findings with HF mortality or recurrence was examined. Myofilament changes, which are apparent in the degenerated cardiomyocytes of DCM, were recognized in 164 patients (66%), and autophagic vacuoles in cardiomyocytes were identified in or near the area of myofilament changes in 86 patients (34%). Morphometrically, fibrosis (odds ratio [OR], 0.96; 95% confidence interval [CI], 0.93 to 0.99) and mitochondrial abnormality (OR, 2.24; 95% CI, 1.23 to 4.08) were independently related with autophagic vacuoles. During the follow-up period of 4.9±3.9 y, 24 patients (10%) died, including 10 (4%) who died of HF, and 67 (27%) were readmitted for HF recurrence. Multivariate analysis identified a family history of DCM (hazard ratio [HR], 2.117; 95% CI, 1.199 to 3.738), hemoglobin level (HR, 0.845; 95% CI, 0.749 to 0.953), myofilament changes (HR, 13.525; 95% CI, 5.340 to 34.255), and autophagic vacuoles (HR, 0.214; 95% CI, 0.114 to 0.400) as independent predictors of death or readmission due to HF recurrence. In conclusion, autophagic vacuoles in cardiomyocytes are associated with a better HF prognosis in patients with DCM, suggesting autophagy may play a role in the prevention of myocardial degeneration.

  3. Polydatin post-treatment alleviates myocardial ischaemia/reperfusion injury by promoting autophagic flux.

    Science.gov (United States)

    Ling, Yuanna; Chen, Guiming; Deng, Yi; Tang, Huixiong; Ling, Long; Zhou, Xiaoming; Song, Xudong; Yang, Pingzhen; Liu, Yingfeng; Li, Zhiliang; Zhao, Cong; Yang, Yufei; Wang, Xianbao; Kitakaze, Masafumi; Liao, Yulin; Chen, Aihua

    2016-09-01

    Polydatin (PD), a resveratrol (RES) glycoside, has a stronger antioxidative effect than RES. It is known that RES is an autophagic enhancer and exerts a cardioprotective effect against ischaemia/reperfusion (I/R) injury. However, the effect of PD post-treatment on myocardial I/R injury remains unclear. In the present study, we investigated the influences of PD post-treatment on myocardial I/R injury and autophagy. C57BL/6 mice underwent left coronary artery (LCA) occlusion and cultured neonatal rat cardiomyocytes (NRCs) subjected to hypoxia were treated with vehicle or PD during reperfusion or re-oxygenation. We noted that PD enhanced autophagy and decreased apoptosis during I/R or hypoxia/reoxygenation (H/R), and this effect was antagonized by co-treatment with adenovirus carrying short hairpin RNA for Beclin 1 and 3-methyladenine (3-MA), an autophagic inhibitor. Compared with vehicle-treated mice, PD-treated mice had a significantly smaller myocardial infarct size (IS) and a higher left ventricular fractional shortening (LVFS) and ejection fraction (EF), whereas these effects were partly reversed by 3-MA. Furthermore, in the PD-treated NRCs, tandem fluorescent mRFP-GFP-LC3 assay showed abundant clearance of autophagosomes with an enhanced autophagic flux, and co-treatment with Bafilomycin A1 (Baf), a lysosomal inhibitor, indicated that PD promoted the degradation of autolysosome. In addition, PD post-treatment reduced mitochondrial membrane potential and cellular reactive oxygen species (ROS) production in NRCs, and these effects were partially blocked by Baf. These findings indicate that PD post-treatment limits myocardial I/R injury by promoting autophagic flux to clear damaged mitochondria to reduce ROS and cell death. © 2016 The Author(s). published by Portland Press Limited on behalf of the Biochemical Society.

  4. Looking at the metabolic consequences of the colchicine-based in vivo autophagic flux assay

    Science.gov (United States)

    Seiliez, Iban; Belghit, Ikram; Gao, Yujie; Skiba-Cassy, Sandrine; Dias, Karine; Cluzeaud, Marianne; Rémond, Didier; Hafnaoui, Nordine; Salin, Bénédicte; Camougrand, Nadine; Panserat, Stéphane

    2016-01-01

    ABSTRACT Monitoring autophagic flux in vivo or in organs remains limited and the ideal methods relative to the techniques possible with cell culture may not exist. Recently, a few papers have demonstrated the feasibility of measuring autophagic flux in vivo by intraperitoneal (IP) injection of pharmacological agents (chloroquine, leupeptin, vinblastine, and colchicine). However, the metabolic consequences of the administration of these drugs remain largely unknown. Here, we report that 0.8 mg/kg/day IP colchicine increased LC3-II protein levels in the liver of fasted trout, supporting the usefulness of this drug for studying autophagic flux in vivo in our model organism. This effect was accompanied by a decrease of plasma glucose concentration associated with a fall in the mRNA levels of gluconeogenesis-related genes. Concurrently, triglycerides and lipid droplets content in the liver increased. In contrast, transcript levels of β-oxidation-related gene Cpt1a dropped significantly. Together, these results match with the reported role of autophagy in the regulation of glucose homeostasis and intracellular lipid stores, and highlight the importance of considering these effects when using colchicine as an in vivo “autophagometer.” PMID:26902586

  5. Sodium nitroprusside induces autophagic cell death in glutathione-depleted osteoblasts.

    Science.gov (United States)

    Son, Min Jeong; Lee, Seong-Beom; Byun, Yu Jeong; Lee, Hwa Ok; Kim, Ho-Shik; Kwon, Oh-Joo; Jeong, Seong-Whan

    2010-01-01

    Previous studies reported that high levels of nitric oxide (NO) induce apoptotic cell death in osteoblasts. We examined molecular mechanisms of cytotoxic injury induced by sodium nitroprusside (SNP), a NO donor, in both glutathione (GSH)-depleted and control U2-OS osteoblasts. Cell viability was reduced by much lower effective concentrations of SNP in GSH-depleted cells compared to normal cells. The data suggest that the level of intracellular GSH is critical in SNP-induced cell death processes of osteoblasts. The level of oxidative stress due to SNP treatments doubled in GSH-depleted cells when measured with fluorochrome H2DCFDA. Pretreatment with the NO scavenger PTIO preserved the viability of cells treated with SNP. Viability of cells treated with SNP was recovered by pretreatment with Wortmannin, an autophagy inhibitor, but not by pretreatment with zVAD-fmk, a pan-specific caspase inhibitor. Large increases of LC3-II were shown by immunoblot analysis of the SNP-treated cells, and the increase was blocked by pretreatment with PTIO or Wortmannin; this implies that under GSH-depleted conditions SNP induces different molecular signaling that lead to autophagic cell death. The ultrastructural morphology of SNP-treated cells in transmission electron microscopy showed numerous autophagic vacuoles. These data suggest NO produces oxidative stress and cellular damage that culminate in autophagic cell death of GSH-depleted osteoblasts. Copyright 2010 Wiley Periodicals, Inc.

  6. An autophagic vacuolar myopathy-like disorder presenting as nonimmune hydrops in a female fetus.

    Science.gov (United States)

    Kepron, Charis; Blumenthal, Andrea; Chitayat, David; Cutz, Ernest; Superti-Furga, Andrea; Keating, Sarah

    2009-01-01

    A 37-year-old woman presented for routine obstetrical care at 15 weeks' gestational age and the fetus was found to have hydrops fetalis. Following elective termination of the pregnancy at 18 weeks' gestational age, pathologic examination of the female conceptus revealed findings suggestive of a lysosomal storage disease within the liver and cardiac muscle. Enzyme assays for beta-galactosidase, neuraminidase, alpha-l-iduronidase, beta-glucuronidase, beta-glucosidase, Morquio disease type A enzyme, beta-fucosidase, alpha-mannosidase, and beta-mannosidase were all normal, ruling out many of the common storage diseases. Electron microscopy identified vacuoles within hepatocytes, Kupffer cells, and cardiac myocytes resembling the autophagic vacuoles characteristic of a group of diseases known as the autophagic vacuolar myopathies (AVMs). Because these diseases are exceptionally rare in females, and because such autophagic vacuoles have never before been described in liver, we propose a novel entity of "AVM-like lysosomal storage disease" presenting as nonimmune hydrops in a female fetus.

  7. MP Resulting in Autophagic Cell Death of Microglia through Zinc Changes against Spinal Cord Injury

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    Dingding Li

    2016-01-01

    Full Text Available Methylprednisolone pulse therapy (MPPT, as a public recognized therapy of spinal cord injury (SCI, is doubted recently, and the exact mechanism of MP on SCI is unclear. This study sought to investigate the exact effect of MP on SCI. We examined the effect of MP in a model of SCI in vivo and an LPS induced model in vitro. We found that administration of MP produced an increase in the Basso, Beattie, and Bresnahan scores and motor neurons counts of injured rats. Besides the number of activated microglia was apparently reduced by MP in vivo, and Beclin-1 dependent autophagic cell death of microglia was induced by MP in LPS induced model. At the same time, MP increases cellular zinc concentration and level of ZIP8, and TPEN could revert effect of MP on autophagic cell death of microglia. Finally, we have found that MP could inhibit NF-κβ in LPS induced model. These results show that the MP could result in autophagic cell death of microglia, which mainly depends on increasing cellular labile zinc, and may be associated with inhibition of NF-κβ, and that MP can produce neuroprotective effect in SCI.

  8. MP Resulting in Autophagic Cell Death of Microglia through Zinc Changes against Spinal Cord Injury.

    Science.gov (United States)

    Li, Dingding; Wang, Guannan; Han, Donghe; Bi, Jing; Li, Chenyuan; Wang, Hongyu; Liu, Zhiyuan; Gao, Wei; Gao, Kai; Yao, Tianchen; Wan, Zhanghui; Li, Haihong; Mei, Xifan

    2016-01-01

    Methylprednisolone pulse therapy (MPPT), as a public recognized therapy of spinal cord injury (SCI), is doubted recently, and the exact mechanism of MP on SCI is unclear. This study sought to investigate the exact effect of MP on SCI. We examined the effect of MP in a model of SCI in vivo and an LPS induced model in vitro. We found that administration of MP produced an increase in the Basso, Beattie, and Bresnahan scores and motor neurons counts of injured rats. Besides the number of activated microglia was apparently reduced by MP in vivo, and Beclin-1 dependent autophagic cell death of microglia was induced by MP in LPS induced model. At the same time, MP increases cellular zinc concentration and level of ZIP8, and TPEN could revert effect of MP on autophagic cell death of microglia. Finally, we have found that MP could inhibit NF-κβ in LPS induced model. These results show that the MP could result in autophagic cell death of microglia, which mainly depends on increasing cellular labile zinc, and may be associated with inhibition of NF-κβ, and that MP can produce neuroprotective effect in SCI.

  9. Testing of components on the shaking table facilities of AEP and contribution to full scale dynamic testing of Kozloduy NPP. Final report

    International Nuclear Information System (INIS)

    Ambriashvili, Y.

    1996-01-01

    This final report summarizes the results of components testing on the shaking table facilities of 'Atomenergoproject' which are considered as a contribution to the full scale dynamic testing of the Kozloduy nuclear power plant Units 5 and 6. It was designed on 1.0 g according to the calculations that were based on accelerograms which included artificial and already known recordings of real earthquakes. Maximum acceleration of the designed spectrum and new spectrum which are recommended are now within the range of frequencies 2.5-20 Hz. Active reactor and the primary loop are seismic stable as well as the tested equipment tested by 'Atomenergoproject'

  10. Andrographolide induces autophagic cell death in human liver cancer cells through cyclophilin D-mediated mitochondrial permeability transition pore.

    Science.gov (United States)

    Chen, Wei; Feng, Lina; Nie, Hao; Zheng, Xiaodong

    2012-11-01

    Liver cancer is the third leading cause of cancer death worldwide and about half of the patients with liver cancer require adjuvant therapy after surgical resection. Therefore, development of novel agents to eradicate cancer cells may constitute a viable approach to treat patients with liver cancer. Andrographolide, a diterpenoid lactone isolated from Andrographis paniculata, is known to possess potent antioxidant, anti-inflammatory, antineoplastic and antiviral properties. In this study, we investigated the cytotoxic effect of andrographolide on human liver cancer cells and explored the cell death mechanism. Andrographolide induced a cell death distinct from apoptosis in multiple human liver cancer cells. The death was characterized by autophagy as evidenced by the accumulation of LC3 II and autophagosomes, and the formation of puncta GFP-LC3. This autophagy as well as cytotoxicity caused by andrographolide could be effectively prevented by 3-methyladenine (a chemical inhibitor of autophagy). Mechanistic study indicated that andrographolide induced autophagic cell death by disruption of mitochondrial transmembrane potential and elevation of reactive oxygen species, which were correlated with mitochondrial permeability transition pore Inhibition of cyclophilin D (a component of MPTP) by cyclosporin A or abrogation of its expression by small interfering RNA significantly suppressed the cytotoxicity of andrographolide, suggesting that cyclophilin D may play an important role in mediating andrographolide-induced cytotoxicity. Taken together, our findings unveil a novel mechanism of drug action by andrographolide in liver cancer cells and suggest that andrographolide may represent a promising novel agent in the treatment of liver cancer.

  11. Inhibition of mTOR improves the impairment of acidification in autophagic vesicles caused by hepatic steatosis

    Energy Technology Data Exchange (ETDEWEB)

    Nakadera, Eisuke [Department of Gastroenterology, Juntendo University School of Medicine, Hongo 2-1-1, Bunkyo-ku, Tokyo 113-8421 (Japan); Yamashina, Shunhei, E-mail: syamashi@juntendo.ac.jp [Department of Gastroenterology, Juntendo University School of Medicine, Hongo 2-1-1, Bunkyo-ku, Tokyo 113-8421 (Japan); Izumi, Kousuke; Inami, Yoshihiro; Sato, Toshifumi; Fukushima, Hirofumi; Kon, Kazuyoshi; Ikejima, Kenichi [Department of Gastroenterology, Juntendo University School of Medicine, Hongo 2-1-1, Bunkyo-ku, Tokyo 113-8421 (Japan); Ueno, Takashi [Division of Proteomics and Biomolecular Science, Juntendo University, School of Medicine, Hongo 2-1-1, Bunkyo-ku, Tokyo 113-8421 (Japan); Watanabe, Sumio [Department of Gastroenterology, Juntendo University School of Medicine, Hongo 2-1-1, Bunkyo-ku, Tokyo 113-8421 (Japan)

    2016-01-22

    Recent investigations revealed that dysfunction of autophagy involved in the progression of chronic liver diseases such as alcoholic and nonalcoholic steatohepatitis and hepatocellular neoplasia. Previously, it was reported that hepatic steatosis disturbs autophagic proteolysis via suppression of both autophagic induction and lysosomal function. Here, we demonstrate that autophagic acidification was altered by a decrease in lysosomal proton pump vacuolar-ATPase (V-ATPase) in steatohepatitis. The number of autophagic vesicles was increased in hepatocytes from obese KKAy mice as compared to control. Similarly, autophagic membrane protein LC3-II and lysosomal protein LAMP-2 expression were enhanced in KKAy mice liver. Nevertheless, both phospho-mTOR and p62 expression were augmented in KKAy mice liver. More than 70% of autophagosomes were stained by LysoTracker Red (LTR) in hepatocytes from control mice; however, the percentage of acidic autolysosomes was decreased in hepatocytes from KKAy mice significantly (40.1 ± 3.48%). Both protein and RNA level of V-ATPase subunits ATP6v1a, ATP6v1b, ATP6v1d in isolated lysosomes were suppressed in KKAy mice as compared to control. Interestingly, incubation with mTOR inhibitor rapamycin increased in the rate of LTR-positive autolysosomes in hepatocytes from KKAy mice and suppressed p62 accumulation in the liver from KKAy mice which correlated to an increase in the V-ATPase subunits expression. These results indicate that down-regulation of V-ATPase due to hepatic steatosis causes autophagic dysfunction via disruption of lysosomal and autophagic acidification. Moreover, activation of mTOR plays a pivotal role on dysregulation of lysosomal and autophagic acidification by modulation of V-ATPase expression and could therefore be a useful therapeutic target to ameliorate dysfunction of autophagy in NAFLD. - Highlights: • Hepatic steatosis causes accumulation of autophagic vesicles in hepatocytes. • Hepatic steatosis disturbs

  12. Herpes Simplex Virus and Interferon Signaling Induce Novel Autophagic Clusters in Sensory Neurons

    Science.gov (United States)

    Katzenell, Sarah

    2016-01-01

    ABSTRACT Herpes simplex virus 1 (HSV-1) establishes lifelong infection in the neurons of trigeminal ganglia (TG), cycling between productive infection and latency. Neuronal antiviral responses are driven by type I interferon (IFN) and are crucial to controlling HSV-1 virulence. Autophagy also plays a role in this neuronal antiviral response, but the mechanism remains obscure. In this study, HSV-1 infection of murine TG neurons triggered unusual clusters of autophagosomes, predominantly in neurons lacking detectable HSV-1 antigen. Treatment of neurons with IFN-β induced a similar response, and cluster formation by infection or IFN treatment was dependent upon an intact IFN-signaling pathway. The autophagic clusters were decorated with both ISG15, an essential effecter of the antiviral response, and p62, a selective autophagy receptor. The autophagic clusters were not induced by rapamycin or starvation, consistent with a process of selective autophagy. While clusters were triggered by other neurotropic herpesviruses, infection with unrelated viruses failed to induce this response. Following ocular infection in vivo, clusters formed exclusively in the infected ophthalmic branch of the TG. Taken together, our results show that infection with HSV and antiviral signaling in TG neurons produce an unorthodox autophagic response. This autophagic clustering is associated with antiviral signaling, the presence of viral genome, and the absence of HSV protein expression and may therefore represent an important neuronal response to HSV infection and the establishment of latency. IMPORTANCE Herpes simplex virus type 1 (HSV-1) is a ubiquitous virus and a significant cause of morbidity and some mortality. It is the causative agent of benign cold sores, but it can also cause blindness and life-threatening encephalitis. The success of HSV-1 is largely due to its ability to establish lifelong latent infections in neurons and to occasionally reactivate. The exact mechanisms by which

  13. Dopaminergic Neuronal Loss, Reduced Neurite Complexity and Autophagic Abnormalities in Transgenic Mice Expressing G2019S Mutant LRRK2

    Science.gov (United States)

    Lin, Brian M.; Stafa, Klodjan; Kim, Jaekwang; Banerjee, Rebecca; Westerlund, Marie; Pletnikova, Olga; Glauser, Liliane; Yang, Lichuan; Liu, Ying; Swing, Deborah A.; Beal, M. Flint; Troncoso, Juan C.; McCaffery, J. Michael; Jenkins, Nancy A.; Copeland, Neal G.; Galter, Dagmar; Thomas, Bobby; Lee, Michael K.; Dawson, Ted M.; Dawson, Valina L.; Moore, Darren J.

    2011-01-01

    Mutations in the leucine-rich repeat kinase 2 (LRRK2) gene cause late-onset, autosomal dominant familial Parkinson's disease (PD) and also contribute to idiopathic PD. LRRK2 mutations represent the most common cause of PD with clinical and neurochemical features that are largely indistinguishable from idiopathic disease. Currently, transgenic mice expressing wild-type or disease-causing mutants of LRRK2 have failed to produce overt neurodegeneration, although abnormalities in nigrostriatal dopaminergic neurotransmission have been observed. Here, we describe the development and characterization of transgenic mice expressing human LRRK2 bearing the familial PD mutations, R1441C and G2019S. Our study demonstrates that expression of G2019S mutant LRRK2 induces the degeneration of nigrostriatal pathway dopaminergic neurons in an age-dependent manner. In addition, we observe autophagic and mitochondrial abnormalities in the brains of aged G2019S LRRK2 mice and markedly reduced neurite complexity of cultured dopaminergic neurons. These new LRRK2 transgenic mice will provide important tools for understanding the mechanism(s) through which familial mutations precipitate neuronal degeneration and PD. PMID:21494637

  14. Dopaminergic neuronal loss, reduced neurite complexity and autophagic abnormalities in transgenic mice expressing G2019S mutant LRRK2.

    Directory of Open Access Journals (Sweden)

    David Ramonet

    2011-04-01

    Full Text Available Mutations in the leucine-rich repeat kinase 2 (LRRK2 gene cause late-onset, autosomal dominant familial Parkinson's disease (PD and also contribute to idiopathic PD. LRRK2 mutations represent the most common cause of PD with clinical and neurochemical features that are largely indistinguishable from idiopathic disease. Currently, transgenic mice expressing wild-type or disease-causing mutants of LRRK2 have failed to produce overt neurodegeneration, although abnormalities in nigrostriatal dopaminergic neurotransmission have been observed. Here, we describe the development and characterization of transgenic mice expressing human LRRK2 bearing the familial PD mutations, R1441C and G2019S. Our study demonstrates that expression of G2019S mutant LRRK2 induces the degeneration of nigrostriatal pathway dopaminergic neurons in an age-dependent manner. In addition, we observe autophagic and mitochondrial abnormalities in the brains of aged G2019S LRRK2 mice and markedly reduced neurite complexity of cultured dopaminergic neurons. These new LRRK2 transgenic mice will provide important tools for understanding the mechanism(s through which familial mutations precipitate neuronal degeneration and PD.

  15. Metabolic, autophagic, and mitophagic activities in cancer initiation and progression

    Directory of Open Access Journals (Sweden)

    Anita Hjelmeland

    2016-04-01

    Full Text Available Cancer is a complex disease marked by uncontrolled cell growth and invasion. These processes are driven by the accumulation of genetic and epigenetic alterations that promote cancer initiation and progression. Contributing to genome changes are the regulation of oxidative stress and reactive species-induced damage to molecules and organelles. Redox regulation, metabolic plasticity, autophagy, and mitophagy play important and interactive roles in cancer hallmarks including sustained proliferation, activated invasion, and replicative immortality. However, the impact of these processes can differ depending on the signaling pathways altered in cancer, tumor type, tumor stage, and/or the differentiation state. Here, we highlight some of the representative studies on the impact of oxidative and nitrosative activities, mitochondrial bioenergetics, metabolism, and autophagy and mitophagy in the context of tumorigenesis. We discuss the implications of these processes for cellular activities in cancer for anti-cancer-based therapeutics.

  16. Cyclic Mechanical Stretching Induces Autophagic Cell Death in Tenofibroblasts Through Activation of Prostaglandin E2 Production

    Directory of Open Access Journals (Sweden)

    Hua Chen

    2015-04-01

    Full Text Available Background/Aims: Autophagic cell death has recently been implicated in the pathophysiology of tendinopathy. Prostaglandin E2 (PGE2, a known inflammatory mediator of tendinitis, inhibits tenofibroblast proliferation in vitro; however, the underlying mechanism is unclear. The present study investigated the relationship between PGE2 production and autophagic cell death in mechanically loaded human patellar tendon fibroblasts (HPTFs in vitro. Methods: Cultured HPTFs were subjected to exogenous PGE2 treatment or repetitive cyclic mechanical stretching. Cell death was determined by flow cytometry with acridine orange/ethidium bromide staining. Induction of autophagy was assessed by autophagy markers including the formation of autophagosomes and autolysosomes (by electron microscopy, AO staining, and formation of GPF-LC3-labeled vacuoles and the expression of LC3-II and BECN1 (by western blot. Stretching-induced PGE2 release was determined by ELISA. Results: Exogenous PGE2 significantly induced cell death and autophagy in HPTFs in a dose-dependent manner. Blocking autophagy using inhibitors 3-methyladenine and chloroquine, or small interfering RNAs against autophagy genes Becn-1 and Atg-5 prevented PGE2-induced cell death. Cyclic mechanical stretching at 8% and 12% magnitudes for 24 h significantly stimulated PGE2 release by HPTFs in a magnitude-dependent manner. In addition, mechanical stretching induced autophagy and cell death. Blocking PGE2 production using COX inhibitors indomethacin and celecoxib significantly reduced stretching-induced autophagy and cell death. Conclusion: Taken together, cyclic mechanical stretching induces autophagic cell death in tenofibroblasts through activation of PGE2 production.

  17. Hyperthermia enhances radiosensitivity of colorectal cancer cells through ROS inducing autophagic cell death.

    Science.gov (United States)

    Ba, Ming-Chen; Long, Hui; Wang, Shuai; Wu, Yin-Bing; Zhang, Bo-Huo; Yan, Zhao-Fei; Yu, Fei-Hong; Cui, Shu-Zhong

    2018-04-01

    Hyperthermia (HT) enhances the anti-cancer effects of radiotherapy (RT), but the precise biochemical mechanisms involved are unclear. This study was aim to investigate if mild HT sensitizes colorectal cancer cells to RT through reactive oxygen species (ROS)-inducing autophagic cell death in a mice model of HCT116 human colorectal cancer. HCT116 mice model were randomly divided into five groups: mock group, hyperthermia group (HT), radiotherapy group (RT), HT + RT group, and HT + RT +N-acetyl L-cysteine (NAC) group (HT + CT + NAC). After four weeks of treatment, cancer growth inhibition, rate and mitochondrial membrane potential were measured with MTT and JC-1 assays, respectively, while ROS were estimated fluorimetrically. The relationship of these parameters to expressions of autophagy-related genes Beclin1, LC3B, and mTOR was analyzed. Gene expression was measured by Real-Time polymerase chain reaction (RT-PCR). There were significant increases in ROS levels and mitochondrial membrane potential in the HT + RT group. ROS levels in the HT + RT group increased more significantly than in any other group. In contrast, ROS levels in the HT + RT + NAC group were significantly decreased relative to the HT + RT group. The number of autophagic bodies in HT + RT group was higher than that of mock group. There were significant increases in the expression of Beclin1 and LC3B genes, while mTOR expression was significantly decreased in the HT + CT group. Treatment with NAC reversed the pattern of these changes. These results indicate that HT enhances the radiosensitivity of colorectal cancer cells to RT through ROS inducing autophagic cell death. © 2017 Wiley Periodicals, Inc.

  18. G9a Inhibition Induces Autophagic Cell Death via AMPK/mTOR Pathway in Bladder Transitional Cell Carcinoma.

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    Feng Li

    Full Text Available G9a has been reported to highly express in bladder transitional cell carcinoma (TCC and G9a inhibition significantly attenuates cell proliferation, but the underlying mechanism is not fully understood. The present study aimed at examining the potential role of autophagy in the anti-proliferation effect of G9a inhibition on TCC T24 and UMUC-3 cell lines in vitro. We found that both pharmaceutical and genetical G9a inhibition significantly attenuated cell proliferation by MTT assay, Brdu incorporation assay and colony formation assay. G9a inhibition induced autophagy like morphology as determined by transmission electron microscope and LC-3 fluorescence assay. In addition, autophagy flux was induced by G9a inhibition in TCC cells, as determined by p62 turnover assay and LC-3 turnover assay. The autophagy induced positively contributed to the inhibition of cell proliferation because the growth attenuation capacity of G9a inhibition was reversed by autophagy inhibitors 3-MA. Mechanically, AMPK/mTOR pathway was identified to be involved in the regulation of G9a inhibition induced autophagy. Intensively activating mTOR by Rheb overexpression attenuated autophagy and autophagic cell death induced by G9a inhibition. In addition, pre-inhibiting AMPK by Compound C attenuated autophagy together with the anti-proliferation effect induced by G9a inhibition while pre-activating AMPK by AICAR enhanced them. In conclusion, our results indicate that G9a inhibition induces autophagy through activating AMPK/mTOR pathway and the autophagy induced positively contributes to the inhibition of cell proliferation in TCC cells. These findings shed some light on the functional role of G9a in cell metabolism and suggest that G9a might be a therapeutic target in bladder TCC in the future.

  19. Infectious Bursal Disease Virus Subverts Autophagic Vacuoles To Promote Viral Maturation and Release.

    Science.gov (United States)

    Wang, Yongqiang; Duan, Yulu; Han, Chunyan; Yao, Shuai; Qi, Xiaole; Gao, Yulong; Maier, Helena J; Britton, Paul; Chen, Lei; Zhang, Lizhou; Gao, Li; Gao, Honglei; Shen, Nan; Wang, Jingfei; Wang, Xiaomei

    2017-03-01

    Autophagy functions as an intrinsic antiviral defense. However, some viruses can subvert or even enhance host autophagic machinery to increase viral replication and pathogenesis. The role of autophagy during avibirnavirus infection, especially late stage infection, remains unclear. In this study, infectious bursal disease virus (IBDV) was used to investigate the role of autophagy in avibirnavirus replication. We demonstrated IBDV induction of autophagy as a significant increase in puncta of LC3 + autophagosomes, endogenous levels of LC3-II, and ultrastructural characteristics typical of autophagosomes during the late stage of infection. Induction of autophagy enhances IBDV replication, whereas inhibition of autophagy impairs viral replication. We also demonstrated that IBDV infection induced autophagosome-lysosome fusion, but without active degradation of their contents. Moreover, inhibition of fusion or of lysosomal hydrolysis activity significantly reduced viral replication, indicating that virions utilized the low-pH environment of acidic organelles to facilitate viral maturation. Using immuno-transmission electron microscopy (TEM), we observed that a large number of intact IBDV virions were arranged in a lattice surrounded by p62 proteins, some of which lay between virions. Additionally, many virions were encapsulated within the vesicular membranes, with an obvious release stage observed by TEM. The autophagic endosomal pathway facilitates low-pH-mediated maturation of viral proteins and membrane-mediated release of progeny virions. IMPORTANCE IBDV is the most extensively studied virus in terms of molecular characteristics and pathogenesis; however, mechanisms underlying the IBDV life cycle require further exploration. The present study demonstrated that autophagy enhances viral replication at the late stage of infection, and the autophagy pathway facilitates IBDV replication complex function and virus assembly, which is critical to completion of the virus life

  20. High-mobility group box 1 released by autophagic cancer-associated fibroblasts maintains the stemness of luminal breast cancer cells.

    Science.gov (United States)

    Zhao, Xi-Long; Lin, Yong; Jiang, Jun; Tang, Zhuo; Yang, Shuai; Lu, Lu; Liang, Yan; Liu, Xue; Tan, Jiao; Hu, Xu-Gang; Niu, Qin; Fu, Wen-Juan; Yan, Ze-Xuan; Guo, De-Yu; Ping, Yi-Fang; Wang, Ji Ming; Zhang, Xia; Kung, Hsiang-Fu; Bian, Xiu-Wu; Yao, Xiao-Hong

    2017-11-01

    Cancer stem cells/cancer-initiating cells (CICs) and their microenvironmental niche play a vital role in malignant tumour recurrence and metastasis. Cancer-associated fibroblasts (CAFs) are major components of the niche of breast cancer-initiating cells (BCICs), and their interactions may profoundly affect breast cancer progression. Autophagy has been considered to be a critical process for CIC maintenance, but whether it is involved in the cross-talk between CAFs and CICs to affect tumourigenesis and pathological significance has not been determined. In this study, we found that the presence of CAFs containing high levels of microtubule-associated protein 1 light chain 3 (LC3II), a marker of autophagosomes, was associated with more aggressive luminal human breast cancer. CAFs in human luminal breast cancer tissues with high autophagy activity enriched BCICs with increased tumourigenicity. Mechanistically, autophagic CAFs released high-mobility group box 1 (HMGB1), which activated its receptor, Toll-like receptor (TLR) 4, expressed by luminal breast cancer cells, to enhance their stemness and tumourigenicity. Furthermore, immunohistochemistry of 180 luminal breast cancers revealed that high LC3II/TLR4 levels predicted an increased relapse rate and a poorer prognosis. Our findings demonstrate that autophagic CAFs play a critical role in promoting the progression of luminal breast cancer through an HMGB1-TLR4 axis, and that both autophagy in CAFs and TLR4 on breast cancer cells constitute potential therapeutic targets. Copyright © 2017 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd. Copyright © 2017 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.

  1. Zinc oxide nanoparticle induced autophagic cell death and mitochondrial damage via reactive oxygen species generation.

    Science.gov (United States)

    Yu, Kyeong-Nam; Yoon, Tae-Jong; Minai-Tehrani, Arash; Kim, Ji-Eun; Park, Soo Jin; Jeong, Min Sook; Ha, Shin-Woo; Lee, Jin-Kyu; Kim, Jun Sung; Cho, Myung-Haing

    2013-06-01

    Zinc oxide nanoparticles (ZnO-np) are used in an increasing number of industrial products such as paint, coating and cosmetics, and in other biological applications. There have been many suggestions of a ZnO-np toxicity paradigm but the underlying molecular mechanisms about the toxicity of ZnO-np remain unclear. This study was done to determine the potential toxicity of ZnO-np and to assess the toxicity mechanism in normal skin cells. Synthesized ZnO-np generated reactive oxygen species (ROS), as determined by electron spin resonance. After uptake into cells, ZnO-np induced ROS in a concentration- and time-dependent manner. To demonstrate ZnO-np toxicity mechanism related to ROS, we detected abnormal autophagic vacuoles accumulation and mitochondria dysfunction after ZnO-np treatment. Furthermore mitochondria membrane potential and adenosine-5'-triphosphate (ATP) production are decreased for culture with ZnO-np. We conclude that ZnO-np leads to cell death through autophagic vacuole accumulation and mitochondria damage in normal skin cells via ROS induction. Accordingly, ZnO-np may cause toxicity and the results highlight and need for careful regulation of ZnO-np production and use. Copyright © 2013 Elsevier Ltd. All rights reserved.

  2. 5-ALA mediated photodynamic therapy induces autophagic cell death via AMP-activated protein kinase

    Directory of Open Access Journals (Sweden)

    Lin Yu-Hsin

    2010-04-01

    Full Text Available Abstract Photodynamic therapy (PDT has been developed as an anticancer treatment, which is based on the tumor-specific accumulation of a photosensitizer that induces cell death after irradiation of light with a specific wavelength. Depending on the subcellular localization of the photosensitizer, PDT could trigger various signal transduction cascades and induce cell death such as apoptosis, autophagy, and necrosis. In this study, we report that both AMP-activated protein kinase (AMPK and mitogen-activated protein kinase (MAPK signaling cascades are activated following 5-aminolevulinic acid (ALA-mediated PDT in both PC12 and CL1-0 cells. Although the activities of caspase-9 and -3 are elevated, the caspase inhibitor zVAD-fmk did not protect cells against ALA-PDT-induced cell death. Instead, autophagic cell death was found in PC12 and CL1-0 cells treated with ALA-PDT. Most importantly, we report here for the first time that it is the activation of AMPK, but not MAPKs that plays a crucial role in mediating autophagic cell death induced by ALA-PDT. This novel observation indicates that the AMPK pathway play an important role in ALA-PDT-induced autophagy.

  3. Fullerenol cytotoxicity in kidney cells is associated with cytoskeleton disruption, autophagic vacuole accumulation, and mitochondrial dysfunction

    International Nuclear Information System (INIS)

    Johnson-Lyles, Denise N.; Peifley, Kimberly; Lockett, Stephen; Neun, Barry W.; Hansen, Matthew; Clogston, Jeffrey; Stern, Stephan T.; McNeil, Scott E.

    2010-01-01

    Water soluble fullerenes, such as the hydroxylated fullerene, fullerenol (C 60 OH x ), are currently under development for diagnostic and therapeutic biomedical applications in the field of nanotechnology. These molecules have been shown to undergo urinary clearance, yet there is limited data available on their renal biocompatibility. Here we examine the biological responses of renal proximal tubule cells (LLC-PK1) exposed to fullerenol. Fullerenol was found to be cytotoxic in the millimolar range, with viability assessed by the sulforhodamine B and trypan blue assays. Fullerenol-induced cell death was associated with cytoskeleton disruption and autophagic vacuole accumulation. Interaction with the autophagy pathway was evaluated in vitro by Lysotracker Red dye uptake, LC3-II marker expression and TEM. Fullerenol treatment also resulted in coincident loss of cellular mitochondrial membrane potential and ATP depletion, as measured by the Mitotracker Red dye and the luciferin-luciferase assays, respectively. Fullerenol-induced ATP depletion and loss of mitochondrial potential were partially ameliorated by co-treatment with the autophagy inhibitor, 3-methyladenine. In vitro fullerenol treatment did not result in appreciable oxidative stress, as measured by lipid peroxide and glutathione content. Based on these data, it is hypothesized that cytoskeleton disruption may be an initiating event in fullerenol cytotoxicity, leading to subsequent autophagy dysfunction and loss of mitochondrial capacity. As nanoparticle-induced cytoskeleton disruption, autophagic vacuole accumulation and mitochondrial dysfunction are commonly reported in the literature, the proposed mechanism may be relevant for a variety of nanomaterials.

  4. Naringin Attenuates Autophagic Stress and Neuroinflammation in Kainic Acid-Treated Hippocampus In Vivo

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    Kyoung Hoon Jeong

    2015-01-01

    Full Text Available Kainic acid (KA is well known as a chemical compound to study epileptic seizures and neuronal excitotoxicity. KA-induced excitotoxicity causes neuronal death by induction of autophagic stress and microglia-derived neuroinflammation, suggesting that the control of KA-induced effects may be important to inhibit epileptic seizures with neuroprotection. Naringin, a flavonoid in grapefruit and citrus fruits, has anti-inflammatory and antioxidative activities, resulting in neuroprotection in animal models from neurodegenerative diseases such as Parkinson’s disease and Alzheimer’s disease. In the present study, we examined its beneficial effects involved in antiautophagic stress and antineuroinflammation in the KA-treated hippocampus. Our results showed that naringin treatment delayed the onset of KA-induced seizures and decreased the occurrence of chronic spontaneous recurrent seizures (SRS in KA-treated mice. Moreover, naringin treatment protected hippocampal CA1 neurons in the KA-treated hippocampus, ameliorated KA-induced autophagic stress, confirmed by the expression of microtubule-associated protein light chain 3 (LC3, and attenuated an increase in tumor necrosis factor-α (TNFα in activated microglia. These results suggest that naringin may have beneficial effects of preventing epileptic events and neuronal death through antiautophagic stress and antineuroinflammation in the hippocampus in vivo.

  5. Acid sphingomyelinase modulates the autophagic process by controlling lysosomal biogenesis in Alzheimer's disease.

    Science.gov (United States)

    Lee, Jong Kil; Jin, Hee Kyung; Park, Min Hee; Kim, Bo-ra; Lee, Phil Hyu; Nakauchi, Hiromitsu; Carter, Janet E; He, Xingxuan; Schuchman, Edward H; Bae, Jae-sung

    2014-07-28

    In Alzheimer's disease (AD), abnormal sphingolipid metabolism has been reported, although the pathogenic consequences of these changes have not been fully characterized. We show that acid sphingomyelinase (ASM) is increased in fibroblasts, brain, and/or plasma from patients with AD and in AD mice, leading to defective autophagic degradation due to lysosomal depletion. Partial genetic inhibition of ASM (ASM(+/-)) in a mouse model of familial AD (FAD; amyloid precursor protein [APP]/presenilin 1 [PS1]) ameliorated the autophagocytic defect by restoring lysosomal biogenesis, resulting in improved AD clinical and pathological findings, including reduction of amyloid-β (Aβ) deposition and improvement of memory impairment. Similar effects were noted after pharmacologic restoration of ASM to the normal range in APP/PS1 mice. Autophagic dysfunction in neurons derived from FAD patient induced pluripotent stem cells (iPSCs) was restored by partial ASM inhibition. Overall, these results reveal a novel mechanism of ASM pathogenesis in AD that leads to defective autophagy due to impaired lysosomal biogenesis and suggests that partial ASM inhibition is a potential new therapeutic intervention for the disease. © 2014 Lee et al.

  6. Ceramides And Stress Signalling Intersect With Autophagic Defects In Neurodegenerative Drosophila blue cheese (bchs) Mutants.

    Science.gov (United States)

    Hebbar, Sarita; Sahoo, Ishtapran; Matysik, Artur; Argudo Garcia, Irene; Osborne, Kathleen Amy; Papan, Cyrus; Torta, Federico; Narayanaswamy, Pradeep; Fun, Xiu Hui; Wenk, Markus R; Shevchenko, Andrej; Schwudke, Dominik; Kraut, Rachel

    2015-12-07

    Sphingolipid metabolites are involved in the regulation of autophagy, a degradative recycling process that is required to prevent neuronal degeneration. Drosophila blue cheese mutants neurodegenerate due to perturbations in autophagic flux, and consequent accumulation of ubiquitinated aggregates. Here, we demonstrate that blue cheese mutant brains exhibit an elevation in total ceramide levels; surprisingly, however, degeneration is ameliorated when the pool of available ceramides is further increased, and exacerbated when ceramide levels are decreased by altering sphingolipid catabolism or blocking de novo synthesis. Exogenous ceramide is seen to accumulate in autophagosomes, which are fewer in number and show less efficient clearance in blue cheese mutant neurons. Sphingolipid metabolism is also shifted away from salvage toward de novo pathways, while pro-growth Akt and MAP pathways are down-regulated, and ER stress is increased. All these defects are reversed under genetic rescue conditions that increase ceramide generation from salvage pathways. This constellation of effects suggests a possible mechanism whereby the observed deficit in a potentially ceramide-releasing autophagic pathway impedes survival signaling and exacerbates neuronal death.

  7. Precise temporal regulation of roughest is required for correct salivary gland autophagic cell death in Drosophila.

    Science.gov (United States)

    Simon, Claudio R; Moda, Livia M R; Octacilio-Silva, Shirlei; Anhezini, Lucas; Machado-Gitai, Luciana C H; Ramos, Ricardo Guelerman P

    2009-07-01

    The Drosophila roughest (rst) locus encodes an immunoglobulin superfamily transmembrane glycoprotein implicated in a variety of embryonic and postembryonic developmental processes. Here we demonstrate a previously unnoticed role for this gene in the autophagic elimination of larval salivary glands during early pupal stages by showing that overexpression of the Rst protein ectodomain in early pupa leads to persistence of salivary glands up to at least 12 hours after head eversion, although with variable penetrance. The same phenotype is observed in individuals carrying the dominant regulatory allele rst(D), but not in loss of function alleles. Analysis of persistent glands at the ultrastructural level showed that programmed cell death starts at the right time but is arrested at an early stage of the process. Finally we describe the expression pattern and intracellular distribution of Rst in wild type and rst(D) mutants, showing that its downregulation in salivary glands at the beginning of pupal stage is an important factor in the correct implementation of the autophagic program of this tissue in space and time. 2009 Wiley-Liss, Inc.

  8. Loss of C9orf72 Enhances Autophagic Activity via Deregulated mTOR and TFEB Signaling.

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    Janet Ugolino

    2016-11-01

    Full Text Available The most common cause of the neurodegenerative diseases amyotrophic lateral sclerosis and frontotemporal dementia is a hexanucleotide repeat expansion in C9orf72. Here we report a study of the C9orf72 protein by examining the consequences of loss of C9orf72 functions. Deletion of one or both alleles of the C9orf72 gene in mice causes age-dependent lethality phenotypes. We demonstrate that C9orf72 regulates nutrient sensing as the loss of C9orf72 decreases phosphorylation of the mTOR substrate S6K1. The transcription factor EB (TFEB, a master regulator of lysosomal and autophagy genes, which is negatively regulated by mTOR, is substantially up-regulated in C9orf72 loss-of-function animal and cellular models. Consistent with reduced mTOR activity and increased TFEB levels, loss of C9orf72 enhances autophagic flux, suggesting that C9orf72 is a negative regulator of autophagy. We identified a protein complex consisting of C9orf72 and SMCR8, both of which are homologous to DENN-like proteins. The depletion of C9orf72 or SMCR8 leads to significant down-regulation of each other's protein level. Loss of SMCR8 alters mTOR signaling and autophagy. These results demonstrate that the C9orf72-SMCR8 protein complex functions in the regulation of metabolism and provide evidence that loss of C9orf72 function may contribute to the pathogenesis of relevant diseases.

  9. Contribution of β-phenethylamine, a component of chocolate and wine, to dopaminergic neurodegeneration: implications for the pathogenesis of Parkinson's disease.

    Science.gov (United States)

    Borah, Anupom; Paul, Rajib; Mazumder, Muhammed Khairujjaman; Bhattacharjee, Nivedita

    2013-10-01

    While the cause of dopaminergic neuronal cell death in Parkinson's disease (PD) is not yet understood, many endogenous molecules have been implicated in its pathogenesis. β-phenethylamine (β-PEA), a component of various food items including chocolate and wine, is an endogenous molecule produced from phenylalanine in the brain. It has been reported recently that long-term administration of β-PEA in rodents causes neurochemical and behavioral alterations similar to that produced by parkinsonian neurotoxins. The toxicity of β-PEA has been linked to the production of hydroxyl radical ((·)OH) and the generation of oxidative stress in dopaminergic areas of the brain, and this may be mediated by inhibition of mitochondrial complex-I. Another significant observation is that administration of β-PEA to rodents reduces striatal dopamine content and induces movement disorders similar to those of parkinsonian rodents. However, no reports are available on the extent of dopaminergic neuronal cell death after administration of β-PEA. Based on the literature, we set out to establish β-PEA as an endogenous molecule that potentially contributes to the progressive development of PD. The sequence of molecular events that could be responsible for dopaminergic neuronal cell death in PD by consumption of β-PEA-containing foods is proposed here. Thus, long-term over-consumption of food items containing β-PEA could be a neurological risk factor having significant pathological consequences.

  10. Carbonaceous components, levoglucosan and inorganic ions in tropical aerosols from Tanzania, East Africa: implication for biomass burning contribution to organic aerosols

    Science.gov (United States)

    Mkoma, S. L.; Kawamura, K.; Fu, P.

    2012-11-01

    Atmospheric aerosol samples of PM2.5 and PM10 were collected at a rural site in Tanzania in 2011 during wet and dry seasons and they were analysed for carbonaceous components, levoglucosan and water-soluble inorganic ions. The mean mass concentrations of PM2.5 and PM10 were 28.2±6.4 μg m-3 and 47±8.2 μg m-3 in wet season, and 39.1±9.8 μg m-3 and 61.4±19.2 μg m-3 in dry season, respectively. Total carbon (TC) accounted for 16-19% of the PM2.5 mass and 13-15% of the PM10 mass. On average, 85.9 to 88.7% of TC in PM2.5 and 87.2 to 90.1% in PM10 was organic carbon (OC), of which 67-72% and 63% was found to be water-soluble organic carbon (WSOC) in PM2.5 and PM10, respectively. Water-soluble potassium (K+) and sulphate (SO42-) in PM2.5 and, sodium (Na+) and SO42- in PM10 were the dominant ionic species. We found, that concentrations of biomass burning tracers (levoglucosan and mannosan) well correlated with non-sea-salt-K+, WSOC and OC in the aerosols from Tanzania, East Africa. Mean contributions of levoglucosan to OC ranged between 3.9-4.2% for PM2.5 and 3.5-3.8% for PM10. This study demonstrates that emissions from biomass- and biofuel-burning activities followed by atmospheric photochemical processes mainly control the air quality in Tanzania.

  11. Dietary L-Lysine Suppresses Autophagic Proteolysis and Stimulates Akt/mTOR Signaling in the Skeletal Muscle of Rats Fed a Low-Protein Diet.

    Science.gov (United States)

    Sato, Tomonori; Ito, Yoshiaki; Nagasawa, Takashi

    2015-09-23

    Amino acids, especially L-leucine, regulate protein turnover in skeletal muscle and have attracted attention as a means of increasing muscle mass in people suffering from malnutrition, aging (sarcopenia), or a bedridden state. We previously showed that oral administration of L-lysine (Lys) by gavage suppressed proteolysis in skeletal muscles of fasted rats. However, the intake of Lys in the absence of other dietary components is unlikely in a non-experimental setting, and other dietary components may interfere with the suppressive effect of Lys on proteolysis. We supplemented Lys to a 10% casein diet and investigated the effect of Lys on proteolysis and autophagy, a major proteolytic system, in the skeletal muscle of rats. The rate of proteolysis was evaluated from 3-methylhisitidine (MeHis) released from isolated muscles, in plasma, and excreted in urine. Supplementing lysine with the 10% casein diet decreased the rate of proteolysis induced by intake of a low-protein diet. The upregulated autophagy activity [light chain 3 (LC3)-II/total LC3] caused by a low-protein diet was reduced, and the Akt/mTOR signaling pathway was activated by Lys. Importantly, continuous feeding of a Lys-rich 10% casein diet for 15 days increased the masses of the soleus and gastrocnemius muscles. Taken together, supplementation of Lys to a low-protein diet suppresses autophagic proteolysis through the Akt/mTOR signaling pathway, and continuous feeding of a Lys-rich diet may increase skeletal muscle mass.

  12. Endurance exercise training induces fat depot-specific differences in basal autophagic activity

    International Nuclear Information System (INIS)

    Tanaka, Goki; Kato, Hisashi; Izawa, Tetsuya

    2015-01-01

    The purpose of this study was to uncover the effect of exercise training on the expression of autophagy marker proteins in epididymal white adipose tissue (eWAT), inguinal WAT (iWAT), and the stromal vascular fraction (SVF) collected from eWAT. Male Wistar rats aged 4–5 weeks were randomly divided into two groups, sedentary control (n = 7) and exercise-trained (n = 7). Rats in the exercise-trained group were exercised on a treadmill set at a 5° incline 5 days/week for 9 weeks. We determined that the expression levels of an autophagosome-associating form of microtubule-associated protein 1 light chain 3 (LC3)-II and of p62 were significantly higher in eWAT from exercise-trained than from control rats, while those of adipose-specific deletion of autophagy-related protein (ATG7) and lysosomal-associated membrane protein type 2A (LAMP2a) showed no difference between groups. However, in iWAT, the expression levels of LC3-II and ATG7 were significantly higher in exercise-trained than in control rats. The expression of p62 was highly correlated with that of peroxisome proliferator-activated receptor γ (PPARγ), a master regulator of adipogenesis and lipid metabolism, in both WAT types (eWAT, r = 0.856, P < 0.05; iWAT, r = 0.762, P < 0.05), whereas LC3-II and PPARγ levels were highly correlated in eWAT (r = 0.765, P < 0.05) but not in iWAT (r = −0.306, ns). In SVF, the expression levels of LC3II, ATG7, and LAMP2a were significantly higher in exercise-trained than in control rats. These results suggest that exercise training suppresses basal autophagy activity in eWAT, but that this activity is enhanced in iWAT and SVF collected from eWAT. Thus, the adaptation of basal autophagic activity following exercise training exhibits fat depot-specific differences. - Highlights: • Autophagy has been associated with obesity and associated diseases. • We examined exercise-associated rat white adipose tissue (WAT) autophagy markers. • Exercise increased

  13. Endurance exercise training induces fat depot-specific differences in basal autophagic activity

    Energy Technology Data Exchange (ETDEWEB)

    Tanaka, Goki; Kato, Hisashi; Izawa, Tetsuya, E-mail: tizawa@mail.doshisha.ac.jp

    2015-10-23

    The purpose of this study was to uncover the effect of exercise training on the expression of autophagy marker proteins in epididymal white adipose tissue (eWAT), inguinal WAT (iWAT), and the stromal vascular fraction (SVF) collected from eWAT. Male Wistar rats aged 4–5 weeks were randomly divided into two groups, sedentary control (n = 7) and exercise-trained (n = 7). Rats in the exercise-trained group were exercised on a treadmill set at a 5° incline 5 days/week for 9 weeks. We determined that the expression levels of an autophagosome-associating form of microtubule-associated protein 1 light chain 3 (LC3)-II and of p62 were significantly higher in eWAT from exercise-trained than from control rats, while those of adipose-specific deletion of autophagy-related protein (ATG7) and lysosomal-associated membrane protein type 2A (LAMP2a) showed no difference between groups. However, in iWAT, the expression levels of LC3-II and ATG7 were significantly higher in exercise-trained than in control rats. The expression of p62 was highly correlated with that of peroxisome proliferator-activated receptor γ (PPARγ), a master regulator of adipogenesis and lipid metabolism, in both WAT types (eWAT, r = 0.856, P < 0.05; iWAT, r = 0.762, P < 0.05), whereas LC3-II and PPARγ levels were highly correlated in eWAT (r = 0.765, P < 0.05) but not in iWAT (r = −0.306, ns). In SVF, the expression levels of LC3II, ATG7, and LAMP2a were significantly higher in exercise-trained than in control rats. These results suggest that exercise training suppresses basal autophagy activity in eWAT, but that this activity is enhanced in iWAT and SVF collected from eWAT. Thus, the adaptation of basal autophagic activity following exercise training exhibits fat depot-specific differences. - Highlights: • Autophagy has been associated with obesity and associated diseases. • We examined exercise-associated rat white adipose tissue (WAT) autophagy markers. • Exercise increased

  14. Lapatinib induces autophagic cell death and differentiation in acute myeloblastic leukemia

    Directory of Open Access Journals (Sweden)

    Chen YJ

    2016-07-01

    Full Text Available Yu-Jen Chen,1–4 Li-Wen Fang,5 Wen-Chi Su,6,7 Wen-Yi Hsu,1 Kai-Chien Yang,1 Huey-Lan Huang8 1Department of Medical Research, 2Department of Radiation Oncology, Mackay Memorial Hospital, 3Institute of Traditional Medicine, School of Medicine, National Yang-Ming University, 4Institute of Pharmacology, Taipei Medical University, Taipei, 5Department of Nutrition, I-Shou University, Kaohsiung, 6Research Center for Emerging Viruses, China Medical University Hospital, 7Graduate Institute of Clinical Medical Science, China Medical University, Taichung, 8Department of Bioscience Technology, College of Health Science, Chang Jung Christian University, Tainan, Taiwan, Republic of China Abstract: Lapatinib is an oral-form dual tyrosine kinase inhibitor of epidermal growth factor receptor (EGFR or ErbB/Her superfamily members with anticancer activity. In this study, we examined the effects and mechanism of action of lapatinib on several human leukemia cells lines, including acute myeloid leukemia (AML, chronic myeloid leukemia (CML, and acute lymphoblastic leukemia (ALL cells. We found that lapatinib inhibited the growth of human AML U937, HL-60, NB4, CML KU812, MEG-01, and ALL Jurkat T cells. Among these leukemia cell lines, lapatinib induced apoptosis in HL-60, NB4, and Jurkat cells, but induced nonapoptotic cell death in U937, K562, and MEG-01 cells. Moreover, lapatinib treatment caused autophagic cell death as shown by positive acridine orange staining, the massive formation of vacuoles as seen by electronic microscopy, and the upregulation of LC3-II, ATG5, and ATG7 in AML U937 cells. Furthermore, autophagy inhibitor 3-methyladenine and knockdown of ATG5, ATG7, and Beclin-1 using short hairpin RNA (shRNA partially rescued lapatinib-induced cell death. In addition, the induction of phagocytosis and ROS production as well as the upregulation of surface markers CD14 and CD68 was detected in lapatinib-treated U937 cells, suggesting the induction of

  15. Aberrant Autophagic Response in The Muscle of A Knock-in Mouse Model of Spinal and Bulbar Muscular Atrophy.

    Science.gov (United States)

    Rusmini, Paola; Polanco, Maria Josefa; Cristofani, Riccardo; Cicardi, Maria Elena; Meroni, Marco; Galbiati, Mariarita; Piccolella, Margherita; Messi, Elio; Giorgetti, Elisa; Lieberman, Andrew P; Milioto, Carmelo; Rocchi, Anna; Aggarwal, Tanya; Pennuto, Maria; Crippa, Valeria; Poletti, Angelo

    2015-10-22

    Spinal and bulbar muscular atrophy (SBMA) is characterized by loss of motoneurons and sensory neurons, accompanied by atrophy of muscle cells. SBMA is due to an androgen receptor containing a polyglutamine tract (ARpolyQ) that misfolds and aggregates, thereby perturbing the protein quality control (PQC) system. Using SBMA AR113Q mice we analyzed proteotoxic stress-induced alterations of HSPB8-mediated PQC machinery promoting clearance of misfolded proteins by autophagy. In muscle of symptomatic AR113Q male mice, we found expression upregulation of Pax-7, myogenin, E2-ubiquitin ligase UBE2Q1 and acetylcholine receptor (AchR), but not of MyoD, and of two E3-ligases (MuRF-1 and Cullin3). TGFβ1 and PGC-1α were also robustly upregulated. We also found a dramatic perturbation of the autophagic response, with upregulation of most autophagic markers (Beclin-1, ATG10, p62/SQSTM1, LC3) and of the HSPB8-mediated PQC response. Both HSPB8 and its co-chaperone BAG3 were robustly upregulated together with other specific HSPB8 interactors (HSPB2 and HSPB3). Notably, the BAG3:BAG1 ratio increased in muscle suggesting preferential misfolded proteins routing to autophagy rather than to proteasome. Thus, mutant ARpolyQ induces a potent autophagic response in muscle cells. Alteration in HSPB8-based PQC machinery may represent muscle-specific biomarkers useful to assess SBMA progression in mice and patients in response to pharmacological treatments.

  16. Mediation of autophagic cell death by type 3 ryanodine receptor (RyR3 in adult hippocampal neural stem cells

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    Kyung Min eChung

    2016-05-01

    Full Text Available Cytoplasmic Ca2+ actively engages in diverse intracellular processes from protein synthesis, folding and trafficking to cell survival and death. Dysregulation of intracellular Ca2+ levels is observed in various neuropathological states including Alzheimer’s and Parkinson’s diseases. Ryanodine receptors (RyRs and IP3 receptors (IP3Rs, the main Ca2+ release channels located in endoplasmic reticulum (ER membranes, are known to direct various cellular events such as autophagy and apoptosis. Here we investigated the intracellular Ca2+-mediated regulation of survival and death of adult hippocampal neural stem (HCN cells utilizing an insulin withdrawal model of autophagic cell death. Despite comparable expression levels of RyR and IP3R transcripts in HCN cells at normal state, the expression levels of RyRs — especially RyR3 — were markedly upregulated upon insulin withdrawal. While treatment with the RyR agonist caffeine significantly promoted the autophagic death of insulin-deficient HCN cells, treatment with its inhibitor dantrolene prevented the induction of autophagy following insulin withdrawal. Furthermore, CRISPR/Cas9-mediated knockout of the RyR3 gene abolished autophagic cell death of HCN cells. This study delineates a distinct, RyR3-mediated ER Ca2+ regulation of autophagy and programmed cell death in neural stem cells. Our findings provide novel insights into the critical, yet understudied mechanisms underlying the regulatory function of ER Ca2+ in neural stem cell biology.

  17. Ethambutol induces impaired autophagic flux and apoptosis in the rat retina

    Directory of Open Access Journals (Sweden)

    Shun-Ping Huang

    2015-08-01

    Full Text Available Ethambutol (EMB, an effective first-line antituberculosis agent, can cause serious visual impairment or irreversible vision loss in a significant number of patients. However, the mechanism underlying this ocular cytotoxicity remains to be elucidated. In this study, we found that there were statistically significant dose- and time-dependent increases in the number of cytoplasmic vacuoles and the level of cell death in EMB-treated RGC-5 cells (retinal ganglion cells. The protein kinase C (PKCδ inhibitor rottlerin markedly reduced the EMB-induced activation of caspase-3 and the subsequent apoptosis of RGC-5 cells. Western blot analysis revealed that the expression levels of class III PI3K, Beclin-1, p62 and LC3-II were upregulated, and LC3 immunostaining results showed activation of the early phase and inhibition of the late stage of autophagy in retinas of the EMB-intraperitoneal (IP-injected rat model. We further demonstrated that exposure to EMB induces autophagosome accumulation, which results from the impaired autophagic flux that is mediated by a PKCδ-dependent pathway, inhibits the PI3K/Akt/mTOR signaling pathway and leads to apoptotic death in retina neuronal cells. These results indicate that autophagy dysregulation in retinal neuronal cells might play a substantial role in EMB-induced optic neuroretinopathy.

  18. Acupuncture promotes mTOR-independent autophagic clearance of aggregation-prone proteins in mouse brain.

    Science.gov (United States)

    Tian, Tian; Sun, Yanhong; Wu, Huangan; Pei, Jian; Zhang, Jing; Zhang, Yi; Wang, Lu; Li, Bin; Wang, Lihua; Shi, Jiye; Hu, Jun; Fan, Chunhai

    2016-01-21

    Acupuncture has historically been practiced to treat medical disorders by mechanically stimulating specific acupoints with fine needles. Despite its well-documented efficacy, its biological basis remains largely elusive. In this study, we found that mechanical stimulation at the acupoint of Yanglingquan (GB34) promoted the autophagic clearance of α-synuclein (α-syn), a well known aggregation-prone protein closely related to Parkinson's disease (PD), in the substantia nigra par compacta (SNpc) of the brain in a PD mouse model. We found the protein clearance arose from the activation of the autophagy-lysosome pathway (ALP) in a mammalian target of rapamycin (mTOR)-independent approach. Further, we observed the recovery in the activity of dopaminergic neurons in SNpc, and improvement in the motor function at the behavior level of PD mice. Whereas acupuncture and rapamycin, a chemical mTOR inhibitor, show comparable α-syn clearance and therapeutic effects in the PD mouse model, the latter adopts a distinctly different, mTOR-dependent, autophagy induction process. Due to this fundamental difference, acupuncture may circumvent adverse effects of the rapamycin treatment. The newly discovered connection between acupuncture and autophagy not only provides a new route to understanding the molecular mechanism of acupuncture but also sheds new light on cost-effective and safe therapy of neurodegenerative diseases.

  19. Eclalbasaponin II induces autophagic and apoptotic cell death in human ovarian cancer cells

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    Yoon Jin Cho

    2016-09-01

    Full Text Available Triterpenoids echinocystic acid and its glycosides, isolated from several Eclipta prostrata, have been reported to possess various biological activities such as anti-inflammatory, anti-bacterial, and anti-diabetic activity. However, the cytotoxicity of the triterpenoids in human cancer cells and their molecular mechanism of action are poorly understood. In the present study, we found that eclalbasaponin II with one glucose moiety has potent cytotoxicity in three ovarian cancer cells and two endometrial cancer cells compared to an aglycone echinocystic acid and eclalbasaponin I with two glucose moiety. Eclalbasaponin II treatment dose-dependently increased sub G1 population. Annexin V staining revealed that eclalbasaponin II induced apoptosis in SKOV3 and A2780 ovarian cancer cells. In addition, eclalbasaponin II-induced cell death was associated with characteristics of autophagy; an increase in acidic vesicular organelle content and elevation of the levels of LC3-II. Interestingly, autophagy inhibitor BaF1 suppressed the eclalbasaponin II-induced apoptosis. Moreover, eclalbasaponin II activated JNK and p38 signaling and inhibited the mTOR signaling. We further demonstrated that pre-treatment with a JNK and p38 inhibitor and mTOR activator attenuated the eclalbasaponin II-induced autophagy. This suggests that eclalbasaponin II induces apoptotic and autophagic cell death through the regulation of JNK, p38, and mTOR signaling in human ovarian cancer cells.

  20. Autophagic degradation of aquaporin-2 is an early event in hypokalemia-induced nephrogenic diabetes insipidus.

    Science.gov (United States)

    Khositseth, Sookkasem; Uawithya, Panapat; Somparn, Poorichaya; Charngkaew, Komgrid; Thippamom, Nattakan; Hoffert, Jason D; Saeed, Fahad; Michael Payne, D; Chen, Shu-Hui; Fenton, Robert A; Pisitkun, Trairak

    2015-12-17

    Hypokalemia (low serum potassium level) is a common electrolyte imbalance that can cause a defect in urinary concentrating ability, i.e., nephrogenic diabetes insipidus (NDI), but the molecular mechanism is unknown. We employed proteomic analysis of inner medullary collecting ducts (IMCD) from rats fed with a potassium-free diet for 1 day. IMCD protein quantification was performed by mass spectrometry using a label-free methodology. A total of 131 proteins, including the water channel AQP2, exhibited significant changes in abundance, most of which were decreased. Bioinformatic analysis revealed that many of the down-regulated proteins were associated with the biological processes of generation of precursor metabolites and energy, actin cytoskeleton organization, and cell-cell adhesion. Targeted LC-MS/MS and immunoblotting studies further confirmed the down regulation of 18 selected proteins. Electron microscopy showed autophagosomes/autophagolysosomes in the IMCD cells of rats deprived of potassium for only 1 day. An increased number of autophagosomes was also confirmed by immunofluorescence, demonstrating co-localization of LC3 and Lamp1 with AQP2 and several other down-regulated proteins in IMCD cells. AQP2 was also detected in autophagosomes in IMCD cells of potassium-deprived rats by immunogold electron microscopy. Thus, enhanced autophagic degradation of proteins, most notably including AQP2, is an early event in hypokalemia-induced NDI.

  1. Autophagic or necrotic cell death triggered by distinct motifs of the differentiation factor DIF-1.

    Science.gov (United States)

    Luciani, M F; Kubohara, Y; Kikuchi, H; Oshima, Y; Golstein, P

    2009-04-01

    Autophagic or necrotic cell death (ACD and NCD, respectively), studied in the model organism Dictyostelium which offers unique advantages, require triggering by the same differentiation-inducing factor DIF-1. To initiate these two types of cell death, does DIF-1 act through only one or through two distinct recognition structures? Such distinct structures may recognize distinct motifs of DIF-1. To test this albeit indirectly, DIF-1 was modified at one or two of several positions, and the corresponding derivatives were tested for their abilities to induce ACD or NCD. The results strongly indicated that distinct biochemical motifs of DIF-1 were required to trigger ACD or NCD, and that these motifs were separately recognized at the onset of ACD or NCD. In addition, both ACD and NCD were induced more efficiently by DIF-1 than by either its precursors or its immediate catabolite. These results showed an unexpected relation between a differentiation factor, the cellular structures that recognize it, the cell death types it can trigger and the metabolic state of the cell. The latter seems to guide the choice of the signaling pathway to cell death, which in turn imposes the cell death type and the recognition pattern of the differentiation factor.

  2. BH3 Mimetics Reactivate Autophagic Cell Death in Anoxia-Resistant Malignant Glioma Cells

    Directory of Open Access Journals (Sweden)

    Holger Hetschko

    2008-08-01

    Full Text Available Here, we investigated the specific roles of Bcl-2 family members in anoxia tolerance of malignant glioma. Flow cytometry analysis of cell death in 17 glioma cell lines revealed drastic differences in their sensitivity to oxygen withdrawal (<0.1% O2. Cell death correlated with mitochondrial depolarization, cytochrome C release, and translocation of green fluorescent protein (GFP-tagged light chain 3 to autophagosomes but occurred in the absence of caspase activation or phosphatidylserine exposure. In both sensitive and tolerant glioma cell lines, anoxia caused a significant up-regulation of BH3-only genes previously implicated in mediating anoxic cell death in other cell types (BNIP3, NIX, PUMA, and Noxa. In contrast, we detected a strong correlation between anoxia resistance and high expression levels of antiapoptotic Bcl-2 family proteins Bcl-xL, Bcl-2, and Mcl-1 that function to neutralize the proapoptotic activity of BH3-only proteins. Importantly, inhibition of both Bcl-2 and Bcl-xL with the small-molecule BH3 mimetics HA14-1 and BH3I-2′ and by RNA interference reactivated anoxia-induced autophagic cell death in previously resistant glioma cells. Our data suggest that endogenous BH3-only protein induction may not be able to compensate for the high expression of antiapoptotic Bcl-2 family proteins in anoxia-resistant astrocytomas. They also support the conjecture that BH3 mimetics may represent an exciting new approach for the treatment of malignant glioma.

  3. 17-AAG increases autophagic removal of mutant androgen receptor in spinal and bulbar muscular atrophy.

    Science.gov (United States)

    Rusmini, Paola; Simonini, Francesca; Crippa, Valeria; Bolzoni, Elena; Onesto, Elisa; Cagnin, Monica; Sau, Daniela; Ferri, Nicola; Poletti, Angelo

    2011-01-01

    Several types of motorneuron diseases are linked to neurotoxic mutant proteins. These acquire aberrant conformations (misfolding) that trigger deleterious downstream events responsible for neuronal dysfunction and degeneration. The pharmacological removal of misfolded proteins might thus be useful in these diseases. We utilized a peculiar motorneuronal disease model, spinobulbar muscular atrophy (SBMA), in which the neurotoxicity of the protein involved, the mutant androgen receptor (ARpolyQ), can be modulated by its ligand testosterone (T). 17-(allylamino)-17-demethoxygeldanamycin (17-AAG) has already been proven to exert beneficial action in SBMA. Here we demonstrated that 17-AAG exerts its pro-degradative activity on mutant ARpolyQ without impacting on proteasome functions. 17-AAG removes ARpolyQ misfolded species and aggregates by activating the autophagic system. We next analyzed the 17-AAG effects on two proteins (SOD1 and TDP-43) involved in related motorneuronal diseases, such as amyotrophic lateral sclerosis (ALS). In these models 17-AAG was unable to counteract protein aggregation. Copyright © 2010 Elsevier Inc. All rights reserved.

  4. Zanthoxylum fruit extract from Japanese pepper promotes autophagic cell death in cancer cells.

    Science.gov (United States)

    Nozaki, Reo; Kono, Toru; Bochimoto, Hiroki; Watanabe, Tsuyoshi; Oketani, Kaori; Sakamaki, Yuichi; Okubo, Naoto; Nakagawa, Koji; Takeda, Hiroshi

    2016-10-25

    Zanthoxylum fruit, obtained from the Japanese pepper plant (Zanthoxylum piperitum De Candolle), and its extract (Zanthoxylum fruit extract, ZFE) have multiple physiological activities (e.g., antiviral activity). However, the potential anticancer activity of ZFE has not been fully examined. In this study, we investigated the ability of ZFE to induce autophagic cell death (ACD). ZFE caused remarkable autophagy-like cytoplasmic vacuolization, inhibited cell proliferation, and ultimately induced cell death in the human cancer cell lines DLD-1, HepG2, and Caco-2, but not in A549, MCF-7, or WiDr cells. ZFE increased the level of LC3-II protein, a marker of autophagy. Knockdown of ATG5 using siRNA inhibited ZFE-induced cytoplasmic vacuolization and cell death. Moreover, in cancer cells that could be induced to undergo cell death by ZFE, the extract increased the phosphorylation of c-Jun N-terminal kinase (JNK), and the JNK inhibitor SP600125 attenuated both vacuolization and cell death. Based on morphology and expression of marker proteins, ZFE-induced cell death was neither apoptosis nor necrosis. Normal intestinal cells were not affected by ZFE. Taken together, our findings show that ZFE induces JNK-dependent ACD, which appears to be the main mechanism underlying its anticancer activity, suggesting a promising starting point for anticancer drug development.

  5. Resveratrol attenuated hydrogen peroxide-induced myocardial apoptosis by autophagic flux

    Directory of Open Access Journals (Sweden)

    Chih-Yang Huang

    2016-05-01

    Full Text Available Background: Resveratrol is a Sirt-1-specific activator, which also exerts cardioprotective effects that regulate redox signalling during oxidative stress and autophagy during cardiovascular disease (CVD. Objective: This study investigated the protective effects of resveratrol against hydrogen peroxide-induced damage in cardiomyocytes. Design: In this article, hydrogen peroxide-induced autophagy and apoptosis in H9c2 cardiomyoblasts were studied at an increasing concentration from 0 to 100 µM. Results: Resveratrol pretreatment with concentrations of 10, 20, and 50 µM inhibits autophagic apoptosis by increasing p-Akt and Bcl-2 protein levels in H9c2 cells. Interestingly, resveratrol treatment activates the Beclin-1, LC3, p62, and the lysosome-associated protein LAMP2a within 24 h of administration. Conclusions: These results suggest that resveratrol-regulated autophagy may play a role in degrading damaged organelles in H9c2 cells rather than causing apoptosis, and this may be a possible mechanism by which resveratrol protects the heart during CVD.

  6. High-fat diet increases autophagic flux in pancreatic beta cells in vivo and ex vivo in mice.

    Science.gov (United States)

    Chu, Kwan Yi; O'Reilly, Liam; Ramm, Georg; Biden, Trevor J

    2015-09-01

    Defective beta cell function during lipid oversupply and type 2 diabetes is associated with dysregulation of lysosomal function and autophagy. Whether this dysregulation represents augmentation or inhibition is unclear because of technical limitations in assaying autophagy. The current aim was to determine the effects of high-fat feeding on true autophagic flux in beta cells in vivo in mice, and to establish the relationship between autophagy, endoplasmic reticulum (ER) stress and apoptosis. Green fluorescent protein-microtubule-associated protein 1 light chain 3 (GFP-LC3) mice were fed chow or high-fat diets for 8-10 weeks and injected with 100 mg kg(-1) day(-1) chloroquine for 5 days, prior to being killed, to block clearance of autophagic markers. Pancreases and livers were fixed and GFP-LC3 aggregates or autophagosomes were detected by fluorescence or electron microscopy, respectively. Independently, islets isolated from chow or high-fat-fed mice were treated for 2 h with chloroquine ex vivo, and immunoblotting was performed for markers of autophagy (LC3 lipidation - LC3II and p62/SQSTM1), ER stress (C/EBP homology protein [CHOP], phosphorylated eukaryotic initiation factor 2α [p-eIFα] and inositol requiring enzyme 1α [p-IRE1α]) and apoptosis (cleaved caspase-3). Numbers of autophagosomes and GFP puncta were increased in beta cells by combined high-fat feeding and chloroquine injection, indicative of enhanced autophagic flux. By contrast, GFP puncta were attenuated in liver under the same conditions. Relative to chow-fed controls, islets isolated from fat-fed mice exhibited higher LC3II levels when treated ex vivo with chloroquine. The combination of high-fat feeding and acute chloroquine treatment induced CHOP, p-eIF2α and caspase-3, but not either treatment alone. We provide the first in vivo demonstrations that high-fat feeding increases autophagic flux in pancreatic beta cells, and that this serves to protect against induction of terminal ER stress. We

  7. The antioxidant function of sestrins is mediated by promotion of autophagic degradation of Keap1 and Nrf2 activation and by inhibition of mTORC1.

    Science.gov (United States)

    Rhee, Sue Goo; Bae, Soo Han

    2015-11-01

    Sestrins 1 to 3 constitute a family of proteins that are induced in mammalian cells in response to environmental stressors. Despite their apparent lack of intrinsic catalytic antioxidant activity, Sestrins protect cells from oxidative stress by lowering intracellular levels of H2O2. Here we review the mechanisms by which various types of cellular stress induce Sestrin gene transcription as well as those underlying the antioxidant function of these proteins. Several transcriptional factors, including p53, HIF-1, FoxO, C/EBP-β, ATF4, Nrf2, and PGC-1α, contribute directly to the transcriptional activation of Sestrin genes in response to various types of stress. The antioxidant function of Sestrins is mediated by two main pathways. In one pathway, Sestrins promote the p62-dependent autophagic degradation of Keap1 and thereby upregulate Nrf2 signaling and the consequent expression of genes for antioxidant enzymes. In the second pathway, Sestrins block mTORC1 activation and thereby attenuate reactive oxygen species accumulation. This inhibition of mTORC1 activity is achieved either via the AMPK-dependent phosphorylation and activation of TSC2 and consequent inhibition of the GTPase Rheb or via inhibition of the GTPase Rag and consequent prevention of the lysosomal localization of mTORC1 triggered by amino acids. Elucidation of how these pathways operate individually or cooperatively under different stress conditions awaits further study. Copyright © 2015. Published by Elsevier Inc.

  8. Contribution of β-phenethylamine, a component of chocolate and wine, to dopaminergic neurodegeneration: implications for the pathogenesis of Parkinson’s disease

    OpenAIRE

    Borah, Anupom; Paul, Rajib; Mazumder, Muhammed Khairujjaman; Bhattacharjee, Nivedita

    2013-01-01

    While the cause of dopaminergic neuronal cell death in Parkinson’s disease (PD) is not yet understood, many endogenous molecules have been implicated in its pathogenesis. β-phenethylamine (β-PEA), a component of various food items including chocolate and wine, is an endogenous molecule produced from phenylalanine in the brain. It has been reported recently that long-term administration of β-PEA in rodents causes neurochemical and behavioral alterations similar to that produced by parkinsonian...

  9. Contribution of Vaccine-Induced Immunity toward either the HA or the NA Component of Influenza Viruses Limits Secondary Bacterial Complications▿

    OpenAIRE

    Huber, Victor C.; Peltola, Ville; Iverson, Amy R.; McCullers, Jonathan A.

    2010-01-01

    Secondary bacterial infections contribute to morbidity and mortality from influenza. Vaccine effectiveness is typically assessed using prevention of influenza, not secondary infections, as an endpoint. We vaccinated mice with formalin-inactivated influenza virus vaccine preparations containing disparate HA and NA proteins and demonstrated an ability to induce the appropriate anti-HA and anti-NA immune profiles. Protection from both primary viral and secondary bacterial infection was demonstra...

  10. Contribution of components of Green Supply Chain Execution-Supply Loops in Green Supply Chain Performance measurement-A Pilot Empirical Study of the Indian Automobile Manufacturing Sector

    OpenAIRE

    Mohd. Asif Gandhi

    2017-01-01

    This paper is one of the several extensions of the research works done by [5]. Green Supply Chain Practices have been known to have an impact on Green Supply Chain Performance [5].This paper tests empirically through a pilot study of the Indian Automobile Manufacturing Sector, the contribution of the three variables constituting the construct Green Supply Chain Execution-Supply Loops in Green Supply Chain Performance measurement. Also the paper establishes the reliability of the questionnaire...

  11. Electrical Excitation of the Pulmonary Venous Musculature May Contribute to the Formation of the Last Component of the High Frequency Signal of the P Wave

    Directory of Open Access Journals (Sweden)

    Junko Abe, MD

    2005-01-01

    Full Text Available Pulmonary veins (PVs have been shown to play an important role in the induction and perpetuation of focal AF. Fifty-one patients with AF, and 24 patients without AF as control subjects, were enrolled in this study. Signal-averaged P-wave recording was performed, and the filtered P wave duration (FPD, the root-mean-square voltage for the last 20, 30 and 40 ms (RMS20, 30, and 40, respectively were compared. In 7 patients with AF, these parameters were compared before and after the catheter ablation. The FPD was significantly longer and the RMS20 was smaller in the patients with AF than those without AF. Because RMS30 was widely distributed between 2 and 10 µV, the AF group was sub-divided into two groups; Group 1 was comprised of the patients with an RMS30 ≧5.0 µV, and group 2, <5.0 µV. In group 1, short-coupled PACs were more frequently documented on Holter monitoring, and exercise testing more readily induced AF. After successful electrical disconnection between the LA and PVs, each micropotential parameter was significantly attenuated. These results indicate that the high frequency signal amplitude of the last component of the P wave is relatively high in patients with AF triggered by focal repetitive excitations most likely originating from the PVs. That is, attenuation by the LA-PV electrical isolation, and thus the high frequency P signals of the last component, may contain the electrical excitation of the PV musculature.

  12. Interference with the Autophagic Process as a Viral Strategy to Escape from the Immune Control: Lesson from Gamma Herpesviruses

    Directory of Open Access Journals (Sweden)

    Roberta Santarelli

    2015-01-01

    Full Text Available We summarized the most recent findings on the role of autophagy in antiviral immune response. We described how viruses have developed strategies to subvert the autophagic process. A particular attention has been given to Epstein-Barr and Kaposi’s sarcoma associated Herpesvirus, viruses studied for many years in our laboratory. These two viruses belong to γ-Herpesvirus subfamily and are associated with several human cancers. Besides the effects on the immune response, we have described how autophagy subversion by viruses may also concur to the enhancement of their replication and to viral tumorigenesis.

  13. Contribution to the study of recovery mechanisms to be considered in the selection of MOS-type components used in radiative environments

    International Nuclear Information System (INIS)

    Quittard, O.

    1999-12-01

    The generalized use of commercial devices in a radiative environment (nuclear power plant, spatial) raises the problem of the sensitivity of electronic equipment to the radiation induced dose effect. Irradiation of electronic devices has varying impact on their electrical characteristics, according to the concomitant bias scenario. Under bias, there is a process of continuous degradation; but recovery will occur if subsequent irradiation is performed without bias voltage. This phenomenon is known as RICN (Radiation-Induced Charge Neutralization). On the other hand, increasingly widespread use of radiation-sensitive commercial off-the-shelf components (COTS) has raised interest in exploring the degradation and recovery phenomena encountered during the irradiation as a function of bias. In this work, a general method for selecting MOS devices is presented which takes into account their operating conditions (temperature, bias). After a description of the physical phenomena responsible for the oxide-trapped charge evolution, we present the RICN annealing and their implications on devices selection in a radiative environment. The tests describes in this study were performed on SRAMs and on a set of CMOS inverts from three manufacturers. In the last section, we compare our analytical model of RICN annealing with experimental data. (authors)

  14. USP44 Is an Integral Component of N-CoR that Contributes to Gene Repression by Deubiquitinating Histone H2B.

    Science.gov (United States)

    Lan, Xianjiang; Atanassov, Boyko S; Li, Wenqian; Zhang, Ying; Florens, Laurence; Mohan, Ryan D; Galardy, Paul J; Washburn, Michael P; Workman, Jerry L; Dent, Sharon Y R

    2016-11-22

    Decreased expression of the USP44 deubiquitinase has been associated with global increases in H2Bub1 levels during mouse embryonic stem cell (mESC) differentiation. However, whether USP44 directly deubiquitinates histone H2B or how its activity is targeted to chromatin is not known. We identified USP44 as an integral subunit of the nuclear receptor co-repressor (N-CoR) complex. USP44 within N-CoR deubiquitinates H2B in vitro and in vivo, and ablation of USP44 impairs the repressive activity of the N-CoR complex. Chromatin immunoprecipitation (ChIP) experiments confirmed that USP44 recruitment reduces H2Bub1 levels at N-CoR target loci. Furthermore, high expression of USP44 correlates with reduced levels of H2Bub1 in the breast cancer cell line MDA-MB-231. Depletion of either USP44 or TBL1XR1 impairs the invasiveness of MDA-MB-231 cells in vitro and causes an increase of global H2Bub1 levels. Our findings indicate that USP44 contributes to N-CoR functions in regulating gene expression and is required for efficient invasiveness of triple-negative breast cancer cells. Copyright © 2016 The Author(s). Published by Elsevier Inc. All rights reserved.

  15. The Root Hair Specific SYP123 Regulates the Localization of Cell Wall Components and Contributes to Rizhobacterial Priming of Induced Systemic Resistance

    Directory of Open Access Journals (Sweden)

    Cecilia Rodriguez-Furlán

    2016-07-01

    Full Text Available Root hairs are important for nutrient and water uptake and are also critically involved the interaction with soil inhabiting microbiota. Root hairs are tubular-shaped outgrowths that emerge from trichoblasts. This polarized elongation is maintained and regulated by a robust mechanism involving the endomembrane secretory and endocytic system. Members of the syntaxin family of SNAREs (soluble N-ethylmaleimide-sensitive factor attachment protein receptor in plants (SYP, have been implicated in regulation of the fusion of vesicles with the target membranes in both exocytic and endocytic pathways. One member of this family, SYP123, is expressed specifically in the root hairs and accumulated in the growing tip region. This study shows evidence of the SYP123 role in polarized trafficking using knockout insertional mutant plants. We were able to observe defects in the deposition of cell wall proline rich protein PRP3 and cell wall polysaccharides. In a complementary strategy, similar results were obtained using a plant expressing a dominant negative soluble version of SYP123 (SP2 fragment lacking the transmembrane domain. The evidence presented indicates that SYP123 is also regulating PRP3 protein distribution by recycling by endocytosis. We also present evidence that indicates that SYP123 is necessary for the response of roots to plant growth promoting rhizobacterium (PGPR in order to trigger trigger induced systemic response (ISR. Plants with a defective SYP123 function were unable to mount a systemic acquired resistance (SAR in response to bacterial pathogen infection and induced systemic resistance (ISR upon interaction with rhizobacteria. These results indicated that SYP123 was involved in the polarized localization of protein and polysaccharides in growing root hairs and that this activity also contributed to the establishment of effective plant defense responses. Root hairs represent very plastic structures were many biotic and abiotic factors

  16. The Root Hair Specific SYP123 Regulates the Localization of Cell Wall Components and Contributes to Rizhobacterial Priming of Induced Systemic Resistance.

    Science.gov (United States)

    Rodriguez-Furlán, Cecilia; Salinas-Grenet, Hernán; Sandoval, Omar; Recabarren, Camilo; Arraño-Salinas, Paulina; Soto-Alvear, Sylvana; Orellana, Ariel; Blanco-Herrera, Francisca

    2016-01-01

    Root hairs are important for nutrient and water uptake and are also critically involved the interaction with soil inhabiting microbiota. Root hairs are tubular-shaped outgrowths that emerge from trichoblasts. This polarized elongation is maintained and regulated by a robust mechanism involving the endomembrane secretory and endocytic system. Members of the syntaxin family of SNAREs (soluble N-ethylmaleimide-sensitive factor attachment protein receptor) in plants (SYP), have been implicated in regulation of the fusion of vesicles with the target membranes in both exocytic and endocytic pathways. One member of this family, SYP123, is expressed specifically in the root hairs and accumulated in the growing tip region. This study shows evidence of the SYP123 role in polarized trafficking using knockout insertional mutant plants. We were able to observe defects in the deposition of cell wall proline rich protein PRP3 and cell wall polysaccharides. In a complementary strategy, similar results were obtained using a plant expressing a dominant negative soluble version of SYP123 (SP2 fragment) lacking the transmembrane domain. The evidence presented indicates that SYP123 is also regulating PRP3 protein distribution by recycling by endocytosis. We also present evidence that indicates that SYP123 is necessary for the response of roots to plant growth promoting rhizobacterium (PGPR) in order to trigger trigger induced systemic response (ISR). Plants with a defective SYP123 function were unable to mount a systemic acquired resistance in response to bacterial pathogen infection and ISR upon interaction with rhizobacteria. These results indicated that SYP123 was involved in the polarized localization of protein and polysaccharides in growing root hairs and that this activity also contributed to the establishment of effective plant defense responses. Root hairs represent very plastic structures were many biotic and abiotic factors can affect the number, anatomy and physiology of

  17. The Root Hair Specific SYP123 Regulates the Localization of Cell Wall Components and Contributes to Rizhobacterial Priming of Induced Systemic Resistance

    Science.gov (United States)

    Rodriguez-Furlán, Cecilia; Salinas-Grenet, Hernán; Sandoval, Omar; Recabarren, Camilo; Arraño-Salinas, Paulina; Soto-Alvear, Sylvana; Orellana, Ariel; Blanco-Herrera, Francisca

    2016-01-01

    Root hairs are important for nutrient and water uptake and are also critically involved the interaction with soil inhabiting microbiota. Root hairs are tubular-shaped outgrowths that emerge from trichoblasts. This polarized elongation is maintained and regulated by a robust mechanism involving the endomembrane secretory and endocytic system. Members of the syntaxin family of SNAREs (soluble N-ethylmaleimide-sensitive factor attachment protein receptor) in plants (SYP), have been implicated in regulation of the fusion of vesicles with the target membranes in both exocytic and endocytic pathways. One member of this family, SYP123, is expressed specifically in the root hairs and accumulated in the growing tip region. This study shows evidence of the SYP123 role in polarized trafficking using knockout insertional mutant plants. We were able to observe defects in the deposition of cell wall proline rich protein PRP3 and cell wall polysaccharides. In a complementary strategy, similar results were obtained using a plant expressing a dominant negative soluble version of SYP123 (SP2 fragment) lacking the transmembrane domain. The evidence presented indicates that SYP123 is also regulating PRP3 protein distribution by recycling by endocytosis. We also present evidence that indicates that SYP123 is necessary for the response of roots to plant growth promoting rhizobacterium (PGPR) in order to trigger trigger induced systemic response (ISR). Plants with a defective SYP123 function were unable to mount a systemic acquired resistance in response to bacterial pathogen infection and ISR upon interaction with rhizobacteria. These results indicated that SYP123 was involved in the polarized localization of protein and polysaccharides in growing root hairs and that this activity also contributed to the establishment of effective plant defense responses. Root hairs represent very plastic structures were many biotic and abiotic factors can affect the number, anatomy and physiology of

  18. Benzyl isothiocyanate causes FoxO1-mediated autophagic death in human breast cancer cells.

    Directory of Open Access Journals (Sweden)

    Dong Xiao

    Full Text Available Benzyl isothiocyanate (BITC, a constituent of edible cruciferous vegetables, inhibits growth of breast cancer cells but the mechanisms underlying growth inhibitory effect of BITC are not fully understood. Here, we demonstrate that BITC treatment causes FoxO1-mediated autophagic death in cultured human breast cancer cells. The BITC-treated breast cancer cells (MDA-MB-231, MCF-7, MDA-MB-468, BT-474, and BRI-JM04 and MDA-MB-231 xenografts from BITC-treated mice exhibited several features characteristic of autophagy, including appearance of double-membrane vacuoles (transmission electron microscopy and acidic vesicular organelles (acridine orange staining, cleavage of microtubule-associated protein 1 light chain 3 (LC3, and/or suppression of p62 (p62/SQSTM1 or sequestosome 1 expression. On the other hand, a normal human mammary epithelial cell line (MCF-10A was resistant to BITC-induced autophagy. BITC-mediated inhibition of MDA-MB-231 and MCF-7 cell viability was partially but statistically significantly attenuated in the presence of autophagy inhibitors 3-methyl adenine and bafilomycin A1. Stable overexpression of Mn-superoxide dismutase, which was fully protective against apoptosis, conferred only partial protection against BITC-induced autophagy. BITC treatment decreased phosphorylation of mTOR and its downstream targets (P70s6k and 4E-BP1 in cultured MDA-MB-231 and MCF-7 cells and MDA-MB-231 xenografts, but activation of mTOR by transient overexpression of its positive regulator Rheb failed to confer protection against BITC-induced autophagy. Autophagy induction by BITC was associated with increased expression and acetylation of FoxO1. Furthermore, autophagy induction and cell growth inhibition resulting from BITC exposure were significantly attenuated by small interfering RNA knockdown of FoxO1. In conclusion, the present study provides novel insights into the molecular circuitry of BITC-induced cell death involving FoxO1-mediated autophagy.

  19. Phospholipase C-related catalytically inactive protein participates in the autophagic elimination of Staphylococcus aureus infecting mouse embryonic fibroblasts.

    Directory of Open Access Journals (Sweden)

    Kae Harada-Hada

    Full Text Available Autophagy is an intrinsic host defense system that recognizes and eliminates invading bacterial pathogens. We have identified microtubule-associated protein 1 light chain 3 (LC3, a hallmark of autophagy, as a binding partner of phospholipase C-related catalytically inactive protein (PRIP that was originally identified as an inositol trisphosphate-binding protein. Here, we investigated the involvement of PRIP in the autophagic elimination of Staphylococcus aureus in infected mouse embryonic fibroblasts (MEFs. We observed significantly more LC3-positive autophagosome-like vacuoles enclosing an increased number of S. aureus cells in PRIP-deficient MEFs than control MEFs, 3 h and 4.5 h post infection, suggesting that S. aureus proliferates in LC3-positive autophagosome-like vacuoles in PRIP-deficient MEFs. We performed autophagic flux analysis using an mRFP-GFP-tagged LC3 plasmid and found that autophagosome maturation is significantly inhibited in PRIP-deficient MEFs. Furthermore, acidification of autophagosomes was significantly inhibited in PRIP-deficient MEFs compared to the wild-type MEFs, as determined by LysoTracker staining and time-lapse image analysis performed using mRFP-GFP-tagged LC3. Taken together, our data show that PRIP is required for the fusion of S. aureus-containing autophagosome-like vacuoles with lysosomes, indicating that PRIP is a novel modulator in the regulation of the innate immune system in non-professional phagocytic host cells.

  20. Overexpression of the autophagic beclin-1 protein clears mutant ataxin-3 and alleviates Machado-Joseph disease.

    Science.gov (United States)

    Nascimento-Ferreira, Isabel; Santos-Ferreira, Tiago; Sousa-Ferreira, Lígia; Auregan, Gwennaëlle; Onofre, Isabel; Alves, Sandro; Dufour, Noëlle; Colomer Gould, Veronica F; Koeppen, Arnulf; Déglon, Nicole; Pereira de Almeida, Luís

    2011-05-01

    Machado-Joseph disease, also known as spinocerebellar ataxia type 3, is the most common of the dominantly inherited ataxias worldwide and is characterized by mutant ataxin-3 misfolding, intracellular accumulation of aggregates and neuronal degeneration. Here we investigated the implication of autophagy, the major pathway for organelle and protein turnover, in the accumulation of mutant ataxin-3 aggregates and neurodegeneration found in Machado-Joseph disease and we assessed whether specific stimulation of this pathway could mitigate the disease. Using tissue from patients with Machado-Joseph disease, transgenic mice and a lentiviral-based rat model, we found an abnormal expression of endogenous autophagic markers, accumulation of autophagosomes and decreased levels of beclin-1, a crucial protein in the early nucleation step of autophagy. Lentiviral vector-mediated overexpression of beclin-1 led to stimulation of autophagic flux, mutant ataxin-3 clearance and overall neuroprotective effects in neuronal cultures and in a lentiviral-based rat model of Machado-Joseph disease. These data demonstrate that autophagy is a key degradation pathway, with beclin-1 playing a significant role in alleviating Machado-Joseph disease pathogenesis.

  1. Polyphenols purified from the Brazilian aroeira plant (Schinus terebinthifolius, Raddi) induce apoptotic and autophagic cell death of DU145 cells.

    Science.gov (United States)

    Queires, L C S; Fauvel-Lafètve, F; Terry, S; De la Taille, A; Kouyoumdjian, J C; Chopin, D K; Vacherot, F; Rodrigues, L E A; Crépin, M

    2006-01-01

    Polyphenols extracted from many plants have shown antiproliferative and antitumor activities in a wide range of carcinogenesis models. The antiproliferative effects of polyphenols purified from the Brazilian aroeira plant (Schinus terebinthifolius, Raddi) were investigated on the androgen-insensitive DU145 human prostatic carcinoma cell line. A F3 fraction purified from leaf extract inhibited the DU145 cell proliferation more than 30-fold compared to the crude extract. By flow cytometric analysis, the polyphenol fraction was demonstrated to induce G0/G1 cell growth arrest and cell apoptosis. This apoptosis was evidenced by caspase 3 stimulation in F3-treated cells as compared to crude extract treated cells. The acid phosphatase activity of lysosomes was strongly activated in the lysosomal fraction of the F3-treated DU145 cells. This lysosomal activation, together with the appearance of autophagic vacuoles, suggests that "type 2 physiological cell death" was also involved in this antiproliferative effect. HPLC analysis of this F3 fraction showed 18 different subfractions. Among these subfractions, F3-3, F3-7 and F3-13 strongly inhibited DU145 cell proliferation in a dose-dependent manner. However, the nature of these polyphenols remains unknown since only one (Isoquercitrin) of the tested pure polyphenols co-migrated with F3-13. Since lysosomotropic drugs are considered as possible regulators of lysosome activity, aroeira polyphenols could target lysosomes of prostatic cancer cells to induce autophagic cell death.

  2. Neuroprotective effects of Activin A on endoplasmic reticulum stress-mediated apoptotic and autophagic PC12 cell death

    Directory of Open Access Journals (Sweden)

    Long-xing Xue

    2017-01-01

    Full Text Available Activin A, a member of the transforming growth factor-beta superfamily, plays a neuroprotective role in multiple neurological diseases. Endoplasmic reticulum (ER stress-mediated apoptotic and autophagic cell death is implicated in a wide range of diseases, including cerebral ischemia and neurodegenerative diseases. Thapsigargin was used to induce PC12 cell death, and Activin A was used for intervention. Our results showed that Activin A significantly inhibited morphological changes in thapsigargin-induced apoptotic cells, and the expression of apoptosis-associated proteins [cleaved-caspase-12, C/EBP homologous protein (CHOP and cleaved-caspase-3] and biomarkers of autophagy (Beclin-1 and light chain 3, and downregulated the expression of thapsigargin-induced ER stress-associated proteins [inositol requiring enzyme-1 (IRE1, tumor necrosis factor receptor-associated factor 2 (TRAF2, apoptosis signal-regulating kinase 1 (ASK1, c-Jun N-terminal kinase (JNK and p38]. The inhibition of thapsigargin-induced cell death was concentration-dependent. These findings suggest that administration of Activin A protects PC12 cells against ER stress-mediated apoptotic and autophagic cell death by inhibiting the activation of the IRE1-TRAF2-ASK1-JNK/p38 cascade.

  3. Reserve Component Contribution to Imagery Intelligence

    National Research Council Canada - National Science Library

    Stafford, Ann

    2003-01-01

    .... Because raw imagery has limited value until it has been exploited, the increased volume of raw imagery demands an enhanced ability for combatant commanders and the National Imagery and Mapping Agency (NIMA...

  4. miR-34a Modulates Angiotensin II-Induced Myocardial Hypertrophy by Direct Inhibition of ATG9A Expression and Autophagic Activity

    Science.gov (United States)

    Huang, He; Ye, Jing; Pan, Wei; Zhong, Yun; Cheng, Chuanfang; You, Xiangyu; Liu, Benrong; Xiong, Longgen; Liu, Shiming

    2014-01-01

    Cardiac hypertrophy is characterized by thickening myocardium and decreasing in heart chamber volume in response to mechanical or pathological stress, but the underlying molecular mechanisms remain to be defined. This study investigated altered miRNA expression and autophagic activity in pathogenesis of cardiac hypertrophy. A rat model of myocardial hypertrophy was used and confirmed by heart morphology, induction of cardiomyocyte autophagy, altered expression of autophagy-related ATG9A, LC3 II/I and p62 proteins, and decrease in miR-34a expression. The in vitro data showed that in hypertrophic cardiomyocytes induced by Ang II, miR-34a expression was downregulated, whereas ATG9A expression was up-regulated. Moreover, miR-34a was able to bind to ATG9A 3′-UTR, but not to the mutated 3′-UTR and inhibited ATG9A protein expression and autophagic activity. The latter was evaluated by autophagy-related LC3 II/I and p62 levels, TEM, and flow cytometry in rat cardiomyocytes. In addition, ATG9A expression induced either by treatment of rat cardiomyocytes with Ang II or ATG9A cDNA transfection upregulated autophagic activity and cardiomyocyte hypertrophy in both morphology and expression of hypertrophy-related genes (i.e., ANP and β-MHC), whereas knockdown of ATG9A expression downregulated autophagic activity and cardiomyocyte hypertrophy. However, miR-34a antagonized Ang II-stimulated myocardial hypertrophy, whereas inhibition of miR-34a expression aggravated Ang II-stimulated myocardial hypertrophy (such as cardiomyocyte hypertrophy-related ANP and β-MHC expression and cardiomyocyte morphology). This study indicates that miR-34a plays a role in regulation of Ang II-induced cardiomyocyte hypertrophy by inhibition of ATG9A expression and autophagic activity. PMID:24728149

  5. MicroRNA-20a inhibits autophagic process by targeting ATG7 and ATG16L1 and favors mycobacterial survival in macrophage cells.

    Directory of Open Access Journals (Sweden)

    Le Guo

    2016-10-01

    Full Text Available Autophagy plays important roles in the host immune response against mycobacterial infection. Mycobacterium tuberculosis (M. tuberculosis can live in macrophages owing to its ability to evade attacks by regulating autophagic response. MicroRNAs (miRNAs are small noncoding, endogenously encoded RNA which plays critical roles in precise regulation of macrophage functions. Whether miRNAs specifically influence the activation of macrophage autophagy during M. tuberculosis infection are largely unknown. In this study, we demonstrate that BCG infection of macrophages resulted in enhanced expression of miRNA-20a, which inhibits autophagic process by targeting ATG7 and ATG16L1 and promotes BCG survival in macrophages. Forced overexpression of miR-20a decreased the expression levels of LC3-II and the number of LC3 puncta in macrophages, and promoted BCG survival in macrophages, while transfection with miR-20a inhibitor had the opposite effect. Moreover, the inhibitory effect of miR-20a on autophagy was further confimed by transmission electron microscopy (TEM analysis. Quantification of autophagosomes per cellular cross-section revealed a significant reduction upon transfection with miR-20a mimic, but transfection with miR-20a inhibitor increased the number of autophagosomes per cellular cross-section. Moreover, silencing of ATG7 significantly inhibited autophagic response, and transfection with ATG7 siRNA plus miR-20a mimic could further decrease autophagic response. Collectively, our data reveal that miR-20a inhibits autophagic response and promotes BCG survival in macrophages by targeting ATG7 and ATG16L1, which may have implications for a better understanding of pathogenesis of M. tuberculosis infection.

  6. microRNA-20a Inhibits Autophagic Process by Targeting ATG7 and ATG16L1 and Favors Mycobacterial Survival in Macrophage Cells.

    Science.gov (United States)

    Guo, Le; Zhao, Jin; Qu, Yuliang; Yin, Runting; Gao, Qian; Ding, Shuqin; Zhang, Ying; Wei, Jun; Xu, Guangxian

    2016-01-01

    Autophagy plays important roles in the host immune response against mycobacterial infection. Mycobacterium tuberculosis ( M. tuberculosis ) can live in macrophages owing to its ability to evade attacks by regulating autophagic response. MicroRNAs (miRNAs) are small noncoding, endogenously encoded RNA which plays critical roles in precise regulation of macrophage functions. Whether miRNAs specifically influence the activation of macrophage autophagy during M. tuberculosis infection are largely unknown. In this study, we demonstrate that BCG infection of macrophages resulted in enhanced expression of miRNA-20a, which inhibits autophagic process by targeting ATG7 and ATG16L1 and promotes BCG survival in macrophages. Forced overexpression of miR-20a decreased the expression levels of LC3-II and the number of LC3 puncta in macrophages, and promoted BCG survival in macrophages, while transfection with miR-20a inhibitor had the opposite effect. Moreover, the inhibitory effect of miR-20a on autophagy was further confirmed by transmission electron microscopy (TEM) analysis. Quantification of autophagosomes per cellular cross-section revealed a significant reduction upon transfection with miR-20a mimic, but transfection with miR-20a inhibitor increased the number of autophagosomes per cellular cross-section. Moreover, silencing of ATG7 significantly inhibited autophagic response, and transfection with ATG7 siRNA plus miR-20a mimic could further decrease autophagic response. Collectively, our data reveal that miR-20a inhibits autophagic response and promotes BCG survival in macrophages by targeting ATG7 and ATG16L1, which may have implications for a better understanding of pathogenesis of M. tuberculosis infection.

  7. In vivo effect of an antilipolytic drug (3,5'-dimethylpyrazole) on autophagic proteolysis and autophagy-related gene expression in rat liver

    International Nuclear Information System (INIS)

    Donati, Alessio; Ventruti, Annamaria; Cavallini, Gabriella; Masini, Matilde; Vittorini, Simona; Chantret, Isabelle; Codogno, Patrice; Bergamini, Ettore

    2008-01-01

    Autophagy is an intracellular pathway induced by starvation, inhibited by nutrients, that is responsible for degradation of long-lived proteins and altered cell organelles. This process is involved in cell maintenance could be induced by antilipolytic drugs and may have anti-aging effects [A. Donati, The involvement of macroautophagy in aging and anti-aging interventions, Mol. Aspects Med. 27 (2006) 455-470]. We analyzed the effect of an intraperitoneal injection of an antilipolytic agent (3,5'-dimethylpyrazole, DMP, 12 mg/kg b.w.), that mimics nutrient shortage on autophagy and expression of autophagic genes in the liver of male 3-month-old Sprague-Dawley albino rats. Autophagy was evaluated by observing electron micrographs of the liver autophagosomal compartment and by monitoring protein degradation assessed by the release of valine into the bloodstream. LC3 gene expression, whose product is one of the best known markers of autophagy, was also monitored. As expected, DMP decreased the plasma levels of free fatty acids, glucose, and insulin and increased autophagic vacuoles and proteolysis. DMP treatment caused an increase in the expression of the LC3 gene although this occurred later than the induction of authophagic proteolysis caused by DMP. Glucose treatment rescued the effects caused by DMP on glucose and insulin plasma levels and negatively affected the rate of autophagic proteolysis, but did not suppress the positive regulatory effect on LC3 mRNA levels. In conclusion, antilipolytic drugs may induce both autophagic proteolysis and higher expression of an autophagy-related gene and the effect on autophagy gene expression might not be secondary to the stimulation of autophagic proteolysis

  8. Staurosporine-induced cell death in Tetrahymena thermophila has mixed characteristics of both apoptotic and autophagic degeneration

    DEFF Research Database (Denmark)

    Christensen, S T; Chemnitz, J; Straarup, E M

    1998-01-01

    phosphorylation of the PKC-specific substrate, myelin basic protein fragment 4-14. Our results show that cell death in the presence of staurosporine is associated with morphological and ultrastructural changes similar to both apoptosis and autophagic degeneration, but these in turn can be postponed or prevented...... by 8-bromo-cyclic GMP, protoporphyrin IX, hemin or actinomycin D, although phorbol ester and insulin were ineffective. The results support the notion that staurosporine-induced cell death is an active process, associated with and/or requiring de novo RNA synthesis.......Staurosporine blocks signal transduction associated with cell survival, proliferation and chemosensory behaviour in the ciliated protozoan, Tetrahymena thermophila. Staurosporine inhibits cell proliferation and in vivo protein phosphorylation induced by phorbol ester. It also reduces the in vitro...

  9. Paraquat, but not maneb, induces synucleinopathy and tauopathy in striata of mice through inhibition of proteasomal and autophagic pathways.

    Directory of Open Access Journals (Sweden)

    Jonathan Wills

    Full Text Available SNCA and MAPT genes and environmental factors are important risk factors of Parkinson's disease [PD], the second-most common neurodegenerative disease. The agrichemicals maneb and paraquat selectively target dopaminergic neurons, leading to parkinsonism, through ill-defined mechanisms. In the current studies we have analyzed the ability of maneb and paraquat, separately and together, to induce synucleinopathy and tauopathy in wild type mice. Maneb was ineffective in increasing α-synuclein [α-Syn] or p-Tau levels. By contrast, paraquat treatment of mice resulted in robust accumulation of α-Syn and hyperphosphorylation of Tau in striata, through activation of p-GSK-3β, a major Tau kinase. Co-treatment with maneb did not enhance the effects of paraquat. Increased hyperacetylation of α-tubulin was observed in paraquat-treated mice, suggesting cytoskeleton remodeling. Paraquat, but not maneb, inhibited soluble proteasomal activity on a peptide substrate but this was not associated with a decreased expression of 26S proteasome subunits. Both paraquat and maneb treatments increased levels of the autophagy inhibitor, mammalian target of rapamycin, mTOR, suggesting impaired axonal autophagy, despite increases in certain autophagic proteins, such as beclin 1 and Agt12. Autophagic flux was also impaired, as ratios of LC3 II to LC3 I were reduced in treated animals. Increased mTOR was also observed in postmortem human PD striata, where there was a reduction in the LC3 II to LC3 I ratio. Heat shock proteins were either increased or unchanged upon paraquat-treatment suggesting that chaperone-mediated autophagy is not hampered by the agrichemicals. These studies provide novel insight into the mechanisms of action of these agrichemicals, which indicate that paraquat is much more toxic than maneb, via its inhibitory effects on proteasomes and autophagy, which lead to accumulation of α-Syn and p-Tau.

  10. Mild hyperthermia enhances sensitivity of gastric cancer cells to chemotherapy through reactive oxygen species-induced autophagic death.

    Science.gov (United States)

    Ba, Ming-Chen; Long, Hui; Cui, Shu-Zhong; Gong, Yuan-Feng; Yan, Zhao-Fei; Wang, Shuai; Wu, Yin-Bing

    2017-06-01

    Mild hyperthermia enhances anti-cancer effects of chemotherapy, but the precise biochemical mechanisms involved are not clear. This study was carried out to investigate whether mild hyperthermia sensitizes gastric cancer cells to chemotherapy through reactive oxygen species-induced autophagic death. In total, 20 BABL/c mice of MKN-45 human gastric cancer tumor model were divided into hyperthermia + chemotherapy group, hyperthermia group, chemotherapy group, N-acetyl-L-cysteine group, and mock group. Reactive oxygen species production and expression of autophagy-related genes Beclin1, LC3B, and mammalian target of rapamycin were determined. The relationships between tumor growth regression, expression of autophagy-related genes, and reactive oxygen species production were evaluated. Tumor size and wet weight of hyperthermia + chemotherapy group was significantly decreased relative to values from hyperthermia group, chemotherapy group, N-acetyl-L-cysteine group, and mock group ( F = 6.92, p Reactive oxygen species production was significantly higher in hyperthermia + chemotherapy group than in hyperthermia, chemotherapy, and mock groups. The expression levels of Beclin1 and LC3B were significantly higher, while those of mammalian target of rapamycin were significantly lower in hyperthermia + chemotherapy group than in hyperthermia, chemotherapy, and mock groups. Tumor growth regression was consistent with changes in reactive oxygen species production and expression of autophagy-related genes. N-acetyl-L-cysteine inhibited changes in the expression of the autophagy-related genes and also suppressed reactive oxygen species production and tumor growth. Hyperthermia + chemotherapy increase expression of autophagy-related genes Beclin1 and LC3B, decrease expression of mammalian target of rapamycin, and concomitantly increase reactive oxygen species generation. These results strongly indicate that mild hyperthermia enhances sensitivity of gastric

  11. In Vivo Evidence for Lysosome Depletion and Impaired Autophagic Clearance in Hereditary Spastic Paraplegia Type SPG11.

    Science.gov (United States)

    Varga, Rita-Eva; Khundadze, Mukhran; Damme, Markus; Nietzsche, Sandor; Hoffmann, Birgit; Stauber, Tobias; Koch, Nicole; Hennings, J Christopher; Franzka, Patricia; Huebner, Antje K; Kessels, Michael M; Biskup, Christoph; Jentsch, Thomas J; Qualmann, Britta; Braulke, Thomas; Kurth, Ingo; Beetz, Christian; Hübner, Christian A

    2015-08-01

    Hereditary spastic paraplegia (HSP) is characterized by a dying back degeneration of corticospinal axons which leads to progressive weakness and spasticity of the legs. SPG11 is the most common autosomal-recessive form of HSPs and is caused by mutations in SPG11. A recent in vitro study suggested that Spatacsin, the respective gene product, is needed for the recycling of lysosomes from autolysosomes, a process known as autophagic lysosome reformation. The relevance of this observation for hereditary spastic paraplegia, however, has remained unclear. Here, we report that disruption of Spatacsin in mice indeed causes hereditary spastic paraplegia-like phenotypes with loss of cortical neurons and Purkinje cells. Degenerating neurons accumulate autofluorescent material, which stains for the lysosomal protein Lamp1 and for p62, a marker of substrate destined to be degraded by autophagy, and hence appears to be related to autolysosomes. Supporting a more generalized defect of autophagy, levels of lipidated LC3 are increased in Spatacsin knockout mouse embryonic fibrobasts (MEFs). Though distinct parameters of lysosomal function like processing of cathepsin D and lysosomal pH are preserved, lysosome numbers are reduced in knockout MEFs and the recovery of lysosomes during sustained starvation impaired consistent with a defect of autophagic lysosome reformation. Because lysosomes are reduced in cortical neurons and Purkinje cells in vivo, we propose that the decreased number of lysosomes available for fusion with autophagosomes impairs autolysosomal clearance, results in the accumulation of undegraded material and finally causes death of particularly sensitive neurons like cortical motoneurons and Purkinje cells in knockout mice.

  12. Benzo[a]pyrene Induces Autophagic and Pyroptotic Death Simultaneously in HL-7702 Human Normal Liver Cells.

    Science.gov (United States)

    Yuan, Li; Liu, Junyi; Deng, Hong; Gao, Chunxia

    2017-11-08

    As a common polycyclic aromatic hydrocarbon compound, benzo[a]pyrene (BaP) is readily produced in processing of oil and fatty foods. It is not only a strong carcinogen but also a substance with strong immunotoxicity and reproduction toxicity. Autophagy and pyroptosis are two types of programmed cell death. Whether or not BaP damages body tissues via autophagy or pyroptosis remains unknown. The present study investigated the effects of BaP on autophagy and pyroptosis in HL-7702 cells. The results showed that BaP induced cell death in HL-7702 cells enhanced the intracellular levels of ROS and arrested the cell cycle at the S phase. Additionally, BaP resulted in cell death through autophagy and pyroptosis. Compared with the BaP group, the autophagy inhibitor 3-MA significantly (p < 0.01) inhibited the release of LDH by 70.53% ± 0.46 and NO by 50.36% ± 0.80, the increase of electrical conductivity by 12.08% ± 0.55, and the expressions of pyroptotic marker proteins (Caspase-1, Cox-2, IL-1β, IL-18). The pyroptosis inhibitor Ac-YVAD-CM also notably (p < 0.01) blocked BaP-induced autophagic cell death characterized by the increase of autophagic vacuoles and overexpression of Beclin-1 and LC3-II. In conclusion, BaP led to injury by inducing autophagy and pyroptosis simultaneously, the two of which coexisted and promoted each other in HL-7702 cells.

  13. HEPES activates a MiT/TFE-dependent lysosomal-autophagic gene network in cultured cells: A call for caution.

    Science.gov (United States)

    Tol, Marc J; van der Lienden, Martijn J C; Gabriel, Tanit L; Hagen, Jacob J; Scheij, Saskia; Veenendaal, Tineke; Klumperman, Judith; Donker-Koopman, Wilma E; Verhoeven, Arthur J; Overkleeft, Hermen; Aerts, Johannes M; Argmann, Carmen A; van Eijk, Marco

    2018-02-17

    In recent years, the lysosome has emerged as a highly dynamic, transcriptionally regulated organelle that is integral to nutrient-sensing and metabolic rewiring. This is coordinated by a lysosome-to-nucleus signaling nexus in which MTORC1 controls the subcellular distribution of the microphthalmia-transcription factor E (MiT/TFE) family of "master lysosomal regulators". Yet, despite the importance of the lysosome in cellular metabolism, the impact of traditional in vitro culture media on lysosomal dynamics and/or MiT/TFE localization has not been fully appreciated. Here, we identify HEPES, a chemical buffering agent that is broadly applied in cell culture, as a potent inducer of lysosome biogenesis. Supplementation of HEPES to cell growth media is sufficient to decouple the MiT/TFE family members-TFEB, TFE3 and MITF-from regulatory mechanisms that control their cytosolic retention. Increased MiT/TFE nuclear import in turn drives the expression of a global network of lysosomal-autophagic and innate host-immune response genes, altering lysosomal dynamics, proteolytic capacity, autophagic flux, and inflammatory signaling. In addition, siRNA-mediated MiT/TFE knockdown effectively blunted HEPES-induced lysosome biogenesis and gene expression profiles. Mechanistically, we show that MiT/TFE activation in response to HEPES requires its macropinocytic ingestion and aberrant lysosomal storage/pH, but is independent of MTORC1 signaling. Altogether, our data underscore the cautionary use of chemical buffering agents in cell culture media due to their potentially confounding effects on experimental results.

  14. Alpha-hemolysin is required for the activation of the autophagic pathway in Staphylococcus aureus-infected cells.

    Science.gov (United States)

    Mestre, María Belén; Fader, Claudio M; Sola, Claudia; Colombo, María Isabel

    2010-01-01

    Staphylococcus aureus is a pathogen that causes serious infectious diseases eventually leading to septic and toxic shock. Classically S. aureus has been considered an extracellular pathogen, but cumulative evidence indicates that it invades cells and replicates intracellularly leading to staphylococcal persistence and chronic disease. It has been previously shown that this pathogen localizes to LC3-labeled compartments and subverts the autophagy pathway. One of the key features of S. aureus infection is the production of a series of virulence factors, including secreted enzymes and toxins. In the present report we present evidence that the pore-forming toxin alpha-hemolysin (Hla) is a S. aureus secreted factor which participates in the activation of the autophagic pathway. In addition, our results indicate that although the toxin elicits an autophagic response this pathway is dysfunctional as indicated by the accumulation of the LC3-II form in cell lysates obtained from intoxicated cells. In addition, not only the purified Hla toxin but also the toxin-secreting pathogen prevented the maturation of autophagosomes. Interestingly, in cells infected with the wild-type strain of S. aureus the bacteria-containing compartments which recruited LC3 onto the limiting membrane did not accumulate the acidotropic probe LysoTracker. In contrast, those phagosomes containing the Hla(-) mutant (unable to produce the toxin) localized in an acidic compartment unlabeled by LC3. These results suggest that the LC3 protein is recruited only to those damaged vacuoles (i.e., perforated by the toxin), perhaps as an attempt to protect the cells. Furthermore, we have demonstrated that the toxin-dependent activation of autophagy (although it is regulated by calcium and requires Atg5) is independent of both PI3Kinase activity and Beclin 1 suggesting the involvement of a non-canonical autophagy pathway.

  15. SET overexpression in HEK293 cells regulates mitochondrial uncoupling proteins levels within a mitochondrial fission/reduced autophagic flux scenario

    Energy Technology Data Exchange (ETDEWEB)

    Almeida, Luciana O.; Goto, Renata N. [Department of Clinical Analyses, Toxicology and Food Sciences, School of Pharmaceutical Sciences of Ribeirão Preto, University of São Paulo, Ribeirão Preto, SP (Brazil); Neto, Marinaldo P.C. [Department of Physics and Chemistry, School of Pharmaceutical Sciences of Ribeirão Preto, University of São Paulo, Ribeirão Preto, SP (Brazil); Sousa, Lucas O. [Department of Clinical Analyses, Toxicology and Food Sciences, School of Pharmaceutical Sciences of Ribeirão Preto, University of São Paulo, Ribeirão Preto, SP (Brazil); Curti, Carlos [Department of Physics and Chemistry, School of Pharmaceutical Sciences of Ribeirão Preto, University of São Paulo, Ribeirão Preto, SP (Brazil); Leopoldino, Andréia M., E-mail: andreiaml@usp.br [Department of Clinical Analyses, Toxicology and Food Sciences, School of Pharmaceutical Sciences of Ribeirão Preto, University of São Paulo, Ribeirão Preto, SP (Brazil)

    2015-03-06

    We hypothesized that SET, a protein accumulated in some cancer types and Alzheimer disease, is involved in cell death through mitochondrial mechanisms. We addressed the mRNA and protein levels of the mitochondrial uncoupling proteins UCP1, UCP2 and UCP3 (S and L isoforms) by quantitative real-time PCR and immunofluorescence as well as other mitochondrial involvements, in HEK293 cells overexpressing the SET protein (HEK293/SET), either in the presence or absence of oxidative stress induced by the pro-oxidant t-butyl hydroperoxide (t-BHP). SET overexpression in HEK293 cells decreased UCP1 and increased UCP2 and UCP3 (S/L) mRNA and protein levels, whilst also preventing lipid peroxidation and decreasing the content of cellular ATP. SET overexpression also (i) decreased the area of mitochondria and increased the number of organelles and lysosomes, (ii) increased mitochondrial fission, as demonstrated by increased FIS1 mRNA and FIS-1 protein levels, an apparent accumulation of DRP-1 protein, and an increase in the VDAC protein level, and (iii) reduced autophagic flux, as demonstrated by a decrease in LC3B lipidation (LC3B-II) in the presence of chloroquine. Therefore, SET overexpression in HEK293 cells promotes mitochondrial fission and reduces autophagic flux in apparent association with up-regulation of UCP2 and UCP3; this implies a potential involvement in cellular processes that are deregulated such as in Alzheimer's disease and cancer. - Highlights: • SET, UCPs and autophagy prevention are correlated. • SET action has mitochondrial involvement. • UCP2/3 may reduce ROS and prevent autophagy. • SET protects cell from ROS via UCP2/3.

  16. Paraquat, but Not Maneb, Induces Synucleinopathy and Tauopathy in Striata of Mice through Inhibition of Proteasomal and Autophagic Pathways

    Science.gov (United States)

    Wills, Jonathan; Credle, Joel; Oaks, Adam W.; Duka, Valeriy; Lee, Jae-Hoon; Jones, Jessica; Sidhu, Anita

    2012-01-01

    SNCA and MAPT genes and environmental factors are important risk factors of Parkinson's disease [PD], the second-most common neurodegenerative disease. The agrichemicals maneb and paraquat selectively target dopaminergic neurons, leading to parkinsonism, through ill-defined mechanisms. In the current studies we have analyzed the ability of maneb and paraquat, separately and together, to induce synucleinopathy and tauopathy in wild type mice. Maneb was ineffective in increasing α-synuclein [α-Syn] or p-Tau levels. By contrast, paraquat treatment of mice resulted in robust accumulation of α-Syn and hyperphosphorylation of Tau in striata, through activation of p-GSK-3β, a major Tau kinase. Co-treatment with maneb did not enhance the effects of paraquat. Increased hyperacetylation of α-tubulin was observed in paraquat-treated mice, suggesting cytoskeleton remodeling. Paraquat, but not maneb, inhibited soluble proteasomal activity on a peptide substrate but this was not associated with a decreased expression of 26S proteasome subunits. Both paraquat and maneb treatments increased levels of the autophagy inhibitor, mammalian target of rapamycin, mTOR, suggesting impaired axonal autophagy, despite increases in certain autophagic proteins, such as beclin 1 and Agt12. Autophagic flux was also impaired, as ratios of LC3 II to LC3 I were reduced in treated animals. Increased mTOR was also observed in postmortem human PD striata, where there was a reduction in the LC3 II to LC3 I ratio. Heat shock proteins were either increased or unchanged upon paraquat-treatment suggesting that chaperone-mediated autophagy is not hampered by the agrichemicals. These studies provide novel insight into the mechanisms of action of these agrichemicals, which indicate that paraquat is much more toxic than maneb, via its inhibitory effects on proteasomes and autophagy, which lead to accumulation of α-Syn and p-Tau. PMID:22292029

  17. Identification of novel autophagic Radix Polygalae fraction by cell membrane chromatography and UHPLC-(Q)TOF-MS for degradation of neurodegenerative disease proteins

    OpenAIRE

    An-Guo Wu; Vincent Kam-Wai Wong; Wu Zeng; Liang Liu; Betty Yuen-Kwan Law

    2015-01-01

    With its traditional use in relieving insomnia and anxiety, our previous study has identified onjisaponin B from Radix Polygalae (RP), as a novel autophagic enhancer with potential neuroprotective effects. In current study, we have further identified a novel active fraction from RP, contains 17 major triterpenoid saponins including the onjisaponin B, by the combinational use of cell membrane chromatography (CMC) and ultra-performance liquid chromatography coupled to (quadrupole) time-of-fligh...

  18. Novel monofunctional platinum (II) complex Mono-Pt induces apoptosis-independent autophagic cell death in human ovarian carcinoma cells, distinct from cisplatin.

    Science.gov (United States)

    Guo, Wen-Jie; Zhang, Yang-Miao; Zhang, Li; Huang, Bin; Tao, Fei-Fei; Chen, Wei; Guo, Zi-Jian; Xu, Qiang; Sun, Yang

    2013-07-01

    Failure to engage apoptosis appears to be a leading mechanism of resistance to traditional platinum drugs in patients with ovarian cancer. Therefore, an alternative strategy to induce cell death is needed for the chemotherapy of this apoptosis-resistant cancer. Here we report that autophagic cell death, distinct from cisplatin-induced apoptosis, is triggered by a novel monofunctional platinum (II) complex named Mono-Pt in human ovarian carcinoma cells. Mono-Pt-induced cell death has the following features: cytoplasmic vacuolation, caspase-independent, no nuclear fragmentation or chromatin condensation, and no apoptotic bodies. These characteristics integrally indicated that Mono-Pt, rather than cisplatin, initiated a nonapoptotic cell death in Caov-3 ovarian carcinoma cells. Furthermore, incubation of the cells with Mono-Pt but not with cisplatin produced an increasing punctate distribution of microtubule-associated protein 1 light chain 3 (LC3), and an increasing ratio of LC3-II to LC3-I. Mono-Pt also caused the formation of autophagic vacuoles as revealed by monodansylcadaverine staining and transmission electron microscopy. In addition, Mono-Pt-induced cell death was significantly inhibited by the knockdown of either BECN1 or ATG7 gene expression, or by autophagy inhibitors 3-methyladenine, chloroquine and bafilomycin A 1. Moreover, the effect of Mono-Pt involved the AKT1-MTOR-RPS6KB1 pathway and MAPK1 (ERK2)/MAPK3 (ERK1) signaling, since the MTOR inhibitor rapamycin increased, while the MAPK1/3 inhibitor U0126 decreased Mono-Pt-induced autophagic cell death. Taken together, our results suggest that Mono-Pt exerts anticancer effect via autophagic cell death in apoptosis-resistant ovarian cancer. These findings lead to increased options for anticancer platinum drugs to induce cell death in cancer.

  19. Other components

    International Nuclear Information System (INIS)

    Anon.

    1993-01-01

    This chapter includes descriptions of electronic and mechanical components which do not merit a chapter to themselves. Other hardware requires mention because of particularly high tolerance or intolerance of exposure to radiation. A more systematic analysis of radiation responses of structures which are definable by material was given in section 3.8. The components discussed here are field effect transistors, transducers, temperature sensors, magnetic components, superconductors, mechanical sensors, and miscellaneous electronic components

  20. Reduced cathepsins B and D cause impaired autophagic degradation that can be almost completely restored by overexpression of these two proteases in Sap C-deficient fibroblasts.

    Science.gov (United States)

    Tatti, Massimo; Motta, Marialetizia; Di Bartolomeo, Sabrina; Scarpa, Susanna; Cianfanelli, Valentina; Cecconi, Francesco; Salvioli, Rosa

    2012-12-01

    Saposin (Sap) C deficiency, a rare variant form of Gaucher disease, is due to mutations in the Sap C coding region of the prosaposin (PSAP) gene. Sap C is required as an activator of the lysosomal enzyme glucosylceramidase (GCase), which catalyzes glucosylceramide (GC) degradation. Deficit of either GCase or Sap C leads to the accumulation of undegraded GC and other lipids in lysosomes of monocyte/macrophage lineage. Recently, we reported that Sap C mutations affecting a cysteine residue result in increased autophagy. Here, we characterized the basis for the autophagic dysfunction. We analyzed Sap C-deficient and GCase-deficient fibroblasts and observed that autophagic disturbance was only associated with lack of Sap C. By a combined fluorescence microscopy and biochemical studies, we demonstrated that the accumulation of autophagosomes in Sap C-deficient fibroblasts is not due to enhanced autophagosome formation but to delayed degradation of autolysosomes caused, in part, to decreased amount and reduced enzymatic activity of cathepsins B and D. On the contrary, in GCase-deficient fibroblasts, the protein level and enzymatic activity of cathepsin D were comparable with control fibroblasts, whereas those of cathepsin B were almost doubled. Moreover, the enhanced expression of both these lysosomal proteases in Sap C-deficient fibroblasts resulted in close to functional autophagic degradation. Our data provide a novel example of altered autophagy as secondary event resulting from insufficient lysosomal function.

  1. Asparagine slows down the breakdown of storage lipid and degradation of autophagic bodies in sugar-starved embryo axes of germinating lupin seeds.

    Science.gov (United States)

    Borek, Sławomir; Paluch-Lubawa, Ewelina; Pukacka, Stanisława; Pietrowska-Borek, Małgorzata; Ratajczak, Lech

    2017-02-01

    The research was conducted on embryo axes of yellow lupin (Lupinus luteus L.), white lupin (Lupinus albus L.) and Andean lupin (Lupinus mutabilis Sweet), which were isolated from imbibed seeds and cultured for 96h in vitro under different conditions of carbon and nitrogen nutrition. Isolated embryo axes were fed with 60mM sucrose or were sugar-starved. The effect of 35mM asparagine (a central amino acid in the metabolism of germinating lupin seeds) and 35mM nitrate (used as an inorganic kind of nitrogen) on growth, storage lipid breakdown and autophagy was investigated. The sugar-starved isolated embryo axes contained more total lipid than axes fed with sucrose, and the content of this storage compound was even higher in sugar-starved isolated embryo axes fed with asparagine. Ultrastructural observations showed that asparagine significantly slowed down decomposition of autophagic bodies, and this allowed detailed analysis of their content. We found peroxisomes inside autophagic bodies in cells of sugar-starved Andean lupin embryo axes fed with asparagine, which led us to conclude that peroxisomes may be degraded during autophagy in sugar-starved isolated lupin embryo axes. One reason for the slower degradation of autophagic bodies was the markedly lower lipolytic activity in axes fed with asparagine. Copyright © 2016 The Author(s). Published by Elsevier GmbH.. All rights reserved.

  2. The integral membrane protein ITM2A, a transcriptional target of PKA-CREB, regulates autophagic flux via interaction with the vacuolar ATPase.

    Science.gov (United States)

    Namkoong, Sim; Lee, Kang Il; Lee, Jin I; Park, Rackhyun; Lee, Eun-Ju; Jang, Ik-Soon; Park, Junsoo

    2015-01-01

    The PKA-CREB signaling pathway is involved in many cellular processes including autophagy. Recent studies demonstrated that PKA-CREB inhibits autophagy in yeast; however, the role of PKA-CREB signaling in mammalian cell autophagy has not been fully characterized. Here, we report that the integral membrane protein ITM2A expression is positively regulated by PKA-CREB signaling and ITM2A expression interferes with autophagic flux by interacting with vacuolar ATPase (v-ATPase). The ITM2A promoter contains a CRE element, and mutation at the CRE consensus site decreases the promoter activity. Forskolin treatment and PKA expression activate the ITM2A promoter confirming that ITM2A expression is dependent on the PKA-CREB pathway. ITM2A expression results in the accumulation of autophagosomes and interferes with autolysosome formation by blocking autophagic flux. We demonstrated that ITM2A physically interacts with v-ATPase and inhibits lysosomal function. These results support the notion that PKA-CREB signaling pathway regulates ITM2A expression, which negatively regulates autophagic flux by interfering with the function of v-ATPase.

  3. Phosphorylation of p62 by AMP-activated protein kinase mediates autophagic cell death in adult hippocampal neural stem cells.

    Science.gov (United States)

    Ha, Shinwon; Jeong, Seol-Hwa; Yi, Kyungrim; Chung, Kyung Min; Hong, Caroline Jeeyeon; Kim, Seong Who; Kim, Eun-Kyoung; Yu, Seong-Woon

    2017-08-18

    In the adult brain, programmed death of neural stem cells is considered to be critical for tissue homeostasis and cognitive function and is dysregulated in neurodegeneration. Previously, we have reported that adult rat hippocampal neural (HCN) stem cells undergo autophagic cell death (ACD) following insulin withdrawal. Because the apoptotic capability of the HCN cells was intact, our findings suggested activation of unique molecular mechanisms linking insulin withdrawal to ACD rather than apoptosis. Here, we report that phosphorylation of autophagy-associated protein p62 by AMP-activated protein kinase (AMPK) drives ACD and mitophagy in HCN cells. Pharmacological inhibition of AMPK or genetic ablation of the AMPK α2 subunit by clustered regularly interspaced short palindromic repeats (CRISPR)/Cas9 genome editing suppressed ACD, whereas AMPK activation promoted ACD in insulin-deprived HCN cells. We found that following insulin withdrawal AMPK phosphorylated p62 at a novel site, Ser-293/Ser-294 (in rat and human p62, respectively). Phosphorylated p62 translocated to mitochondria and induced mitophagy and ACD. Interestingly, p62 phosphorylation at Ser-293 was not required for staurosporine-induced apoptosis in HCN cells. To the best of our knowledge, this is the first report on the direct phosphorylation of p62 by AMPK. Our data suggest that AMPK-mediated p62 phosphorylation is an ACD-specific signaling event and provide novel mechanistic insight into the molecular mechanisms in ACD. © 2017 by The American Society for Biochemistry and Molecular Biology, Inc.

  4. Paeoniflorin protects HUVECs from AGE-BSA-induced injury via an autophagic pathway by acting on the RAGE.

    Science.gov (United States)

    Chen, Yufang; Du, Xing; Zhou, Yande; Zhang, Yanlin; Yang, Yaping; Liu, Zhihua; Liu, Chunfeng; Xie, Ying

    2015-01-01

    The aim of our study was to investigate the protective effects of Paeoniflorin (PF) against injury induced by AGE-modified bovine serum albumin (AGE-BSA) in human umbilical vein endothelial cells (HUVECs), and to examine the underlying mechanisms of these effects. A 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl tetrazolium bromide (MTT) assay was used to determine cell viability. Protein expression levels were determined by western blotting. For function-blocking experiments, we used small interfering RNA molecules (siRNA) for function-blocking experiments. At 6 h, we found that 100 μg/mL AGE-BSA reduced the viability of HUVECs. However, pretreatment with PF restored cell viability in a dose-dependent manner. AGE-BSA increased the levels of microtubule-associated protein light chain 3-II (LC3-II) and the receptor for advanced glycation end products (RAGE). Expression of p62 protein was also increased, but not at a statistically significant level. Pretreatment with PF further increased levels of LC3-II and RAGE, but reduced the expression of p62. In cells transfected with Atg5 and RAGE siRNA, cell viability and expression of LC3-II decreased in both the AGE-BSA and PF + AGE-BSA treatments. PF can protect HUVECs from AGE-BSA-induced injury by upregulating autophagy and promoting the completion of autophagy flux. RAGE plays an important role in this autophagic protection effect.

  5. Andrographolide Induces Autophagic Cell Death and Inhibits Invasion and Metastasis of Human Osteosarcoma Cells in An Autophagy-Dependent Manner

    Directory of Open Access Journals (Sweden)

    Ying Liu

    2017-11-01

    Full Text Available Background/Aims: Osteosarcoma (OS is the most common primary malignant tumor of bone tissue. Although treatment effectiveness has improved, the OS survival rate has fluctuated in recent years. Andrographolide (AG has been reported to have antitumor activity against a variety of tumors. Our aim was to investigate the effects and potential mechanisms of AG in human osteosarcoma. Methods: Cell viability and morphological changes were assessed by MTT and live/dead assays. Apoptosis was detected using Annexin V-FITC/PI double staining, DAPI, and caspase-3 assays. Autophagy was detected with mRFP-GFP-LC3 adenovirus transfection and western blot. Cell migration and invasion were detected by wound healing assay and Transwell® experiments. Results: AG dose-dependently reduced the viability of osteosarcoma cells. No increase in apoptosis was detected in AG-treated human OS MG-63 and U-2OS cells, and the pan-caspase inhibitor z-VAD did not attenuate AG-induced cell death. However, AG induced autophagy by suppressing PI3K/Akt/mTOR and enhancing JNK signaling pathways. 3-MA and Beclin-1 siRNA could reverse the cytotoxic effects of AG. In addition, AG inhibited the invasion and metastasis of OS, and this effect could be reversed with Beclin-1 siRNA. Conclusion: AG inhibits viability and induces autophagic death in OS cells. AG-induced autophagy inhibits the invasion and metastasis of OS.

  6. Andrographolide Induces Autophagic Cell Death and Inhibits Invasion and Metastasis of Human Osteosarcoma Cells in An Autophagy-Dependent Manner.

    Science.gov (United States)

    Liu, Ying; Zhang, Yan; Zou, Jilong; Yan, Lixin; Yu, Xiufeng; Lu, Peng; Wu, Xiaomeng; Li, Qiaozhi; Gu, Rui; Zhu, Daling

    2017-01-01

    Osteosarcoma (OS) is the most common primary malignant tumor of bone tissue. Although treatment effectiveness has improved, the OS survival rate has fluctuated in recent years. Andrographolide (AG) has been reported to have antitumor activity against a variety of tumors. Our aim was to investigate the effects and potential mechanisms of AG in human osteosarcoma. Cell viability and morphological changes were assessed by MTT and live/dead assays. Apoptosis was detected using Annexin V-FITC/PI double staining, DAPI, and caspase-3 assays. Autophagy was detected with mRFP-GFP-LC3 adenovirus transfection and western blot. Cell migration and invasion were detected by wound healing assay and Transwell® experiments. AG dose-dependently reduced the viability of osteosarcoma cells. No increase in apoptosis was detected in AG-treated human OS MG-63 and U-2OS cells, and the pan-caspase inhibitor z-VAD did not attenuate AG-induced cell death. However, AG induced autophagy by suppressing PI3K/Akt/mTOR and enhancing JNK signaling pathways. 3-MA and Beclin-1 siRNA could reverse the cytotoxic effects of AG. In addition, AG inhibited the invasion and metastasis of OS, and this effect could be reversed with Beclin-1 siRNA. AG inhibits viability and induces autophagic death in OS cells. AG-induced autophagy inhibits the invasion and metastasis of OS. © 2017 The Author(s). Published by S. Karger AG, Basel.

  7. Autophagic dysfunction in a lysosomal storage disorder due to impaired proteolysis

    OpenAIRE

    Elrick, Matthew J.; Lieberman, Andrew P.

    2013-01-01

    Alterations in macroautophagy (hereafter referred to as “autophagy”) are a common feature of lysosomal storage disorders, and have been hypothesized to play a major role in the pathogenesis of these diseases. We have recently reported multiple defects in autophagy contributing to the lysosomal storage disorder Niemann-Pick type C (NPC). These include increased formation of autophagosomes, slowed turnover of autophagosomes secondary to impaired lysosomal proteolysis, and delivery of stored lip...

  8. Electronic components

    CERN Document Server

    Colwell, Morris A

    1976-01-01

    Electronic Components provides a basic grounding in the practical aspects of using and selecting electronics components. The book describes the basic requirements needed to start practical work on electronic equipment, resistors and potentiometers, capacitance, and inductors and transformers. The text discusses semiconductor devices such as diodes, thyristors and triacs, transistors and heat sinks, logic and linear integrated circuits (I.C.s) and electromechanical devices. Common abbreviations applied to components are provided. Constructors and electronics engineers will find the book useful

  9. Component testing

    International Nuclear Information System (INIS)

    Hutchings, M.T.; Schofield, Peter; Seymour, W.A.J.

    1986-01-01

    A method for non-destructive testing of an industrial component to ascertain if it is a single crystal, and to find the crystal orientations of those parts of the component which are single crystals, involves irradiating the component with a monochromatic collimated neutron beam. Diffracted neutron beams are observed live by means of LiF/ZnS composite screen, an image intensifier and a television camera and screen. (author)

  10. Changes in biodiversity and trade-offs among ecosystem services, stakeholders, and components of well-being: the contribution of the International Long-Term Ecological Research network (ILTER to Programme on Ecosystem Change and Society (PECS

    Directory of Open Access Journals (Sweden)

    Manuel Maass

    2016-09-01

    Full Text Available The International Long-Term Ecological Research (ILTER network comprises > 600 scientific groups conducting site-based research within 40 countries. Its mission includes improving the understanding of global ecosystems and informs solutions to current and future environmental problems at the global scales. The ILTER network covers a wide range of social-ecological conditions and is aligned with the Programme on Ecosystem Change and Society (PECS goals and approach. Our aim is to examine and develop the conceptual basis for proposed collaboration between ILTER and PECS. We describe how a coordinated effort of several contrasting LTER site-based research groups contributes to the understanding of how policies and technologies drive either toward or away from the sustainable delivery of ecosystem services. This effort is based on three tenets: transdisciplinary research; cross-scale interactions and subsequent dynamics; and an ecological stewardship orientation. The overarching goal is to design management practices taking into account trade-offs between using and conserving ecosystems toward more sustainable solutions. To that end, we propose a conceptual approach linking ecosystem integrity, ecosystem services, and stakeholder well-being, and as a way to analyze trade-offs among ecosystem services inherent in diverse management options. We also outline our methodological approach that includes: (i monitoring and synthesis activities following spatial and temporal trends and changes on each site and by documenting cross-scale interactions; (ii developing analytical tools for integration; (iii promoting trans-site comparison; and (iv developing conceptual tools to design adequate policies and management interventions to deal with trade-offs. Finally, we highlight the heterogeneity in the social-ecological setting encountered in a subset of 15 ILTER sites. These study cases are diverse enough to provide a broad cross-section of contrasting

  11. A Becn1 mutation mediates hyperactive autophagic sequestration of amyloid oligomers and improved cognition in Alzheimer's disease.

    Directory of Open Access Journals (Sweden)

    Altea Rocchi

    2017-08-01

    Full Text Available Impairment of the autophagy pathway has been observed during the pathogenesis of Alzheimer's disease (AD, a neurodegenerative disorder characterized by abnormal deposition of extracellular and intracellular amyloid β (Aβ peptides. Yet the role of autophagy in Aβ production and AD progression is complex. To study whether increased basal autophagy plays a beneficial role in Aβ clearance and cognitive improvement, we developed a novel genetic model to hyperactivate autophagy in vivo. We found that knock-in of a point mutation F121A in the essential autophagy gene Beclin 1/Becn1 in mice significantly reduces the interaction of BECN1 with its inhibitor BCL2, and thus leads to constitutively active autophagy even under non-autophagy-inducing conditions in multiple tissues, including brain. Becn1F121A-mediated autophagy hyperactivation significantly decreases amyloid accumulation, prevents cognitive decline, and restores survival in AD mouse models. Using an immunoisolation method, we found biochemically that Aβ oligomers are autophagic substrates and sequestered inside autophagosomes in the brain of autophagy-hyperactive AD mice. In addition to genetic activation of autophagy by Becn1 gain-of-function, we also found that ML246, a small-molecule autophagy inducer, as well as voluntary exercise, a physiological autophagy inducer, exert similar Becn1-dependent protective effects on Aβ removal and memory in AD mice. Taken together, these results demonstrate that genetically disrupting BECN1-BCL2 binding hyperactivates autophagy in vivo, which sequestrates amyloid oligomers and prevents AD progression. The study establishes new approaches to activate autophagy in the brain, and reveals the important function of Becn1-mediated autophagy hyperactivation in the prevention of AD.

  12. Time course of programmed cell death, which included autophagic features, in hybrid tobacco cells expressing hybrid lethality.

    Science.gov (United States)

    Ueno, Naoya; Nihei, Saori; Miyakawa, Naoto; Hirasawa, Tadashi; Kanekatsu, Motoki; Marubashi, Wataru; van Doorn, Wouter G; Yamada, Tetsuya

    2016-12-01

    PCD with features of vacuolar cell death including autophagy-related features were detected in hybrid tobacco cells, and detailed time course of features of vacuolar cell death were established. A type of interspecific Nicotiana hybrid, Nicotiana suaveolens × N. tabacum exhibits temperature-sensitive lethality. This lethality results from programmed cell death (PCD) in hybrid seedlings, but this PCD occurs only in seedlings and suspension-cultured cells grown at 28 °C, not those grown at 36 °C. Plant PCD can be classified as vacuolar cell death or necrotic cell death. Induction of autophagy, vacuolar membrane collapse and actin disorganization are each known features of vacuolar cell death, but observed cases of PCD showing all these features simultaneously are rare. In this study, these features of vacuolar cell death were evident in hybrid tobacco cells expressing hybrid lethality. Ion leakage, plasma membrane disruption, increased activity of vacuolar processing enzyme, vacuolar membrane collapse, and formation of punctate F-actin foci were each evident in these cells. Transmission electron microscopy revealed that macroautophagic structures formed and tonoplasts ruptured in these cells. The number of cells that contained monodansylcadaverine (MDC)-stained structures and the abundance of nine autophagy-related gene transcripts increased just before cell death at 28 °C; these features were not evident at 36 °C. We assessed whether an autophagic inhibitor, wortmannin (WM), influenced lethality in hybrid cells. After the hybrid cell began to die, WM suppressed increases in ion leakage and cell deaths, and it decreased the number of cells containing MDC-stained structures. These results showed that several features indicative of autophagy and vacuolar cell death were evident in the hybrid tobacco cells subject to lethality. In addition, we documented a detailed time course of these vacuolar cell death features.

  13. Improving nuclear envelope dynamics by EBV BFRF1 facilitates intranuclear component clearance through autophagy.

    Science.gov (United States)

    Liu, Guan-Ting; Kung, Hsiu-Ni; Chen, Chung-Kuan; Huang, Cheng; Wang, Yung-Li; Yu, Cheng-Pu; Lee, Chung-Pei

    2018-02-26

    Although a vesicular nucleocytoplasmic transport system is believed to exist in eukaryotic cells, the features of this pathway are mostly unknown. Here, we report that the BFRF1 protein of the Epstein-Barr virus improves vesicular transport of nuclear envelope (NE) to facilitate the translocation and clearance of nuclear components. BFRF1 expression induces vesicles that selectively transport nuclear components to the cytoplasm. With the use of aggregation-prone proteins as tools, we found that aggregated nuclear proteins are dispersed when these BFRF1-induced vesicles are formed. BFRF1-containing vesicles engulf the NE-associated aggregates, exit through from the NE, and putatively fuse with autophagic vacuoles. Chemical treatment and genetic ablation of autophagy-related factors indicate that autophagosome formation and autophagy-linked FYVE protein-mediated autophagic proteolysis are involved in this selective clearance of nuclear proteins. Remarkably, vesicular transport, elicited by BFRF1, also attenuated nuclear aggregates accumulated in neuroblastoma cells. Accordingly, induction of NE-derived vesicles by BFRF1 facilitates nuclear protein translocation and clearance, suggesting that autophagy-coupled transport of nucleus-derived vesicles can be elicited for nuclear component catabolism in mammalian cells.-Liu, G.-T., Kung, H.-N., Chen, C.-K., Huang, C., Wang, Y.-L., Yu, C.-P., Lee, C.-P. Improving nuclear envelope dynamics by EBV BFRF1 facilitates intranuclear component clearance through autophagy.

  14. Araguspongine C Induces Autophagic Death in Breast Cancer Cells through Suppression of c-Met and HER2 Receptor Tyrosine Kinase Signaling

    Directory of Open Access Journals (Sweden)

    Mohamed R. Akl

    2015-01-01

    Full Text Available Receptor tyrosine kinases are key regulators of cellular growth and proliferation. Dysregulations of receptor tyrosine kinases in cancer cells may promote tumorigenesis by multiple mechanisms including enhanced cell survival and inhibition of cell death. Araguspongines represent a group of macrocyclic oxaquinolizidine alkaloids isolated from the marine sponge Xestospongia species. This study evaluated the anticancer activity of the known oxaquinolizidine alkaloids araguspongines A, C, K and L, and xestospongin B against breast cancer cells. Araguspongine C inhibited the proliferation of multiple breast cancer cell lines in vitro in a dose-dependent manner. Interestingly, araguspongine C-induced autophagic cell death in HER2-overexpressing BT-474 breast cancer cells was characterized by vacuole formation and upregulation of autophagy markers including LC3A/B, Atg3, Atg7, and Atg16L. Araguspongine C-induced autophagy was associated with suppression of c-Met and HER2 receptor tyrosine kinase activation. Further in-silico docking studies and cell-free Z-LYTE assays indicated the potential of direct interaction between araguspongine C and the receptor tyrosine kinases c-Met and HER2 at their kinase domains. Remarkably, araguspongine C treatment resulted in the suppression of PI3K/Akt/mTOR signaling cascade in breast cancer cells undergoing autophagy. Induction of autophagic death in BT-474 cells was also associated with decreased levels of inositol 1,4,5-trisphosphate receptor upon treatment with effective concentration of araguspongine C. In conclusion, results of this study are the first to reveal the potential of araguspongine C as an inhibitor to receptor tyrosine kinases resulting in the induction of autophagic cell death in breast cancer cells.

  15. Component-oriented programming

    NARCIS (Netherlands)

    Bosch, J; Szyperski, C; Weck, W; Buschmann, F; Buchmann, AP; Cilia, MA

    2003-01-01

    This report covers the eighth Workshop on Component-Oriented Programming (WCOP). WCOP has been affiliated with ECOOP since its inception in 1996. The report summarizes the contributions made by authors of accepted position papers as well as those made by all attendees of the workshop sessions.

  16. Physiological response of Pichia pastoris GS115 to methanol-induced high level production of the Hepatitis B surface antigen: catabolic adaptation, stress responses, and autophagic processes.

    Science.gov (United States)

    Vanz, Ana Leticia; Lünsdorf, Heinrich; Adnan, Ahmad; Nimtz, Manfred; Gurramkonda, Chandrasekhar; Khanna, Navin; Rinas, Ursula

    2012-08-08

    ERAD pathway and through the proteasome. However, the amount of HBsAg did not show any significant decline during the cultivation revealing its general protection from proteolytic degradation. During the methanol fed-batch phase, induction of vacuolar proteases (e.g. strong increase of APR1) and constitutive autophagic processes were observed. Vacuolar enclosures were mainly found around peroxisomes and not close to HBsAg deposits and, thus, were most likely provoked by peroxisomal components damaged by reactive oxygen species generated by methanol oxidation. In the methanol fed-batch phase P. pastoris is exposed to dual stress; stress resulting from methanol degradation and stress resulting from the production of the recombinant protein leading to the induction of oxidative stress and unfolded protein response pathways, respectively. Finally, the modest increase of methanol assimilatory enzymes compared to the strong increase of methanol dissimilatory enzymes suggests here a potential to increase methanol incorporation into biomass/product through metabolic enhancement of the methanol assimilatory pathway.

  17. Physiological response of Pichia pastoris GS115 to methanol-induced high level production of the Hepatitis B surface antigen: catabolic adaptation, stress responses, and autophagic processes

    Science.gov (United States)

    2012-01-01

    proceed via the ERAD pathway and through the proteasome. However, the amount of HBsAg did not show any significant decline during the cultivation revealing its general protection from proteolytic degradation. During the methanol fed-batch phase, induction of vacuolar proteases (e.g. strong increase of APR1) and constitutive autophagic processes were observed. Vacuolar enclosures were mainly found around peroxisomes and not close to HBsAg deposits and, thus, were most likely provoked by peroxisomal components damaged by reactive oxygen species generated by methanol oxidation. Conclusions In the methanol fed-batch phase P. pastoris is exposed to dual stress; stress resulting from methanol degradation and stress resulting from the production of the recombinant protein leading to the induction of oxidative stress and unfolded protein response pathways, respectively. Finally, the modest increase of methanol assimilatory enzymes compared to the strong increase of methanol dissimilatory enzymes suggests here a potential to increase methanol incorporation into biomass/product through metabolic enhancement of the methanol assimilatory pathway. PMID:22873405

  18. Studying p53 family proteins in yeast: Induction of autophagic cell death and modulation by interactors and small molecules

    Energy Technology Data Exchange (ETDEWEB)

    Leão, Mariana; Gomes, Sara; Bessa, Cláudia; Soares, Joana; Raimundo, Liliana [REQUIMTE, Laboratório de Microbiologia, Departamento de Ciências Biológicas, Faculdade de Farmácia, Universidade do Porto, Rua de Jorge Viterbo Ferreira n. 164, 4050-313 Porto (Portugal); Monti, Paola; Fronza, Gilberto [Mutagenesis Unit, Istituto di Ricerca e Cura a Carattere Scientifico Azienda Ospedaliera Universitaria San Martino-IST-Istituto Nazionale per la Ricerca sul Cancro, 16132 Genoa (Italy); Pereira, Clara [REQUIMTE, Laboratório de Microbiologia, Departamento de Ciências Biológicas, Faculdade de Farmácia, Universidade do Porto, Rua de Jorge Viterbo Ferreira n. 164, 4050-313 Porto (Portugal); Saraiva, Lucília, E-mail: lucilia.saraiva@ff.up.pt [REQUIMTE, Laboratório de Microbiologia, Departamento de Ciências Biológicas, Faculdade de Farmácia, Universidade do Porto, Rua de Jorge Viterbo Ferreira n. 164, 4050-313 Porto (Portugal)

    2015-01-01

    In this work, the yeast Saccharomyces cerevisiae was used to individually study human p53, p63 (full length and truncated forms) and p73. Using this cell system, the effect of these proteins on cell proliferation and death, and the influence of MDM2 and MDMX on their activities were analyzed. When expressed in yeast, wild-type p53, TAp63, ΔNp63 and TAp73 induced growth inhibition associated with S-phase cell cycle arrest. This growth inhibition was accompanied by reactive oxygen species production and autophagic cell death. Furthermore, they stimulated rapamycin-induced autophagy. On the contrary, none of the tested p53 family members induced apoptosis either per se or after apoptotic stimuli. As previously reported for p53, also TAp63, ΔNp63 and TAp73 increased actin expression levels and its depolarization, suggesting that ACT1 is also a p63 and p73 putative yeast target gene. Additionally, MDM2 and MDMX inhibited the activity of all tested p53 family members in yeast, although the effect was weaker on TAp63. Moreover, Nutlin-3a and SJ-172550 were identified as potential inhibitors of the p73 interaction with MDM2 and MDMX, respectively. Altogether, the yeast-based assays herein developed can be envisaged as a simplified cell system to study the involvement of p53 family members in autophagy, the modulation of their activities by specific interactors (MDM2 and MDMX), and the potential of new small molecules to modulate these interactions. - Highlights: • p53, p63 and p73 are individually studied in the yeast S. cerevisiae. • p53 family members induce ROS production, cell cycle arrest and autophagy in yeast. • p53 family members increase actin depolarization and expression levels in yeast. • MDM2 and MDMX inhibit the activity of p53 family members in yeast. • Yeast can be a useful tool to study the biology and drugability of p53, p63 and p73.

  19. Studying p53 family proteins in yeast: Induction of autophagic cell death and modulation by interactors and small molecules

    International Nuclear Information System (INIS)

    Leão, Mariana; Gomes, Sara; Bessa, Cláudia; Soares, Joana; Raimundo, Liliana; Monti, Paola; Fronza, Gilberto; Pereira, Clara; Saraiva, Lucília

    2015-01-01

    In this work, the yeast Saccharomyces cerevisiae was used to individually study human p53, p63 (full length and truncated forms) and p73. Using this cell system, the effect of these proteins on cell proliferation and death, and the influence of MDM2 and MDMX on their activities were analyzed. When expressed in yeast, wild-type p53, TAp63, ΔNp63 and TAp73 induced growth inhibition associated with S-phase cell cycle arrest. This growth inhibition was accompanied by reactive oxygen species production and autophagic cell death. Furthermore, they stimulated rapamycin-induced autophagy. On the contrary, none of the tested p53 family members induced apoptosis either per se or after apoptotic stimuli. As previously reported for p53, also TAp63, ΔNp63 and TAp73 increased actin expression levels and its depolarization, suggesting that ACT1 is also a p63 and p73 putative yeast target gene. Additionally, MDM2 and MDMX inhibited the activity of all tested p53 family members in yeast, although the effect was weaker on TAp63. Moreover, Nutlin-3a and SJ-172550 were identified as potential inhibitors of the p73 interaction with MDM2 and MDMX, respectively. Altogether, the yeast-based assays herein developed can be envisaged as a simplified cell system to study the involvement of p53 family members in autophagy, the modulation of their activities by specific interactors (MDM2 and MDMX), and the potential of new small molecules to modulate these interactions. - Highlights: • p53, p63 and p73 are individually studied in the yeast S. cerevisiae. • p53 family members induce ROS production, cell cycle arrest and autophagy in yeast. • p53 family members increase actin depolarization and expression levels in yeast. • MDM2 and MDMX inhibit the activity of p53 family members in yeast. • Yeast can be a useful tool to study the biology and drugability of p53, p63 and p73

  20. Disruption of the vacuolar-type H+-ATPase complex in liver causes MTORC1-independent accumulation of autophagic vacuoles and lysosomes.

    Science.gov (United States)

    Kissing, Sandra; Rudnik, Sönke; Damme, Markus; Lüllmann-Rauch, Renate; Ichihara, Atsuhiro; Kornak, Uwe; Eskelinen, Eeva-Liisa; Jabs, Sabrina; Heeren, Jörg; De Brabander, Jef K; Haas, Albert; Saftig, Paul

    2017-04-03

    The vacuolar-type H + -translocating ATPase (v-H + -ATPase) has been implicated in the amino acid-dependent activation of the mechanistic target of rapamycin complex 1 (MTORC1), an important regulator of macroautophagy. To reveal the mechanistic links between the v-H + -ATPase and MTORC1, we destablilized v-H + -ATPase complexes in mouse liver cells by induced deletion of the essential chaperone ATP6AP2. ATP6AP2-mutants are characterized by massive accumulation of endocytic and autophagic vacuoles in hepatocytes. This cellular phenotype was not caused by a block in endocytic maturation or an impaired acidification. However, the degradation of LC3-II in the knockout hepatocytes appeared to be reduced. When v-H + -ATPase levels were decreased, we observed lysosome association of MTOR and normal signaling of MTORC1 despite an increase in autophagic marker proteins. To better understand why MTORC1 can be active when v-H + -ATPase is depleted, the activation of MTORC1 was analyzed in ATP6AP2-deficient fibroblasts. In these cells, very little amino acid-elicited activation of MTORC1 was observed. In contrast, insulin did induce MTORC1 activation, which still required intracellular amino acid stores. These results suggest that in vivo the regulation of macroautophagy depends not only on v-H + -ATPase-mediated regulation of MTORC1.

  1. Monitoring protein turnover during phosphate starvation-dependent autophagic degradation using a photoconvertible fluorescent protein aggregate in tobacco BY-2 cells.

    Science.gov (United States)

    Tasaki, Maiko; Asatsuma, Satoru; Matsuoka, Ken

    2014-01-01

    We have developed a system for quantitative monitoring of autophagic degradation in transformed tobacco BY-2 cells using an aggregate-prone protein comprised of cytochrome b5 (Cyt b5) and a tetrameric red fluorescent protein (RFP). Unfortunately, this system is of limited use for monitoring the kinetics of autophagic degradation because the proteins synthesized before and after induction of autophagy cannot be distinguished. To overcome this problem, we developed a system using kikume green-red (KikGR), a photoconvertible and tetrameric fluorescent protein that changes its fluorescence from green to red upon irradiation with purple light. Using the fusion protein of Cyt b5 and KikGR together with a method for the bulk conversion of KikGR, which we had previously used to convert the Golgi-localized monomeric KikGR fusion protein, we were able to monitor both the growth and de novo formation of aggregates. Using this system, we found that tobacco cells do not cease protein synthesis under conditions of phosphate (Pi)-starvation. Induction of autophagy under Pi-starvation, but not under sugar- or nitrogen-starvation, was specifically inhibited by phosphite, which is an analog of Pi with a different oxidation number. Therefore, the mechanism by which BY-2 cells can sense Pi-starvation and induce autophagy does not involve sensing a general decrease in energy supply and a specific Pi sensor might be involved in the induction of autophagy under Pi-starvation.

  2. Monitoring protein turnover during phosphate starvation-dependent autophagic degradation using a photoconvertible fluorescent protein aggregate in tobacco BY-2 cells

    Directory of Open Access Journals (Sweden)

    Maiko eTasaki

    2014-04-01

    Full Text Available We have developed a system for quantitative monitoring of autophagic degradation in transformed tobacco BY-2 cells using an aggregate-prone protein comprised of cytochrome b5 (Cyt b5 and a tetrameric red fluorescent protein (RFP. Unfortunately, this system is of limited use for monitoring the kinetics of autophagic degradation because the proteins synthesized before and after induction of autophagy cannot be distinguished. To overcome this problem, we developed a system using kikume green-red (KikGR, a photoconvertible and tetrameric fluorescent protein that changes its fluorescence from green to red upon irradiation with purple light. Using the fusion protein of Cyt b5 and KikGR together with a method for the bulk conversion of KikGR, which we had previously used to convert the Golgi-localized monomeric KikGR fusion protein, we were able to monitor both the growth and de novo formation of aggregates. Using this system, we found that tobacco cells do not cease protein synthesis under conditions of phosphate (Pi-starvation. Induction of autophagy under Pi-starvation, but not under sugar- or nitrogen-starvation, was specifically inhibited by phosphite, which is an analog of Pi with a different oxidation number. Therefore, the mechanism by which BY-2 cells can sense Pi-starvation and induce autophagy does not involve sensing a general decrease in energy supply and a specific Pi sensor might be involved in the induction of autophagy under Pi-starvation.

  3. Effect of natural uranium on the UMR-106 osteoblastic cell line: impairment of the autophagic process as an underlying mechanism of uranium toxicity.

    Science.gov (United States)

    Pierrefite-Carle, Valérie; Santucci-Darmanin, Sabine; Breuil, Véronique; Gritsaenko, Tatiana; Vidaud, Claude; Creff, Gaelle; Solari, Pier Lorenzo; Pagnotta, Sophie; Al-Sahlanee, Rasha; Auwer, Christophe Den; Carle, Georges F

    2017-04-01

    Natural uranium (U), which is present in our environment, exerts a chemical toxicity, particularly in bone where it accumulates. Generally, U is found at oxidation state +VI in its oxocationic form [Formula: see text] in aqueous media. Although U(VI) has been reported to induce cell death in osteoblasts, the cells in charge of bone formation, the molecular mechanism for U(VI) effects in these cells remains poorly understood. The objective of our study was to explore U(VI) effect at doses ranging from 5 to 600 µM, on mineralization and autophagy induction in the UMR-106 model osteoblastic cell line and to determine U(VI) speciation after cellular uptake. Our results indicate that U(VI) affects mineralization function, even at subtoxic concentrations (metal exposure. We observed that U(VI) was able to rapidly activate autophagy but an inhibition of the autophagic flux was observed after 24 h. Thus, our results indicate that U(VI) perturbs osteoblastic functions by reducing mineralization capacity. Our study identifies for the first time U(VI) in the form of meta-autunite in mammalian cells. In addition, U(VI)-mediated inhibition of the autophagic flux may be one of the underlying mechanisms leading to the decreased mineralization and the toxicity observed in osteoblasts.

  4. Assessing Basal and Acute Autophagic Responses in the Adult Drosophila Nervous System: The Impact of Gender, Genetics and Diet on Endogenous Pathway Profiles.

    Directory of Open Access Journals (Sweden)

    Eric P Ratliff

    Full Text Available The autophagy pathway is critical for the long-term homeostasis of cells and adult organisms and is often activated during periods of stress. Reduced pathway efficacy plays a central role in several progressive neurological disorders that are associated with the accumulation of cytotoxic peptides and protein aggregates. Previous studies have shown that genetic and transgenic alterations to the autophagy pathway impacts longevity and neural aggregate profiles of adult Drosophila. In this study, we have identified methods to measure the acute in vivo induction of the autophagy pathway in the adult fly CNS. Our findings indicate that the genotype, age, and gender of adult flies can influence pathway responses. Further, we demonstrate that middle-aged male flies exposed to intermittent fasting (IF had improved neuronal autophagic profiles. IF-treated flies also had lower neural aggregate profiles, maintained more youthful behaviors and longer lifespans, when compared to ad libitum controls. In summary, we present methodology to detect dynamic in vivo changes that occur to the autophagic profiles in the adult Drosophila CNS and that a novel IF-treatment protocol improves pathway response in the aging nervous system.

  5. cAMP and EPAC Are Key Players in the Regulation of the Signal Transduction Pathway Involved in the α-Hemolysin Autophagic Response

    Science.gov (United States)

    Mestre, María Belén; Colombo, María Isabel

    2012-01-01

    Staphylococcus aureus is a microorganism that causes serious diseases in the human being. This microorganism is able to escape the phagolysosomal pathway, increasing intracellular bacterial survival and killing the eukaryotic host cell to spread the infection. One of the key features of S. aureus infection is the production of a series of virulence factors, including secreted enzymes and toxins. We have shown that the pore-forming toxin α-hemolysin (Hla) is the S. aureus–secreted factor responsible for the activation of the autophagic pathway and that this response occurs through a PI3K/Beclin1-independent form. In the present report we demonstrate that cAMP has a key role in the regulation of this autophagic response. Our results indicate that cAMP is able to inhibit the autophagy induced by Hla and that PKA, the classical cAMP effector, does not participate in this regulation. We present evidence that EPAC and Rap2b, through calpain activation, are the proteins involved in the regulation of Hla-induced autophagy. Similar results were obtained in cells infected with different S. aureus strains. Interestingly, in this report we show, for the first time to our knowledge, that both EPAC and Rap2b are recruited to the S. aureus–containing phagosome. We believe that our findings have important implications in understanding innate immune processes involved in intracellular pathogen invasion of the host cell. PMID:22654658

  6. ER Stress and Autophagic Perturbations Lead to Elevated Extracellular α-Synuclein in GBA-N370S Parkinson's iPSC-Derived Dopamine Neurons

    Directory of Open Access Journals (Sweden)

    Hugo J.R. Fernandes

    2016-03-01

    Full Text Available Heterozygous mutations in the glucocerebrosidase gene (GBA represent the strongest common genetic risk factor for Parkinson's disease (PD, the second most common neurodegenerative disorder. However, the molecular mechanisms underlying this association are still poorly understood. Here, we have analyzed ten independent induced pluripotent stem cell (iPSC lines from three controls and three unrelated PD patients heterozygous for the GBA-N370S mutation, and identified relevant disease mechanisms. After differentiation into dopaminergic neurons, we observed misprocessing of mutant glucocerebrosidase protein in the ER, associated with activation of ER stress and abnormal cellular lipid profiles. Furthermore, we observed autophagic perturbations and an enlargement of the lysosomal compartment specifically in dopamine neurons. Finally, we found increased extracellular α-synuclein in patient-derived neuronal culture medium, which was not associated with exosomes. Overall, ER stress, autophagic/lysosomal perturbations, and elevated extracellular α-synuclein likely represent critical early cellular phenotypes of PD, which might offer multiple therapeutic targets.

  7. Bioinert Anodic Alumina Nanotubes for Targeting of Endoplasmic Reticulum Stress and Autophagic Signaling: A Combinatorial Nanotube-Based Drug Delivery System for Enhancing Cancer Therapy.

    Science.gov (United States)

    Wang, Ye; Kaur, Gagandeep; Chen, Yuting; Santos, Abel; Losic, Dusan; Evdokiou, Andreas

    2015-12-16

    Although nanoparticle-based targeted delivery systems have gained promising achievements for cancer therapy, the development of sophisticated strategies with effective combinatorial therapies remains an enduring challenge. Herein, we report the fabrication of a novel nanomaterial, so-called anodic alumina nanotubes (AANTs) for proof-of-concept cancer therapy by targeting cell signaling networks. This strategy is to target autophagic and endoplasmic reticulum (ER) stress signaling by using thapsigargin (TG)-loaded AANTs cotreated with an autophagy inhibitor 3-methyladenine (3-MA). We first show that AANTs are nontoxic and can activate autophagy in different cell types including human fibroblast cells (HFF), human monocyte cells (THP-1), and human breast cancer cells (MDA-MB 231-TXSA). Treatment with 3-MA at a nontoxic dose reduced the level of autophagy induced by AANTs, and consequently sensitized breast cancer cells to AANTs-induced cellular stresses. To target autophagic and ER stress signaling networking, breast cancer cells were treated with 3-MA together with AANTs loaded with the prototype ER stress inducer TG. We demonstrated that 3-MA enhanced the cancer cell killing effect of AANTs loaded with TG. This effect was associated with enhanced ER stress signaling due to the combination effect of TG and 3-MA. These findings not only demonstrate the excellent biocompatibility of AANTs as novel biomaterials but also provide new opportunities for developing ER- and autophagy-targeted delivery systems for future clinical cancer therapy.

  8. cAMP and EPAC are key players in the regulation of the signal transduction pathway involved in the α-hemolysin autophagic response.

    Directory of Open Access Journals (Sweden)

    María Belén Mestre

    Full Text Available Staphylococcus aureus is a microorganism that causes serious diseases in the human being. This microorganism is able to escape the phagolysosomal pathway, increasing intracellular bacterial survival and killing the eukaryotic host cell to spread the infection. One of the key features of S. aureus infection is the production of a series of virulence factors, including secreted enzymes and toxins. We have shown that the pore-forming toxin α-hemolysin (Hla is the S. aureus-secreted factor responsible for the activation of the autophagic pathway and that this response occurs through a PI3K/Beclin1-independent form. In the present report we demonstrate that cAMP has a key role in the regulation of this autophagic response. Our results indicate that cAMP is able to inhibit the autophagy induced by Hla and that PKA, the classical cAMP effector, does not participate in this regulation. We present evidence that EPAC and Rap2b, through calpain activation, are the proteins involved in the regulation of Hla-induced autophagy. Similar results were obtained in cells infected with different S. aureus strains. Interestingly, in this report we show, for the first time to our knowledge, that both EPAC and Rap2b are recruited to the S. aureus-containing phagosome. We believe that our findings have important implications in understanding innate immune processes involved in intracellular pathogen invasion of the host cell.

  9. Component Rhinoplasty

    OpenAIRE

    Mohmand, Muhammad Humayun; Ahmad, Muhammad

    2014-01-01

    BACKGROUND According to statistics of American Society of Plastic Surgeons, cosmetic rhinoplasty was the second most frequently performed cosmetic surgery. This study shares the experiences with component rhinoplasty. METHODS From 2004 to 2010, all patients underwent aesthetic nasal surgery were enrolled. The patients requiring only correction of septal deviation and those presenting with cleft lip nasal deformity were excluded. All procedures were performed under general anaesthesia with ope...

  10. Hyperfrequency components

    Science.gov (United States)

    1994-09-01

    The document has a collection of 19 papers (11 on technologies, 8 on applications) by 26 authors and coauthors. Technological topics include: evolution from conventional HEMT's double heterojunction and planar types of pseudomorphic HEMT's; MMIC R&D and production aspects for very-low-noise, low-power, and very-low-noise, high-power applications; hyperfrequency CAD tools; parametric measurements of hyperfrequency components on plug-in cards for design and in-process testing uses; design of Class B power amplifiers and millimetric-wave, bigrid-transistor mixers, exemplifying combined use of three major types of physical simulation in electrical modeling of microwave components; FET's for power amplification at up to 110 GHz; production, characterization, and nonlinear applications of resonant tunnel diodes. Applications topics include: development of active modules for major European programs; tubes versus solid-state components in hyperfrequency applications; status and potentialities of national and international cooperative R&D on MMIC's and CAD of hyperfrequency circuitry; attainable performance levels in multifunction MMIC applications; state of the art relative of MESFET power amplifiers (Bands S, C, X, Ku); creating a hyperfrequency functions library, of parametrizable reference cells or macrocells; and design of a single-stage, low-noise, band-W amplifier toward development of a three-stage amplifier.

  11. Variance Components

    CERN Document Server

    Searle, Shayle R; McCulloch, Charles E

    1992-01-01

    WILEY-INTERSCIENCE PAPERBACK SERIES. The Wiley-Interscience Paperback Series consists of selected books that have been made more accessible to consumers in an effort to increase global appeal and general circulation. With these new unabridged softcover volumes, Wiley hopes to extend the lives of these works by making them available to future generations of statisticians, mathematicians, and scientists. ". . .Variance Components is an excellent book. It is organized and well written, and provides many references to a variety of topics. I recommend it to anyone with interest in linear models.".

  12. Study of the contribution of the different components of atmospheric cosmic radiation in dose received by the aircraft crew; Avaliacao da contribuicao dos diferentes componentes da radiacao cosmica atmosferica na dose em tripulacoes de aeronaves

    Energy Technology Data Exchange (ETDEWEB)

    Pereira, Marlon A.; Prado, Adriane C.M., E-mail: adriane.acm@hotmail.com, E-mail: marlon@ieav.cta.br [Instituto Tecnologico de Aeronautica (ITA/DCTA), Sao Jose dos Campos, SP (Brazil); Federico, Claudio A.; Goncalez, Odair L., E-mail: claudiofederico@ieav.cta.br, E-mail: odairl@ieav.cta.br [Instituto de Estudos Avancados (IEAv/DCTA), Sao Jose dos Campos, SP (Brazil)

    2014-07-01

    The crews and aircraft passengers are exposed to atmospheric cosmic radiation. The flow of this radiation is modulated by the solar cycle and space weather, varying with the geomagnetic latitude and altitude. This paper presents a study of the contributions of radiation in total ambient dose equivalent of the crews depending on flight altitude up to 20 km, during maximum and minimum solar and in equatorial and polar regions. The results of calculations of the particle flows generated by the EXPACS and QARM codes are used. The particles evaluated that contributing significantly in the ambient dose equivalent are neutrons, protons, electrons, positrons, alphas, photons, muons and charged pions. This review allows us to characterize the origin of the dose received by crews and also support a project of a dosimetric system suitable for this ionizing radiation field in aircraft and on the ground.

  13. Contributions: SAGE

    Indian Academy of Sciences (India)

    First page Back Continue Last page Overview Graphics. Contributions: SAGE. Space Alternating Generalized Expectation (SAGE) Maximization algorithm provides an iterative approach to parameter estimation when direct maximization of the likelihood function may be infeasible. Complexity is less in those applications ...

  14. Various Contributions

    Indian Academy of Sciences (India)

    First page Back Continue Last page Overview Graphics. Various Contributions. Developed an Off –Diagonal MIMO Canceller to mitigate Upstream Crosstalk in VDSL. Developed a low complexity, Expectation Maximization based iterative Crosstalk cancellation. Developed an optimal way of computational complexity ...

  15. [Expression of autophagy related gene BECLIN-1 and number of autophagic vacuoles in bone marrow mononuclear cells from 40 myelodysplastic syndromes patients and their significance].

    Science.gov (United States)

    Hu, Bin; Yue, Qin-Fang; Chen, Ye; Bu, Fan-Dan; Sun, Chun-Yan; Liu, Xin-Yue

    2015-02-01

    The purpose of this study was to detect the expression level of autophagy related gene BECLIN-1 and the number of autophagic vacuoles in bone marrow mononuclear cells (BMMNC) from myelodysplastic syndrome(MDS) patients and to explore their difference in different stage of MDS and relationship between their difference and disease characteristics. The BMMNC from 9 normal controls, 19 cases of low-risk MDS, 14 cases of high-risk MDS and 7 cases of MDS-transformed AML were collected. The expression level of BECLIN-1 was detected by real time PCR (RT-PCR) and the amount of autophagic vacuoles was counted by transmission electron microscopy. The expression level of BECLIN-1 in BMMNC from patients with low-risk group was obviously higher than that in BMMNC from normal controls; the expression level of BECLIN-1 in BMMNC from patients of hgh risk group was higher than that in BMMNC of normal group, but there was no statistical significance (P > 0.05); the expression level of BECLIN-1 in BMMNC from patients with MDS-transformed AML group was significanly lower than that in BMMNC of normal group (P vacuoles in BMMNC from patients with low-risk and high-risk MDS groups was more than that in normal control, but there was no stetistcal significance (P > 0.05), while the amount of autopuagic vecuoles in BMMNC from patients of MDS-transformed AML group was significantly less (P vacuoles in BMMNC from patients with MDS progression and patients with MDS-transformed AML are gradually declining. The autophagy may be associated with disease progression.

  16. Micromechanical modelling of heterogeneous materials in transient conditions: contributions for the study of the ageing of structural components under service; Modelisation micromecanique des materiaux heterogenes en regimes transitoires: contributions en vue de l'etude du vieillissement des structures en service

    Energy Technology Data Exchange (ETDEWEB)

    Masson, R.

    2010-12-20

    considering the particular situation where regions of the representative volume element have ill-defined mechanical properties. In the linear elastic case, new bounds for the effective behaviour are derived by marrying the structural analysis and a variational approach. This last work opens on important prospects for further works: more tightened bounds, nonlinear behaviours,... Considering homogenisation methods, further works are precisely defined, in particular for polycrystalline materials. In that situation, the field of investigation widens clearly (Fatigue, Large strains,...) thanks to the internal variables formulation proposed. Lastly, the simulation of irradiation effects constitutes the third topic of interest for the years to come, the general objective being to better predict the effects of the swelling strains induced by irradiation on the behaviour of structural components under service. (author) [French] La modelisation du comportement mecanique des materiaux de structure se nourrit de plus en plus de parametres microstructuraux. Dans ce cadre, les methodes d'homogeneisation presentent l'avantage de fournir des methodes deductives qui, a partir des proprietes et de la repartition spatiale des heterogeneites, deduisent les proprietes effectives du materiau considere. Neanmoins de nombreuses applications soulevent encore des difficultes. C'est en particulier le cas des materiaux de structure presentant un comportement elasto-viscoplastique et soumis a un trajet de chargement non monotone et non isotherme. Progresser sur le traitement par homogeneisation de ces situations concretes constitue precisement le fil conducteur des differentes contributions presentees dans ce memoire d'HDR. Dans le cas elastique lineaire, de nouvelles expressions pour le calcul du tenseur d'Eshelby sont tout d'abord etablies afin d'ameliorer l'efficacite des methodes d'homogeneisation habituellement proposees. Toujours pour des comportements

  17. Src mediates extracellular signal-regulated kinase 1/2 activation and autophagic cell death induced by cardiac glycosides in human non-small cell lung cancer cell lines.

    Science.gov (United States)

    Wang, Yan; Zhan, Yuechen; Xu, Rong; Shao, Rongguang; Jiang, Jiandong; Wang, Zhen

    2015-06-01

    Aberrant Na(+) /K(+) -ATPases (NKA) expression is closely related to the incidence and development of cancer, making NKA targeted cancer therapy more intriguing. Cardiac glycosides (CGs) belong to NKA inhibitors and possess potent anti-cancer properties in many cancers. Our previous work demonstrates that CGs family member digoxin or ouabain induces autophagic cell death in human non-small cell lung cancer (NSCLC) cell lines through regulation of both mammalian target of rapamycin and extracellular signal-regulated kinase 1/2 (ERK1/2) pathway. However, what acts as an upstream regulator of ERK1/2 activation during autophagy induction remains obscure. In the present study, the role of Src in the ERK1/2 signaling pathway as well as autophagic cell death induced by either digoxin or ouabain was examined in A549 and H460 cells. Src is significantly activated simultaneously with mitogen-activated protein kinase kinase 1/2 (MEK1/2) and ERK1/2 activation upon the drug treatment. Moreover, Src inhibitor PP2 could block either drug induced MEK1/2 and ERK1/2 phosphorylation, together with autophagic phenotypes in the cells. Knockdown of Src with siRNA causes the similar effect as PP2, both of which markedly alleviate the drugs' cytotoxicity. In addition, increased levels of intracellular reactive oxygen species (ROS) are found to be involved in Src mediated autophagy. Together, this work provides evidences showing that Src mediates MEK1/2 and ERK1/2 pathway as well as ROS generation, and regulates autophagic cell death induced by the cardiac glycosides. These observations may further help understand the molecular mechanisms of autophagy induced by NKA inhibitors in NSCLC cells. © 2014 Wiley Periodicals, Inc.

  18. Attenuation of Aβ25–35-induced parallel autophagic and apoptotic cell death by gypenoside XVII through the estrogen receptor-dependent activation of Nrf2/ARE pathways

    International Nuclear Information System (INIS)

    Meng, Xiangbao; Wang, Min; Sun, Guibo; Ye, Jingxue; Zhou, Yanhui; Dong, Xi; Wang, Tingting; Lu, Shan; Sun, Xiaobo

    2014-01-01

    Amyloid-beta (Aβ) has a pivotal function in the pathogenesis of Alzheimer's disease. To investigate Aβ neurotoxicity, we used an in vitro model that involves Aβ 25–35 -induced cell death in the nerve growth factor-induced differentiation of PC12 cells. Aβ 25–35 (20 μM) treatment for 24 h caused apoptotic cell death, as evidenced by significant cell viability reduction, LDH release, phosphatidylserine externalization, mitochondrial membrane potential disruption, cytochrome c release, caspase-3 activation, PARP cleavage, and DNA fragmentation in PC12 cells. Aβ 25–35 treatment led to autophagic cell death, as evidenced by augmented GFP-LC3 puncta, conversion of LC3-I to LC3-II, and increased LC3-II/LC3-I ratio. Aβ 25–35 treatment induced oxidative stress, as evidenced by intracellular ROS accumulation and increased production of mitochondrial superoxide, malondialdehyde, protein carbonyl, and 8-OHdG. Phytoestrogens have been proved to be protective against Aβ-induced neurotoxicity and regarded as relatively safe targets for AD drug development. Gypenoside XVII (GP-17) is a novel phytoestrogen isolated from Gynostemma pentaphyllum or Panax notoginseng. Pretreatment with GP-17 (10 μM) for 12 h increased estrogen response element reporter activity, activated PI3K/Akt pathways, inhibited GSK-3β, induced Nrf2 nuclear translocation, augmented antioxidant responsive element enhancer activity, upregulated heme oxygenase 1 (HO-1) expression and activity, and provided protective effects against Aβ 25–35 -induced neurotoxicity, including oxidative stress, apoptosis, and autophagic cell death. In conclusion, GP-17 conferred protection against Aβ 25–35 -induced neurotoxicity through estrogen receptor-dependent activation of PI3K/Akt pathways, inactivation of GSK-3β and activation of Nrf2/ARE/HO-1 pathways. This finding might provide novel insights into understanding the mechanism for neuroprotective effects of phytoestrogens or gypenosides

  19. Systematic analysis of human cells lacking ATG8 proteins uncovers roles for GABARAPs and the CCZ1/MON1 regulator C18orf8/RMC1 in macro and selective autophagic flux.

    Science.gov (United States)

    Pontano Vaites, Laura; Paulo, Joao A; Huttlin, Edward L; Harper, J Wade

    2017-10-16

    Selective and macro autophagy sequester specific organelles/substrates or bulk cytoplasm, respectively, inside autophagosomes as cargo for delivery to lysosomes. The mammalian ATG8 orthologues (MAP1LC3A/B/C and GABARAP/L1/L2) are ubiquitin (UB)-like proteins conjugated to the autophagosome membrane and are thought to facilitate cargo receptor recruitment, vesicle maturation, and lysosomal fusion. To elucidate the molecular functions of the ATG8 proteins, we engineered cells lacking genes for each subfamily as well as all six mammalian ATG8s. Loss of GABARAPs alone attenuates autophagic flux basally and in response to macro or selective autophagic stimuli including PARKIN-dependent mitophagy, and cells lacking all ATG8 proteins accumulate cytoplasmic UB aggregates, which are resolved following ectopic expression of individual GABARAPs. Autophagosomes from cells lacking GABARAPs had reduced lysosomal content by quantitative proteomics, consistent with fusion defects, but accumulated regulators of late endosome (LE)/autophagosome maturation. Through interaction proteomics of proteins accumulating in GABARAP/L1/L2-deficient cells, we identified C18orf8/RMC1 as a new subunit of the CCZ1-MON1 RAB7 guanine exchange factor (GEF) that positively regulates RAB7 recruitment to LE/autophagosomes. This work defines unique roles for GABARAP and LC3 subfamilies in macro and selective autophagy and demonstrates how analysis of autophagic machinery in the absence of flux can identify new regulatory circuits. Copyright © 2017 American Society for Microbiology.

  20. Atg16L1, an essential factor for canonical autophagy, participates in hormone secretion from PC12 cells independently of autophagic activity

    Science.gov (United States)

    Ishibashi, Koutaro; Uemura, Takefumi; Waguri, Satoshi; Fukuda, Mitsunori

    2012-01-01

    Autophagy is a bulk degradation system in all eukaryotic cells and regulates a variety of biological activities in higher eukaryotes. Recently involvement of autophagy in the regulation of the secretory pathway has also been reported, but the molecular mechanism linking autophagy with the secretory pathway remains largely unknown. Here we show that Atg16L1, an essential protein for canonical autophagy, is localized on hormone-containing dense-core vesicles in neuroendocrine PC12 cells and that knockdown of Atg16L1 causes a dramatic reduction in the level of hormone secretion independently of autophagic activity. We also find that Atg16L1 interacts with the small GTPase Rab33A and that this interaction is required for the dense-core vesicle localization of Atg16L1 in PC12 cells. Our findings indicate that Atg16L1 regulates not only autophagy in all cell types, but also secretion from dense-core vesicles, presumably by acting as a Rab33A effector, in particular cell types. PMID:22740627

  1. 1-Hydroxy-3-[(E)-4-(piperazine-diium)but-2-enyloxy]-9,10-anthraquinone ditrifluoroactate induced autophagic cell death in human PC3 cells.

    Science.gov (United States)

    Huang, A-Mei; Lin, Kai-Wei; Lin, Wei-Hong; Wu, Li-Hung; Chang, Hao-Chun; Ni, Chujun; Wang, Danny Ling; Hsu, Hsue-Yin; Su, Chun-Li; Shih, Chiaho

    2018-02-01

    The autophagy of human prostate cancer cells (PC3 cells) induced by a new anthraquinone derivative, 1-Hydroxy-3-[(E)-4-(piperazine-diium)but-2-enyloxy]-9,10-anthraquinone ditrifluoroactate (PA) was investigated, and the relationship between autophagy and reactive oxygen species (ROS) generation was studied. The results indicated that PA induced PC3 cell death in a time- and dose-dependent manner, could inhibit PC3 cell growth by G1 phase cell cycle arrest and corresponding decrease in the G2/M cell population and induced S-phase arrest accompanied by a significant decrease G2/M and G1 phase numbers after PC3 cells treated with PA for 48 h, and increased the accumulation of autophagolysosomes and microtubule-associated protein LC3-ll, a marker of autophagy. However, these phenomenon were not observed in the group pretreated with the autophagy inhibitor 3-MA or Bafilomycin A1 (BAF), suggesting that PA induced PC3 cell autophagy. In addition, we found that PA triggered ROS generation in cells, while the levels of ROS decreased in the N-acetylcysteine (NAC) co-treatment, indicating that PA-mediated autophagy was partly blocked by NAC. In summary, the autophagic cell death of human PC3 cells mediated by PA-triggered ROS generation. Copyright © 2017 Elsevier B.V. All rights reserved.

  2. Dietary fat composition influences glomerular and proximal convoluted tubule cell structure and autophagic processes in kidneys from calorie-restricted mice.

    Science.gov (United States)

    Calvo-Rubio, Miguel; Burón, M Isabel; López-Lluch, Guillermo; Navas, Plácido; de Cabo, Rafael; Ramsey, Jon J; Villalba, José M; González-Reyes, José A

    2016-06-01

    Calorie restriction (CR) has been repeatedly shown to prevent cancer, diabetes, hypertension, and other age-related diseases in a wide range of animals, including non-human primates and humans. In rodents, CR also increases lifespan and is a powerful tool for studying the aging process. Recently, it has been reported in mice that dietary fat plays an important role in determining lifespan extension with 40% CR. In these conditions, animals fed lard as dietary fat showed an increased longevity compared with mice fed soybean or fish oils. In this paper, we study the effect of these dietary fats on structural and physiological parameters of kidney from mice maintained on 40% CR for 6 and 18 months. Analyses were performed using quantitative electron microcopy techniques and protein expression in Western blots. CR mitigated most of the analyzed age-related parameters in kidney, such as glomerular basement membrane thickness, mitochondrial mass in convoluted proximal tubules and autophagic markers in renal homogenates. The lard group showed improved preservation of several renal structures with aging when compared to the other CR diet groups. These results indicate that dietary fat modulates renal structure and function in CR mice and plays an essential role in the determination of health span in rodents. © 2016 The Authors. Aging Cell published by the Anatomical Society and John Wiley & Sons Ltd.

  3. Contribution to the study of recovery mechanisms to be considered in the selection of MOS-type components used in radiative environments; Contribution a l'etude des mecanismes de guerison intervenant dans la selection des composants de type MOS utilises en environnements radiatifs

    Energy Technology Data Exchange (ETDEWEB)

    Quittard, O

    1999-12-01

    The generalized use of commercial devices in a radiative environment (nuclear power plant, spatial) raises the problem of the sensitivity of electronic equipment to the radiation induced dose effect. Irradiation of electronic devices has varying impact on their electrical characteristics, according to the concomitant bias scenario. Under bias, there is a process of continuous degradation; but recovery will occur if subsequent irradiation is performed without bias voltage. This phenomenon is known as RICN (Radiation-Induced Charge Neutralization). On the other hand, increasingly widespread use of radiation-sensitive commercial off-the-shelf components (COTS) has raised interest in exploring the degradation and recovery phenomena encountered during the irradiation as a function of bias. In this work, a general method for selecting MOS devices is presented which takes into account their operating conditions (temperature, bias). After a description of the physical phenomena responsible for the oxide-trapped charge evolution, we present the RICN annealing and their implications on devices selection in a radiative environment. The tests describes in this study were performed on SRAMs and on a set of CMOS inverts from three manufacturers. In the last section, we compare our analytical model of RICN annealing with experimental data. (authors)

  4. The contribution of fat component to gestational weight gain

    Directory of Open Access Journals (Sweden)

    V N Pokusaeva

    2013-12-01

    Full Text Available Objective: to estimate the role of adipose tissue in gestational weight gain (GWG and preferential fat deposition among normal-weight women. Subjects and methods: prospective cohort study of 84 pregnancies: maternal body mass index 18,5–24,9 kg/m2, singleton term pregnancy, nondiabetic women, somatically well. GWG and skinfold thickness were evaluated in the 1st, 2nd, 3d trimesters, on the 3d day after delivery. Results: fat mass gain in low GWG was similar to recommended GWG and in the high-GWG group was greater one. Women with recommended and low GWG returned to their initial fat level on the 3d day after delivery, in excessive weight gain fat significantly increased (р=0,025. Compared to initial recommended GWG resulted in triceps skinfold thicknesses loss (р=0,001, in abdominal skinfold gained nothing and in thighs skinfold thicknesses increasing (р=0,021. Inadequate GWG leads to fat loss in arms (р=0,017, fat of abdominal area and thighs return to initial level. In excessive GWG fat in the upper trunk and arms not changed, in the lower area (thighs significantly increased compared to initial level (р=0,001 or other groups (р=0,001. Conclusion: excessive GWG was associated with greater adipose tissue cumulation and its deposition preferentially over the thighs. Inadequate GWG was clearly linked to low fat-free mass gain.

  5. Early assessment of dementia: the contribution of different memory components

    NARCIS (Netherlands)

    Spaan, P.E.; Raaijmakers, J.G.; Jonker, C.

    2005-01-01

    A broad memory test battery (reflecting explicit and implicit memory functioning) was administered to a heterogeneous sample of initially nondemented, community-dwelling elderly subjects. To examine the profile of preclinical dementia, subjects were tested twice: At baseline, all subjects were

  6. Evidence of biological activity of Mentha species extracts on apoptotic and autophagic targets on murine RAW264.7 and human U937 monocytic cells.

    Science.gov (United States)

    Brahmi, Fatiha; Hadj-Ahmed, Samia; Zarrouk, Amira; Bezine, Maryem; Nury, Thomas; Madani, Khodir; Chibane, Mohamed; Vejux, Anne; Andreoletti, Pierre; Boulekbache-Makhlouf, Lila; Lizard, Gérard

    2017-12-01

    Mints (Lamiaceae) are used as traditional remedies for the treatment of several diseases. Their extracts are recognized as anti-inflammatory compounds. This study characterized the cytotoxic effects of Mentha spicata L. (MS), Mentha pulegium L. (MP) and Mentha rotundifolia (L). Huds (MR) on macrophage cells (RAW264.7; U937) and determined their impact on apoptosis and autophagy, which can play a role in controlling inflammation. The extracts were prepared in culture medium and tested from 25 to 400 μg/mL after 24-48 h of treatment. To show the effect of the aqueous ethanol (50%) extracts on apoptosis and authophagy, the presence of cleaved caspase-3, and the conversion of LC3-I to LC3-II was evaluated by Western blotting. Compared with the MTT assay, crystal violet showed a pronounced decrease in the number of cells with all extracts at 48 h. Calculated IC 50 values were 257.31, 207.82 and 368.02 μg/mL for MS, MP and MR, respectively. A significant increase in PI positive cells was observed with all extracts at 200-400 μg/mL. Mitochondrial dysfunctions and nuclear morphological changes were detected with MS and MR extracts at 400 μg/mL. At this concentration, no cleaved caspase-3 was found whereas stabilized caspase-3 in its dimeric form was identified. MS and MR extracts also favour LC3-I to LC3-II conversion which is a criterion of autophagy. The cytotoxic profiles depend on the extracts considered; MS extract showed the strong activity. However, all the mint extracts studied interact with the apoptotic and autophagic pathways at elevated concentrations.

  7. 17-AAG post-treatment ameliorates memory impairment and hippocampal CA1 neuronal autophagic death induced by transient global cerebral ischemia.

    Science.gov (United States)

    Li, Jianxiong; Yang, Fei; Guo, Jia; Zhang, Rongrong; Xing, Xiangfeng; Qin, Xinyue

    2015-06-12

    Neuro-inflammation plays an important role in global cerebral ischemia (GCI). The 72-kDa heat shock protein (Hsp70) has been reported to be involved in the inflammatory response of many central nervous system diseases. Preclinical findings implicate that 17-allylamino-demethoxygeldanamycin (17-AAG), an anticancer drug in clinical, provide neuroprotection actions in a rat model of traumatic brain injury, and the beneficial effects of 17-AAG were specifically due to up-regulation of Hsp70. However, no experiments have tested whether 17-AAG has beneficial or harmful effects in the setting of GCI. The present study was designed to determine the hypothesis that administration of 17-AAG could attenuate cerebral infarction and improve neuronal survival, thereby ameliorating memory impairment in a rat model of GCI. Furthermore, to test whether any neuroprotective effect of 17-AAG was associated with inflammatory response and neuronal autophagy, we examined the expression of multiplex inflammatory cytokine levels as well as autophagy-associate protein in hippocampal CA1 of rat brain. Our results showed that post-GCI administration of 17-AAG significantly protected rats against GCI induced brain injury, and 17-AAG is also an effective antagonist of the inflammatory response and thereby ameliorates hippocampal CA1 neuronal autophagic death. We therefore believe that the present study provides novel clues in understanding the mechanisms by which 17-AAG exerts its neuroprotective activity in GCI. All data reveal that 17-AAG might be a potential neuroprotective agent for ischemic stroke. Copyright © 2015 Elsevier B.V. All rights reserved.

  8. 1,1-Bis(3'-indolyl-1-(p-substituted phenylmethanes induce autophagic cell death in estrogen receptor negative breast cancer

    Directory of Open Access Journals (Sweden)

    Chadalapaka Gayathri

    2010-12-01

    Full Text Available Abstract Background A novel series of methylene-substituted DIMs (C-DIMs, namely 1,1-bis(3'-indolyl-1-(p-substituted phenylmethanes containing t-butyl (DIM-C-pPhtBu and phenyl (DIM-C-pPhC6H5 groups inhibit proliferation of invasive estrogen receptor-negative MDA-MB-231 and MDA-MB-453 human breast cancer cell lines with IC50 values between 1-5 uM. The main purpose of this study was to investigate the pathways of C-DIM-induced cell death. Methods The effects of the C-DIMs on apoptotic, necrotic and autophagic cell death were determined using caspase inhibitors, measurement of lactate dehydrogenase release, and several markers of autophagy including Beclin and light chain associated protein 3 expression (LC3. Results The C-DIM compounds did not induce apoptosis and only DIM-C-pPhCF3 exhibited necrotic effects. However, treatment of MDA-MB-231 and MDA-MB-453 cells with C-DIMs resulted in accumulation of LC3-II compared to LC3-I protein, a characteristic marker of autophagy, and transient transfection of green fluorescent protein-LC3 also revealed that treatment with C-DIMs induced a redistribution of LC3 to autophagosomes after C-DIM treatment. In addition, the autofluorescent drug monodansylcadaverine (MDC, a specific autophagolysosome marker, accumulated in vacuoles after C-DIM treatment, and western blot analysis of lysates from cells treated with C-DIMs showed that the Beclin 1/Bcl-2 protein ratio increased. Conclusion The results suggest that C-DIM compounds may represent a new mechanism-based agent for treating drug-resistant ER-negative breast tumors through induction of autophagy.

  9. 1,1-Bis(3'-indolyl)-1-(p-substituted phenyl)methanes induce autophagic cell death in estrogen receptor negative breast cancer.

    Science.gov (United States)

    Vanderlaag, Kathy; Su, Yunpeng; Frankel, Arthur E; Burghardt, Robert C; Barhoumi, Rola; Chadalapaka, Gayathri; Jutooru, Indira; Safe, Stephen

    2010-12-03

    A novel series of methylene-substituted DIMs (C-DIMs), namely 1,1-bis(3'-indolyl)-1-(p-substituted phenyl)methanes containing t-butyl (DIM-C-pPhtBu) and phenyl (DIM-C-pPhC6H5) groups inhibit proliferation of invasive estrogen receptor-negative MDA-MB-231 and MDA-MB-453 human breast cancer cell lines with IC50 values between 1-5 uM. The main purpose of this study was to investigate the pathways of C-DIM-induced cell death. The effects of the C-DIMs on apoptotic, necrotic and autophagic cell death were determined using caspase inhibitors, measurement of lactate dehydrogenase release, and several markers of autophagy including Beclin and light chain associated protein 3 expression (LC3). The C-DIM compounds did not induce apoptosis and only DIM-C-pPhCF3 exhibited necrotic effects. However, treatment of MDA-MB-231 and MDA-MB-453 cells with C-DIMs resulted in accumulation of LC3-II compared to LC3-I protein, a characteristic marker of autophagy, and transient transfection of green fluorescent protein-LC3 also revealed that treatment with C-DIMs induced a redistribution of LC3 to autophagosomes after C-DIM treatment. In addition, the autofluorescent drug monodansylcadaverine (MDC), a specific autophagolysosome marker, accumulated in vacuoles after C-DIM treatment, and western blot analysis of lysates from cells treated with C-DIMs showed that the Beclin 1/Bcl-2 protein ratio increased. The results suggest that C-DIM compounds may represent a new mechanism-based agent for treating drug-resistant ER-negative breast tumors through induction of autophagy.

  10. A novel strategy inducing autophagic cell death in Burkitt's lymphoma cells with anti-CD19-targeted liposomal rapamycin

    International Nuclear Information System (INIS)

    Ono, K; Sato, T; Iyama, S; Tatekoshi, A; Hashimoto, A; Kamihara, Y; Horiguchi, H; Kikuchi, S; Kawano, Y; Takada, K; Hayashi, T; Miyanishi, K; Sato, Y; Takimoto, R; Kobune, M; Kato, J

    2014-01-01

    Relapsed or refractory Burkitt's lymphoma often has a poor prognosis in spite of intensive chemotherapy that induces apoptotic and/or necrotic death of lymphoma cells. Rapamycin (Rap) brings about autophagy, and could be another treatment. Further, anti-CD19-targeted liposomal delivery may enable Rap to kill lymphoma cells specifically. Rap was encapsulated by anionic liposome and conjugated with anti-CD19 antibody (CD19-GL-Rap) or anti-CD2 antibody (CD2-GL-Rap) as a control. A fluorescent probe Cy5.5 was also liposomized in the same way (CD19 or CD2-GL-Cy5.5) to examine the efficacy of anti-CD19-targeted liposomal delivery into CD19-positive Burkitt's lymphoma cell line, SKW6.4. CD19-GL-Cy5.5 was more effectively uptaken into SKW6.4 cells than CD2-GL-Cy5.5 in vitro. When the cells were inoculated subcutaneously into nonobese diabetic/severe combined immunodeficiency mice, intravenously administered CD19-GL-Cy5.5 made the subcutaneous tumor fluorescent, while CD2-GL-Cy5.5 did not. Further, CD19-GL-Rap had a greater cytocidal effect on not only SKW6.4 cells but also Burkitt's lymphoma cells derived from patients than CD2-GL-Rap in vitro. The specific toxicity of CD19-GL-Rap was cancelled by neutralizing anti-CD19 antibody. The survival period of mice treated with intravenous CD19-GL-Rap was significantly longer than that of mice treated with CD2-GL-Rap after intraperitoneal inoculation of SKW6.4 cells. Anti-CD19-targeted liposomal Rap could be a promising lymphoma cell-specific treatment inducing autophagic cell death

  11. Mitigating component performance variation

    Science.gov (United States)

    Gara, Alan G.; Sylvester, Steve S.; Eastep, Jonathan M.; Nagappan, Ramkumar; Cantalupo, Christopher M.

    2018-01-09

    Apparatus and methods may provide for characterizing a plurality of similar components of a distributed computing system based on a maximum safe operation level associated with each component and storing characterization data in a database and allocating non-uniform power to each similar component based at least in part on the characterization data in the database to substantially equalize performance of the components.

  12. Variability and component composition

    NARCIS (Netherlands)

    T. van der Storm (Tijs)

    2004-01-01

    textabstractIn component-based product populations, feature models have to be described at the component level to be able to benefit from a product family approach. As a consequence, composition of components becomes very complex. We describe how component-level variability can be managed in the

  13. Component framework support for developing device drivers

    OpenAIRE

    Michiels, Sam; Kenens, Peter; Matthijs, Frank; Walravens, Dirk; Berbers, Yolande; Verbaeten, Pierre

    2000-01-01

    In this paper, we advocate the use of component framework technology for developing state-of-the-art system software. Relevant contributions of DiPS (Distrinet Protocol Stack), a component framework, include its anonymous interaction model, connectors for handling non-functional issues such as the concurrency model, and builder support. DiPS has effectively been used in industrial protocol stacks. This paper shows how we are using the DiPS component framework to build and support flexib...

  14. Autophagy-dependent secretion: contribution to tumor progression

    Directory of Open Access Journals (Sweden)

    Tom Keulers

    2016-11-01

    Full Text Available Autophagy is best known as a lysosomal degradation and recycling pathway to maintain cellular homeostasis. During autophagy, cytoplasmic content is recognized and packed in autophagic vacuoles, or autophagosomes, and targeted for degradation. However, during the last years, it has become evident that the role of autophagy is not restricted to degradation alone but also mediates unconventional forms of secretion. Furthermore, cells with defects in autophagy apparently are able to reroute their cargo, like mitochondria, to the extracellular environment; effects that contribute to an array of pathologies. In this review we discuss the current knowledge of the physiological roles of autophagy-dependent secretion, i.e. the effect on inflammation and insulin/ hormone secretion. Finally, we focus on the effects of autophagy-dependent secretion on the tumour microenvironment and tumour progression. The autophagy mediated secreted factors may stimulate cellular proliferation via auto- and paracrine signaling. The autophagy mediated release of immune modulating proteins change the immunosuppresive tumor microenvironment and may promote an invasive phenotype. These effects may be either direct or indirect through facilitating formation of the mobilized vesicle, aid in anterograde trafficking or alterations in homeostasis and/or autonomous cell signaling.

  15. Lipophagy Contributes to Testosterone Biosynthesis in Male Rat Leydig Cells.

    Science.gov (United States)

    Ma, Yi; Zhou, Yan; Zhu, Yin-Ci; Wang, Si-Qi; Ping, Ping; Chen, Xiang-Feng

    2018-02-01

    In recent years, autophagy was found to regulate lipid metabolism through a process termed lipophagy. Lipophagy modulates the degradation of cholesteryl esters to free cholesterol (FC), which is the substrate of testosterone biosynthesis. However, the role of lipophagy in testosterone production is unknown. To investigate this, primary rat Leydig cells and varicocele rat models were administered to inhibit or promote autophagy, and testosterone, lipid droplets (LDs), total cholesterol (TC), and FC were evaluated. The results demonstrated that inhibiting autophagy in primary rat Leydig cells reduced testosterone production. Further studies demonstrated that inhibiting autophagy increased the number and size of LDs and the level of TC, but decreased the level of FC. Furthermore, hypoxia promoted autophagy in Leydig cells. We found that short-term hypoxia stimulated testosterone secretion; however, the inhibition of autophagy abolished stimulated testosterone release. Hypoxia decreased the number and size of LDs in Leydig cells, but the changes could be largely rescued by blocking autophagy. In experimental varicocele rat models, the administration of autophagy inhibitors substantially reduced serum testosterone. These data demonstrate that autophagy contributes to testosterone biosynthesis at least partially through degrading intracellular LDs/TC. Our observations might reveal an autophagic regulatory mode regarding testosterone biosynthesis. Copyright © 2018 Endocrine Society.

  16. Reusable Component Services

    Data.gov (United States)

    U.S. Environmental Protection Agency — The Reusable Component Services (RCS) is a super-catalog of components, services, solutions and technologies that facilitates search, discovery and collaboration in...

  17. Software component quality evaluation

    Science.gov (United States)

    Clough, A. J.

    1991-01-01

    The paper describes a software inspection process that can be used to evaluate the quality of software components. Quality criteria, process application, independent testing of the process and proposed associated tool support are covered. Early results indicate that this technique is well suited for assessing software component quality in a standardized fashion. With automated machine assistance to facilitate both the evaluation and selection of software components, such a technique should promote effective reuse of software components.

  18. Reactor component automatic grapple

    International Nuclear Information System (INIS)

    Greenaway, P.R.

    1982-01-01

    A grapple for handling nuclear reactor components in a medium such as liquid sodium which, upon proper seating and alignment of the grapple with the component as sensed by a mechanical logic integral to the grapple, automatically seizes the component. The mechanical logic system also precludes seizure in the absence of proper seating and alignment. (author)

  19. Principal component analysis

    NARCIS (Netherlands)

    Bro, R.; Smilde, A.K.

    2014-01-01

    Principal component analysis is one of the most important and powerful methods in chemometrics as well as in a wealth of other areas. This paper provides a description of how to understand, use, and interpret principal component analysis. The paper focuses on the use of principal component analysis

  20. Supply chain components

    Directory of Open Access Journals (Sweden)

    Vieraşu, T.

    2011-01-01

    Full Text Available In this article I will go through three main logistics components, which are represented by: transportation, inventory and facilities, and the three secondary logistical components: information, production location, price and how they determine performance of any supply chain. I will discuss then how these components are used in the design, planning and operation of a supply chain. I will also talk about some obstacles a supply chain manager may encounter.

  1. Supply chain components

    OpenAIRE

    Vieraşu, T.; Bălăşescu, M.

    2011-01-01

    In this article I will go through three main logistics components, which are represented by: transportation, inventory and facilities, and the three secondary logistical components: information, production location, price and how they determine performance of any supply chain. I will discuss then how these components are used in the design, planning and operation of a supply chain. I will also talk about some obstacles a supply chain manager may encounter.

  2. Hot gas path component

    Science.gov (United States)

    Lacy, Benjamin Paul; Kottilingam, Srikanth Chandrudu; Porter, Christopher Donald; Schick, David Edward

    2017-09-12

    Various embodiments of the disclosure include a turbomachine component. and methods of forming such a component. Some embodiments include a turbomachine component including: a first portion including at least one of a stainless steel or an alloy steel; and a second portion joined with the first portion, the second portion including a nickel alloy including an arced cooling feature extending therethrough, the second portion having a thermal expansion coefficient substantially similar to a thermal expansion coefficient of the first portion, wherein the arced cooling feature is located within the second portion to direct a portion of a coolant to a leakage area of the turbomachine component.

  3. CORE COMPONENT POT

    Energy Technology Data Exchange (ETDEWEB)

    MARTIN RL; OMBERG RP

    1975-12-19

    The core component pot is an open top vessel used to hold both new and irradiated core components for storage in the IDS and for holding the components submerged in sodium while being trasported inside CLEM. The top of the CCP is equipped with a grapple lip which is engaged by the hoisting grapples. Heat for maintaining the preheat of new components and dissipation of decay heat of irradiated fuel assemblies is conducted between the wall of the pot and the surrounding environment by thermal radiation and convection.

  4. Towards Cognitive Component Analysis

    DEFF Research Database (Denmark)

    Hansen, Lars Kai; Ahrendt, Peter; Larsen, Jan

    2005-01-01

    Cognitive component analysis (COCA) is here defined as the process of unsupervised grouping of data such that the ensuing group structure is well-aligned with that resulting from human cognitive activity. We have earlier demonstrated that independent components analysis is relevant for representi...

  5. 4-Acetylantroquinonol B suppresses autophagic flux and improves cisplatin sensitivity in highly aggressive epithelial cancer through the PI3K/Akt/mTOR/p70S6K signaling pathway.

    Science.gov (United States)

    Liu, Mingche; Bamodu, Oluwaseun Adebayo; Huang, Wen-Chien; Zucha, Muhammad Ary; Lin, Yen-Kuang; Wu, Alexander T H; Huang, Chun-Chih; Lee, Wei-Hwa; Yuan, Chiou-Chung; Hsiao, M; Deng, Li; Tzeng, Yew-Min; Yeh, Chi-Tai

    2017-06-15

    Targeting residual self-renewing, chemoresistant cancerous cells may represent the key to overcoming therapy resistance. The entry of these quiescent cells into an activated state is associated with high metabolic demand and autophagic flux. Therefore, modulating the autophagy pathway in aggressive carcinomas may be beneficial as a therapeutic modality. In this study, we evaluated the anti-tumor activities of 4-acetylantroquinonol B (4-AAQB) in chemoresistant ovarian cancer cells, particularly its ability to modulate autophagy through autophagy-related genes (Atg). Atg-5 was overexpressed in invasive ovarian cancer cell lines and tissue (OR: 5.133; P=0.027) and depleting Atg-5 in ES-2 cell lines significantly induced apoptosis. 4-AAQB effectively suppressed viability of various subtypes of ovarian cancer. Cells with higher cisplatin-resistance were more responsive to 4-AAQB. For the first time, we demonstrate that 4-AAQB significantly suppress Atg-5 and Atg-7 expression with decreased autophagic flux in ovarian cancer cells via inhibition of the PI3K/Akt/mTOR/p70S6K signaling pathway. Similar to Atg-5 silencing, 4-AAQB-induced autophagy inhibition significantly enhanced cell death in vitro. These results are comparable to those of hydroxychloroquine (HCQ). In addition, 4-AAQB/cisplatin synergistically induced apoptosis in ovarian cancer cells. In vivo, 4-AAQB/cisplatin also significantly induced apoptosis and autophagy in an ES-2 mouse xenografts model. This is the first report demonstrating the efficacy of 4-AAQB alone or in combination with cisplatin on the suppression of ovarian cancer via Atg-5-dependent autophagy. We believe these findings will be beneficial in the development of a novel anti-ovarian cancer therapeutic strategy. Copyright © 2017 Elsevier Inc. All rights reserved.

  6. CONTRIBUTION OF INDIRECT TAXES

    Directory of Open Access Journals (Sweden)

    CHIRCULESCU MARIA FELICIA

    2015-08-01

    Full Text Available The work is based on the fact that at any time and in any society, taxation is regarded as undesirable for all taxpayers. The existence and it's manifestation is justified, because the operation of any company involves costs that must be covered by sufficient resources. Since ancient times, each state has adopted its own tax system, more or less perfected, as the state has experienced a greater or lesser economic and military power At the base of this work stays the fact that tax systems are a key factor influencing the overall efficiency of the economy. They determine the size tendency to save, invest and work, influencing the increase in production and employment, which is essential sights integral economic strategy, making tax reform an important component of economic reform. This paper aims to analyze the indirect taxes and their contribution to the public revenues in Romania, the purpose paper contains an analysis based on statistical series as indirect taxation is where tax harmonization was possible. Through analyzes, the paper aims to provide answers to the problem of the contradiction between the growing need for budgetary revenues, which entails a continuous amplification and diversification of taxation, on the one hand, and the need to stimulate economic development, on the other hand. The harmonization of indirect taxation had been achieved since this touches the free movement of goods and the freedom to supply services, not being able to say the same thing about direct taxation, which is why the European Community Treaty does not specify expressly the alignment of direct taxation, considering that direct taxation is a matter of Internal Policies that, for a country free option.

  7. Explosive Components Facility

    Data.gov (United States)

    Federal Laboratory Consortium — The 98,000 square foot Explosive Components Facility (ECF) is a state-of-the-art facility that provides a full-range of chemical, material, and performance analysis...

  8. Space laser components reliability

    OpenAIRE

    Riede, Wolfgang; Schroeder, Helmut

    2015-01-01

    Space environment presents unique challenges for operation of optics and optical coatings as part of laser systems. Besides testing components and sub-systems on the component qualification level, the extended testing of complete laser systems like flight modules under acceptance level conditions is an effective way to determine the reliability and long term stability, mitigating the mission risk. Hence, optics as part of high power space laser systems have to be extensively tested in view...

  9. Refractory alloy component fabrication

    International Nuclear Information System (INIS)

    Young, W.R.

    1984-01-01

    Purpose of this report is to describe joining procedures, primarily welding techniques, which were developed to construct reliable refractory alloy components and systems for advanced space power systems. Two systems, the Nb-1Zr Brayton Cycle Heat Receiver and the T-111 Alloy Potassium Boiler Development Program, are used to illustrate typical systems and components. Particular emphasis is given to specific problems which were eliminated during the development efforts. Finally, some thoughts on application of more recent joining technology are presented. 78 figures

  10. Component fragility research program

    International Nuclear Information System (INIS)

    Tsai, N.C.; Mochizuki, G.L.; Holman, G.S.

    1989-11-01

    To demonstrate how ''high-level'' qualification test data can be used to estimate the ultimate seismic capacity of nuclear power plant equipment, we assessed in detail various electrical components tested by the Pacific Gas ampersand Electric Company for its Diablo Canyon plant. As part of our Phase I Component Fragility Research Program, we evaluated seismic fragility for five Diablo Canyon components: medium-voltage (4kV) switchgear; safeguard relay board; emergency light battery pack; potential transformer; and station battery and racks. This report discusses our Phase II fragility evaluation of a single Westinghouse Type W motor control center column, a fan cooler motor controller, and three local starters at the Diablo Canyon nuclear power plant. These components were seismically qualified by means of biaxial random motion tests on a shaker table, and the test response spectra formed the basis for the estimate of the seismic capacity of the components. The seismic capacity of each component is referenced to the zero period acceleration (ZPA) and, in our Phase II study only, to the average spectral acceleration (ASA) of the motion at its base. For the motor control center, the seismic capacity was compared to the capacity of a Westinghouse Five-Star MCC subjected to actual fragility tests by LLNL during the Phase I Component Fragility Research Program, and to generic capacities developed by the Brookhaven National Laboratory for motor control center. Except for the medium-voltage switchgear, all of the components considered in both our Phase I and Phase II evaluations were qualified in their standard commercial configurations or with only relatively minor modifications such as top bracing of cabinets. 8 refs., 67 figs., 7 tabs

  11. Impact test of components

    International Nuclear Information System (INIS)

    Borsoi, L.; Buland, P.; Labbe, P.

    1987-01-01

    Stops with gaps are currently used to support components and piping: it is simple, low cost, efficient and permits free thermal expansion. In order to keep the nonlinear nature of stops, such design is often modeled by beam elements (for the component) and nonlinear springs (for the stops). This paper deals with the validity and the limits of these models through the comparison of computational and experimental results. The experimental results come from impact laboratory tests on a simplified mockup. (orig.)

  12. Component-Oriented Programming (WCOP 2004)

    NARCIS (Netherlands)

    Bosch, J.; Szyperski, C.; Weck, W.; Malenfant, J; Ostvold, BM

    2004-01-01

    This report covers the ninth Workshop on Component-Oriented Programming (WCOP). WCOP has been affiliated with ECOOP since its inception in 1996. The report summarizes the contributions made by authors of accepted position papers as well as those made by all attendees of the workshop sessions.

  13. Encyclopedia of Software Components

    Science.gov (United States)

    Warren, Lloyd V. (Inventor); Beckman, Brian C. (Inventor)

    1997-01-01

    Intelligent browsing through a collection of reusable software components is facilitated with a computer having a video monitor and a user input interface such as a keyboard or a mouse for transmitting user selections, by presenting a picture of encyclopedia volumes with respective visible labels referring to types of software, in accordance with a metaphor in which each volume includes a page having a list of general topics under the software type of the volume and pages having lists of software components for each one of the generic topics, altering the picture to open one of the volumes in response to an initial user selection specifying the one volume to display on the monitor a picture of the page thereof having the list of general topics and altering the picture to display the page thereof having a list of software components under one of the general topics in response to a next user selection specifying the one general topic, and then presenting a picture of a set of different informative plates depicting different types of information about one of the software components in response to a further user selection specifying the one component.

  14. Multiscale principal component analysis

    International Nuclear Information System (INIS)

    Akinduko, A A; Gorban, A N

    2014-01-01

    Principal component analysis (PCA) is an important tool in exploring data. The conventional approach to PCA leads to a solution which favours the structures with large variances. This is sensitive to outliers and could obfuscate interesting underlying structures. One of the equivalent definitions of PCA is that it seeks the subspaces that maximize the sum of squared pairwise distances between data projections. This definition opens up more flexibility in the analysis of principal components which is useful in enhancing PCA. In this paper we introduce scales into PCA by maximizing only the sum of pairwise distances between projections for pairs of datapoints with distances within a chosen interval of values [l,u]. The resulting principal component decompositions in Multiscale PCA depend on point (l,u) on the plane and for each point we define projectors onto principal components. Cluster analysis of these projectors reveals the structures in the data at various scales. Each structure is described by the eigenvectors at the medoid point of the cluster which represent the structure. We also use the distortion of projections as a criterion for choosing an appropriate scale especially for data with outliers. This method was tested on both artificial distribution of data and real data. For data with multiscale structures, the method was able to reveal the different structures of the data and also to reduce the effect of outliers in the principal component analysis

  15. A abordagem de questões ambientais: contribuições de formadores de professores de componentes curriculares da área de ensino de química Addressing environmental issues: the contribution of teacher-trainers of chemistry teaching curricular components

    Directory of Open Access Journals (Sweden)

    Carlos Alberto Marques

    2013-01-01

    Full Text Available This paper presents the results of a study involving current teachers of the chemistry teaching curricular components of twelve Chemistry licentiate courses at state universities in the South and South-east of Brazil. The aim was to analyse how these curricular components can work together to address environmental issues in Chemistry teacher-training. From analysis of the interviews, it can be ascertained for example that environmental themes in the curricular components analysed are treated with differing levels of intensity and perspectives, and in some cases, have a more illustrative character regarding chemistry concepts.

  16. Cognitive Component Analysis

    DEFF Research Database (Denmark)

    Feng, Ling

    2008-01-01

    of audio contexts along with pattern recognition methods to map components to known contexts. It also involves looking for the right representations for auditory inputs, i.e. the data analytic processing pipelines invoked by human brains. The main ideas refer to Cognitive Component Analysis, defined......This dissertation concerns the investigation of the consistency of statistical regularities in a signaling ecology and human cognition, while inferring appropriate actions for a speech-based perceptual task. It is based on unsupervised Independent Component Analysis providing a rich spectrum...... as the process of unsupervised grouping of generic data such that the ensuing group structure is well-aligned with that resulting from human cognitive activity. Its hypothesis runs ecologically: features which are essentially independent in a context defined ensemble, can be efficiently coded as sparse...

  17. Solid state lighting component

    Energy Technology Data Exchange (ETDEWEB)

    Yuan, Thomas; Keller, Bernd; Tarsa, Eric; Ibbetson, James; Morgan, Frederick; Dowling, Kevin; Lys, Ihor

    2017-10-17

    An LED component according to the present invention comprising an array of LED chips mounted on a submount with the LED chips capable of emitting light in response to an electrical signal. The array can comprise LED chips emitting at two colors of light wherein the LED component emits light comprising the combination of the two colors of light. A single lens is included over the array of LED chips. The LED chip array can emit light of greater than 800 lumens with a drive current of less than 150 milli-Amps. The LED chip component can also operate at temperatures less than 3000 degrees K. In one embodiment, the LED array is in a substantially circular pattern on the submount.

  18. Review of water footprint components of grain

    Science.gov (United States)

    Ahmad, Wan Amiza Amneera Wan; Meriam Nik Sulaiman, Nik; Zalina Mahmood, Noor

    2017-06-01

    Burgeoning global population, economic development, agriculture and prevailing climate pattern are among aspects contributed to water scarcity. In low and middle income countries, agriculture takes the highest share among water user sector. Demand for grain is widespread all over the globe. Hence, this study review published papers regarding quantification of water footprint of grain. Review shows there are various methods in quantifying water footprint. In ascertaining water footprint, three (green, blue, grey) or two (green, blue) components of water footprint involved. However, there was a study introduced new term in evaluating water footprint, white water footprint. The vulnerability of varying methods is difficulty in conducting comparative among water footprint. Salient source in contributing high water footprint also varies. In some studies, green water footprint play major role. Conversely, few studies found out blue water footprint most contributing component in water footprint. This fluctuate pattern influenced by various aspects, namely, regional climatic characteristics, crop yield and crop types.

  19. Electronic components and systems

    CERN Document Server

    Dennis, W H

    2013-01-01

    Electronic Components and Systems focuses on the principles and processes in the field of electronics and the integrated circuit. Covered in the book are basic aspects and physical fundamentals; different types of materials involved in the field; and passive and active electronic components such as capacitors, inductors, diodes, and transistors. Also covered in the book are topics such as the fabrication of semiconductors and integrated circuits; analog circuitry; digital logic technology; and microprocessors. The monograph is recommended for beginning electrical engineers who would like to kn

  20. Component Reengineering Workshops

    DEFF Research Database (Denmark)

    Hansen, Klaus Marius; Christensen, Henrik Bærbak

    2004-01-01

    In mature domains, a number of competing product lines may emerge, and from the point of view of customers of such product lines, reengineering and reuse of assets across product lines from different vendors becomes important. To address this issue we present a low-cost approach, component...... reengineering workshops, for assessing reengineering costs of reusing components between different product lines. The approach works on the level of software architectures, and relies critically on input from various (technical) stakeholders. It has been validated through case studies that are also presented...

  1. Social Contributions in Romania

    Directory of Open Access Journals (Sweden)

    Attila Gyorgy

    2012-12-01

    Full Text Available Social contributions have an important impact on payroll policy. Also, social contributions represent a significant budgetary revenue item which can be viewed at the edge between taxation and insurance. Social contributions in Romania experienced many changes which ended in 2008. Nowadays, they are within a long transaction period towards partial externalization of the insurance activity to privately managed funds. The aim of this paper is to analyse the homogeneity of Romanian social security public scheme using annual data extracted from 2002-2009.The main findings reveal that social contributions reached the pinnacle of diversification, being too many, some of them with a small contribution rates; fiscal reforms which reduced contribution rates advantaged employers, and state will be interested to externalize this activity as far private sector will be able to assume this responsibility and the budgetary effects are acceptable for the public finance.

  2. Spain's nuclear components industry

    International Nuclear Information System (INIS)

    Kaibel, E.

    1985-01-01

    Spanish industrial participation in supply of components for nuclear power plants has grown steadily over the last fifteen years. The share of Spanish companies in work for the five second generation nuclear power plants increased to 50% of total capital investments. The necessity to maintain Spanish technology and production in the nuclear field is emphasized

  3. Grey component analysis

    NARCIS (Netherlands)

    Westerhuis, J.A.; Derks, E.P.P.A.; Hoefsloot, H.C.J.; Smilde, A.K.

    2007-01-01

    The interpretation of principal component analysis (PCA) models of complex biological or chemical data can be cumbersome because in PCA the decomposition is performed without any knowledge of the system at hand. Prior information of the system is not used to improve the interpretation. In this paper

  4. Molecular Models Candy Components

    Science.gov (United States)

    Coleman, William F.

    2007-01-01

    An explanation of various principles of chemistry in a paper by Fanny Ennever by the use of candy is described. The paper explains components of sucrose and the invert sugar that results from the hydrolysis of sucrose and will help students in determining whether the products are indeed hydrates of carbon.

  5. Component lifetime modelling

    NARCIS (Netherlands)

    Verweij, J.F.; Verweij, J.F.; Brombacher, A.C.; Brombacher, A.C.; Lunenborg, M.M.; Lunenborg, M.M.

    1994-01-01

    There are two approaches to component lifetime modelling. The first one uses a reliability prediction method as described in the (military) handbooks with the appropriate models and parameters. The advantages are: (a) It takes into account all possible failure mechanisms. (b) It is easy to use. The

  6. Euler principal component analysis

    NARCIS (Netherlands)

    Liwicki, Stephan; Tzimiropoulos, Georgios; Zafeiriou, Stefanos; Pantic, Maja

    Principal Component Analysis (PCA) is perhaps the most prominent learning tool for dimensionality reduction in pattern recognition and computer vision. However, the ℓ 2-norm employed by standard PCA is not robust to outliers. In this paper, we propose a kernel PCA method for fast and robust PCA,

  7. Validating Timed Component Contracts

    DEFF Research Database (Denmark)

    Le Guilly, Thibaut; Liu, Shaoying; Olsen, Petur

    2015-01-01

    This paper presents a technique for testing software components with contracts that specify functional behavior, synchronization, as well as timing behavior. The approach combines elements from unit testing with model-based testing techniques for timed automata. The technique is implemented...... in an online testing tool, and we demonstrate its use on a concrete use case....

  8. ITER plasma facing components

    International Nuclear Information System (INIS)

    Kuroda, T.; Vieider, G.; Akiba, M.

    1991-01-01

    This document summarizes results of the Conceptual Design Activities (1988-1990) for the International Thermonuclear Experimental Reactor (ITER) project, namely those that pertain to the plasma facing components of the reactor vessel, of which the main components are the first wall and the divertor plates. After an introduction and an executive summary, the principal functions of the plasma-facing components are delineated, i.e., (i) define the low-impurity region within which the plasma is produced, (ii) absorb the electromagnetic radiation and charged-particle flux from the plasma, and (iii) protect the blanket/shield components from the plasma. A list of critical design issues for the divertor plates and the first wall is given, followed by discussions of the divertor plate design (including the issues of material selection, erosion lifetime, design concepts, thermal and mechanical analysis, operating limits and overall lifetime, tritium inventory, baking and conditioning, safety analysis, manufacture and testing, and advanced divertor concepts) and the first wall design (armor material and design, erosion lifetime, overall design concepts, thermal and mechanical analysis, lifetime and operating limits, tritium inventory, baking and conditioning, safety analysis, manufacture and testing, an alternative first wall design, and the limiters used instead of the divertor plates during start-up). Refs, figs and tabs

  9. Digital Components in Swedish NPP Power Systems

    International Nuclear Information System (INIS)

    Karlsson, Mattias; Eriksson, Tage

    2015-01-01

    Swedish nuclear power plants have over the last 20 years of operation modernised or exchanged several systems and components of the electrical power system. Within these works, new components based on digital technology have been employed in order to realize functionality that was previously achieved by using electro-mechanical or analogue technology. Components and systems such as relay protection, rectifiers, inverters, variable speed drives and diesel-generator sets are today equipped with digital components. Several of the systems and components fulfil functions with a safety-role in the NPP. Recently, however, a number of incidents have occurred which highlight deficiencies in the design or HMI of the equipment, which warrants questions whether there are generic problems with some applications of digital components that needs to be addressed. The use of digital components has presented cost effective solutions, or even the only available solution on the market enabling a modernisation. The vast majority of systems using digital components have been operating without problems and often contribute to improved safety but the challenge of non-detectable, or non-identifiable, failure modes remain. In this paper, the extent to which digital components are used in Swedish NPP power systems will be presented including a description of typical applications. Based on data from maintenance records and fault reports, as well as interviews with designers and maintenance personnel, the main areas where problems have been encountered and where possible risks have been identified will be described. The paper intends to investigate any 'tell-tales' that could give signals of unwanted behaviour. Furthermore, particular benefits experienced by using digital components will be highlighted. The paper will also discuss the safety relevance of these findings and suggest measures to improve safety in the application of digital components in power systems. (authors)

  10. Safety engineering with COTS components

    International Nuclear Information System (INIS)

    O'Halloran, Mark; Hall, Jon G.; Rapanotti, Lucia

    2017-01-01

    Safety-critical systems are becoming more widespread, complex and reliant on software. Increasingly they are engineered through (COTS) (Commercial Off The Shelf) components to alleviate the spiralling costs and development time, often in the context of complex supply chains. A parallel increased concern for safety has resulted in a variety of safety standards, with a growing consensus that a safety life cycle is needed which is fully integrated with the design and development life cycle, to ensure that safety has appropriate influence on the design decisions as system development progresses. In this article we explore the application of an integrated approach to safety engineering in which assurance drives the engineering process. The paper reports on the outcome of a case study on a live industrial project with a view to evaluate: its suitability for application in a real-world safety engineering setting; its benefits and limitations in counteracting some of the difficulties of safety engineering with (COTS) components across supply chains; and, its effectiveness in generating evidence which can contribute directly to the construction of safety cases. - Highlights: • Assurance as effective driver for COTS-based safety-critical system development. • Engages stakeholders, captures requirements and provides rich traceability. • Shares appropriate safety requirements across the supply chain.

  11. Developing a Model Component

    Science.gov (United States)

    Fields, Christina M.

    2013-01-01

    The Spaceport Command and Control System (SCCS) Simulation Computer Software Configuration Item (CSCI) is responsible for providing simulations to support test and verification of SCCS hardware and software. The Universal Coolant Transporter System (UCTS) was a Space Shuttle Orbiter support piece of the Ground Servicing Equipment (GSE). The initial purpose of the UCTS was to provide two support services to the Space Shuttle Orbiter immediately after landing at the Shuttle Landing Facility. The UCTS is designed with the capability of servicing future space vehicles; including all Space Station Requirements necessary for the MPLM Modules. The Simulation uses GSE Models to stand in for the actual systems to support testing of SCCS systems during their development. As an intern at Kennedy Space Center (KSC), my assignment was to develop a model component for the UCTS. I was given a fluid component (dryer) to model in Simulink. I completed training for UNIX and Simulink. The dryer is a Catch All replaceable core type filter-dryer. The filter-dryer provides maximum protection for the thermostatic expansion valve and solenoid valve from dirt that may be in the system. The filter-dryer also protects the valves from freezing up. I researched fluid dynamics to understand the function of my component. The filter-dryer was modeled by determining affects it has on the pressure and velocity of the system. I used Bernoulli's Equation to calculate the pressure and velocity differential through the dryer. I created my filter-dryer model in Simulink and wrote the test script to test the component. I completed component testing and captured test data. The finalized model was sent for peer review for any improvements. I participated in Simulation meetings and was involved in the subsystem design process and team collaborations. I gained valuable work experience and insight into a career path as an engineer.

  12. Major contributions to science

    International Nuclear Information System (INIS)

    Martin, Andre

    1991-01-01

    It may look difficult to describe the scientific contributions of Léon Van Hove, who started his career as a pure mathematician, and then a mathematical physicist, and ended it as a phenomenologist and an adseveral of Léon's students, in particular N. Hugenholtz. In this domain, his contributions were numerous and fundamental

  13. Attenuation of Aβ{sub 25–35}-induced parallel autophagic and apoptotic cell death by gypenoside XVII through the estrogen receptor-dependent activation of Nrf2/ARE pathways

    Energy Technology Data Exchange (ETDEWEB)

    Meng, Xiangbao; Wang, Min [Key Laboratory of Bioactive Substances and Resources Utilization of Chinese Herbal Medicine, Ministry of Education, Institute of Medicinal Plant Development, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100193 (China); Sun, Guibo, E-mail: sunguibo@126.com [Key Laboratory of Bioactive Substances and Resources Utilization of Chinese Herbal Medicine, Ministry of Education, Institute of Medicinal Plant Development, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100193 (China); Ye, Jingxue [Jilin Agricultural University, Changchun, Jilin 130021 (China); Zhou, Yanhui [Center of Cardiology, People' s Hospital of Jilin Province, Changchun, 130021, Jilin (China); Dong, Xi [Wenzhou Medical University, Wenzhou, Zhejiang 325035 (China); Wang, Tingting; Lu, Shan [Key Laboratory of Bioactive Substances and Resources Utilization of Chinese Herbal Medicine, Ministry of Education, Institute of Medicinal Plant Development, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100193 (China); Sun, Xiaobo, E-mail: sun_xiaobo163@163.com [Key Laboratory of Bioactive Substances and Resources Utilization of Chinese Herbal Medicine, Ministry of Education, Institute of Medicinal Plant Development, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100193 (China)

    2014-08-15

    Amyloid-beta (Aβ) has a pivotal function in the pathogenesis of Alzheimer's disease. To investigate Aβ neurotoxicity, we used an in vitro model that involves Aβ{sub 25–35}-induced cell death in the nerve growth factor-induced differentiation of PC12 cells. Aβ{sub 25–35} (20 μM) treatment for 24 h caused apoptotic cell death, as evidenced by significant cell viability reduction, LDH release, phosphatidylserine externalization, mitochondrial membrane potential disruption, cytochrome c release, caspase-3 activation, PARP cleavage, and DNA fragmentation in PC12 cells. Aβ{sub 25–35} treatment led to autophagic cell death, as evidenced by augmented GFP-LC3 puncta, conversion of LC3-I to LC3-II, and increased LC3-II/LC3-I ratio. Aβ{sub 25–35} treatment induced oxidative stress, as evidenced by intracellular ROS accumulation and increased production of mitochondrial superoxide, malondialdehyde, protein carbonyl, and 8-OHdG. Phytoestrogens have been proved to be protective against Aβ-induced neurotoxicity and regarded as relatively safe targets for AD drug development. Gypenoside XVII (GP-17) is a novel phytoestrogen isolated from Gynostemma pentaphyllum or Panax notoginseng. Pretreatment with GP-17 (10 μM) for 12 h increased estrogen response element reporter activity, activated PI3K/Akt pathways, inhibited GSK-3β, induced Nrf2 nuclear translocation, augmented antioxidant responsive element enhancer activity, upregulated heme oxygenase 1 (HO-1) expression and activity, and provided protective effects against Aβ{sub 25–35}-induced neurotoxicity, including oxidative stress, apoptosis, and autophagic cell death. In conclusion, GP-17 conferred protection against Aβ{sub 25–35}-induced neurotoxicity through estrogen receptor-dependent activation of PI3K/Akt pathways, inactivation of GSK-3β and activation of Nrf2/ARE/HO-1 pathways. This finding might provide novel insights into understanding the mechanism for neuroprotective effects of phytoestrogens

  14. Bayesian Independent Component Analysis

    DEFF Research Database (Denmark)

    Winther, Ole; Petersen, Kaare Brandt

    2007-01-01

    In this paper we present an empirical Bayesian framework for independent component analysis. The framework provides estimates of the sources, the mixing matrix and the noise parameters, and is flexible with respect to choice of source prior and the number of sources and sensors. Inside the engine...... in a Matlab toolbox, is demonstrated for non-negative decompositions and compared with non-negative matrix factorization.......In this paper we present an empirical Bayesian framework for independent component analysis. The framework provides estimates of the sources, the mixing matrix and the noise parameters, and is flexible with respect to choice of source prior and the number of sources and sensors. Inside the engine...

  15. Adaptable component frameworks

    DEFF Research Database (Denmark)

    Katajainen, Jyrki; Simonsen, Bo

    2009-01-01

    for vector, which is undoubtedly the most used container of the C++ standard library. In particular, we specify the details of a vector implementation that is safe with respect to referential integrity and strong exception safety. Additionally, we report the experiences and lessons learnt from......The CPH STL is a special edition of the STL, the containers and algorithms part of the C++ standard library. The specification of the generic components of the STL is given in the C++ standard. Any implementation of the STL, e.g. the one that ships with your standard-compliant C++ compiler, should...... the development of component frameworks which we hope to be of benefit to persons engaged in the design and implementation of generic software libraries....

  16. Bacterial Cell Wall Components

    Science.gov (United States)

    Ginsberg, Cynthia; Brown, Stephanie; Walker, Suzanne

    Bacterial cell-surface polysaccharides cells are surrounded by a variety of cell-surface structures that allow them to thrive in extreme environments. Components of the cell envelope and extracellular matrix are responsible for providing the cells with structural support, mediating intercellular communication, allowing the cells to move or to adhere to surfaces, protecting the cells from attack by antibiotics or the immune system, and facilitating the uptake of nutrients. Some of the most important cell wall components are polysaccharide structures. This review discusses the occurrence, structure, function, and biosynthesis of the most prevalent bacterial cell surface polysaccharides: peptidoglycan, lipopolysaccharide, arabinogalactan, and lipoarabinomannan, and capsular and extracellular polysaccharides. The roles of these polysaccharides in medicine, both as drug targets and as therapeutic agents, are also described.

  17. Components of the environment

    International Nuclear Information System (INIS)

    Klinda, J.; Lieskovska, Z.

    1998-01-01

    This report of the Ministry of the Environment of the Slovak Republic deals with the components of the environment. The results of monitoring of air (emission situation), ambient air quality, atmospheric precipitation, tropospheric ozone, water (surface water, groundwater resources, waste water and drinking water), geological factors (geothermal energy, fuel deposits, ore deposits, non-metallic ore deposits), soil (area statistics, soil contamination. soil reaction and active extractable aluminium, soil erosion), flora and fauna (national strategy of biodiversity protection) are presented

  18. Fabricating nuclear components

    International Nuclear Information System (INIS)

    Anon.

    1977-01-01

    Activities of the Nuclear Engineering Division of Vickers Ltd., particularly fabrication of long slim tubular components for power reactors and the construction of irradiation loops and rigs, are outlined. The processes include hydraulic forming for fabrication of various types of tubes and outer cases of fuel transfer buckets, various specialised welding operations including some applications of the TIG process, and induction brazing of specialised assemblies. (U.K.)

  19. Surface mount component jig

    Science.gov (United States)

    Kronberg, James W.

    1990-08-07

    A device for bending and trimming the pins of a dual-inline-package component and the like for surface mounting rather than through mounting to a circuit board comprises, in a first part, in pin cutter astride a holder having a recess for holding the component, a first spring therebetween, and, in a second part, two flat members pivotally interconnected by a hinge and urged to an upward peaked position from a downward peaked position by a second spring. As a downward force is applied to the pin cutter it urges the holder downward, assisted by the first spring and a pair of ridges riding on shoulders of the holder, to carry the component against the upward peaked flat members which guide the pins outwardly. As the holder continues downwardly, the flat members pivot to the downward peaked position bending the pins upwardly against the sides of the holder. When the downward movement is met with sufficient resistance, the ridges of the pin cutter ride over the holder's shoulders to continue downward to cut any excess length of pin.

  20. Inkjet deposited circuit components

    Science.gov (United States)

    Bidoki, S. M.; Nouri, J.; Heidari, A. A.

    2010-05-01

    All-printed electronics as a means of achieving ultra-low-cost electronic circuits has attracted great interest in recent years. Inkjet printing is one of the most promising techniques by which the circuit components can be ultimately drawn (i.e. printed) onto the substrate in one step. Here, the inkjet printing technique was used to chemically deposit silver nanoparticles (10-200 nm) simply by ejection of silver nitrate and reducing solutions onto different substrates such as paper, PET plastic film and textile fabrics. The silver patterns were tested for their functionality to work as circuit components like conductor, resistor, capacitor and inductor. Different levels of conductivity were achieved simply by changing the printing sequence, inks ratio and concentration. The highest level of conductivity achieved by an office thermal inkjet printer (300 dpi) was 5.54 × 105 S m-1 on paper. Inkjet deposited capacitors could exhibit a capacitance of more than 1.5 nF (parallel plate 45 × 45 mm2) and induction coils displayed an inductance of around 400 µH (planar coil 10 cm in diameter). Comparison of electronic performance of inkjet deposited components to the performance of conventionally etched items makes the technique highly promising for fabricating different printed electronic devices.

  1. GMES Space Component: Programme overview

    Science.gov (United States)

    Aschbacher, J.; Milagro-Perez, M. P.

    2012-04-01

    The European Union (EU) and the European Space Agency (ESA) have developed the Global Monitoring for Environment and Security (GMES) programme as Europe's answer to the vital need for joined-up data about our climate, environment and security. Through a unique combination of satellite, atmospheric and Earth-based monitoring systems, the initiative will provide new insight into the state of the land, sea and air, providing policymakers, scientists, businesses and the public with accurate and timely information. GMES capabilities include monitoring and forecasting of climatic change, flood risks, soil and coastal erosion, crop and fish resources, air pollution, greenhouse gases, iceberg distribution and snow cover, among others. To accomplish this, GMES has been divided into three main components: Space, In-situ and Services. The Space Component, led by ESA, comprises five types of new satellites called Sentinels that are being developed by ESA specifically to meet the needs of GMES, the first of which to be launched in 2013. These missions carry a range of technologies, such as radar and multi-spectral imaging instruments for land, ocean and atmospheric monitoring. In addition, access to data from the so-called Contributing Missions guarantees that European space infrastructure is fully used for GMES. An integrated Ground Segment ensures access to Sentinels and Contributing Missions data. The in-situ component, under the coordination of the European Environment Agency (EEA), is composed of atmospheric and Earth based monitoring systems, and based on established networks and programmes at European and international levels. The European Commission is in charge of implementing the services component of GMES and of leading GMES overall. GMES services, fed with data from the Space and In-situ components, will provide essential information in five main domains, atmosphere, ocean and land monitoring as well as emergency response and security. Climate change has been added

  2. Durability of building materials and components

    CERN Document Server

    Delgado, JMPQ

    2013-01-01

    Durability of Building Materials and Components provides a collection of recent research works to contribute to the systematization and dissemination of knowledge related to the long-term performance and durability of construction and, simultaneously, to show the most recent advances in this domain. It includes a set of new developments in the field of durability, service life prediction methodologies, the durability approach for historical and old buildings, asset and maintenance management and on the durability of materials, systems and components. The book is divided in several chapters that intend to be a resume of the current state of knowledge for benefit of professional colleagues.

  3. Welding of structural components and vessels

    International Nuclear Information System (INIS)

    1989-01-01

    'Welding of structural components and vessels' was chosen as the guiding topic for the 17th special conference in Munich so that current problems of this important area of application for welding engineering could be discussed in detail. The following topics were in the focus of the discussions: developments in steel, steel production and steel processing, reports on the practical application of welding in the manufacture of containers and pipes, quality assurance, product liability, safety considerations regarding creep-stressed components, problems of welding in large structures. 7 of the total number of 12 contributions were recorded separately for the data base ENERGY. (orig./MM) [de

  4. T-stresses for internally cracked components

    International Nuclear Information System (INIS)

    Fett, T.

    1997-12-01

    The failure of cracked components is governed by the stresses in the vicinity of the crack tip. The singular stress contribution is characterised by the stress intensity factor K, the first regular stress term is represented by the so-called T-stress. T-stress solutions for components containing an internal crack were computed by application of the Bundary Collocation Method (BCM). The results are compiled in form of tables or approximative relations. In addition a Green's function of T-stresses is proposed for internal cracks which enables to compute T-stress terms for any given stress distribution in the uncracked body. (orig.) [de

  5. Analysis Components Investigation Report

    Science.gov (United States)

    2014-10-01

    ssification a the marg ford and h ures such ge of this l s integratio PREVIOUS WRI ities. For in annotating ame meanin ck by valid rest. These ansion...ent to rder. order. rder el has d to the val, and learning , which ibrary is oo! and feature ovides a Analys 4 4 1 is Component THIS DOCU... learn m tor Machin sed to give to re-rank be execut he model w s the follow ed by any the trainin ciated with ation of the the docume all terms

  6. Impedance of accelerator components

    International Nuclear Information System (INIS)

    Corlett, J.N.

    1996-05-01

    As demands for high luminosity and low emittance particle beams increase, an understanding of the electromagnetic interaction of these beams with their vacuum chamber environment becomes more important in order to maintain the quality of the beam. This interaction is described in terms of the wake field in time domain, and the beam impedance in frequency domain. These concepts are introduced, and related quantities such as the loss factor are presented. The broadband Q = 1 resonator impedance model is discussed. Perturbation and coaxial wire methods of measurement of real components are reviewed

  7. Automotive component failures

    CSIR Research Space (South Africa)

    Heyes, AM

    1998-06-01

    Full Text Available [ However\\ in the presence of a stress concentration the ultimate tensile stress can be exceeded before the ultimate shear stress is reached\\ resulting in a tensile failure 0 [ 2[6[ Metallo`raphy and Ener`y Dispersive Spectroscopy "EDS# A microspecimen...\\ Vol[ 4\\ No[ 1\\ pp[ 018 030\\ 0887 0887 Elsevier Science Ltd[ All rights reserved\\ Pergamon Printed in Great Britain 0249 5296:87 ,08[99 9[99 PII] S0249 5296"87#99909 6 AUTOMOTIVE COMPONENT FAILURES A[ M[ HEYES Advanced Engineering and Testing...

  8. Food Components and Supplements

    DEFF Research Database (Denmark)

    Parlesak, Alexandr

    2012-01-01

    .g., secondary plant metabolites such as flavonoids), or as contaminants that enter the food chain at different stages or during the food production process. For these components, a wide spectrum of biological effects was observed that ranges from health-threatening impacts (e.g., polycyclic aromatic amines...... acting as carcinogens) to health-protective effects (e.g., flavonoids ameliorating detrimental effects of mitochondrial oxidative stress). In particular, secondary plant metabolites along with vitamins, specific types of macronutrients and live bacteria (probiotics) as well as substances promoting...

  9. Mesh Retrieval by Components

    Science.gov (United States)

    Tal, Ayellet; Zuckerberger, Emanuel

    This paper examines the application of the human vision theories of Marr and Biederman to the retrieval of three-dimensional objects. The key idea is to represent an object by an attributed graph that consists of the object's meaningful components as nodes, where each node is fit to a basic shape. A system that realizes this approach was built and tested on a database of about 400 objects and achieves promising results. It is shown that this representation of 3D objects is very compact. Moreover, it gives rise to a retrieval algorithm that is invariant to non-rigid transformations and does not require normalization.

  10. Prognostics for Microgrid Components

    Science.gov (United States)

    Saxena, Abhinav

    2012-01-01

    Prognostics is the science of predicting future performance and potential failures based on targeted condition monitoring. Moving away from the traditional reliability centric view, prognostics aims at detecting and quantifying the time to impending failures. This advance warning provides the opportunity to take actions that can preserve uptime, reduce cost of damage, or extend the life of the component. The talk will focus on the concepts and basics of prognostics from the viewpoint of condition-based systems health management. Differences with other techniques used in systems health management and philosophies of prognostics used in other domains will be shown. Examples relevant to micro grid systems and subsystems will be used to illustrate various types of prediction scenarios and the resources it take to set up a desired prognostic system. Specifically, the implementation results for power storage and power semiconductor components will demonstrate specific solution approaches of prognostics. The role of constituent elements of prognostics, such as model, prediction algorithms, failure threshold, run-to-failure data, requirements and specifications, and post-prognostic reasoning will be explained. A discussion on performance evaluation and performance metrics will conclude the technical discussion followed by general comments on open research problems and challenges in prognostics.

  11. Interactions between photodegradation components

    Directory of Open Access Journals (Sweden)

    Abdollahi Yadollah

    2012-09-01

    Full Text Available Abstract Background The interactions of p-cresol photocatalytic degradation components were studied by response surface methodology. The study was designed by central composite design using the irradiation time, pH, the amount of photocatalyst and the p-cresol concentration as variables. The design was performed to obtain photodegradation % as actual responses. The actual responses were fitted with linear, two factor interactions, cubic and quadratic model to select an appropriate model. The selected model was validated by analysis of variance which provided evidences such as high F-value (845.09, very low P-value (2 = 0.999, adjusted R-squared (Radj2 = 0.998, predicted R-squared (Rpred2 = 0.994 and the adequate precision (95.94. Results From the validated model demonstrated that the component had interaction with irradiation time under 180 min of the time while the interaction with pH was above pH 9. Moreover, photocatalyst and p-cresol had interaction at minimal amount of photocatalyst (p-cresol. Conclusion These variables are interdependent and should be simultaneously considered during the photodegradation process, which is one of the advantages of the response surface methodology over the traditional laboratory method.

  12. Chondrites and their Components

    Science.gov (United States)

    Scott, E. R. D.; Krot, A. N.

    2003-12-01

    What are Chondrites?Chondrites are meteorites that provide the best% clues to the origin of the solar system. They are the oldest known rocks - their components formed during the birth of the solar system ca. 4,567 Ma - and their abundances of nonvolatile elements are close to those in the solar photosphere. Chondrites are broadly ultramafic in composition, consisting largely of iron, magnesium, silicon, and oxygen. The most abundant constituents of chondrites are chondrules, which are igneous particles that crystallized rapidly in minutes to hours. They are composed largely of olivine and pyroxene, commonly contain metallic Fe,Ni and are 0.01-10 mm in size. Some chondrules are rounded as they were once entirely molten but many are irregular in shape because they were only partly melted or because they accreted other particles as they solidified. Chondrites themselves were never molten. The definition of a chondrite has expanded recently with the discovery in Antarctica and the Sahara Desert of extraordinary meteorites with chondrules 10-100 μm in size, and chondrites so rich in metallic Fe,Ni that they were initially classified as iron meteorites with silicate inclusions. Thus, in meteoritics, as in other fields of planetary science, new discoveries sometimes require definitions to be modified.Chondrites are so diverse in their mineralogical and textural characteristics that it is not possible to describe a typical chondrite. We show one with diversely textured chondrules including prominent, aesthetically pleasing, rounded chondrules (Figure 1(a)), and another with more uniformly textured chondrules (Figure 1(b)). Owing to the high abundance of rounded or droplet chondrules in the abundant, so-called "ordinary" chondrites ( Figure 1(a)), studies of the origin of chondrules have commonly been based on these chondrites. (7K)Figure 1. Maps showing magnesium concentrations in two chondrites: (a) PCA91082, a CR2 carbonaceous chondrite, and (b) Tieschitz, an H/L3

  13. Modeling accelerator structures and RF components

    International Nuclear Information System (INIS)

    Ko, K., Ng, C.K.; Herrmannsfeldt, W.B.

    1993-03-01

    Computer modeling has become an integral part of the design and analysis of accelerator structures RF components. Sophisticated 3D codes, powerful workstations and timely theory support all contributed to this development. We will describe our modeling experience with these resources and discuss their impact on ongoing work at SLAC. Specific examples from R ampersand D on a future linear collide and a proposed e + e - storage ring will be included

  14. Component Based Testing with ioco

    NARCIS (Netherlands)

    van der Bijl, H.M.; Rensink, Arend; Tretmans, G.J.

    Component based testing concerns the integration of components which have already been tested separately. We show that, with certain restrictions, the ioco-test theory for conformance testing is suitable for component based testing, in the sense that the integration of fully conformant components is

  15. Component Composition Using Feature Models

    DEFF Research Database (Denmark)

    Eichberg, Michael; Klose, Karl; Mitschke, Ralf

    2010-01-01

    In general, components provide and require services and two components are bound if the first component provides a service required by the second component. However, certain variability in services - w.r.t. how and which functionality is provided or required - cannot be described using standard i...

  16. Component failure data handbook

    International Nuclear Information System (INIS)

    Gentillon, C.D.

    1991-04-01

    This report presents generic component failure rates that are used in reliability and risk studies of commercial nuclear power plants. The rates are computed using plant-specific data from published probabilistic risk assessments supplemented by selected other sources. Each data source is described. For rates with four or more separate estimates among the sources, plots show the data that are combined. The method for combining data from different sources is presented. The resulting aggregated rates are listed with upper bounds that reflect the variability observed in each rate across the nuclear power plant industry. Thus, the rates are generic. Both per hour and per demand rates are included. They may be used for screening in risk assessments or for forming distributions to be updated with plant-specific data

  17. Impedance and component heating

    CERN Document Server

    Métral, E; Mounet, N; Pieloni, T; Salvant, B

    2015-01-01

    The impedance is a complex function of frequency, which represents, for the plane under consideration (longitudinal, horizontal or vertical), the force integrated over the length of an element, from a “source” to a “test” wave, normalized by their charges. In general, the impedance in a given plane is a nonlinear function of the test and source transverse coordinates, but it is most of the time sufficient to consider only the first few linear terms. Impedances can influence the motion of trailing particles, in the longitudinal and in one or both transverse directions, leading to energy loss, beam instabilities, or producing undesirable secondary effects such as excessive heating of sensitive components at or near the chamber wall, called beam-induced RF heating. The LHC performance limitations linked to impedances encountered during the 2010-2012 run are reviewed and the currently expected situation during the HL-LHC era is discussed.

  18. Food Components and Supplements

    DEFF Research Database (Denmark)

    Parlesak, Alexandr

    2012-01-01

    The major part of food consists of chemical compounds that can be used for energy production, biological synthesis, or maintenance of metabolic processes by the host. These components are defined as nutrients, and can be categorized into macronutrients (proteins, carbohydrates, triglycerides......, and alcohol), minerals, and micronutrients. The latter category comprises 13 vitamins and a hand full of trace elements. Many micronutrients are used as food supplements and are ingested at doses exceeding the amounts that can be consumed along with food by a factor of 10–100. Both macro- and micronutrients...... can interact with enzyme systems related to xenobiotic metabolism either by regulation of their expression or direct interference with their enzymatic activity. During food consumption, we consume a wide range of xenobiotics along with the consumable food, either as an original part of the food (e...

  19. High thermal load component

    International Nuclear Information System (INIS)

    Fuse, Toshiaki; Tachikawa, Nobuo.

    1996-01-01

    A cooling tube made of a pure copper is connected to the inner portion of an armour (heat resistant member) made of an anisotropic carbon/carbon composite (CFC) material. The CFC material has a high heat conductivity in longitudinal direction of fibers and has low conductivity in perpendicular thereto. Fibers extending in the armour from a heat receiving surface just above the cooling tube are directly connected to the cooling tube. A portion of the fibers extending from a heat receiving surface other than portions not just above the cooling tube is directly bonded to the cooling tube. Remaining fibers are disposed so as to surround the cooling tube. The armour and the cooling tube are soldered using an active metal flux. With such procedures, high thermal load components for use in a thermonuclear reactor are formed, which are excellent in a heat removing characteristic and hardly causes defects such as crackings and peeling. (I.N.)

  20. Autonomous component carrier selection

    DEFF Research Database (Denmark)

    Garcia, Luis Guilherme Uzeda; Pedersen, Klaus; Mogensen, Preben

    2009-01-01

    management and efficient system operation. Due to the expected large number of user-deployed cells, centralized network planning becomes unpractical and new scalable alternatives must be sought. In this article, we propose a fully distributed and scalable solution to the interference management problem......Low-power base stations such as e.g. Femto-cells are one of the candidates for high data rate provisioning in local areas, such as residences, apartment complexes, business offices and outdoor hotspot scenarios. Unfortunately, the benefits are not without new challenges in terms of interference...... in local areas, basing our study case on LTE-Advanced. We present extensive network simulation results to demonstrate that a simple and robust interference management scheme, called autonomous component carrier selection allows each cell to select the most attractive frequency configuration; improving...

  1. Solar bowl component efficiencies

    International Nuclear Information System (INIS)

    O'Hair, E.A.; Green, B.L.

    1992-01-01

    Battelle Pacific Northwest Laboratory has published two volumes on the economic evaluation of various proposed configurations and plant sizes for the four solar thermal technologies. These are the latest in a series of publications sponsored by the Department of Energy (DOE) on plant and operational costs and are more complete in that they include calculations of electrical output. These latest Battelle volumes use the 1976 solar data from Barstow, Calif., and by calculating or estimating the energy conversion efficiency of each element in the process from sun to electricity predict the output and cost of electricity from different plant sizes for each of the four technologies. In this paper a comparison is presented of the component efficiencies developed by Battelle and those of the solar bowl at Crosbyton, Tex

  2. How Many Separable Sources? Model Selection In Independent Components Analysis

    DEFF Research Database (Denmark)

    Woods, Roger P.; Hansen, Lars Kai; Strother, Stephen

    2015-01-01

    Unlike mixtures consisting solely of non-Gaussian sources, mixtures including two or more Gaussian components cannot be separated using standard independent components analysis methods that are based on higher order statistics and independent observations. The mixed Independent Components Analysis....../Principal Components Analysis (mixed ICA/PCA) model described here accommodates one or more Gaussian components in the independent components analysis model and uses principal components analysis to characterize contributions from this inseparable Gaussian subspace. Information theory can then be used to select from...... among potential model categories with differing numbers of Gaussian components. Based on simulation studies, the assumptions and approximations underlying the Akaike Information Criterion do not hold in this setting, even with a very large number of observations. Cross-validation is a suitable, though...

  3. National contributions to observed global warming

    International Nuclear Information System (INIS)

    Matthews, H Damon; Graham, Tanya L; Keverian, Serge; Lamontagne, Cassandra; Seto, Donny; Smith, Trevor J

    2014-01-01

    There is considerable interest in identifying national contributions to global warming as a way of allocating historical responsibility for observed climate change. This task is made difficult by uncertainty associated with national estimates of historical emissions, as well as by difficulty in estimating the climate response to emissions of gases with widely varying atmospheric lifetimes. Here, we present a new estimate of national contributions to observed climate warming, including CO 2 emissions from fossil fuels and land-use change, as well as methane, nitrous oxide and sulfate aerosol emissions While some countries’ warming contributions are reasonably well defined by fossil fuel CO 2 emissions, many countries have dominant contributions from land-use CO 2 and non-CO 2 greenhouse gas emissions, emphasizing the importance of both deforestation and agriculture as components of a country’s contribution to climate warming. Furthermore, because of their short atmospheric lifetime, recent sulfate aerosol emissions have a large impact on a country’s current climate contribution We show also that there are vast disparities in both total and per-capita climate contributions among countries, and that across most developed countries, per-capita contributions are not currently consistent with attempts to restrict global temperature change to less than 2 °C above pre-industrial temperatures. (paper)

  4. Optical communication components

    Science.gov (United States)

    Eldada, Louay

    2004-03-01

    We review and contrast key technologies developed to address the optical components market for communication applications. We first review the component requirements from a network perspective. We then look at different material systems, compare their properties, and describe the functions achieved to date in each of them. The material systems reviewed include silica fiber, silica on silicon, silicon on insulator, silicon oxynitride, sol-gels, polymers, thin-film dielectrics, lithium niobate, indium phosphide, gallium arsenide, magneto-optic materials, and birefringent crystals. We then describe the most commonly used classes of optical device technology and present their pros and cons as well as the functions achieved to date in each of them. The technologies reviewed include passive, actuation, and active technologies. The passive technologies described include fused fibers, dispersion-compensating fiber, beam steering, Bragg gratings, diffraction gratings, holographic elements, thin-film filters, photonic crystals, microrings, and birefringent elements. The actuation technologies include thermo-optics, electro-optics, acousto-optics, magneto-optics, electroabsorption, liquid crystals, total internal reflection technologies, and mechanical actuation. The active technologies include heterostructures, quantum wells, rare-earth doping, dye doping, Raman amplification, and semiconductor amplification. We also investigate the use of different material systems and device technologies to achieve building-block functions, including lasers, amplifiers, detectors, modulators, polarization controllers, couplers, filters, switches, attenuators, isolators, circulators, wavelength converters, chromatic dispersion compensators, and polarization mode dispersion compensators. Some of the technologies presented are well established in the industry and in some cases have reached the commodity stage, others have recently become ready for commercial introduction, while some others

  5. Autophagy Contributes to the Death/Survival Balance in Cancer PhotoDynamic Therapy

    Directory of Open Access Journals (Sweden)

    Luciana Dini

    2012-08-01

    Full Text Available Autophagy is an important cellular program with a “double face” role, since it promotes either cell survival or cell death, also in cancer therapies. Its survival role occurs by recycling cell components during starvation or removing stressed organelles; when damage becomes extensive, autophagy provides another programmed cell death pathway, known as Autophagic Cell Death (ACD. The induction of autophagy is a common outcome in PhotoDynamic Therapy (PDT, a two-step process involving the irradiation of photosensitizer (PS-loaded cancer cells. Upon tissue oxygen interaction, PS provokes immediate and direct Reactive Oxygen Species (ROS-induced damage to Endoplasmic Reticulum (ER, mitochondria, plasma membrane, and/or lysosomes. The main biological effects carried out in cancer PDT are direct cytotoxicity to tumor cells, vasculature damage and induction of inflammatory reactions stimulating immunological responses. The question about the role of autophagy in PDT and its putative immunological impact is hotly controversial and largely studied in recent times. This review deals with the induction of autophagy in PDT protocols and its dual role, also considering its interrelationship with apoptosis, the preferential cell death program triggered in the photodynamic process.

  6. Modified planar functions and their components

    DEFF Research Database (Denmark)

    Anbar Meidl, Nurdagül; Meidl, Wilfried Meidl

    2017-01-01

    functions in odd characteristic as a vectorial bent function. We finally point out that though these components behave somewhat different than the multivariate bent4 functions, they are bent or semibent functions shifted by a certain quadratic term, a property which they share with their multivariate......Zhou ([20]) introduced modified planar functions in order to describe (2n; 2n; 2n; 1) relative difference sets R as a graph of a function on the finite field F2n, and pointed out that projections of R are difference sets that can be described by negabent or bent4 functions, which are Boolean...... functions given in multivariate form. One of the objectives of this paper is to contribute to the understanding of these component functions of modified planar functions. Moreover, we obtain a description of modified planar functions by their components which is similar to that of the classical planar...

  7. Computational Support for the Selection of Energy Saving Building Components

    NARCIS (Netherlands)

    De Wilde, P.J.C.J.

    2004-01-01

    Buildings use energy for heating, cooling and lighting, contributing to the problems of exhaustion of fossil fuel supplies and environmental pollution. In order to make buildings more energy-efficient an extensive set of âenergy saving building componentsâ has been developed that contributes to

  8. Folliculin contributes to VHL tumor suppressing activity in renal cancer through regulation of autophagy.

    Directory of Open Access Journals (Sweden)

    Prabhat Bastola

    Full Text Available Von Hippel-Lindau tumor suppressor (VHL is lost in the majority of clear cell renal cell carcinomas (ccRCC. Folliculin (FLCN is a tumor suppressor whose function is lost in Birt-Hogg-Dubé syndrome (BHD, a disorder characterized by renal cancer of multiple histological types including clear cell carcinoma, cutaneous fibrofolliculoma, and pneumothorax. Here we explored whether there is connection between VHL and FLCN in clear cell renal carcinoma cell lines and tumors. We demonstrate that VHL regulates expression of FLCN at the mRNA and protein levels in RCC cell lines, and that FLCN protein expression is decreased in human ccRCC tumors with VHL loss, as compared with matched normal kidney tissue. Knockdown of FLCN results in increased formation of tumors by RCC cells with wild-type VHL in orthotopic xenografts in nude mice, an indication that FLCN plays a role in the tumor-suppressing activity of VHL. Interestingly, FLCN, similarly to VHL, is necessary for the activity of LC3C-mediated autophagic program that we have previously characterized as contributing to the tumor suppressing activity of VHL. The results show the existence of functional crosstalk between two major tumor suppressors in renal cancer, VHL and FLCN, converging on regulation of autophagy.

  9. Newton's Contributions to Optics

    Indian Academy of Sciences (India)

    Home; Journals; Resonance – Journal of Science Education; Volume 11; Issue 12. Newton's Contributions to Optics. Arvind Kumar. General Article Volume 11 Issue 12 December 2006 pp 10-20. Fulltext. Click here to view fulltext PDF. Permanent link: http://www.ias.ac.in/article/fulltext/reso/011/12/0010-0020. Keywords.

  10. Newton's Contributions to Optics

    Indian Academy of Sciences (India)

    Home; Journals; Resonance – Journal of Science Education; Volume 11; Issue 12. Newton's Contributions to Optics. Arvind Kumar. General Article Volume 11 Issue 12 December 2006 pp 10-20. Fulltext. Click here to view fulltext PDF. Permanent link: https://www.ias.ac.in/article/fulltext/reso/011/12/0010-0020. Keywords.

  11. Newton's Contributions to Optics

    Indian Academy of Sciences (India)

    Newton's Contributions to Optics. Arvind Kumar is Director,. Homi Bhabha Centre for. Science Education,. Mumbai. His main areas of interest are theoretical physics and physics education. He has been involved ... early 1666, when he was a scholar at Trinity College, Cambridge. He aligned a triangular prism in the path of a ...

  12. Fisher's Contributions to Statistics

    Indian Academy of Sciences (India)

    research workers of various disciplines in designing their studies and in analysing data thereof. He is also called upon to advise organisations like the ... such visual aids. It is believed that this situation helped him develop a keen geometrical sense. Fisher's contributions to statistics have also given rise to a number of bitter ...

  13. Radiation damage in components

    International Nuclear Information System (INIS)

    Takano, Tomehachi

    1977-01-01

    The performance change of typical capacitors and resistors in electronic components by Co-60 γ-irradiation from the 1320 Ci source was examined in the range of 10 5 to 10 8 R. Specifically, the characteristic change during irradiation and the recovery after irradiation were continuously observed. The capacity change is +2.4% at maximum in ceramic and metallized paper capacitors, and -2.4% at maximum in mylar and paper capacitors. It is also +-0.4% at maximum in mica and polystyrene capacitors. Some of these capacitors showed the recovery of the capacity change, but the others did not. Dielectric loss varied by 15% at larger dose in some capacitors, and the recovery was not observed. While, the insulation resistance of the resistors of 10 15 Ω or more lowered to 10 13 Ω or less after 10 to 30 sec. irradiation, but recovered soon nearly to the initial values after irradiation was interrupted. The resistance change of carbon film resistors is about 0.2 to 2%, and recovered to the initial values in 100 hours after irradiation. The resistance change of composition resistors is large over the range of -13 to +35%, besides, no sign of recovery was seen. In carbon film resistors, the surface insulated type indicated far better results which are assumed to be caused by the selection of element materials and the forming of coating materials. (Wakatsuki, Y.)

  14. Control component structure

    International Nuclear Information System (INIS)

    Walton, L.A.

    1982-01-01

    This invention provides a control component structure comprising: a spider having a plurality of arms, at least one spider bore formed in said plurality of arms, said spider bore including an enlarged recess and a small recess with an upright truncated conical section forming a transition from the enlarged recess to the small recess, and a burnable poison rod including a tube terminating in transverse end, a plug with a chamfered end that leads into a cylindrical portion, said cylindrical portion of the plug snugly fitting within the tube and terminating in a radially protruding shoulder which engages the transverse end of the tube to which it is welded, and a stem protruding in the longitudinal direction from the central portion of the shoulder having a longitudinal stem bore extending through about half of the length of the stem, at least part of the stem which defines the stem bore being fixed within the truncated conical section, the enlarged recess and the small recess of the spider by outward deformation of that part of the stem in order to releasably attach the rod to the spider, said stem being adapted to substantially reshape itself by movement of the rod in a longitudinal direction with respect to the spider bore, while maintaining the structural integrity of the poison rod and maintaining the structural integrity of the spider

  15. Magnesium for Crashworthy Components

    Science.gov (United States)

    Abbott, T.; Easton, M.; Schmidt, R.

    Most applications of magnesium in automobiles are for nonstructural components. However, the light weight properties of magnesium make it attractive in structural applications where energy absorption in a crash is critical. Because most deformation in a crash occurs as bending rather than simple tension or compression, the advantages of magnesium are greater than anticipated simply from tensile strength to weight ratios. The increased thickness possible with magnesium strongly influences bending behavior and theoretical calculations suggest almost an order of magnitude greater energy absorption with magnesium compared to the same weight of steel. The strain rate sensitivity of steel is of concern for energy absorption. Mild steels exhibit a distinct yield point which increases with strain rate. At strain rates typical of vehicle impact, this can result in strain localization and poor energy absorption. Magnesium alloys with relatively low aluminum contents exhibit strain rate sensitivity, however, this is manifest as an increase in work hardening and tensile / yield ratio. This behavior suggests that the performance of magnesium alloys in terms of energy absorption actually improves at high strain rates.

  16. Security Components of Globalization

    Directory of Open Access Journals (Sweden)

    Florin Iftode

    2015-05-01

    Full Text Available The objective of this paper is our intention to present what are the main connections between globalization and international security. In terms of global security we can perceive the globalization as a process by which global state is represented by the UN, with a single world system, represented by major security organizations and with global effects. We will present from the beginning the main theoretical aspects that define the phenomenon of globalization, and then our contribution in assessing the implications of this phenomenon on the regional and global security. The results of our research are materialized in the last part of the paper. They emphasize the personal assessments on how the phenomenon of globalization has direct effect on global security. When talking about government, we think of norms, rules and decisionmaking procedures in the management of international life. The value that we add to the new scientific interpretation of the definition of globalization is represented, primarily, by the valuable bibliographic used resources and the original approach on the concept that refers to the links between globalization and security. This article may be, at any time, a starting point in an interesting research direction in the field of global security.

  17. Abstracts of contributed papers

    Energy Technology Data Exchange (ETDEWEB)

    1994-08-01

    This volume contains 571 abstracts of contributed papers to be presented during the Twelfth US National Congress of Applied Mechanics. Abstracts are arranged in the order in which they fall in the program -- the main sessions are listed chronologically in the Table of Contents. The Author Index is in alphabetical order and lists each paper number (matching the schedule in the Final Program) with its corresponding page number in the book.

  18. Contributions to statistics

    CERN Document Server

    Mahalanobis, P C

    1965-01-01

    Contributions to Statistics focuses on the processes, methodologies, and approaches involved in statistics. The book is presented to Professor P. C. Mahalanobis on the occasion of his 70th birthday. The selection first offers information on the recovery of ancillary information and combinatorial properties of partially balanced designs and association schemes. Discussions focus on combinatorial applications of the algebra of association matrices, sample size analogy, association matrices and the algebra of association schemes, and conceptual statistical experiments. The book then examines latt

  19. Contributions to sampling statistics

    CERN Document Server

    Conti, Pier; Ranalli, Maria

    2014-01-01

    This book contains a selection of the papers presented at the ITACOSM 2013 Conference, held in Milan in June 2013. ITACOSM is the bi-annual meeting of the Survey Sampling Group S2G of the Italian Statistical Society, intended as an international  forum of scientific discussion on the developments of theory and application of survey sampling methodologies and applications in human and natural sciences. The book gathers research papers carefully selected from both invited and contributed sessions of the conference. The whole book appears to be a relevant contribution to various key aspects of sampling methodology and techniques; it deals with some hot topics in sampling theory, such as calibration, quantile-regression and multiple frame surveys, and with innovative methodologies in important topics of both sampling theory and applications. Contributions cut across current sampling methodologies such as interval estimation for complex samples, randomized responses, bootstrap, weighting, modeling, imputati...

  20. Towards Prognostics for Electronics Components

    Data.gov (United States)

    National Aeronautics and Space Administration — Electronics components have an increasingly critical role in avionics systems and in the development of future aircraft systems. Prognostics of such components is...

  1. Software Components for Web Services

    OpenAIRE

    Ramachandran, Muthu; Nair, T. R. Gopalakrsihnan; Selvarani, R.

    2010-01-01

    Service-oriented computing has emerged as the new area to address software as a service. This paper proposes a model for component based development for service-oriented systems and have created best practice guidelines on software component design.

  2. Statistics of Shared Components in Complex Component Systems

    Science.gov (United States)

    Mazzolini, Andrea; Gherardi, Marco; Caselle, Michele; Cosentino Lagomarsino, Marco; Osella, Matteo

    2018-04-01

    Many complex systems are modular. Such systems can be represented as "component systems," i.e., sets of elementary components, such as LEGO bricks in LEGO sets. The bricks found in a LEGO set reflect a target architecture, which can be built following a set-specific list of instructions. In other component systems, instead, the underlying functional design and constraints are not obvious a priori, and their detection is often a challenge of both scientific and practical importance, requiring a clear understanding of component statistics. Importantly, some quantitative invariants appear to be common to many component systems, most notably a common broad distribution of component abundances, which often resembles the well-known Zipf's law. Such "laws" affect in a general and nontrivial way the component statistics, potentially hindering the identification of system-specific functional constraints or generative processes. Here, we specifically focus on the statistics of shared components, i.e., the distribution of the number of components shared by different system realizations, such as the common bricks found in different LEGO sets. To account for the effects of component heterogeneity, we consider a simple null model, which builds system realizations by random draws from a universe of possible components. Under general assumptions on abundance heterogeneity, we provide analytical estimates of component occurrence, which quantify exhaustively the statistics of shared components. Surprisingly, this simple null model can positively explain important features of empirical component-occurrence distributions obtained from large-scale data on bacterial genomes, LEGO sets, and book chapters. Specific architectural features and functional constraints can be detected from occurrence patterns as deviations from these null predictions, as we show for the illustrative case of the "core" genome in bacteria.

  3. Components of Burden: Interventive Implications.

    Science.gov (United States)

    Kosberg, Jordan I.; And Others

    1990-01-01

    Studied 127 informal caregivers of Alzheimer's disease patients to determine correlates of 5 components of burden as measured by Cost of Care Index. Significant relationships between predictor variables and burden components suggest that global scores and measures of burden do not identify specific problem areas relative to various components of…

  4. Performance Engineering Technology for Scientific Component Software

    Energy Technology Data Exchange (ETDEWEB)

    Malony, Allen D.

    2007-05-08

    Large-scale, complex scientific applications are beginning to benefit from the use of component software design methodology and technology for software development. Integral to the success of component-based applications is the ability to achieve high-performing code solutions through the use of performance engineering tools for both intra-component and inter-component analysis and optimization. Our work on this project aimed to develop performance engineering technology for scientific component software in association with the DOE CCTTSS SciDAC project (active during the contract period) and the broader Common Component Architecture (CCA) community. Our specific implementation objectives were to extend the TAU performance system and Program Database Toolkit (PDT) to support performance instrumentation, measurement, and analysis of CCA components and frameworks, and to develop performance measurement and monitoring infrastructure that could be integrated in CCA applications. These objectives have been met in the completion of all project milestones and in the transfer of the technology into the continuing CCA activities as part of the DOE TASCS SciDAC2 effort. In addition to these achievements, over the past three years, we have been an active member of the CCA Forum, attending all meetings and serving in several working groups, such as the CCA Toolkit working group, the CQoS working group, and the Tutorial working group. We have contributed significantly to CCA tutorials since SC'04, hosted two CCA meetings, participated in the annual ACTS workshops, and were co-authors on the recent CCA journal paper [24]. There are four main areas where our project has delivered results: component performance instrumentation and measurement, component performance modeling and optimization, performance database and data mining, and online performance monitoring. This final report outlines the achievements in these areas for the entire project period. The submitted progress

  5. Specific distribution of the autophagic protein GABARAPL1/GEC1 in the developing and adult mouse brain and identification of neuronal populations expressing GABARAPL1/GEC1.

    Directory of Open Access Journals (Sweden)

    Jaclyn Nicole Le Grand

    Full Text Available Macroautophagy is a highly conserved cellular degradation process, regulated by autophagy-related (atg factors, in which a double membrane autophagosome engulfs cytoplasmic components to target them for degradation. In yeast, the Atg8 protein is indispensable for autophagosome formation. In mammals, this is complicated by the presence of six Atg8 homologues grouped into the GABARAP and MAP1LC3 subfamilies. Although these proteins share a high similarity, their transcript expression, regulation and protein interactions differ, suggesting they may display individual properties and specific functions. GABARAPL1/GEC1 is a member of the GABARAP subfamily and its mRNA is the most highly expressed Atg8 homologue in the central nervous system. Consequently, we performed an in depth study of GABARAPL1 distribution in the developing and adult murine brain. Our results show that GABARAPL1 brain expression is visible as early as embryonic day 11 and progressively increases to a maximum level in the adult. Immunohistochemical staining was detected in both fibers and immature neurons in embryos but was restrained to neurons in adult tissue. By E17, intense punctate-like structures were visible and these accumulated in cortical primary neurons treated with the autophagosome/lysosome fusion inhibitor Bafilomycin A1 (Baf A1, suggesting that they represent autophagosomes. Finally, GABARAPL1 expression was particularly intense in motoneurons in the embryo and in neurons involved in somatomotor and neuroendocrine functions in the adult, particularly in the substantia nigra pars compacta, a region affected in Parkinson's disease. Our study of cerebral GABARAPL1 protein expression provides insight into its role in the development and homeostasis of the mouse brain.

  6. IL-33 Provides Neuroprotection through Suppressing Apoptotic, Autophagic and NF-κB-Mediated Inflammatory Pathways in a Rat Model of Recurrent Neonatal Seizure

    Directory of Open Access Journals (Sweden)

    Yuan Gao

    2017-12-01

    Full Text Available Interleukin-33 (IL-33 is a novel identified chromatin-associated cytokine of IL-1 family cytokines. It signals through a heterodimer comprised of ST2L and IL-1RAcp, and plays a crucial role in many diseases. However, very little is known about the role and underlying intricate mechanisms of IL-33 in recurrent neonatal seizure (RNS. To determine whether IL-33 plays an important regulatory role, we established a neonatal seizure model in this study. Rats were subjected to recurrent seizures induced by inhaling volatile flurothyl. Recombinant IL-33 or PBS were also administered by intraperitoneally (IP before surgery, respectively. Here, our current results indicated that RNS contributed to a significant reduction in IL-33 and its specific receptor (ST2L expressions in cortex. While, in hippocampus, RNS induced an increase in IL-33 and ST2L evidently, compared with Sham group. After injection with IL-33, however, a remarkable increase in total IL-33 was detected both in brain cortex and hippocampus. In addition, IL-33 was mainly co-localized in the nuclear of GFAP+ astrocytes and the cytoplasm of the Iba-1+ microglia and IL-33+/NeuN+ merged cells. In parallel, ST2L was expressed mainly in the membrane of GFAP+ astrocytes, Iba-1+ microglia and NeuN+ neurons, respectively. Furthermore, administration of IL-33 improved RNS-induced behavioral deficits, promoted bodyweight gain, and ameliorated spatial learning and memory ability. Moreover, IL-33 pretreatment blocked the activation of NF-κB, resisted inflammatory cytokines IL-1β and TNF-α increase, as well as suppressed apoptosis and autophagy activation after RNS. Collectively, IL-33 provides potential neuroprotection through suppressing apoptosis, autophagy and at least in part by NF-κB-mediated inflammatory pathways after RNS.

  7. Unblockable Compositions of Software Components

    DEFF Research Database (Denmark)

    Dong, Ruzhen; Faber, Johannes; Liu, Zhiming

    2012-01-01

    . To this end, we develop an algorithm to compute the unblockable interaction behavior, called the interface model of a component, from its execution model. Based on this model, we introduce composition operators for the components and prove important compositionality results, showing the conditions under which......We present a new automata-based interface model describing the interaction behavior of software components. Contrary to earlier component- or interface-based approaches, the interface model we propose specifies all the non-blockable interaction behaviors of a component with any environment...

  8. Tank waste isotope contributions

    International Nuclear Information System (INIS)

    VANKEUREN, J.C.

    1999-01-01

    This document presents the results of a calculation to determine the relative contribution of selected isotopes to the inhalation and ingestion doses for a postulated release of Hanford tank waste. The fraction of the dose due to 90 Sr, 90 Y, 137 Cs and the alpha emitters for single shell solids and liquids, double shell solids and liquids, aging waste solids and liquids and all solids and liquids. An effective dose conversion factor was also calculated for the alpha emitters for each composite of the tank waste

  9. Application of fuzzy-MOORA method: Ranking of components for reliability estimation of component-based software systems

    Directory of Open Access Journals (Sweden)

    Zeeshan Ali Siddiqui

    2016-01-01

    Full Text Available Component-based software system (CBSS development technique is an emerging discipline that promises to take software development into a new era. As hardware systems are presently being constructed from kits of parts, software systems may also be assembled from components. It is more reliable to reuse software than to create. It is the glue code and individual components reliability that contribute to the reliability of the overall system. Every component contributes to overall system reliability according to the number of times it is being used, some components are of critical usage, known as usage frequency of component. The usage frequency decides the weight of each component. According to their weights, each component contributes to the overall reliability of the system. Therefore, ranking of components may be obtained by analyzing their reliability impacts on overall application. In this paper, we propose the application of fuzzy multi-objective optimization on the basis of ratio analysis, Fuzzy-MOORA. The method helps us find the best suitable alternative, software component, from a set of available feasible alternatives named software components. It is an accurate and easy to understand tool for solving multi-criteria decision making problems that have imprecise and vague evaluation data. By the use of ratio analysis, the proposed method determines the most suitable alternative among all possible alternatives, and dimensionless measurement will realize the job of ranking of components for estimating CBSS reliability in a non-subjective way. Finally, three case studies are shown to illustrate the use of the proposed technique.

  10. Contributing to Functionality

    DEFF Research Database (Denmark)

    Törpel, Bettina

    2006-01-01

    advocated in this paper, emerges in the specific dynamic interplay of actors, objectives, structures, practices and means. In this view, functionality is the result of creating, harnessing and inhabiting computer supported joint action spaces. The successful creation and further development of a computer......The objective of this paper is the design of computer supported joint action spaces. It is argued against a view of functionality as residing in computer applications. In such a view the creation of functionality is equivalent to the creation of computer applications. Functionality, in the view...... supported joint action space comprises a whole range of appropriate design contributions. The approach is illustrated by the example of the creation of the computer supported joint action space "exchange network of voluntary union educators". As part of the effort a group of participants created...

  11. Biometric relationships of ocular components in esotropic amblyopia

    Directory of Open Access Journals (Sweden)

    Iara Debert

    2012-02-01

    Full Text Available PURPOSE: To investigate the contribution of the individual ocular components, i.e. anterior chamber depth, lens thickness and vitreous chamber depth, to total axial length in patients with esotropic amblyopia. METHODS: The study population consisted of 74 children, aged between 5 and 8 years: thirty-seven patients with esotropic amblyopia and 37 healthy volunteers (control group. The participants underwent a comprehensive ophthalmological examination, including cycloplegic refraction and A-scan ultrasonography. Anterior chamber depth, lens thickness, vitreous chamber depth and total axial length were recorded. Paired Student's t-tests were used to compare biometric measurements between amblyopic eyes and their fellow eyes and between right and left eyes in the control group. To evaluate the contribution of the ocular components to the total axial length, we report the individual components as a percentage of total axial length. RESULTS: The comparison between amblyopic and fellow eyes regarding the individual contribution from ocular components to the total axial length revealed greater contribution from lens thickness (P=0.001 and smaller contribution from vitreous chamber depth (P=0.001 in amblyopic eyes, despite similar contribution from anterior chamber depth (P=0.434. The comparison between right and left eyes in the control group showed similar contributions from anterior chamber depth (P=0.620, lens thickness (P=0.721, and vitreous chamber depth (P=0.483. CONCLUSIONS: This study shows differences between amblyopic and non-amblyopic eyes when the total axial length is broken down into the individual contribution from the ocular components.

  12. Contribuição dos componentes e composição química de pastagens em sistemas forrageiros constituídos por diferentes leguminosas Components contribution and chemical composition of pastures in forage systems with different legumes

    Directory of Open Access Journals (Sweden)

    Clair Jorge Olivo

    2010-12-01

    Full Text Available Realizou-se o presente trabalho com o objetivo de avaliar a composição química de dois sistemas forrageiros, tendo como componentes comuns o capim-elefante, o azevém e as espécies de crescimento espontâneo, variando em um sistema o consórcio com o trevo branco, e, em outro, com o amendoim forrageiro. Para avaliação, foram usados quatro piquetes com 0,25ha cada um. Como animais experimentais, foram utilizadas vacas em lactação da raça Holandesa. O delineamento experimental utilizado foi o inteiramente casualizado, com dois tratamentos (sistemas forrageiros e duas repetições (piquetes. Para análise de proteína bruta (PB, fibra em detergente neutro (FDN e fibra em detergente ácido (FDA, foram retiradas amostras através de simulação de pastejo. A participação dos componentes dos sistemas forrageiros variou segundo as leguminosas componentes. O sistema composto por amendoim forrageiro permitiu suportar maior carga no período estival. Os valores médios (pré e pós-pastejo para PB, FDN e FDA foram de 18,76; 71,46; 34,87% para o sistema forrageiro constituído com o trevo branco e de 19,31; 71,19 e 35,40%. Os resultados foram similares entre os sistemas forrageiros.The aim of this research was to evaluate the chemical composition of two pasture-based systems having as common components the elephantgrass, ryegrass and spontaneous growth species, in one system the white clover and, in another system, the forage peanut. Four paddocks, each one with 0.25ha, were used in the evaluation. Holstein cows were used in the evaluation. The experimental design was completely randomized, with two treatments (pasture-based systems, two replications (paddocks. To analyze the crude protein (CP, neutral detergent fiber (NDF and acid detergent fiber (ADF, hand-plucked samples were collected. Composition of forage systems changes according to its legumes compounds. Forage peanut system allowed a greater stocking rate in hot season. The mean values

  13. Demographic components of seasonality of pregnancy.

    Science.gov (United States)

    Kallan, J E; Udry, J R

    1989-01-01

    Previous studies of the seasonality of pregnancy and birth have typically been based on monthly numbers or proportions of pregnancies or births (i.e. their distribution throughout the year) without any explicit accounting of the size of the population actually at risk of pregnancy by month. From data on monthly populations at risk and monthly probabilities of pregnancy this paper determines the relative contribution of each component to the monthly distribution of pregnancies. The data come from the National Survey of Family Growth, Cycle III. While there is some seasonality in the size of the at-risk population, it contributes little to the overall monthly variation of pregnancy, which is determined mainly by seasonality of pregnancy probability (fecundability).

  14. Deterrence and WMD Terrorism: Calibrating Its Potential Contributions to Risk Reduction

    National Research Council Canada - National Science Library

    Roberts, Brad

    2007-01-01

    .... Those potential contributions can be brought into focus by disaggregating the militant Islamic extremist movement into the various components relevant to the intentions and capabilities for WMD terrorism...

  15. Open Component Portability Infrastructure (OPENCPI)

    Science.gov (United States)

    2013-03-01

    Integrated Circuit ( ASIC ) processor components. As used here, the HDL was applied to the Verilog, the Very High Speed Integrated Circuit (VHSIC...and a number of existing tests were migrated and ported into it. The motivation for selecting a unit test framework was to improve and enforce the...Interface ASIC Application-Specific Integrated Circuit BSV Bluespec System Verilog CBD Component-Based Development CDK Component Developer’s Kit

  16. Active Component Responsibility in Reserve Component Pre- and Postmobilization Training

    Science.gov (United States)

    2015-01-01

    President Lyndon Johnson refused to mobi- lize the RCs (MacCarley, 2012, pp. 38–39). 8 Active Component Responsibility in Reserve Component...ARFORGENwhitePaper1aug2011v3g2g.pdf Pernin, Christopher G., Dwayne M. Butler, Louay Constant, Lily Geyer, Duncan Long, Dan Madden, John E. Peters, James D. Powers

  17. Gamma dose effects valuation on micro computing components

    International Nuclear Information System (INIS)

    Joffre, F.

    1995-01-01

    Robotics in hostile environment raises the problem of micro computing components resistance with gamma radiation cumulated dose. The current aim is to reach a dose of 3000 grays with industrial components. A methodology and an instrumentation adapted to test this type of components have been developed. The aim of this work is to present the advantages and disadvantages bound to the use of industrial components in the presence of gamma radiation. After an analysis of the criteria allowing to justify the technological choices, the different steps which characterize the selection and the assessment methodology used are explained. The irradiation and measures means now operational are mentioned. Moreover, the supply aspects of the chosen components for the design of an industrialized system is taken into account. These selection and assessment components contribute to the development and design of computers for civil nuclear robotics. (O.M.)

  18. SBA Network Components & Software Inventory

    Data.gov (United States)

    Small Business Administration — SBA’s Network Components & Software Inventory contains a complete inventory of all devices connected to SBA’s network including workstations, servers, routers,...

  19. Components selection for ageing management

    International Nuclear Information System (INIS)

    Mingiuc, C.; Vidican, D.

    2002-01-01

    Full text: The paper presents a synthesis of methods and activities realized for the selection of critical components to assure plant safety and availability (as electricity supplier). There are presented main criteria for selection, screening process. For the resulted categories of components shall be applied different category of maintenance (condition oriented, scheduled or corrective), function of the importance and financial effort necessary to fulfil the task. 1. Systems and components screening for plant safety assurance For the systems selection, from Safety point of view, was necessary first, to define systems which are dangerous in case of failure (mainly by rupture/ release of radioactivity) and the safety systems which have to mitigate the effects. This is realized based on accident analysis (from Safety Report). Also where taken in to account the 4 basic Safety Principles: 'Reactor shut down; Residual heat removal; Radioactivity products confinement; NPP status monitoring in normal and accident conditions'. Following step is to establish safety support systems, which have to action to assure main safety systems operation. This could be realized based on engineering judgement, or on PSA Level I analysis. Finally shall be realized chains of the support systems, which have to work, till primary systems. For the critical components selection, was realized a Failure Mode and Effect Analysis (FMEA), considering the components effects of failures, on system safety function. 2. Systems and components screening for plant availability assurance The work was realized in two steps: Systems screening; Components screening The systems screening, included: General, analyze of the plant systems list and the definition of those which clearly have to run continue to assure the nominal power; Realization of a complex diagram to define interdependence between the systems (e.g. PHT and auxiliaries, moderator and auxiliaries, plant electrical diagram); Fill of special

  20. APS beamline standard components handbook

    Energy Technology Data Exchange (ETDEWEB)

    Kuzay, T.M.

    1992-01-01

    It is clear that most Advanced Photon Source (APS) Collaborative Access Team (CAT) members would like to concentrate on designing specialized equipment related to their scientific programs rather than on routine or standard beamline components. Thus, an effort is in progress at the APS to identify standard and modular components of APS beamlines. Identifying standard components is a nontrivial task because these components should support diverse beamline objectives. To assist with this effort, the APS has obtained advice and help from a Beamline Standardization and Modularization Committee consisting of experts in beamline design, construction, and operation. The staff of the Experimental Facilities Division identified various components thought to be standard items for beamlines, regardless of the specific scientific objective of a particular beamline. A generic beamline layout formed the basis for this identification. This layout is based on a double-crystal monochromator as the first optical element, with the possibility of other elements to follow. Pre-engineering designs were then made of the identified standard components. The Beamline Standardization and Modularization Committee has reviewed these designs and provided very useful input regarding the specifications of these components. We realize that there will be other configurations that may require special or modified components. This Handbook in its current version (1.1) contains descriptions, specifications, and pre-engineering design drawings of these standard components. In the future, the APS plans to add engineering drawings of identified standard beamline components. Use of standard components should result in major cost reductions for CATs in the areas of beamline design and construction.

  1. APS beamline standard components handbook

    International Nuclear Information System (INIS)

    Kuzay, T.M.

    1992-01-01

    It is clear that most Advanced Photon Source (APS) Collaborative Access Team (CAT) members would like to concentrate on designing specialized equipment related to their scientific programs rather than on routine or standard beamline components. Thus, an effort is in progress at the APS to identify standard and modular components of APS beamlines. Identifying standard components is a nontrivial task because these components should support diverse beamline objectives. To assist with this effort, the APS has obtained advice and help from a Beamline Standardization and Modularization Committee consisting of experts in beamline design, construction, and operation. The staff of the Experimental Facilities Division identified various components thought to be standard items for beamlines, regardless of the specific scientific objective of a particular beamline. A generic beamline layout formed the basis for this identification. This layout is based on a double-crystal monochromator as the first optical element, with the possibility of other elements to follow. Pre-engineering designs were then made of the identified standard components. The Beamline Standardization and Modularization Committee has reviewed these designs and provided very useful input regarding the specifications of these components. We realize that there will be other configurations that may require special or modified components. This Handbook in its current version (1.1) contains descriptions, specifications, and pre-engineering design drawings of these standard components. In the future, the APS plans to add engineering drawings of identified standard beamline components. Use of standard components should result in major cost reductions for CATs in the areas of beamline design and construction

  2. Ergonomics Contribution in Maintainability

    Science.gov (United States)

    Teymourian, Kiumars; Seneviratne, Dammika; Galar, Diego

    2017-09-01

    The objective of this paper is to describe an ergonomics contribution in maintainability. The economical designs, inputs and training helps to increase the maintainability indicators for industrial devices. This analysis can be helpful, among other cases, to compare systems, to achieve a better design regarding maintainability requirements, to improve this maintainability under specific industrial environment and to foresee maintainability problems due to eventual changes in a device operation conditions. With this purpose, this work first introduces the notion of ergonomics and human factors, maintainability and the implementation of assessment of human postures, including some important postures to perform maintenance activities. A simulation approach is used to identify the critical posture of the maintenance personnel and implements the defined postures with minimal loads on the personnel who use the equipment in a practical scenario. The simulation inputs are given to the designers to improve the workplace/equipment in order to high level of maintainability. Finally, the work concludes summarizing the more significant aspects and suggesting future research.

  3. Contribution to postnonclassical psychopathology.

    Directory of Open Access Journals (Sweden)

    Quintino-Aires J.

    2014-09-01

    Full Text Available Any psychological paradigm needs a psychopathological system that helps professionals to describe and explain the behavioral expressions that deviate from “normal” (whether this term is used with the semantic property of statistical or ideal adaptations. In this work, I seek to present the system that I have been developing since 1998 among the psychologists at the Instituto Vegotsky de Lisboa (Vygotsky Institute of Lisbon, Portugal, to understand psychopathology with regard to the vygotskian approach. It was conceived and designed according to the work of Rita Mendes Leal and her contribution to socioemotional development theory, AR Luria’s systemic and dynamic theory of the human brain, the theory of Activity (dyatel’nost of AN Leont’ev, and the psychopathological German school of E Kraepelin, presented and disseminated in Portugal in the early twentieth century by Professor Sobral Cid. It is intended to be a proposal to colleagues who are interested in postnonclassical psychology and a request for arguments.

  4. Deep overbite malocclusion: analysis of the underlying components.

    Science.gov (United States)

    El-Dawlatly, Mostafa M; Fayed, Mona M Salah; Mostafa, Yehya A

    2012-10-01

    A deepbite malocclusion should not be approached as a disease entity; instead, it should be viewed as a clinical manifestation of underlying discrepancies. The aim of this study was to investigate the various skeletal and dental components of deep bite malocclusion, the significance of the contribution of each, and whether there are certain correlations between them. Dental and skeletal measurements were made on lateral cephalometric radiographs and study models of 124 patients with deepbite. These measurements were statistically analyzed. An exaggerated curve of Spee was the greatest shared dental component (78%), significantly higher than any other component (P = 0.0335). A decreased gonial angle was the greatest shared skeletal component (37.1%), highly significant compared with the other components (P = 0.0019). A strong positive correlation was found between the ramus/Frankfort horizontal angle and the gonial angle; weaker correlations were found between various components. An exaggerated curve of Spee and a decreased gonial angle were the greatest contributing components. This analysis of deepbite components could help clinicians design individualized mechanotherapies based on the underlying cause, rather than being biased toward predetermined mechanics when treating patients with a deepbite malocclusion. Copyright © 2012 American Association of Orthodontists. Published by Mosby, Inc. All rights reserved.

  5. Secure coupling of hardware components

    NARCIS (Netherlands)

    Hoepman, J.H.; Joosten, H.J.M.; Knobbe, J.W.

    2011-01-01

    A method and a system for securing communication between at least a first and a second hardware components of a mobile device is described. The method includes establishing a first shared secret between the first and the second hardware components during an initialization of the mobile device and,

  6. Active components in food supplements

    NARCIS (Netherlands)

    Siemelink M; Jansen EHJM; Piersma AH; Opperhuizen A; LEO

    2000-01-01

    The growing food supplement market, where supplements are both more diverse and more easily available (e.g. through Internet) formed the backdrop to the inventory of the active components in food supplements. The safety of an increased intake of food components via supplements was also at issue

  7. Statistical inference on variance components

    NARCIS (Netherlands)

    Verdooren, L.R.

    1988-01-01

    In several sciences but especially in animal and plant breeding, the general mixed model with fixed and random effects plays a great role. Statistical inference on variance components means tests of hypotheses about variance components, constructing confidence intervals for them, estimating them,

  8. Domain adaptation via transfer component analysis.

    Science.gov (United States)

    Pan, Sinno Jialin; Tsang, Ivor W; Kwok, James T; Yang, Qiang

    2011-02-01

    Domain adaptation allows knowledge from a source domain to be transferred to a different but related target domain. Intuitively, discovering a good feature representation across domains is crucial. In this paper, we first propose to find such a representation through a new learning method, transfer component analysis (TCA), for domain adaptation. TCA tries to learn some transfer components across domains in a reproducing kernel Hilbert space using maximum mean miscrepancy. In the subspace spanned by these transfer components, data properties are preserved and data distributions in different domains are close to each other. As a result, with the new representations in this subspace, we can apply standard machine learning methods to train classifiers or regression models in the source domain for use in the target domain. Furthermore, in order to uncover the knowledge hidden in the relations between the data labels from the source and target domains, we extend TCA in a semisupervised learning setting, which encodes label information into transfer components learning. We call this extension semisupervised TCA. The main contribution of our work is that we propose a novel dimensionality reduction framework for reducing the distance between domains in a latent space for domain adaptation. We propose both unsupervised and semisupervised feature extraction approaches, which can dramatically reduce the distance between domain distributions by projecting data onto the learned transfer components. Finally, our approach can handle large datasets and naturally lead to out-of-sample generalization. The effectiveness and efficiency of our approach are verified by experiments on five toy datasets and two real-world applications: cross-domain indoor WiFi localization and cross-domain text classification.

  9. Component reliability for electronic systems

    CERN Document Server

    Bajenescu, Titu-Marius I

    2010-01-01

    The main reason for the premature breakdown of today's electronic products (computers, cars, tools, appliances, etc.) is the failure of the components used to build these products. Today professionals are looking for effective ways to minimize the degradation of electronic components to help ensure longer-lasting, more technically sound products and systems. This practical book offers engineers specific guidance on how to design more reliable components and build more reliable electronic systems. Professionals learn how to optimize a virtual component prototype, accurately monitor product reliability during the entire production process, and add the burn-in and selection procedures that are the most appropriate for the intended applications. Moreover, the book helps system designers ensure that all components are correctly applied, margins are adequate, wear-out failure modes are prevented during the expected duration of life, and system interfaces cannot lead to failure.

  10. EMSL Contribution Plan

    Energy Technology Data Exchange (ETDEWEB)

    Campbell, Allison A.

    2008-12-01

    This Contribution Plan is EMSL’s template for achieving our vision of simultaneous excellence in all aspects of our mission as a national scientific user facility. It reflects our understanding of the long-term stewardship we must work toward to meet the scientific challenges faced by the Department of Energy (DOE) and the nation. During the next decade, we will implement the strategies contained in this Plan, working closely with the scientific community, our advisory committees, DOE’s Office of Biological and Environmental Research, and other key stakeholders. This Plan is fully aligned with the strategic plans of DOE, its Office of Science, and the Pacific Northwest National Laboratory (PNNL). We recognize that shifts in science and technology, national priorities, and resources made available through the Federal budget process create planning uncertainties and, ultimately, a highly dynamic planning environment. Accordingly, this Plan should be viewed as a living document and we continually evaluate the changing needs and opportunities posed by our stakeholders (i.e., DOE, users, staff, advisory committees), work closely with them to understand and respond to those changes, and align our strategy accordingly. This Plan is organized around two sections. Section 1 describes our vision and four strategic outcomes: 1) Scientific Innovation, 2) Capabilities that Transform Science, 3) Outstanding Management and Operations, and Engaged and Proactive Users. These outcomes provide the framework for seven critical actions we must take during the next 3 to 5 years: 1) Establishing leadership in EMSL science themes, 2) building and deploying transformational capabilities, 3) integrating computation with experiment, 4) ensuring EMSL’s workforce meets the scientific challenges of the future, 5) creating partnerships, 6) attracting and engaging users in EMSL’s long-term strategy, and 7) building a research infrastructure that meets emerging scientific needs. Section 2

  11. Group Contribution Methods for Phase Equilibrium Calculations.

    Science.gov (United States)

    Gmehling, Jürgen; Constantinescu, Dana; Schmid, Bastian

    2015-01-01

    The development and design of chemical processes are carried out by solving the balance equations of a mathematical model for sections of or the whole chemical plant with the help of process simulators. For process simulation, besides kinetic data for the chemical reaction, various pure component and mixture properties are required. Because of the great importance of separation processes for a chemical plant in particular, a reliable knowledge of the phase equilibrium behavior is required. The phase equilibrium behavior can be calculated with the help of modern equations of state or g(E)-models using only binary parameters. But unfortunately, only a very small part of the experimental data for fitting the required binary model parameters is available, so very often these models cannot be applied directly. To solve this problem, powerful predictive thermodynamic models have been developed. Group contribution methods allow the prediction of the required phase equilibrium data using only a limited number of group interaction parameters. A prerequisite for fitting the required group interaction parameters is a comprehensive database. That is why for the development of powerful group contribution methods almost all published pure component properties, phase equilibrium data, excess properties, etc., were stored in computerized form in the Dortmund Data Bank. In this review, the present status, weaknesses, advantages and disadvantages, possible applications, and typical results of the different group contribution methods for the calculation of phase equilibria are presented.

  12. Component Fragility Research Program: Phase 1 component prioritization

    International Nuclear Information System (INIS)

    Holman, G.S.; Chou, C.K.

    1987-06-01

    Current probabilistic risk assessment (PRA) methods for nuclear power plants utilize seismic ''fragilities'' - probabilities of failure conditioned on the severity of seismic input motion - that are based largely on limited test data and on engineering judgment. Under the NRC Component Fragility Research Program (CFRP), the Lawrence Livermore National Laboratory (LLNL) has developed and demonstrated procedures for using test data to derive probabilistic fragility descriptions for mechanical and electrical components. As part of its CFRP activities, LLNL systematically identified and categorized components influencing plant safety in order to identify ''candidate'' components for future NRC testing. Plant systems relevant to safety were first identified; within each system components were then ranked according to their importance to overall system function and their anticipated seismic capacity. Highest priority for future testing was assigned to those ''very important'' components having ''low'' seismic capacity. This report describes the LLNL prioritization effort, which also included application of ''high-level'' qualification data as an alternate means of developing probabilistic fragility descriptions for PRA applications

  13. DFB component production at IHEP complete

    CERN Multimedia

    2007-01-01

    The last of the components for the 42 DFBs (electrical distribution boxes feeding the strings of superconducting magnets in the LHC) produced for CERN by IHEP Protvino (Russia) were delivered to CERN in January 2007. The DFBs will provide the electrical supply for the superconducting magnets for the LHC, making possible the transition from room temperature down to -268ºC (4.5 K) (see Bulletin No. 37/2006). This important achievement was celebrated on the 14th February 2007 at the IHEP House of Scientists in Protvino in the presence of all the IHEP personnel who contributed to the DFB components production, and with the participation of eight delegates from CERN Management and CERN engineers involved in DFB production. Lyn Evans handed over a present symbolizing the IHEP-CERN collaboration to Nikolaj Tyurin, who offered to Lyn Evans a model of a DFB. Since August 2005, when the components for the first two boxes arrived at CERN, a total of 360 tonnes of raw materials were transported to IHEP on 19 lorries...

  14. Using singular value decomposition of component eigenmodes for interface reduction

    Science.gov (United States)

    Tournaire, Hadrien; Renaud, Franck; Dion, Jean Luc

    2018-02-01

    The aim of this paper is to describe the development of a reduced order model for modal analysis in a design context. The design process of most industrial systems is based on the re-utilization of certain components. Here, we propose a reduction method involving component eigenmodes to recover the modal behaviour of an assembled structure. The contribution of this work is that it uses component eigenmodes to build an interface reduction basis. Lastly, the reduction methodology proposed is compared to the Craig and Bampton method by applying it to two case studies of which one is an industrial model of an open rotor blade.

  15. Protection against neurotoxicity by an autophagic mechanism

    Directory of Open Access Journals (Sweden)

    Kangyong Liu

    2012-05-01

    Full Text Available The objective of the present study was to investigate the effects of 3-n-butylphthalide (NBP on a 1-methyl-4-phenylpyridinium (MPP+-induced cellular model of Parkinson’s disease (PD and to illustrate the potential mechanism of autophagy in this process. For this purpose, rat PC12 pheochromocytoma cells were treated with MPP+ (1 mM for 24 h following pretreatment with NBP (0.1 mM. Cell metabolic viability was determined by the MTT assay and cell ultrastructure was examined by transmission electron microscopy. The intracellular distribution and expression of α-synuclein and microtubule-associated protein light chain 3 (LC3 were detected by immunocytochemistry and Western blotting. Our results demonstrated that: 1 NBP prevented MPP+-induced cytotoxicity in PC12 cells by promoting metabolic viability. 2 NBP induced the accumulation of autophagosomes in MPP+-treated PC12 cells. 3 Further study of the molecular mechanism demonstrated that NBP enhanced the colocalization of α-synuclein and LC3 and up-regulated the protein level of LC3-II. These results demonstrate that NBP protects PC12 cells against MPP+-induced neurotoxicity by activating autophagy-mediated α-synuclein degradation, implying that it may be a potential effective therapeutic agent for the treatment of PD.

  16. Ageing of zirconium alloy components

    Science.gov (United States)

    Chatterjee, S.; Shah, Priti Kotak; Dubey, J. S.

    2008-12-01

    India has two types (pressurized heavy water reactors (PHWRs) and boiling water reactors (BWRs)) of commercial nuclear reactors in operation, in addition to research reactors. Many of the life limiting critical components in these reactors are fabricated from zirconium alloys. The progressive degradation of these components caused by the cumulative exposure of high energy neutron irradiation with increasing period of reactor operation was monitored to assess the degree of ageing. The components/specimens examined included fuel element claddings removed from BWRs, pressure tubes and garter springs removed from PHWRs and calandria tube specimens used in PHWRs. The tests included tension test (for cladding, garter spring), fracture toughness test (for pressure tube), crush test (for garter spring), and measurement of irradiation induced growth (for calandria tube). Results of various tests conducted are presented and applications of the test results are elaborated for residual life estimation/life extension of the components.

  17. Metallurgical Laboratory and Components Testing

    Data.gov (United States)

    Federal Laboratory Consortium — In the field of metallurgy, TTC is equipped to run laboratory tests on track and rolling stock components and materials. The testing lab contains scanning-electron,...

  18. Semantic Issues for Component Technologies

    National Research Council Canada - National Science Library

    Sanders, Beverly

    2001-01-01

    The availability of components that can be assembled together to build customized system promises to decrease software development costs and, one hopes, also increase the reliability of the resulting system...

  19. Component Processes in Analogical Reasoning

    Science.gov (United States)

    Sternberg, Robert J.

    1977-01-01

    Describes alternative theoretical positions regarding (a) the component information processes used in analogical reasoning and (b) strategies for combining these processes. Also presents results from three experiments on analogical reasoning. (Author/RK)

  20. Passive Microwave Components and Antennas

    DEFF Research Database (Denmark)

    State-of-the-art microwave systems always require higher performance and lower cost microwave components. Constantly growing demands and performance requirements of industrial and scientific applications often make employing traditionally designed components impractical. For that reason, the design...... and development process remains a great challenge today. This problem motivated intensive research efforts in microwave design and technology, which is responsible for a great number of recently appeared alternative approaches to analysis and design of microwave components and antennas. This book highlights...... techniques. Modelling and computations in electromagnetics is a quite fast-growing research area. The recent interest in this field is caused by the increased demand for designing complex microwave components, modeling electromagnetic materials, and rapid increase in computational power for calculation...

  1. Employer involvement in defined contribution investment education.

    Science.gov (United States)

    Blau, G; VanDerhei, J L

    2000-01-01

    In this paper the authors consider the personnel problems that may arise for defined contribution plan sponsors if major market corrections cause older employees to delay retirement beyond previous expectations. We move from that basic premise to argue that, given the continued evolution from defined benefit (DB) to defined contribution (DC) retirement plans, employers need to be more "proactive" in educating their employees about their retirement planning. A human resources perspective is used to support this argument, apart from and in addition to legal considerations such as ERISA Section 404(c). Specifics of employer involvement and its place as a component of an organization's culture are discussed. Finally, recommendations are given for employers to consider.

  2. Multiview Bayesian Correlated Component Analysis

    DEFF Research Database (Denmark)

    Kamronn, Simon Due; Poulsen, Andreas Trier; Hansen, Lars Kai

    2015-01-01

    are identical. Here we propose a hierarchical probabilistic model that can infer the level of universality in such multiview data, from completely unrelated representations, corresponding to canonical correlation analysis, to identical representations as in correlated component analysis. This new model, which...... we denote Bayesian correlated component analysis, evaluates favorably against three relevant algorithms in simulated data. A well-established benchmark EEG data set is used to further validate the new model and infer the variability of spatial representations across multiple subjects....

  3. National Guard Special Forces: Enhancing the Contributions of Reserve Component Army Special Operations Forces

    Science.gov (United States)

    2012-01-01

    Jackson, MS Glen Arm, MD 20 Jackson, MS Citronelle , AL Decatur, AL 20 Ft Payne, AL Louisville, KY Figure 2.3 Geographical Distribution of ARNG Special...Grenada, MS HQ/2/20th SFG BSC/2/20th SFG Jackson, MS B/1/20th SFG Citronelle , AL DET 1/B/1/20th Decatur, AL C/3/20th SFG Wauchula, FL A/3/20th SFG

  4. Contribution of Candida albicans cell wall components to recognition by and escape from murine macrophages.

    Science.gov (United States)

    McKenzie, C G J; Koser, U; Lewis, L E; Bain, J M; Mora-Montes, H M; Barker, R N; Gow, N A R; Erwig, L P

    2010-04-01

    The pathogenicity of the opportunistic human fungal pathogen Candida albicans depends on its ability to escape destruction by the host immune system. Using mutant strains that are defective in cell surface glycosylation, cell wall protein synthesis, and yeast-hypha morphogenesis, we have investigated three important aspects of C. albicans innate immune interactions: phagocytosis by primary macrophages and macrophage cell lines, hyphal formation within macrophage phagosomes, and the ability to escape from and kill macrophages. We show that cell wall glycosylation is critically important for the recognition and ingestion of C. albicans by macrophages. Phagocytosis was significantly reduced for mutants deficient in phosphomannan biosynthesis (mmn4Delta, pmr1Delta, and mnt3 mnt5Delta), whereas O- and N-linked mannan defects (mnt1Delta mnt2Delta and mns1Delta) were associated with increased ingestion, compared to the parent wild-type strains and genetically complemented controls. In contrast, macrophage uptake of mutants deficient in cell wall proteins such as adhesins (ece1Delta, hwp1Delta, and als3Delta) and yeast-locked mutants (clb2Delta, hgc1Delta, cph1Delta, efg1Delta, and efg1Delta cph1Delta), was similar to that observed for wild-type C. albicans. Killing of macrophages was abrogated in hypha-deficient strains, significantly reduced in all glycosylation mutants, and comparable to wild type in cell wall protein mutants. The diminished ability of glycosylation mutants to kill macrophages was not a consequence of impaired hyphal formation within macrophage phagosomes. Therefore, cell wall composition and the ability to undergo yeast-hypha morphogenesis are critical determinants of the macrophage's ability to ingest and process C. albicans.

  5. Diverse Multilingual Researchers Contribute Language Acquisition Components to an Integrated Model of Education

    Science.gov (United States)

    Hobbs, Robert Dean

    2012-01-01

    Evidence-based outcomes in the literature have caused adjustments in neuro-psycholinguistic and sociolinguistic perspectives that indicate a need for a current model of education. Implications from research suggest the new model of education should use a multilingual framework: L3 enhances and reinforces L2 and L1, if L2 and L1 are supported. The…

  6. Rapid characterization of seismic sources in Chile: Contribution of the GNSS component

    Science.gov (United States)

    Barrientos, S. E.; Riquelme, S.; Baez, J. C., Sr.

    2017-12-01

    The recently created National Seismological Center (CSN) of the University of Chile was tasked to upgrade the countrýs seismic network in 2013. The upgrade included new 65 collocated accelerometer and broadband instruments together with 130 GNSS devices designed to transmit their data in real time. Forty units of the GNSS devices include the RTX option, a real time 1-Hz positioning capability at 4-cm error level. The observation system is complemented with 297 additional stand-alone strong motion instruments mainly located in basins for seismic engineering purposes. Broadband data can be accessed in real time from IRIS Data Management Service under networks C and C1. Strong motion event data can be retrieved through the CSN database (evtdb.csn.uchile.cl). A server is being established to handle GNSS data requests through an NTRIP Caster. Completion of the connectivity of the GNSS remote units to the main acquisition servers is expected to take place within several months. In addition to the 40 units providing real time positioning through the RTX option, Precise Point Positioning (PPP) algorithms are being tested on the CSN main servers to enable real time estimates every second for all GNSS remote devices. Because of the high earthquake productivity rate in Chile, the RTX system capabilities have been positively tested in two cases already, demonstrating their excellent performance: i) the main aftershock (M7.6) of the April 1, 2014, northern Chile event and ii) the April 24, 2017, (M6.9) event in central Chile. The former produced coastal horizontal static displacements of the order of 30 cm while the latter of the order of 5 cm. In addition to rapid earthquake characterization through static deformation, W-phase displacement waveform inversions are included in the fast analysis providing excellent results. These new applications and methodologies have profoundly impacted the rapid evaluation of the tsunamigenic potential of large earthquakes in the near field.

  7. The two-component system ChtRS contributes to chlorhexidine tolerance in Enterococcus faecium

    NARCIS (Netherlands)

    Guzmán Prieto, Ana M.|info:eu-repo/dai/nl/413649903; Wijngaarden, Jessica; Braat, Johanna C.; Rogers, Malbert R.C.; Majoor, Eline; Brouwer, Ellen C.|info:eu-repo/dai/nl/304815667; Zhang, Xinglin; Bayjanov, Jumamurat R.|info:eu-repo/dai/nl/313070555; Bonten, Marc J.M.|info:eu-repo/dai/nl/123144337; Willems, Rob J.L.|info:eu-repo/dai/nl/106866370; Van Schaik, Willem|info:eu-repo/dai/nl/279958846

    2017-01-01

    Enterococcus faecium is one of the primary causes of nosocomial infections. Disinfectants are commonly used to prevent infections with multidrugresistant E. faecium in hospitals. Worryingly, E. faecium strains that exhibit tolerance to disinfectants have already been described. We aimed to identify

  8. Computer-Based Study Guides II: Educational Components and Advantages.

    Science.gov (United States)

    Harden, R. M.; Smyth, J. J.

    1994-01-01

    Examines the potential contributions of computers to medical education and, in particular, the use of computer-based study guides. Presents the educational functions of various study guide components and lists advantages and disadvantages of computer-based study guides over print-based guides. (LZ)

  9. Evaluation of cutting force uncertainty components in turning

    DEFF Research Database (Denmark)

    Axinte, Dragos Aurelian; Belluco, Walter; De Chiffre, Leonardo

    2000-01-01

    A procedure is proposed for the evaluation of those uncertainty components of a single cutting force measurement in turning that are related to the contributions of the dynamometer calibration and the cutting process itself. Based on an empirical model including errors form both sources, the unce...

  10. BRAF associated autophagy exploitation: BRAF and autophagy inhibitors synergise to efficiently overcome resistance of BRAF mutant colorectal cancer cells.

    Science.gov (United States)

    Goulielmaki, Maria; Koustas, Evangelos; Moysidou, Eirini; Vlassi, Margarita; Sasazuki, Takehiko; Shirasawa, Senji; Zografos, George; Oikonomou, Eftychia; Pintzas, Alexander

    2016-02-23

    Autophagy is the basic catabolic mechanism that involves cell degradation of unnecessary or dysfunctional cellular components. Autophagy has a controversial role in cancer--both in protecting against tumor progression by isolation of damaged organelles, or by potentially contributing to cancer growth. The impact of autophagy in RAS induced transformation still remains to be further analyzed based on the differential effect of RAS isoforms and tumor cell context. In the present study, the effect of KRAS/BRAF/PIK3CA oncogenic pathways on the autophagic cell properties and on main components of the autophagic machinery like p62 (SQSTM1), Beclin-1 (BECN1) and MAP1LC3 (LC3) in colon cancer cells was investigated. This study provides evidence that BRAF oncogene induces the expression of key autophagic markers, like LC3 and BECN1 in colorectal tumor cells. Herein, PI3K/AKT/MTOR inhibitors induce autophagic tumor properties, whereas RAF/MEK/ERK signalling inhibitors reduce expression of autophagic markers. Based on the ineffectiveness of BRAFV600E inhibitors in BRAFV600E bearing colorectal tumors, the BRAF related autophagic properties in colorectal cancer cells are further exploited, by novel combinatorial anti-cancer protocols. Strong evidence is provided here that pre-treatment of autophagy inhibitor 3-MA followed by its combination with BRAFV600E targeting drug PLX4720 can synergistically sensitize resistant colorectal tumors. Notably, colorectal cancer cells are very sensitive to mono-treatments of another autophagy inhibitor, Bafilomycin A1. The findings of this study are expected to provide novel efficient protocols for treatment of otherwise resistant colorectal tumors bearing BRAFV600E, by exploiting the autophagic properties induced by BRAF oncogene.

  11. Brain region specific mitophagy capacity could contribute to selective neuronal vulnerability in Parkinson's disease

    Directory of Open Access Journals (Sweden)

    Zabel Claus

    2011-09-01

    Full Text Available Abstract Parkinson's disease (PD is histologically well defined by its characteristic degeneration of dopaminergic neurons in the substantia nigra pars compacta. Remarkably, divergent PD-related mutations can generate comparable brain region specific pathologies. This indicates that some intrinsic region-specificity respecting differential neuron vulnerability exists, which codetermines the disease progression. To gain insight into the pathomechanism of PD, we investigated protein expression and protein oxidation patterns of three different brain regions in a PD mouse model, the PINK1 knockout mice (PINK1-KO, in comparison to wild type control mice. The dysfunction of PINK1 presumably affects mitochondrial turnover by disturbing mitochondrial autophagic pathways. The three brain regions investigated are the midbrain, which is the location of substantia nigra; striatum, the major efferent region of substantia nigra; and cerebral cortex, which is more distal to PD pathology. In all three regions, mitochondrial proteins responsible for energy metabolism and membrane potential were significantly altered in the PINK1-KO mice, but with very different region specific accents in terms of up/down-regulations. This suggests that disturbed mitophagy presumably induced by PINK1 knockout has heterogeneous impacts on different brain regions. Specifically, the midbrain tissue seems to be most severely hit by defective mitochondrial turnover, whereas cortex and striatum could compensate for mitophagy nonfunction by feedback stimulation of other catabolic programs. In addition, cerebral cortex tissues showed the mildest level of protein oxidation in both PINK1-KO and wild type mice, indicating either a better oxidative protection or less reactive oxygen species (ROS pressure in this brain region. Ultra-structural histological examination in normal mouse brain revealed higher incidences of mitophagy vacuoles in cerebral cortex than in striatum and substantia

  12. Components in models of learning: Different operationalisations and relations between components

    Directory of Open Access Journals (Sweden)

    Mirkov Snežana

    2013-01-01

    Full Text Available This paper provides the presentation of different operationalisations of components in different models of learning. Special emphasis is on the empirical verifications of relations between components. Starting from the research of congruence between learning motives and strategies, underlying the general model of school learning that comprises different approaches to learning, we have analyzed the empirical verifications of factor structure of instruments containing the scales of motives and learning strategies corresponding to these motives. Considering the problems in the conceptualization of the achievement approach to learning, we have discussed the ways of operational sing the goal orientations and exploring their role in using learning strategies, especially within the model of the regulation of constructive learning processes. This model has served as the basis for researching learning styles that are the combination of a large number of components. Complex relations between the components point to the need for further investigation of the constructs involved in various models. We have discussed the findings and implications of the studies of relations between the components involved in different models, especially between learning motives/goals and learning strategies. We have analyzed the role of regulation in the learning process, whose elaboration, as indicated by empirical findings, can contribute to a more precise operationalisation of certain learning components. [Projekat Ministarstva nauke Republike Srbije, br. 47008: Unapređivanje kvaliteta i dostupnosti obrazovanja u procesima modernizacije Srbije i br. 179034: Od podsticanja inicijative, saradnje i stvaralaštva u obrazovanju do novih uloga i identiteta u društvu

  13. The contribution of human activities to climate changes

    OpenAIRE

    Slave, Camelia; Man, Carmen

    2012-01-01

    Some of the components of the climate system, the oceans and biosphere primarily affects the concentration of greenhouse gases in the atmosphere. Plants take CO2 from the atmosphere and convert it in the process of photosynthesis, carbohydrate. In the industrial era, human activities have contributed to increased concentrations of greenhouse gases in the atmosphere. In addition, human activities contribute to climate change by altering the concentration of aerosols and clouds cover. Greatest ...

  14. Pro-apoptotic and pro-autophagic effects of the Aurora kinase A inhibitor alisertib (MLN8237) on human osteosarcoma U-2 OS and MG-63 cells through the activation of mitochondria-mediated pathway and inhibition of p38 MAPK/PI3K/Akt/mTOR signaling pathway.

    Science.gov (United States)

    Niu, Ning-Kui; Wang, Zi-Li; Pan, Shu-Ting; Ding, Hui-Qiang; Au, Giang H T; He, Zhi-Xu; Zhou, Zhi-Wei; Xiao, Guozhi; Yang, Yin-Xue; Zhang, Xueji; Yang, Tianxin; Chen, Xiao-Wu; Qiu, Jia-Xuan; Zhou, Shu-Feng

    2015-01-01

    Osteosarcoma (OS) is the most common malignant bone tumor occurring mostly in children and adolescents between 10 and 20 years of age with poor response to current therapeutics. Alisertib (ALS, MLN8237) is a selective Aurora kinase A inhibitor that displays anticancer effects on several types of cancer. However, the role of ALS in the treatment of OS remains unknown. This study aimed to investigate the effects of ALS on the cell growth, apoptosis, autophagy, and epithelial to mesenchymal transition (EMT) and the underlying mechanisms in two human OS cell lines U-2 OS and MG-63. The results showed that ALS had potent growth inhibitory, pro-apoptotic, pro-autophagic, and EMT inhibitory effects on U-2 OS and MG-63 cells. ALS remarkably induced G2/M arrest and down-regulated the expression levels of cyclin-dependent kinases 1 and 2 and cyclin B1 in both U-2 OS and MG-63 cells. ALS markedly induced mitochondria-mediated apoptosis with a significant increase in the expression of key pro-apoptotic proteins and a decrease in main anti-apoptotic proteins. Furthermore, ALS promoted autophagic cell death via the inhibition of phosphatidylinositol 3-kinase (PI3K)/protein kinase B (Akt)/mammalian target of rapamycin (mTOR) and p38 mitogen-activated protein kinase (p38 MAPK) signaling pathways, and activation of 5'-AMP-dependent kinase (AMPK) signaling pathway. Inducers or inhibitors of apoptosis or autophagy simultaneously altered ALS-induced apoptotic and autophagic death in both U-2 OS and MG-63 cells, suggesting a crosstalk between these two primary modes of programmed cell death. Moreover, ALS suppressed EMT-like phenotypes with a marked increase in the expression of E-cadherin but a decrease in N-cadherin in U-2 OS and MG-63 cells. ALS treatment also induced reactive oxygen species (ROS) generation but inhibited the expression levels of sirtuin 1 and nuclear factor-erythroid-2-related factor 2 (Nrf2) in both cell lines. Taken together, these findings show that ALS promotes

  15. Automated cleaning of electronic components

    International Nuclear Information System (INIS)

    Drotning, W.; Meirans, L.; Wapman, W.; Hwang, Y.; Koenig, L.; Petterson, B.

    1994-01-01

    Environmental and operator safety concerns are leading to the elimination of trichloroethylene and chlorofluorocarbon solvents in cleaning processes that remove rosin flux, organic and inorganic contamination, and particulates from electronic components. Present processes depend heavily on these solvents for manual spray cleaning of small components and subassemblies. Use of alternative solvent systems can lead to longer processing times and reduced quality. Automated spray cleaning can improve the quality of the cleaning process, thus enabling the productive use of environmentally conscious materials, while minimizing personnel exposure to hazardous materials. We describe the development of a prototype robotic system for cleaning electronic components in a spray cleaning workcell. An important feature of the prototype system is the capability to generate the robot paths and motions automatically from the CAD models of the part to be cleaned, and to embed cleaning process knowledge into the automatically programmed operations

  16. Mechanical design of machine components

    CERN Document Server

    Ugural, Ansel C

    2015-01-01

    Mechanical Design of Machine Components, Second Edition strikes a balance between theory and application, and prepares students for more advanced study or professional practice. It outlines the basic concepts in the design and analysis of machine elements using traditional methods, based on the principles of mechanics of materials. The text combines the theory needed to gain insight into mechanics with numerical methods in design. It presents real-world engineering applications, and reveals the link between basic mechanics and the specific design of machine components and machines. Divided into three parts, this revised text presents basic background topics, deals with failure prevention in a variety of machine elements and covers applications in design of machine components as well as entire machines. Optional sections treating special and advanced topics are also included.Key Features of the Second Edition:Incorporates material that has been completely updated with new chapters, problems, practical examples...

  17. The contribution of adhesion signaling to lactogenesis.

    Science.gov (United States)

    Morrison, Bethanie; Cutler, Mary Lou

    2010-10-01

    The mammary gland undergoes hormonally controlled cycles of pubertal maturation, pregnancy, lactation, and involution, and these processes rely on complex signaling mechanisms, many of which are controlled by cell-cell and cell-matrix adhesion. The adhesion of epithelial cells to the extracellular matrix initiates signaling mechanisms that have an impact on cell proliferation, survival, and differentiation throughout lactation. The control of integrin expression on the mammary epithelial cells, the composition of the extracellular matrix and the presence of secreted matricellular proteins all contribute to essential adhesion signaling during lactogenesis. In vitro and in vivo studies, including the results from genetically engineered mice, have shed light on the regulation of these processes at the cell and tissue level and have led to increased understanding of the essential signaling components that are regulated in temporal and cell specific manner during lactogenesis. Recent studies suggest that a secreted matricellular protein, CTGF/CCN2, may play a role in lactogenic differentiation through binding to β1 integrin complexes, enhancing the production of extracellular matrix components and contributions to cell adhesion signaling.

  18. Two component systems: physiological effect of a third component.

    Directory of Open Access Journals (Sweden)

    Baldiri Salvado

    Full Text Available Signal transduction systems mediate the response and adaptation of organisms to environmental changes. In prokaryotes, this signal transduction is often done through Two Component Systems (TCS. These TCS are phosphotransfer protein cascades, and in their prototypical form they are composed by a kinase that senses the environmental signals (SK and by a response regulator (RR that regulates the cellular response. This basic motif can be modified by the addition of a third protein that interacts either with the SK or the RR in a way that could change the dynamic response of the TCS module. In this work we aim at understanding the effect of such an additional protein (which we call "third component" on the functional properties of a prototypical TCS. To do so we build mathematical models of TCS with alternative designs for their interaction with that third component. These mathematical models are analyzed in order to identify the differences in dynamic behavior inherent to each design, with respect to functionally relevant properties such as sensitivity to changes in either the parameter values or the molecular concentrations, temporal responsiveness, possibility of multiple steady states, or stochastic fluctuations in the system. The differences are then correlated to the physiological requirements that impinge on the functioning of the TCS. This analysis sheds light on both, the dynamic behavior of synthetically designed TCS, and the conditions under which natural selection might favor each of the designs. We find that a third component that modulates SK activity increases the parameter space where a bistable response of the TCS module to signals is possible, if SK is monofunctional, but decreases it when the SK is bifunctional. The presence of a third component that modulates RR activity decreases the parameter space where a bistable response of the TCS module to signals is possible.

  19. Radiation effects on eye components

    Science.gov (United States)

    Durchschlag, H.; Fochler, C.; Abraham, K.; Kulawik, B.

    1999-08-01

    The most important water-soluble components of the vertebrate eye (lens proteins, aqueous humor, vitreous, hyaluronic acid, ascorbic acid) have been investigated in aqueous solution, after preceding X- or UV-irradiation. Spectroscopic, chromatographic, electrophoretic, hydrodynamic and analytic techniques have been applied, to monitor several radiation damages such as destruction of aromatic and sulfur-containing amino acids, aggregation, crosslinking, dissociation, fragmentation, and partial unfolding. Various substances were found which were able to protect eye components effectively against radiation, some of them being also of medical relevance.

  20. Actual service life prediction of building components

    DEFF Research Database (Denmark)

    Aagaard, Niels-Jørgen; Brandt, Erik; Hansen, Ernst Jan de Place

    2014-01-01

    , the paper presents an analysis of service life of buildings as such with respect to the use of the building partially based on analysis of data from the nationwide Danish register of buildings and housing as well as turnover in the Danish construction industry from refurbishment and demolition activities......In recent years, sustainability and life cycle cost in the construction industry have been given great attention in many countries due to the heavy climatic and environmental impact from this sector. In Denmark, a sustainability certification scheme for buildings has been developed including...... a condensed method for assessment of life cycle costs for buildings. Estimation of life cycle costs has traditionally been based on predicted service life for building components in terms of technical performance. This paper suggests a method for taking into account other contributing factors...

  1. Incorporating global components into ethics education.

    Science.gov (United States)

    Wang, George; Thompson, Russell G

    2013-03-01

    Ethics is central to science and engineering. Young engineers need to be grounded in how corporate social responsibility principles can be applied to engineering organizations to better serve the broader community. This is crucial in times of climate change and ecological challenges where the vulnerable can be impacted by engineering activities. Taking a global perspective in ethics education will help ensure that scientists and engineers can make a more substantial contribution to development throughout the world. This paper presents the importance of incorporating the global and cross culture components in the ethic education. The authors bring up a question to educators on ethics education in science and engineering in the globalized world, and its importance, necessity, and impendency. The paper presents several methods for discussion that can be used to identify the differences in ethics standards and practices in different countries; enhance the student's knowledge of ethics in a global arena.

  2. Diesel engine management systems and components

    CERN Document Server

    2014-01-01

    This reference book provides a comprehensive insight into todays diesel injection systems and electronic control. It focusses on minimizing emissions and exhaust-gas treatment. Innovations by Bosch in the field of diesel-injection technology have made a significant contribution to the diesel boom. Calls for lower fuel consumption, reduced exhaust-gas emissions and quiet engines are making greater demands on the engine and fuel-injection systems. Contents History of the diesel engine.- Areas of use for diesel engines.- Basic principles of the diesel engine.- Fuels: Diesel fuel.- Fuels: Alternative fuels.- Cylinder-charge control systems.- Basic principles of diesel fuel-injection.- Overview of diesel fuel-injection systems.- Fuel supply to the low pressure stage.- Overview of discrete cylinder systems.- Unit injector system.- Unit pump system.- Overview of common-rail systems.- High pressure components of the common-rail system.- Injection nozzles.- Nozzle holders.- High pressure lines.- Start assist systems.-...

  3. Blue green component and integrated urban design

    Directory of Open Access Journals (Sweden)

    Stanković Srđan M.

    2016-01-01

    Full Text Available This paper aims to demonstrate the hidden potential of blue green components, in a synergetic network, not as separate systems, like used in past. The innovative methodology of the project Blue Green Dream is presented through examples of good practice. A new approach in the project initiate thoughtful planning and remodeling of the settlement for the modern man. Professional and scientific public is looking for way to create more healthy and stimulating place for living. However, offered integrative solutions still remain out of urban and architectural practice. Tested technologies in current projects confirmed measurability of innovative approaches and lessons learned. Scientific and professional contributions are summarized in master's and doctoral theses that have been completed or are in process of writing.

  4. Weighted Components of i-Government Enterprise Architecture

    Science.gov (United States)

    Budiardjo, E. K.; Firmansyah, G.; Hasibuan, Z. A.

    2017-01-01

    Lack of government performance, among others due to the lack of coordination and communication among government agencies. Whilst, Enterprise Architecture (EA) in the government can be use as a strategic planning tool to improve productivity, efficiency, and effectivity. However, the existence components of Government Enterprise Architecture (GEA) do not show level of importance, that cause difficulty in implementing good e-government for good governance. This study is to explore the weight of GEA components using Principal Component Analysis (PCA) in order to discovered an inherent structure of e-government. The results show that IT governance component of GEA play a major role in the GEA. The rest of components that consist of e-government system, e-government regulation, e-government management, and application key operational, contributed more or less the same. Beside that GEA from other countries analyzes using comparative base on comon enterprise architecture component. These weighted components use to construct i-Government enterprise architecture. and show the relative importance of component in order to established priorities in developing e-government.

  5. Robotics-Components and Subsystems

    Indian Academy of Sciences (India)

    Home; Journals; Resonance – Journal of Science Education; Volume 4; Issue 12. Robotics - Components and Subsystems. J R Vengateswaran. General Article Volume 4 Issue 12 December 1999 pp 76-82. Fulltext. Click here to view fulltext PDF. Permanent link: http://www.ias.ac.in/article/fulltext/reso/004/12/0076-0082 ...

  6. Potting procedure for electronic components

    Science.gov (United States)

    Rubino, A. G.; Zimmerman, J.

    1977-01-01

    Potting process is modified to effect a match more closely between embedded electronic components, potting mediums, and thermal environment. Application of room-temperature vulcanizing silicone rubber band cured in modified thermal cycle minimizes coil-to-resin adhesion and thus lowers stresses between transformer and potting compound.

  7. Fabrication of plastic microfluidic components

    Science.gov (United States)

    Martin, Peter M.; Matson, Dean W.; Bennett, Wendy D.; Hammerstrom, D. J.

    1998-09-01

    Plastic components have many advantages, including ease of fabrication, low cost, chemical inertness, lightweight, and disposability. We report on the fabrication of three plastics-based microfluidic components: a motherboard, a dialysis unit, and a metal sensor. Microchannels, headers, and interconnects were produced in thin sheets (>=50 microns) of polyimide, PMMA, polyethylene, and polycarbonate using a direct-write excimer laser micromachining system. Machined sheets were laminated by thermal and adhesive bonding to form leak-tight microfluidic components. The microfluidic motherboard borrowed the `functionality on a chip' concept from the electronics industry and was the heart of a complex microfluidic analytical device. The motherboard platform was designed to be tightly integrated and self-contained (i.e., liquid flows are all confined within machined microchannels), reducing the need for tubing with fluid distribution and connectivity. This concept greatly facilitated system integration and miniaturization. As fabricated, the motherboard consisted of three fluid reservoirs connected to micropumps by microchannels. The fluids could either be pumped independently or mixed in microchannels prior to being directed to exterior analytical components via outlet ports. The microdialysis device was intended to separate electrolytic solutes from low volume samples prior to mass spectrometric analysis. The device consisted of a dialysis membrane laminated between opposed serpentine microchannels containing the sample fluid and a buffer solution. The laminated metal sensor consisted of fluid reservoirs, micro-flow channels, micropumps, mixing channels, reaction channels, and detector circuitry.

  8. Inspection of disposal canisters components

    International Nuclear Information System (INIS)

    Pitkaenen, J.

    2013-12-01

    This report presents the inspection techniques of disposal canister components. Manufacturing methods and a description of the defects related to different manufacturing methods are described briefly. The defect types form a basis for the design of non-destructive testing because the defect types, which occur in the inspected components, affect to choice of inspection methods. The canister components are to nodular cast iron insert, steel lid, lid screw, metal gasket, copper tube with integrated or separate bottom, and copper lid. The inspection of copper material is challenging due to the anisotropic properties of the material and local changes in the grain size of the copper material. The cast iron insert has some acoustical material property variation (attenuation, velocity changes, scattering properties), which make the ultrasonic inspection demanding from calibration point of view. Mainly three different methods are used for inspection. Ultrasonic testing technique is used for inspection of volume, eddy current technique, for copper components only, and visual testing technique are used for inspection of the surface and near surface area

  9. A forgotten component of biodiversity

    Indian Academy of Sciences (India)

    2011-07-08

    Jul 8, 2011 ... Home; Journals; Journal of Biosciences; Volume 36; Issue 4. Clipboard: Helminth richness in Arunachal Pradesh fishes: A forgotten component of biodiversity. Amit Tripathi. Volume 36 Issue 4 September 2011 pp 559-561. Fulltext. Click here to view fulltext PDF. Permanent link:

  10. Factor Analysis via Components Analysis

    Science.gov (United States)

    Bentler, Peter M.; de Leeuw, Jan

    2011-01-01

    When the factor analysis model holds, component loadings are linear combinations of factor loadings, and vice versa. This interrelation permits us to define new optimization criteria and estimation methods for exploratory factor analysis. Although this article is primarily conceptual in nature, an illustrative example and a small simulation show…

  11. COMPONENT ELEMENTS OF MARKETING COMMUNICATIONS

    Directory of Open Access Journals (Sweden)

    G. I. Tamoshina

    2012-01-01

    Full Text Available Marketing communications are the specific communication program of the company. It consists of: advertising, which is intended for informing about commodity and accommodations (services; encouragement of marketing- sales augmentation for acceleration of marketing; straight marketing, that provide with personal contacts, flexibility and ability to make a bargain; public relations - all that components are promoting and uphold the image of the firm.

  12. Intelligent Component Monitoring for Nuclear Power Plants

    Energy Technology Data Exchange (ETDEWEB)

    Lefteri Tsoukalas

    2010-07-30

    Reliability and economy are two major concerns for a nuclear power generation system. Next generation nuclear power reactors are being developed to be more reliable and economic. An effective and efficient surveillance system can generously contribute toward this goal. Recent progress in computer systems and computational tools has made it necessary and possible to upgrade current surveillance/monitoring strategy for better performance. For example, intelligent computing techniques can be applied to develop algorithm that help people better understand the information collected from sensors and thus reduce human error to a new low level. Incidents incurred from human error in nuclear industry are not rare and have been proven costly. The goal of this project is to develop and test an intelligent prognostics methodology for predicting aging effects impacting long-term performance of nuclear components and systems. The approach is particularly suitable for predicting the performance of nuclear reactor systems which have low failure probabilities (e.g., less than 10-6 year-). Such components and systems are often perceived as peripheral to the reactor and are left somewhat unattended. That is, even when inspected, if they are not perceived to be causing some immediate problem, they may not be paid due attention. Attention to such systems normally involves long term monitoring and possibly reasoning with multiple features and evidence, requirements that are not best suited for humans.

  13. Intelligent Component Monitoring for Nuclear Power Plants

    International Nuclear Information System (INIS)

    Tsoukalas, Lefteri

    2010-01-01

    Reliability and economy are two major concerns for a nuclear power generation system. Next generation nuclear power reactors are being developed to be more reliable and economic. An effective and efficient surveillance system can generously contribute toward this goal. Recent progress in computer systems and computational tools has made it necessary and possible to upgrade current surveillance/monitoring strategy for better performance. For example, intelligent computing techniques can be applied to develop algorithm that help people better understand the information collected from sensors and thus reduce human error to a new low level. Incidents incurred from human error in nuclear industry are not rare and have been proven costly. The goal of this project is to develop and test an intelligent prognostics methodology for predicting aging effects impacting long-term performance of nuclear components and systems. The approach is particularly suitable for predicting the performance of nuclear reactor systems which have low failure probabilities (e.g., less than 10 -6 year -1 ). Such components and systems are often perceived as peripheral to the reactor and are left somewhat unattended. That is, even when inspected, if they are not perceived to be causing some immediate problem, they may not be paid due attention. Attention to such systems normally involves long term monitoring and possibly reasoning with multiple features and evidence, requirements that are not best suited for humans.

  14. Principal Component Analysis In Radar Polarimetry

    Directory of Open Access Journals (Sweden)

    A. Danklmayer

    2005-01-01

    Full Text Available Second order moments of multivariate (often Gaussian joint probability density functions can be described by the covariance or normalised correlation matrices or by the Kennaugh matrix (Kronecker matrix. In Radar Polarimetry the application of the covariance matrix is known as target decomposition theory, which is a special application of the extremely versatile Principle Component Analysis (PCA. The basic idea of PCA is to convert a data set, consisting of correlated random variables into a new set of uncorrelated variables and order the new variables according to the value of their variances. It is important to stress that uncorrelatedness does not necessarily mean independent which is used in the much stronger concept of Independent Component Analysis (ICA. Both concepts agree for multivariate Gaussian distribution functions, representing the most random and least structured distribution. In this contribution, we propose a new approach in applying the concept of PCA to Radar Polarimetry. Therefore, new uncorrelated random variables will be introduced by means of linear transformations with well determined loading coefficients. This in turn, will allow the decomposition of the original random backscattering target variables into three point targets with new random uncorrelated variables whose variances agree with the eigenvalues of the covariance matrix. This allows a new interpretation of existing decomposition theorems.

  15. Sustainable Development in Indian Automotive Component Clusters

    Science.gov (United States)

    Bhaskaran, E.

    2013-01-01

    India is the world's second fastest growing auto market and boasts of the sixth largest automobile industry after China, the US, Germany, Japan and Brazil. The Indian auto component industry recorded its highest year-on-year growth of 34.2 % in 2010-2011, raking in revenue of US 39.9 billion; major contribution coming from exports at US five billion and fresh investment from the US at around US two billion. For inclusive growth and sustainable development most of the auto components manufacturers has adopted the cluster development approach. The objective is to study the technical efficiency (θ), peer weights (λ i ), input slacks (S-) and output slacks (S+) of four Auto Component Clusters (ACC) in India. The methodology adopted is using Data Envelopment Analysis of Input Oriented Banker Charnes Cooper Model by taking number of units and number of employments as inputs and sales and exports in crores as an outputs. The non-zero λ i 's represents the weights for efficient clusters. The S > 0 obtained for one ACC reveals the excess no. of units (S-) and employment (S-) and shortage in sales (S+) and exports (S+). However the variable returns to scale are increasing for three clusters, constant for one more cluster and with nil decrease. To conclude, for inclusive growth and sustainable development, the inefficient ACC should increase their turnover and exports, as decrease in no. of enterprises and employment is practically not possible. Moreover for sustainable development, the ACC should strengthen infrastructure interrelationships, technology interrelationships, procurement interrelationships, production interrelationships and marketing interrelationships to increase productivity and efficiency to compete in the world market.

  16. Active and passive contributions to spatial learning.

    Science.gov (United States)

    Chrastil, Elizabeth R; Warren, William H

    2012-02-01

    It seems intuitively obvious that active exploration of a new environment will lead to better spatial learning than will passive exposure. However, the literature on this issue is decidedly mixed-in part, because the concept itself is not well defined. We identify five potential components of active spatial learning and review the evidence regarding their role in the acquisition of landmark, route, and survey knowledge. We find that (1) idiothetic information in walking contributes to metric survey knowledge, (2) there is little evidence as yet that decision making during exploration contributes to route or survey knowledge, (3) attention to place-action associations and relevant spatial relations contributes to route and survey knowledge, although landmarks and boundaries appear to be learned without effort, (4) route and survey information are differentially encoded in subunits of working memory, and (5) there is preliminary evidence that mental manipulation of such properties facilitates spatial learning. Idiothetic information appears to be necessary to reveal the influence of attention and, possibly, decision making in survey learning, which may explain the mixed results in desktop virtual reality. Thus, there is indeed an active advantage in spatial learning, which manifests itself in the task-dependent acquisition of route and survey knowledge.

  17. COP 21: the national contributions

    International Nuclear Information System (INIS)

    Jouette, Isabelle

    2015-01-01

    This article comments the content of the national contributions (the so-called Intended Nationally Determined Contributions or INDC) which every country should have transmitted to the UN before the COP 21. In fact, 148 contributions, i.e. 75 per cent of the expected ones, have been transmitted. The author recalls that the content of these contributions had to obey some principles which had been defined in Lima in 2014, and that each country must identify its objectives in terms of mitigation (reduction of greenhouse gas emissions) and adaptation (reduction of the vulnerability of natural and human systems). The author comments some specific commitments regarding climate, emission reduction, adaptation to climate change, and more particularly evokes the Ethiopian contribution which is considered as exemplary

  18. Clinical usefulness of physiological components obtained by factor analysis

    International Nuclear Information System (INIS)

    Ohtake, Eiji; Murata, Hajime; Matsuda, Hirofumi; Yokoyama, Masao; Toyama, Hinako; Satoh, Tomohiko.

    1989-01-01

    The clinical usefulness of physiological components obtained by factor analysis was assessed in 99m Tc-DTPA renography. Using definite physiological components, another dynamic data could be analyzed. In this paper, the dynamic renal function after ESWL (Extracorporeal Shock Wave Lithotripsy) treatment was examined using physiological components in the kidney before ESWL and/or a normal kidney. We could easily evaluate the change of renal functions by this method. The usefulness of a new analysis using physiological components was summarized as follows: 1) The change of a dynamic function could be assessed in quantity as that of the contribution ratio. 2) The change of a sick condition could be morphologically evaluated as that of the functional image. (author)

  19. Characteristic odor components of essential oil from Scutellaria laeteviolacea.

    Science.gov (United States)

    Miyazawa, Mitsuo; Nomura, Machi; Marumoto, Shinsuke; Mori, Kiyoshige

    2013-01-01

    The essential oils from aerial parts of Scutellaria laeteviolacea was analyzed by gas chromatography (GC) and gas chromatography-mass spectrometry (GC-MS). The characteristic odor components were also detected in the oil using gas chromatography-olfactometry (GC-O) analysis and aroma extraction dilution analysis (AEDA). As a result, 100 components (accounting for 99.11 %) of S. laeteviolacea, were identified. The major components of S. laeteviolacea oil were found to be 1-octen-3-ol (27.72 %), germacrene D (21.67 %),and β-caryophyllene (9.18 %). The GC-O and AEDA results showed that 1-octen-3-ol, germacrene D, germacrene B, and β-caryophyllene were the most characteristic odor components of the oil. These compounds are thought to contribute to the unique flavor of this plant.

  20. Contribution gives the cosmic radiation to the doses for exhibition to the natural radiation in the Cuban population

    International Nuclear Information System (INIS)

    Tomas Zerquera, J.; Peres Sanchez, D.; Prendes Alonso, M

    1998-01-01

    With the objective to specify the preponderant contribution the cosmic component the radiation in the dose that the Cuban population receives you carries out a program she gives mensurations she gives this component in the whole country

  1. Black Component of Dark Matter

    Directory of Open Access Journals (Sweden)

    A. V. Grobov

    2014-01-01

    Full Text Available A mechanism of primordial black hole formation with specific mass spectrum is discussed. It is shown that these black holes could contribute to the energy density of dark matter. Our approach is elaborated in the framework of universal extra dimensions.

  2. Indigenous Foods and Their Contribution to Nutrient Requirements

    African Journals Online (AJOL)

    are cultivated or harvested from the wild for food.9 These underutilised species play a crucial role in food security, income generation, food culture and can contribute to nutrient requirements. Historically, wild plants and animals were the sole dietary components for hunter-gatherer and forager cultures.8 Provision of and ...

  3. Contribution of forest floor fractions to carbon storage and ...

    African Journals Online (AJOL)

    Forest floor carbon stocks, which include different components of litter, hemic and sapric materials, have not been empirically quantified in tropical montane forest, although they influence soil carbon (C) pools. To date, the contribution of arbuscular mycorrhizae in C sequestration potentials in tropical montane forests have ...

  4. Preservation of Fertile Mantle Components at Mid-Ocean Ridge

    Science.gov (United States)

    Montesi, L. G.; Behn, M. D.; Standish, J. J.; Dick, H. J.

    2007-12-01

    Recycled lithosphere is suspected to contribute to the geochemical enrichment not only of Ocean Island Basalts (OIB) but also exceptional Mid-Ocean Ridge Basalts collected at ultraslow ridges. In particular, the chemistry of basalts at volcanic centers along the Southwest Indian Ridge oblique supersegment of 9-16°E is best explained by an exceptionally strong contribution from an enriched mafic component mixed in the upwelling mantle. Why this component is so strong at these volcanic centers can be understood in at least two ways. 1) The mantle underneath each volcanic center is anomalous. Such an explanation is equivalent to appealing to small plume-like features underneath each volcanic center. 2) The fertile component is present everywhere but melt migration gathers the resulting magma toward the volcanic centers. In this contribution, we test the second hypothesis using a numerical melt migration model in which magma rises vertically until it encounter the base of the thermal lithosphere. In the SWIR 9-16°E area, variations in ridge axis azimuth produce a strong relief to the base of the lithosphere, which focuses magma towards the location of the observed volcanic centers. Magma produced off-axis, which is dominated by the fertile component, is focused even more strongly than near-axis magma, explaining the relative enrichment of the surface lava. We compare the expected enrichment pattern with the geochemistry of collected lava and show that, were the ridge straighter or spreading faster, this signal would be more difficult to observe.

  5. Nuclear power plant component protection

    International Nuclear Information System (INIS)

    Michel, E.; Ruf, R.; Dorner, H.

    1976-01-01

    Described is a nuclear power plant installation which includes a concrete biological shield forming a pit in which a reactor pressure vessel is positioned. A steam generator on the outside of the shield is connected with the pressure vessel via coolant pipe lines which extend through the shield, the coolant circulation being provided by a coolant pump which is also on the outside of the shield. To protect these components on the outside of the shield and which are of mainly or substantially cylindrical shape, semicylindrical concrete segments are interfitted around them to form complete outer cylinders which are retained against outward separation radially from the components, by rings of high tensile steel which may be interspaced so closely that they provide, in effect, an outer steel cylinder. The invention is particularly applicable to pressurized-water coolant reactor installations

  6. Cylinder components properties, applications, materials

    CERN Document Server

    2016-01-01

    Owing to the ever-increasing requirements to be met by gasoline and diesel engines in terms of CO2 reduction, emission behavior, weight, and service life, a comprehensive understanding of combustion engine components is essential today. It is no longer possible for professionals in automotive engineering to manage without the corresponding expertise, whether they work in the field of design, development, testing, or maintenance. This technical book provides in-depth answers to questions about design, production, and machining of cylinder components. In this second edition, every section has been revised and expanded to include the latest developments in the combustion engine. Content Piston rings Piston pins and piston pin circlips Bearings Connecting rods Crankcase and cylinder liners Target audience Engineers in the field of engine development and maintenanceLecturers and students in the areas of mechanical engineering, engine technology, and vehicle constructionAnyone interested in technology Publisher MAH...

  7. Mechanical component screening for scanner

    Science.gov (United States)

    Olson, J. L.; Quinn, W. J.

    1972-01-01

    The critical mechanical components of the scan mirror mechanism are described and their evaluation and screening procedures are discussed. A bumper/damper unit is used in the design to reverse motion of the mirror and effect scan and retrace cycles. A wear evaluation was conducted on the bumper impact surfaces that established nylon 6-10 as an acceptable material. The elastomeric dampers were subjected to thermal vacuum tests for condensables and outgassing as well as parametric life tests. The flexure pivots that support the mirror were tested to establish a curve of stress plotted as a function of cycles to failure for rotational operation. The pivots met the life requirement of 150,000,000 cycles at a + or - 2.9 deg amplitude during fatigue testing. Screening procedures were established for dampers and flexure pivots to obtain flight quality components.

  8. Processing of Activated Core Components

    Energy Technology Data Exchange (ETDEWEB)

    Friske, A.; Gestermann, G.; Finkbeiner, R.

    2003-02-26

    Used activated components from the core of a NPP like control elements, water channels from a BWR, and others like in-core measurement devices need to be processed into waste forms suitable for interim storage, and for the final waste repository. Processing of the activated materials can be undertaken by underwater cutting and packaging or by cutting and high-pressure compaction in a hot cell. A hot cell is available in Germany as a joint investment between GNS and the Karlsruhe Research Center at the latter's site. Special transport equipment is available to transport the components ''as-is'' to the hot cell. Newly designed underwater processing equipment has been designed, constructed, and operated for the special application of NPP decommissioning. This equipment integrates an underwater cutting device with an 80 ton force underwater in-drum compactor.

  9. Metal binding by food components

    DEFF Research Database (Denmark)

    Tang, Ning

    For calcium binding: Electrochemical method (calcium ion selective electrode) combined with quantum mechanical calculations (density functional theory) were used to investigate the calcium binding affinity of the amino acids and small glycine peptides. The effects of the ionic strength and p......, synergistic effect in calcium binding was found for the small glycine peptide rather than amino acids mixtures with the enhanced driving force up to -6 kJ/mol. Such study provides useful information for the future development of calcium supplements. For zinc binding: Isothermal titration calorimetry...... titration calorimetry and quantum mechanical calculations. This is due to the zinc binding affinity of the relatively softer ligands (investigated food components) will become much stronger than citrate or phytate when they present together in aqueous solution. This mechanism indicates these food components...

  10. HG ion thruster component testing

    Science.gov (United States)

    Mantenieks, M. A.

    1979-01-01

    Cathodes, isolators, and vaporizers are critical components in determining the performance and lifetime of mercury ion thrusters. The results of life tests of several of these components are reported. A 30-cm thruster CIV test in a bell jar has successfully accumulated over 26,000 hours. The cathode has undergone 65 restarts during the life test without requiring any appreciable increases in starting power. Recently, all restarts have been achieved with only the 44 volt keeper supply with no change required in the starting power. Another ongoing 30-cm Hg thruster cathode test has successfully passed the 10,000 hour mark. A solid-insert, 8-cm thruster cathode has accumulated over 4,000 hours of thruster operation. All starts have been achieved without the use of a high voltage ignitor. The results of this test indicate that the solid impregnated insert is a viable neutralizer cathode for the 8-cm thruster.

  11. Component processes underlying future thinking.

    Science.gov (United States)

    D'Argembeau, Arnaud; Ortoleva, Claudia; Jumentier, Sabrina; Van der Linden, Martial

    2010-09-01

    This study sought to investigate the component processes underlying the ability to imagine future events, using an individual-differences approach. Participants completed several tasks assessing different aspects of future thinking (i.e., fluency, specificity, amount of episodic details, phenomenology) and were also assessed with tasks and questionnaires measuring various component processes that have been hypothesized to support future thinking (i.e., executive processes, visual-spatial processing, relational memory processing, self-consciousness, and time perspective). The main results showed that executive processes were correlated with various measures of future thinking, whereas visual-spatial processing abilities and time perspective were specifically related to the number of sensory descriptions reported when specific future events were imagined. Furthermore, individual differences in self-consciousness predicted the subjective feeling of experiencing the imagined future events. These results suggest that future thinking involves a collection of processes that are related to different facets of future-event representation.

  12. Plasmonic components fabrication via nanoimprint

    DEFF Research Database (Denmark)

    Boltasseva, Alexandra

    2009-01-01

    A review report on nanoimprinted plasmonic components is given. The fabrication of different metal–dielectric geometries and nanostructured surfaces that support either propagating or localized surface plasmon modes is discussed. The main characteristics and advantages of the nanoimprint technology...... for the fabrication of various plasmonic structures are outlined. The discussion of plasmonic waveguiding structures focuses on planar waveguides based on metal strips embedded into a dielectric and on profiled metal surfaces. Nanoimprint-based fabrication of two-dimensional nanostructured plasmonic surfaces...... for enhanced transmission studies and sensor applications is also discussed. Throughout the report, the main fabrication schemes are described, as well as the challenges facing future manufacturing of plasmonic components for device applications....

  13. Tritium in fusion reactor components

    International Nuclear Information System (INIS)

    Watson, J.S.; Fisher, P.W.; Talbot, J.B.

    1980-01-01

    When tritium is used in a fusion energy experiment or reactor, several implications affect and usually restrict the design and operation of the system and involve questions of containment, inventory, and radiation damage. Containment is expected to be particularly important both for high-temperature components and for those components that are prone to require frequent maintenance. Inventory is currently of major significance in cases where safety and environmental considerations limit the experiments to very low levels of tritium. Fewer inventory restrictions are expected as fusion experiments are placed in more-remote locations and as the fusion community gains experience with the use of tritium. However, the advent of power-producing experiments with high-duty cycle will again lead to serious difficulties based principally on tritium availability; cyclic operations with significant regeneration times are the principal problems

  14. Reformulating Component Identification as Document Analysis Problem

    NARCIS (Netherlands)

    Gross, H.G.; Lormans, M.; Zhou, J.

    2007-01-01

    One of the first steps of component procurement is the identification of required component features in large repositories of existing components. On the highest level of abstraction, component requirements as well as component descriptions are usually written in natural language. Therefore, we can

  15. Stochastic Modeling Of Wind Turbine Drivetrain Components

    DEFF Research Database (Denmark)

    Rafsanjani, Hesam Mirzaei; Sørensen, John Dalsgaard

    2014-01-01

    reliable components are needed for wind turbine. In this paper focus is on reliability of critical components in drivetrain such as bearings and shafts. High failure rates of these components imply a need for more reliable components. To estimate the reliability of these components, stochastic models...

  16. Behavior Protocols for Software Components

    Czech Academy of Sciences Publication Activity Database

    Plášil, František; Višňovský, Stanislav

    2002-01-01

    Roč. 28, č. 11 (2002), s. 1056-1076 ISSN 0098-5589 R&D Projects: GA AV ČR IAA2030902; GA ČR GA201/99/0244 Grant - others:Eureka(XE) Pepita project no.2033 Institutional research plan: AV0Z1030915 Keywords : behavior protocols * component-based programming * software architecture Subject RIV: JC - Computer Hardware ; Software Impact factor: 1.170, year: 2002

  17. Introducing and modeling inefficiency contributions

    DEFF Research Database (Denmark)

    Asmild, Mette; Kronborg, Dorte; Matthews, Kent

    2016-01-01

    Whilst Data Envelopment Analysis (DEA) is the most commonly used non-parametric benchmarking approach, the interpretation and application of DEA results can be limited by the fact that radial improvement potentials are identified across variables. In contrast, Multi-directional Efficiency Analysis......-called inefficiency contributions, which are defined as the relative contributions from specific variables to the overall levels of inefficiencies. A statistical model for distinguishing the inefficiency contributions between subgroups is proposed and the method is illustrated on a data set on Chinese banks....

  18. Contributions of Early Versus Later-Generated Cortical Layers to the Development of Laminar Patterns of Ferret Somatosensory Cortex

    National Research Council Canada - National Science Library

    Noctor, Stephen C

    1998-01-01

    .... While it is recognized that the early-generated components of cerebral cortex are essential for the formation of important architectural structures, the contributions of later generated cortical...

  19. Component-based Systems Reconfigurations Using Graph Grammars

    Directory of Open Access Journals (Sweden)

    O. Kouchnarenko

    2016-01-01

    Full Text Available Dynamic reconfigurations can modify the architecture of component-based systems without incurring any system downtime. In this context, the main contribution of the present article is the establishment of correctness results proving component-based systems reconfigurations using graph grammars. New guarded reconfigurations allow us to build reconfigurations based on primitive reconfiguration operations using sequences of reconfigurations and the alternative and the repetitive constructs, while preserving configuration consistency. A practical contribution consists of the implementation of a component-based model using the GROOVE graph transformation tool. Then, after enriching the model with interpreted configurations and reconfigurations in a consistency compatible manner, a simulation relation is exploited to validate component systems’ implementations. This sound implementation is illustrated on a cloud-based multitier application hosting environment managed as a component-based system.

  20. ECN contributions to GLOBAL `95

    Energy Technology Data Exchange (ETDEWEB)

    NONE

    1995-06-01

    This report contains the 9 contributions of the Netherlands Energy Research Foundation ECN to the international conference on evaluation of emerging nuclear fuel cycle systems, GLOBAL `95, held in Versailles, France, on September 11-14, 1995. (orig./GL).

  1. Uncapacitated facility location problems: contributions

    Directory of Open Access Journals (Sweden)

    Galvão Roberto Diéguez

    2004-01-01

    Full Text Available The objective of the present paper is to review my personal contributions in the field of uncapacitated facility location problems. These contributions took place throughout my academic career, from the time I was a Ph.D. student at Imperial College to the present day. They cover approximately 30 years, from 1973 to 2003; they address: algorithms developed for the p-median problem and for a general formulation of uncapacitated location problems; the study of dynamic location models; covering and hierarchical location problems; queuing-based probabilistic location models. The contributions encompass theoretical developments, computational algorithms and practical applications. All work took place in an academic environment, with the invaluable collaboration of colleagues (both in Brazil and abroad and research students at COPPE. Each section in the paper is dedicated to a topic that involves a personal contribution. Every one of them is placed within the context of the existing literature.

  2. Optimization of structures and components

    CERN Document Server

    Muñoz-Rojas, Pablo Andrés

    2013-01-01

    Written by an international group of active researchers in the field, this volume presents innovative formulations and applied procedures for sensitivity analysis and structural design optimization. Eight chapters discuss subjects ranging from recent developments in the determination and application of topological gradients, to the use of evolutionary algorithms and meta-models to solve practical engineering problems. With such a comprehensive set of contributions, the book is a valuable source of information for graduate students and researchers entering or working in the matter.

  3. Component Control System for a Vehicle

    Science.gov (United States)

    Fraser-Chanpong, Nathan (Inventor); Spain, Ivan (Inventor); Dawson, Andrew D. (Inventor); Bluethmann, William J. (Inventor); Lee, Chunhao J. (Inventor); Vitale, Robert L. (Inventor); Guo, Raymond (Inventor); Waligora, Thomas M. (Inventor); Akinyode, Akinjide Akinniyi (Inventor); Reed, Ryan M. (Inventor)

    2016-01-01

    A vehicle includes a chassis, a modular component, and a central operating system. The modular component is supported by the chassis. The central operating system includes a component control system, a primary master controller, and a secondary master controller. The component control system is configured for controlling the modular component. The primary and secondary master controllers are in operative communication with the component control system. The primary and secondary master controllers are configured to simultaneously transmit commands to the component control system. The component control system is configured to accept commands from the secondary master controller only when a fault occurs in the primary master controller.

  4. Unresolved Blazar Component of the Extragalactic Gamma-Ray Background

    Science.gov (United States)

    Stecker, Floyd W.; Venters, T. M.

    2011-01-01

    We present new theoretical estimates of the relative contribution of unresolved blazars and star forming galaxies to the extragalactic gamma-ray background and discuss constraints on the contributions from other possible components. We find that the Fermi data do not rule out a scenario in which the extragalactic gamma-ray background is dominated by emission from unresolved blazars. The spectrum of unresolved FSRQs, when accounting for the energy dependent effects of source confusion, could be consistent with the combined spectrum of the low energy EGRET extragalactic gamma-ray background measurements and the Fermi-LAT measurements above 200 MeV.

  5. Experimental qualification of nuclear components

    International Nuclear Information System (INIS)

    Alliot, P.; Fronte, T.; Genty, F.

    1988-01-01

    In the process of showing the adequacy of the seismic design of French PWR reactor, Fermat has repeatedly used dynamic testing on actual nuclear reactor components both on site and in manufacturing shops. The objective and results of a few representative examples of this on-site experimental verification are presented in this paper: the experimental dynamic analysis of a manipulator crane; the investigation of the seismic behaviour of fuel storage racks equipped with aseismic bearing devices. Difficulties to select satisfactory testing methods are also discussed for the particular case of the electrical cabinets. (author)

  6. Management of Talar Component Subsidence.

    Science.gov (United States)

    Li, Shu-Yuan; Myerson, Mark S

    2017-06-01

    Component subsidence has been found to be the top complication that leads to failure of the total ankle arthroplasty (TAA). The cause of subsidence formation is unclear, and is multifactorial. Talar subsidence is more frequently met than tibial subsidence, and the subsequent big bone loss is demanding to handle. As a revision treatment option, neither a revision TAA nor a salvage ankle and/or hindfoot arthrodesis procedure is easy to perform or can obtain a definite outcome. The Salto XT can be used to treat most of the TAA systems available for use in the United States with acceptable short-term outcomes. Copyright © 2017 Elsevier Inc. All rights reserved.

  7. Magnetooptical current transformer. 2: Components.

    Science.gov (United States)

    Aulich, H; Beck, W; Douklias, N; Harms, H; Papp, A; Schneider, H

    1980-11-15

    In this second part, the most important components of a magnetooptical current transformer are described and their suitability is discussed. Today He-Ne gas lasers and laser diodes seem to meet best the requirements of the light source. Single-mode optical fibers are capable of transmitting polarized light without depolarization. A fiber coil wound on a special coil former is used as a measuring sensor. Two P-I-N photodiodes, together with an analog electronic circuit, transform the optical into an electrical measuring signal.

  8. Lifetime of superheated steam components

    International Nuclear Information System (INIS)

    Stoklossa, K.H.; Oude-Hengel, H.H.; Kraechter, H.J.

    1974-01-01

    The current evaluation schemes in use for judging the lifetime expectations of superheated steam components are compared with each other. The influence of pressure and temperature fluctuations, the differences in the strength of the wall, and the spread band of constant-strainrates are critically investigated. The distribution of these contributory effects are demonstrated in the hight of numerous measuring results. As an important supplement to these evaluation schemes a newly developed technique is introduced which is designed to calculate failure probabilities. (orig./RW) [de

  9. ANTHROPOLOGICAL COMPONENT OF DESCARTES’ ONTOLOGY

    Directory of Open Access Journals (Sweden)

    Anatolii M. Malivskyi

    2014-06-01

    Full Text Available The purpose of the article is to outline and comprehend the Descartes’ theory about anthropological component of ontology as the most important part of his philosophy. The accomplishment of this purpose covers the successive solution of the following tasks: 1 review of the research literature concerning the problem of human’s presence and the individual nature of truth; 2 emphasize the ambivalence of the basic intention of his legacy; 3 justify the thesis about constitutivity of human’s presence and comprehend passions as the form of disclosure of ontology’s anthropological component. Methodology. The use of the euristic potential of phenomenology, postpositivism and postmodernism makes it possible to emphasize the multiple-layer and multiple-meaning classical philosophy works, to comprehend the limitation and scarcity of the naïve-enlightening vision of human nature and to look for a new reception of European classics that provides the overcoming of established nihilism and pessimism concerning the interpretation of human nature. Scientific novelty. It is the first time that anthropological component of Descartes’ ontology became an object of particular attention. It previously lacked attention because of following main reasons: 1 traditional underestimating of the fact of Descartes’ legacy incompleteness as an unrealized anthropological project and 2 lack of proper attention to the individual nature of truth. The premise for its constructive overcoming is the attention to ambivalence of the basic intention and the significance of ethics in the philosopher’s legacy. His texts and research literature allow confirming the constitutive nature of human’s presence and passions as the key form of disclosure of the ontology anthropological component. Conclusions. The established tradition of interpretation the Descartes’ philosophizing nature as the filiation process of impersonal knowledge loses its cogency these days. The

  10. Anthropological Component of Descartes’ Ontology

    Directory of Open Access Journals (Sweden)

    Anatolii M. Malivskyi

    2014-06-01

    Full Text Available The purpose of the article is to outline and comprehend the Descartes’ theory about anthropological component of ontology as the most important part of his philosophy. The accomplishment of this purpose covers the successive solution of the following tasks: 1 review of the research literature concerning the problem of human’s presence and the individual nature of truth; 2 emphasize the ambivalence of the basic intention of his legacy; 3 justify the thesis about constitutivity of human’s presence and comprehend passions as the form of disclosure of ontology’s anthropological component. Methodology. The use of the euristic potential of phenomenology, postpositivism and postmodernism makes it possible to emphasize the multiple-layer and multiple-meaning classical philosophy works, to comprehend the limitation and scarcity of the naïve-enlightening vision of human nature and to look for a new reception of European classics that provides the overcoming of established nihilism and pessimism concerning the interpretation of human nature. Scientific novelty. It is the first time that anthropological component of Descartes’ ontology became an object of particular attention. It previously lacked attention because of following main reasons: 1 traditional underestimating of the fact of Descartes’ legacy incompleteness as an unrealized anthropological project and 2 lack of proper attention to the individual nature of truth. The premise for its constructive overcoming is the attention to ambivalence of the basic intention and the significance of ethics in the philosopher’s legacy. His texts and research literature allow confirming the constitutive nature of human’s presence and passions as the key form of disclosure of the ontology anthropological component. Conclusions. The established tradition of interpretation the Descartes’ philosophizing nature as the filiation process of impersonal knowledge loses its cogency these days. The

  11. A flexible framework for sparse simultaneous component based data integration

    Directory of Open Access Journals (Sweden)

    Van Deun Katrijn

    2011-11-01

    Full Text Available Abstract 1 Background High throughput data are complex and methods that reveal structure underlying the data are most useful. Principal component analysis, frequently implemented as a singular value decomposition, is a popular technique in this respect. Nowadays often the challenge is to reveal structure in several sources of information (e.g., transcriptomics, proteomics that are available for the same biological entities under study. Simultaneous component methods are most promising in this respect. However, the interpretation of the principal and simultaneous components is often daunting because contributions of each of the biomolecules (transcripts, proteins have to be taken into account. 2 Results We propose a sparse simultaneous component method that makes many of the parameters redundant by shrinking them to zero. It includes principal component analysis, sparse principal component analysis, and ordinary simultaneous component analysis as special cases. Several penalties can be tuned that account in different ways for the block structure present in the integrated data. This yields known sparse approaches as the lasso, the ridge penalty, the elastic net, the group lasso, sparse group lasso, and elitist lasso. In addition, the algorithmic results can be easily transposed to the context of regression. Metabolomics data obtained with two measurement platforms for the same set of Escherichia coli samples are used to illustrate the proposed methodology and the properties of different penalties with respect to sparseness across and within data blocks. 3 Conclusion Sparse simultaneous component analysis is a useful method for data integration: First, simultaneous analyses of multiple blocks offer advantages over sequential and separate analyses and second, interpretation of the results is highly facilitated by their sparseness. The approach offered is flexible and allows to take the block structure in different ways into account. As such

  12. A flexible framework for sparse simultaneous component based data integration.

    Science.gov (United States)

    Van Deun, Katrijn; Wilderjans, Tom F; van den Berg, Robert A; Antoniadis, Anestis; Van Mechelen, Iven

    2011-11-15

    High throughput data are complex and methods that reveal structure underlying the data are most useful. Principal component analysis, frequently implemented as a singular value decomposition, is a popular technique in this respect. Nowadays often the challenge is to reveal structure in several sources of information (e.g., transcriptomics, proteomics) that are available for the same biological entities under study. Simultaneous component methods are most promising in this respect. However, the interpretation of the principal and simultaneous components is often daunting because contributions of each of the biomolecules (transcripts, proteins) have to be taken into account. We propose a sparse simultaneous component method that makes many of the parameters redundant by shrinking them to zero. It includes principal component analysis, sparse principal component analysis, and ordinary simultaneous component analysis as special cases. Several penalties can be tuned that account in different ways for the block structure present in the integrated data. This yields known sparse approaches as the lasso, the ridge penalty, the elastic net, the group lasso, sparse group lasso, and elitist lasso. In addition, the algorithmic results can be easily transposed to the context of regression. Metabolomics data obtained with two measurement platforms for the same set of Escherichia coli samples are used to illustrate the proposed methodology and the properties of different penalties with respect to sparseness across and within data blocks. Sparse simultaneous component analysis is a useful method for data integration: First, simultaneous analyses of multiple blocks offer advantages over sequential and separate analyses and second, interpretation of the results is highly facilitated by their sparseness. The approach offered is flexible and allows to take the block structure in different ways into account. As such, structures can be found that are exclusively tied to one data platform

  13. A flexible framework for sparse simultaneous component based data integration

    Science.gov (United States)

    2011-01-01

    1 Background High throughput data are complex and methods that reveal structure underlying the data are most useful. Principal component analysis, frequently implemented as a singular value decomposition, is a popular technique in this respect. Nowadays often the challenge is to reveal structure in several sources of information (e.g., transcriptomics, proteomics) that are available for the same biological entities under study. Simultaneous component methods are most promising in this respect. However, the interpretation of the principal and simultaneous components is often daunting because contributions of each of the biomolecules (transcripts, proteins) have to be taken into account. 2 Results We propose a sparse simultaneous component method that makes many of the parameters redundant by shrinking them to zero. It includes principal component analysis, sparse principal component analysis, and ordinary simultaneous component analysis as special cases. Several penalties can be tuned that account in different ways for the block structure present in the integrated data. This yields known sparse approaches as the lasso, the ridge penalty, the elastic net, the group lasso, sparse group lasso, and elitist lasso. In addition, the algorithmic results can be easily transposed to the context of regression. Metabolomics data obtained with two measurement platforms for the same set of Escherichia coli samples are used to illustrate the proposed methodology and the properties of different penalties with respect to sparseness across and within data blocks. 3 Conclusion Sparse simultaneous component analysis is a useful method for data integration: First, simultaneous analyses of multiple blocks offer advantages over sequential and separate analyses and second, interpretation of the results is highly facilitated by their sparseness. The approach offered is flexible and allows to take the block structure in different ways into account. As such, structures can be found that are

  14. Parametric functional principal component analysis.

    Science.gov (United States)

    Sang, Peijun; Wang, Liangliang; Cao, Jiguo

    2017-09-01

    Functional principal component analysis (FPCA) is a popular approach in functional data analysis to explore major sources of variation in a sample of random curves. These major sources of variation are represented by functional principal components (FPCs). Most existing FPCA approaches use a set of flexible basis functions such as B-spline basis to represent the FPCs, and control the smoothness of the FPCs by adding roughness penalties. However, the flexible representations pose difficulties for users to understand and interpret the FPCs. In this article, we consider a variety of applications of FPCA and find that, in many situations, the shapes of top FPCs are simple enough to be approximated using simple parametric functions. We propose a parametric approach to estimate the top FPCs to enhance their interpretability for users. Our parametric approach can also circumvent the smoothing parameter selecting process in conventional nonparametric FPCA methods. In addition, our simulation study shows that the proposed parametric FPCA is more robust when outlier curves exist. The parametric FPCA method is demonstrated by analyzing several datasets from a variety of applications. © 2017, The International Biometric Society.

  15. Components of Adenovirus Genome Packaging

    Science.gov (United States)

    Ahi, Yadvinder S.; Mittal, Suresh K.

    2016-01-01

    Adenoviruses (AdVs) are icosahedral viruses with double-stranded DNA (dsDNA) genomes. Genome packaging in AdV is thought to be similar to that seen in dsDNA containing icosahedral bacteriophages and herpesviruses. Specific recognition of the AdV genome is mediated by a packaging domain located close to the left end of the viral genome and is mediated by the viral packaging machinery. Our understanding of the role of various components of the viral packaging machinery in AdV genome packaging has greatly advanced in recent years. Characterization of empty capsids assembled in the absence of one or more components involved in packaging, identification of the unique vertex, and demonstration of the role of IVa2, the putative packaging ATPase, in genome packaging have provided compelling evidence that AdVs follow a sequential assembly pathway. This review provides a detailed discussion on the functions of the various viral and cellular factors involved in AdV genome packaging. We conclude by briefly discussing the roles of the empty capsids, assembly intermediates, scaffolding proteins, portal vertex and DNA encapsidating enzymes in AdV assembly and packaging. PMID:27721809

  16. Bioactive Components in Fish Venoms

    Science.gov (United States)

    Ziegman, Rebekah; Alewood, Paul

    2015-01-01

    Animal venoms are widely recognized excellent resources for the discovery of novel drug leads and physiological tools. Most are comprised of a large number of components, of which the enzymes, small peptides, and proteins are studied for their important bioactivities. However, in spite of there being over 2000 venomous fish species, piscine venoms have been relatively underrepresented in the literature thus far. Most studies have explored whole or partially fractioned venom, revealing broad pharmacology, which includes cardiovascular, neuromuscular, cytotoxic, inflammatory, and nociceptive activities. Several large proteinaceous toxins, such as stonustoxin, verrucotoxin, and Sp-CTx, have been isolated from scorpaenoid fish. These form pores in cell membranes, resulting in cell death and creating a cascade of reactions that result in many, but not all, of the physiological symptoms observed from envenomation. Additionally, Natterins, a novel family of toxins possessing kininogenase activity have been found in toadfish venom. A variety of smaller protein toxins, as well as a small number of peptides, enzymes, and non-proteinaceous molecules have also been isolated from a range of fish venoms, but most remain poorly characterized. Many other bioactive fish venom components remain to be discovered and investigated. These represent an untapped treasure of potentially useful molecules. PMID:25941767

  17. Induced radioactivity in LDEF components

    Science.gov (United States)

    Harmon, B. A.; Fishman, G. J.; Parnell, T. A.; Laird, C. E.

    1992-01-01

    A systematic study of the induced radioactivity of the Long Duration Exposure Facility (LDEF) is being carried out in order to gather information about the low earth orbit radiation environment and its effects on materials. The large mass of the LDEF spacecraft, its stabilized configuration, and long mission duration have presented an opportunity to determine space radiation-induced radioactivities with a precision not possible before. Data presented include preliminary activities for steel and aluminum structural samples, and activation subexperiment foils. Effects seen in the data show a clear indication of the trapped proton anisotropy in the South Atlantic Anomaly and suggest contributions from different sources of external radiation fluxes.

  18. The Contribution of IVS to IGGOS

    Science.gov (United States)

    Nothnagel, A.

    2002-05-01

    Since its inauguration in 1999, the International VLBI Service for Geodesy and Astrometry has made significant progress in the coordination and utilisation of worldwide VLBI resources. Improving the visibility of the IVS components to a wider public in turn led to a higher motivation of the individuals to contribute to the global effort. Not only the number of IVS components but also their investments in terms of funds and manpower demonstrate the increased awareness of the importance of this joint international endeavour. The different demands of the users but also of the contributors often require the definition of priorities which are only being acceptable due to the existence of a strong umbrella organisation like the IVS. Significant progress has also been made in the area of routine data analysis and combination of results. By now, six IVS Analysis Centers provide the redundancy necessary for a robust combination of the results. The use of ITRF2000 station coordinates as the basis for the IVS combined EOP series is the most recent step towards the generation of a consistent chain from the quasi-inertial frame of radio sources to system Earth.

  19. Making High-Tensile-Strength Amalgam Components

    Science.gov (United States)

    Grugel, Richard

    2008-01-01

    Structural components made of amalgams can be made to have tensile strengths much greater than previously known to be possible. Amalgams, perhaps best known for their use in dental fillings, have several useful attributes, including room-temperature fabrication, corrosion resistance, dimensional stability, and high compressive strength. However, the range of applications of amalgams has been limited by their very small tensile strengths. Now, it has been discovered that the tensile strength of an amalgam depends critically on the sizes and shapes of the particles from which it is made and, consequently, the tensile strength can be greatly increased through suitable choice of the particles. Heretofore, the powder particles used to make amalgams have been, variously, in the form of micron-sized spheroids or flakes. The tensile reinforcement contributed by the spheroids and flakes is minimal because fracture paths simply go around these particles. However, if spheroids or flakes are replaced by strands having greater lengths, then tensile reinforcement can be increased significantly. The feasibility of this concept was shown in an experiment in which electrical copper wires, serving as demonstration substitutes for copper powder particles, were triturated with gallium by use of a mortar and pestle and the resulting amalgam was compressed into a mold. The tensile strength of the amalgam specimen was then measured and found to be greater than 10(exp 4) psi (greater than about 69 MPa). Much remains to be done to optimize the properties of amalgams for various applications through suitable choice of starting constituents and modification of the trituration and molding processes. The choice of wire size and composition are expected to be especially important. Perusal of phase diagrams of metal mixtures could give insight that would enable choices of solid and liquid metal constituents. Finally, whereas heretofore, only binary alloys have been considered for amalgams

  20. 75 FR 34388 - Employee Contribution Elections and Contribution Allocations

    Science.gov (United States)

    2010-06-17

    ... describes: (a) That default employee contributions equal to 3 percent of the employee's basic pay will be... From the Federal Register Online via the Government Publishing Office #0; #0;Proposed Rules #0... Employees' Retirement System Act of 1986 (FERSA), Public Law 99-335, 100 Stat. 514. The TSP provisions of...

  1. Hemodynamic response based mixture model to estimate micro- and macro-vasculature contributions in functional MRI

    CERN Document Server

    Singh, Manbir; Sungkarat, Witaya; Zhou, Yongxia

    2003-01-01

    A multi-componet model reflecting the temporal characteristics of micro- and macro-vasculature hemodynamic responses was used to fit the time-course of voxels in functional MRI (fMRI). The number of relevant components, the latency of the first component, the time- separation among the components, their relative amplitude and possible interpretation in terms of partial volume contributions of micro- and macro-components to the time-course data were investigated. Analysis of a reversing checkerboard experiment revealed that there was no improvement in the filing beyond two components. Using a two-component model, the fractional abundances of the micro- and macro-vasculature were estimated in individual voxels. These results suggest the potential of a mixture-model approach to mitigate partial volume effects and separate contributions of vascular components within a voxel in fMRI.

  2. Research for the thermal change. Contributions

    International Nuclear Information System (INIS)

    Szczepanski, Petra; Wunschick, Franziska; Martin, Niklas

    2016-01-01

    The energy transition in the heating sector is not a sure-fire success and it is too slow. This is alarming since the heating / cooling sector is responsible for more than half of the final energy demand. That the ''thermal change'' has accelerated hardly despite many efforts by politics, industry and research in recent years, is the reason for the scientists the FVEE institutes to examine the perspectives of renewable energy and the need to increase efficiency in the heating sector systematically. therefore FVEE-2015 Annual Meeting, is entitled ''Research for the thermal change''. The contributions of this conference proceedings present the latest research results and show ways to implement the heat change technically, economically and politically. They are dedicated to the drivers, but also the barriers of heat change. The authors report on innovative projects to provide buildings with heat from geothermal energy, biomass and solar thermal energy. Several contributions are dedicated to the application of efficient components, such as thermal insulation, thermal storage and heat pumps. [de

  3. Development of radiation hardness components for ITER remote maintenance

    International Nuclear Information System (INIS)

    Obara, Kenjiro; Kakudate, Satoshi; Oka, Kiyoshi; Ito, Akira; Yagi, Toshiaki; Morita, Yousuke

    1998-01-01

    In the ITER, in-vessel remote handling is required to assemble and maintain in-vessel components in DT operations. Since in-vessel remote handling systems must operate under intense gamma ray radiation exceeding 30 kGy/h, their components must have sufficiently high radiation hardness to allow maintenance long enough in ITER in-vessel environments. Thus, extensive radiation tests and quality improvement, including optimization of material compositions, have been conducted through the ITER R and D program to develop radiation hardness components that meet radiation doses from 10 to 100 MGy at 10 kGy/h. This paper presents the latest on radiation hardness component development conducted by the Japan Home Team as a contribution to the ITER. The remote handling components tested are categorized for use in robotic or viewing systems, or as common components. Radiation tests have been conducted on commercially available products for screening, on modified products, and on new products to improve the radiation hardness. (author)

  4. Development of radiation hardness components for ITER remote maintenance

    Energy Technology Data Exchange (ETDEWEB)

    Obara, Kenjiro; Kakudate, Satoshi; Oka, Kiyoshi; Ito, Akira [Japan Atomic Energy Research Inst., Tokai, Ibaraki (Japan). Tokai Research Establishment; Yagi, Toshiaki; Morita, Yousuke

    1998-04-01

    In the ITER, in-vessel remote handling is required to assemble and maintain in-vessel components in DT operations. Since in-vessel remote handling systems must operate under intense gamma ray radiation exceeding 30 kGy/h, their components must have sufficiently high radiation hardness to allow maintenance long enough in ITER in-vessel environments. Thus, extensive radiation tests and quality improvement, including optimization of material compositions, have been conducted through the ITER R and D program to develop radiation hardness components that meet radiation doses from 10 to 100 MGy at 10 kGy/h. This paper presents the latest on radiation hardness component development conducted by the Japan Home Team as a contribution to the ITER. The remote handling components tested are categorized for use in robotic or viewing systems, or as common components. Radiation tests have been conducted on commercially available products for screening, on modified products, and on new products to improve the radiation hardness. (author)

  5. Indigenous procurement of nuclear components at Tarapur (Paper No. 013)

    International Nuclear Information System (INIS)

    Verma, D.K.; Moss, V.J.

    1987-02-01

    The Tarapur Atomic Power Station (TAPS) was the first nuclear power station in developing countries and the first twin BWR units in the world. The Station has two units of boiling water reactor of very early design; along with its turbo-generator and supporting systems; constructed by M/s. I.G.E. on turnkey basis. Based on vendor recommendations initial operating spares for 5 years of operation were purchased from original equipment manufacturers. This does not call for the participation of the ultimate user; in the design, development, manufacture and quality control and user's participation remained confined to assemble the acceptable component(s) procured from original source in the assembly. As early as 1972, Plant initiated indigenising the nuclear components by gradually increasing the contribution of indigenous industry with due participation of the departmental agencies. Procurement of nuclear components requires development of engineering to an extent; where interphase communication between TAPS and counterpart indigenous industry is practicable to motivate them. Feedback from operation and maintenance practices is also utilised effectively. For some of the components initial sample were developed at TAPS and subsequently bulk fabrication was taken by industry. This paper describes manufacture, quality control during the process of manufacture and procurement of indigenous nuclear components relevant to Tarapur Atomic Power Station. (author)

  6. Characterization of components and materials for EMC barriers

    OpenAIRE

    Lundgren, Urban

    2004-01-01

    This thesis presents contributions to work for better methodologies for addressing Electromagnetic Compatibility (EMC) issues. In particular measurement methods are reviewed and devised for acquiring data on barriers used for EMC. Such data is used for characterization, modeling and model verification of barriers. The concept of EMC barriers is introduced as a general view of filter components, separation of conductors (crosstalk problems), electromagnetic shielding etc. The aim is to find me...

  7. Charm contribution to bulk viscosity

    Science.gov (United States)

    Laine, M.; Sohrabi, Kiyoumars A.

    2015-02-01

    In the range of temperatures reached in future heavy ion collision experiments, hadronic pair annihilations and creations of charm quarks may take place within the lifetime of the plasma. As a result, charm quarks may increase the bulk viscosity affecting the early stages of hydrodynamic expansion. Assuming thermalisation, we estimate the charm contribution to bulk viscosity within the same effective kinetic theory framework in which the light parton contribution has been computed previously. The time scale at which this physics becomes relevant is related to the width of the transport peak associated with the trace anomaly correlator and is found to be fm/c for MeV.

  8. Understanding symmetrical components for power system modeling

    CERN Document Server

    Das, J C

    2017-01-01

    This book utilizes symmetrical components for analyzing unbalanced three-phase electrical systems, by applying single-phase analysis tools. The author covers two approaches for studying symmetrical components; the physical approach, avoiding many mathematical matrix algebra equations, and a mathematical approach, using matrix theory. Divided into seven sections, topics include: symmetrical components using matrix methods, fundamental concepts of symmetrical components, symmetrical components –transmission lines and cables, sequence components of rotating equipment and static load, three-phase models of transformers and conductors, unsymmetrical fault calculations, and some limitations of symmetrical components.

  9. On Bayesian Principal Component Analysis

    Czech Academy of Sciences Publication Activity Database

    Šmídl, Václav; Quinn, A.

    2007-01-01

    Roč. 51, č. 9 (2007), s. 4101-4123 ISSN 0167-9473 R&D Projects: GA MŠk(CZ) 1M0572 Institutional research plan: CEZ:AV0Z10750506 Keywords : Principal component analysis ( PCA ) * Variational bayes (VB) * von-Mises–Fisher distribution Subject RIV: BC - Control Systems Theory Impact factor: 1.029, year: 2007 http://www.sciencedirect.com/science?_ob=ArticleURL&_udi=B6V8V-4MYD60N-6&_user=10&_coverDate=05%2F15%2F2007&_rdoc=1&_fmt=&_orig=search&_sort=d&view=c&_acct=C000050221&_version=1&_urlVersion=0&_userid=10&md5=b8ea629d48df926fe18f9e5724c9003a

  10. Components of attention in synesthesia

    DEFF Research Database (Denmark)

    Sørensen, Thomas Alrik; Nordfang, Maria; Pedersen, Michael Nygaard

    2013-01-01

    One of the most common forms of synesthesia is between colors and graphemes (Colizoli, Murre, & Rouw, 2012). Numerous studies have investigated different aspects of attention and synesthesia, e.g. effects of Stroop-like interference by colors that are incongruent with the synesthetic experience...... synesthesia (Mattingley, 2009). Results from the present experiment show that synesthesia affects both speed of processing (C) and the number of objects that can be retained in visual short-term memory (K). Participants were faster at encoding characters that were colored congruently with their synesthesia....... Here we attempt to isolate how speci¿ c components of attention are affected by grapheme-color synesthesia. Eight carefully screened healthy participants with synesthesia reported the letters in brie¿ y presented, post-masked arrays of letters and digits. On half the trials, the letters and digits were...

  11. Component codification and identification systems

    International Nuclear Information System (INIS)

    Pannenbaecker, K.

    1977-01-01

    The lecture covers the codification in power stations during the erection phase and commercial operation phase. A diagram gives a survey. There are three basic-codifications for application; 1) Kraftwerk-Kennzeichen-System (KKS) for marking each component in orientated systems, for marking electrical orientated positions in cubicals, switch gears etc. and for marking rooms in buildings; 2) Ordnungssystem (OS) for cost calculation and ordering; 3) Unterlagenarten-Schluessel (UAS) for letters, reports etc. and for documentation. The OS is developed on the principle of cost account number and is therefore close to the organization of each supplier and his special form of design and constrution. KKS has only to mark hardware. Therefore all German owners, consultants, authorities and suppliers develop KKS together and conform to it in DIN 407119. (ORU) [de

  12. LCA profiles for building components:

    DEFF Research Database (Denmark)

    Marsh, Rob

    2016-01-01

    , a new approach explores how environmental information on building components can be simplified for strategic use early in the design process in a Danish context. In this paper, life cycle assessments (LCAs) are undertaken for several hundred typical external wall solutions, based on relevant standards....... A full bivariate linear regression analysis is performed, showing statistically significant correlations with strong direct relationships between environmental impact categories. A simplified LCA profile consisting of total primary energy, global warming potential and acidification potential is developed....... This simplified LCA profile presents environmental data in a more understandable way, creating a strategic overview that can be easily used by non-technical clients and construction professionals in the early design stages. This has a scientific and statistical validity generated by environmental assessment...

  13. Rosin components identified in diapers.

    Science.gov (United States)

    Karlberg, A T; Magnusson, K

    1996-03-01

    As part of the investigation of sources of exposure to rosin allergens, disposable diapers (napkins) common on the Swedish market were analyzed, using gas chromatography, to detect the main rosin compounds. Rosin components were detected in all diapers, the highest amounts in those from the 2 major producers. In these diapers, more rosin was found in the top layer, which is in close contact with the skin than in the fluff. Despite the possibly minimal risk of induction of sensitization to rosin allergens in diapers, there is a real risk of elicitation of dermatitis in sensitive individuals, especially since penetration is enhanced by occlusion and irritation. Such material is not only used for infant diapers, but also for adult incontinence products and feminine hygiene products.

  14. The magnet components database system

    International Nuclear Information System (INIS)

    Baggett, M.J.; Leedy, R.; Saltmarsh, C.; Tompkins, J.C.

    1990-01-01

    The philosophy, structure, and usage of MagCom, the SSC magnet components database, are described. The database has been implemented in Sybase (a powerful relational database management system) on a UNIX-based workstation at the Superconducting Super Collider Laboratory (SSCL); magnet project collaborators can access the database via network connections. The database was designed to contain the specifications and measured values of important properties for major materials, plus configuration information (specifying which individual items were used in each cable, coil, and magnet) and the test results on completed magnets. The data will facilitate the tracking and control of the production process as well as the correlation of magnet performance with the properties of its constituents. 3 refs., 9 figs

  15. Comparisons of PRD [power-reactivity-decrements] components for various EBR-II configurations

    International Nuclear Information System (INIS)

    Meneghetti, D.; Kucera, D.A.

    1986-01-01

    Comparison of detailed calculations of contributions by region and component of the power-reactivity-decrements (PRD) for four differing loading configurations of the Experimental Breeder Reactor-II (EBR-II) are given. The linear components and Doppler components are calculated. The non-linear (primarily subassembly bowing) components are deduced by differences relative to measured total PRD values. Variations in linear components range from about 10% to as much as about 100% depending upon the component. The deduced non-linear components differ both in magnitude and sign as functions of reactor power. Effects of differing assumptions of the nature of the fuel-to-clad interactions upon the PRD components are also calculated

  16. Components of Insurance Firm Value and the Present Value of Liabilities

    OpenAIRE

    David F. Babbel

    1998-01-01

    In this paper, we discuss the relation between the market value of insurance company owners' equity and various components that contribute to that value. The effect of firm insolvency risk on each component of value is discussed in turn. One natural consequence of this analysis is a conceptual framework for estimating the value of insurance liabilities.

  17. A probabilistic model for component-based shape synthesis

    KAUST Repository

    Kalogerakis, Evangelos

    2012-07-01

    We present an approach to synthesizing shapes from complex domains, by identifying new plausible combinations of components from existing shapes. Our primary contribution is a new generative model of component-based shape structure. The model represents probabilistic relationships between properties of shape components, and relates them to learned underlying causes of structural variability within the domain. These causes are treated as latent variables, leading to a compact representation that can be effectively learned without supervision from a set of compatibly segmented shapes. We evaluate the model on a number of shape datasets with complex structural variability and demonstrate its application to amplification of shape databases and to interactive shape synthesis. © 2012 ACM 0730-0301/2012/08-ART55.

  18. Anisotropic magnetoresistance components in (Ga,Mn)As.

    Science.gov (United States)

    Rushforth, A W; Výborný, K; King, C S; Edmonds, K W; Campion, R P; Foxon, C T; Wunderlich, J; Irvine, A C; Vasek, P; Novák, V; Olejník, K; Sinova, Jairo; Jungwirth, T; Gallagher, B L

    2007-10-05

    We explore the basic physical origins of the noncrystalline and crystalline components of the anisotropic magnetoresistance (AMR) in (Ga,Mn)As. The sign of the noncrystalline AMR is found to be determined by the form of spin-orbit coupling in the host band and by the relative strengths of the nonmagnetic and magnetic contributions to the Mn impurity potential. We develop experimental methods yielding directly the noncrystalline and crystalline AMR components which are then analyzed independently. We report the observation of an AMR dominated by a large uniaxial crystalline component and show that AMR can be modified by local strain relaxation. Generic implications of our findings for other dilute moment systems are discussed.

  19. Library thermohydraulic components for training simulators

    International Nuclear Information System (INIS)

    Castelao Caruana, M. J.; Di Benedetto, A.; Pierini, J.P.

    2013-01-01

    The thermohydraulic components Library was modeled in MatLab/Simulink®. This library owns Pipe type components (pump, control valve and / or heaters), storage tanks (Open, Closed and Equilibrium Water Vapor-Air) and Heat Exchangers (Co-Current, Counter-Current and U-tubes). Each component can be attached to other components through the component library Header, in order to create a more complex thermal-hydraulic system which in turn can interact with other thermal-hydraulic systems. (author)

  20. Maxwell's Contributions to Thermal Physics

    Indian Academy of Sciences (India)

    Home; Journals; Resonance – Journal of Science Education; Volume 8; Issue 5. Maxwell's Contributions to Thermal Physics. Sisir Bhanja. General Article Volume 8 Issue 5 May 2003 pp 57-72. Fulltext. Click here to view fulltext PDF. Permanent link: http://www.ias.ac.in/article/fulltext/reso/008/05/0057-0072. Keywords.

  1. The Jewish contribution to medicine

    African Journals Online (AJOL)

    1989-07-15

    Jul 15, 1989 ... History of Medicine. The Jewish contribution to medicine. Part 11. The 19th and 20th centuries. H.DUBOVSKY. Summary. Despite the opening of German universities to Jews in the .... private practice since religious prejudice prevented him from ..... investigations in orphanages and prisons he established a.

  2. Contributions of Maxwell to Electromagnetism

    Indian Academy of Sciences (India)

    Home; Journals; Resonance – Journal of Science Education; Volume 8; Issue 5. Contributions of Maxwell to Electromagnetism. P V Panat. General Article Volume 8 Issue 5 May 2003 pp 17-29. Fulltext. Click here to view fulltext PDF. Permanent link: http://www.ias.ac.in/article/fulltext/reso/008/05/0017-0029. Keywords.

  3. The Jewish contribution to medicine

    African Journals Online (AJOL)

    Their contribution to the an may be gauged by their forming 30%1 of Nobel Prize winners for medicine while constituting a fraction of 1% of the total world population. Garrison,2 Talbot,3 Roth4 and the Encyclopaedia Judaica5 were consulted for Jewish identification. The laner authority includes those of 'Jewish origin', ...

  4. Financial Network Systemic Risk Contributions

    NARCIS (Netherlands)

    Hautsch, N.; Schaumburg, J.; Schienle, M.

    2015-01-01

    We propose the realized systemic risk beta as a measure of financial companies' contribution to systemic risk, given network interdependence between firms' tail risk exposures. Conditional on statistically pre-identified network spillover effects and market and balance sheet information, we define

  5. CONTRIBUTIONS OF SUSHRUTA TO ANATOMY

    African Journals Online (AJOL)

    2005-08-08

    Aug 8, 2005 ... Probably, the exhaustive knowledge of basic sciences he had would have made him a versatile surgeon. This article has compiled the contributions of this great stalwart to anatomy and interprets his perspective towards teaching this subject. Keywords: Sushruta, Dissection, Cadaver, Anatomy, Preservation.

  6. JC Bose's Contributions to Chronobiology

    Indian Academy of Sciences (India)

    1122 printed pages offour monograph volumes. Reproduced here are his contributions to chronobiology in ... to J C Bose's work in the first monograph written on the subject of circadian clocks in German in 1958, ... account from his many passages in his inimitable English prose,. _ _ _ _ _ _ _ _ ,AAAAA, _ _ _ _ _ _ _ _. 54.

  7. Incentives and opportunities for reducing the cobalt content in reactor core components

    International Nuclear Information System (INIS)

    Ocken, H.

    1985-01-01

    Cobalt in core components contributes to radiation field buildup on out-of-core surfaces. Core components containing cobalt-base alloys and cobalt as an impurity are identified. The use of cobalt-free wear-resistant alloys and construction materials with lower impurity levels of cobalt is disused. It is argued that such measures are cost effective. Lower radiation fields and disposal costs will offset higher raw material costs. Component performance will not be affected. (author)

  8. The search for putative unifying genetic factors for components of the metabolic syndrome

    DEFF Research Database (Denmark)

    Sjögren, M; Lyssenko, V; Jonsson, Anna Elisabet

    2008-01-01

    The metabolic syndrome is a cluster of factors contributing to increased risk of cardiovascular disease and type 2 diabetes but unifying mechanisms have not been identified. Our aim was to study whether common variations in 17 genes previously associated with type 2 diabetes or components...... of the metabolic syndrome and variants in nine genes with inconsistent association with at least two components of the metabolic syndrome would also predict future development of components of the metabolic syndrome, individually or in combination....

  9. Neural components of altruistic punishment

    Directory of Open Access Journals (Sweden)

    Emily eDu

    2015-02-01

    Full Text Available Altruistic punishment, which occurs when an individual incurs a cost to punish in response to unfairness or a norm violation, may play a role in perpetuating cooperation. The neural correlates underlying costly punishment have only recently begun to be explored. Here we review the current state of research on the neural basis of altruism from the perspectives of costly punishment, emphasizing the importance of characterizing elementary neural processes underlying a decision to punish. In particular, we emphasize three cognitive processes that contribute to the decision to altruistically punish in most scenarios: inequity aversion, cost-benefit calculation, and social reference frame to distinguish self from others. Overall, we argue for the importance of understanding the neural correlates of altruistic punishment with respect to the core computations necessary to achieve a decision to punish.

  10. Radiation Effects on Superconducting Fusion Magnet Components

    Science.gov (United States)

    Weber, Harald W.

    Nuclear fusion devices based on the magnetic confinement principle heavily rely on the existence and performance of superconducting magnets and have always significantly contributed to advancing superconductor and magnet technology to their limits. In view of the presently ongoing construction of the tokamak device ITER and the stellerator device Wendelstein 7X and their record breaking parameters concerning size, complexity of design, stored energy, amperage, mechanical and magnetic forces, critical current densities and stability requirements, it is deemed timely to review another critical parameter that is practically unique to these devices, namely the radiation response of all magnet components to the lifetime fluence of fast neutrons and gamma rays produced by the fusion reactions of deuterium and tritium. I will review these radiation effects in turn for the currently employed standard "technical" low temperature superconductors NbTi and Nb3Sn, the stabilizing material (Cu) as well as the magnet insulation materials and conclude by discussing the potential of high temperature superconducting materials for future generations of fusion devices, such as DEMO.

  11. Components of foreign object management as

    Directory of Open Access Journals (Sweden)

    V.Yu. Gordopolov

    2016-12-01

    Full Text Available In the article the components of foreign economic activity as objects of accounting and management, and analysis of current legislation and scientific literature that allowed classification form shapes and types of foreign economic activities that contribute to the planning process in the enterprise, as well as building an effective system of management and accounting, economic analysis and internal control. As part of the classification described basic forms, types of foreign trade, especially their implementation and legal regulation. On the basis of basic forms and types of foreign trade, set a number of problems conceptual-categorical apparatus applicable law. A nine treatments categories–operations of foreign economic activity of fixing specific legal acts. Operations of foreign economic activity (import transactions, export transactions, international transactions, securities, credit and foreign payment transactions, foreign rental operations, international leasing, foreign exchange transactions, foreign investments and operations associated with the joint activity identified as about objects accounting in foreign trade and is divided according to types of business entities (operating, financial and investment.

  12. Processed foods: contributions to nutrition.

    Science.gov (United States)

    Weaver, Connie M; Dwyer, Johanna; Fulgoni, Victor L; King, Janet C; Leveille, Gilbert A; MacDonald, Ruth S; Ordovas, Jose; Schnakenberg, David

    2014-06-01

    Both fresh and processed foods make up vital parts of the food supply. Processed food contributes to both food security (ensuring that sufficient food is available) and nutrition security (ensuring that food quality meets human nutrient needs). This ASN scientific statement focuses on one aspect of processed foods: their nutritional impacts. Specifically, this scientific statement 1) provides an introduction to how processed foods contribute to the health of populations, 2) analyzes the contribution of processed foods to "nutrients to encourage" and "constituents to limit" in the American diet as recommended by the Dietary Guidelines for Americans, 3) identifies the responsibilities of various stakeholders in improving the American diet, and 4) reviews emerging technologies and the research needed for a better understanding of the role of processed foods in a healthy diet. Analyses of the NHANES 2003-2008 show that processed foods provide both nutrients to encourage and constituents to limit as specified in the 2010 Dietary Guidelines for Americans. Of the nutrients to encourage, processed foods contributed 55% of dietary fiber, 48% of calcium, 43% of potassium, 34% of vitamin D, 64% of iron, 65% of folate, and 46% of vitamin B-12. Of the constituents to limit, processed foods contributed 57% of energy, 52% of saturated fat, 75% of added sugars, and 57% of sodium. Diets are more likely to meet food guidance recommendations if nutrient-dense foods, either processed or not, are selected. Nutrition and food science professionals, the food industry, and other stakeholders can help to improve the diets of Americans by providing a nutritious food supply that is safe, enjoyable, affordable, and sustainable by communicating effectively and accurately with each other and by working together to improve the overall knowledge of consumers. © 2014 American Society for Nutrition.

  13. Does Impaired Gallbladder Function Contribute to the Development of Barrett's Esophagus and Esophageal Adenocarcinoma?

    LENUS (Irish Health Repository)

    Nassr, Ayman O

    2011-06-01

    Esophageal adenocarcinoma is aetiologically associated with gastro-esophageal reflux, but the mechanisms responsible for the metaplasia-dysplasia sequence are unknown. Bile components are implicated. Impaired gallbladder function may contribute to duodenogastric reflux (DGR) and harmful GERD.

  14. Bioactive Egg Components and Inflammation

    Directory of Open Access Journals (Sweden)

    Catherine J. Andersen

    2015-09-01

    Full Text Available Inflammation is a normal acute response of the immune system to pathogens and tissue injury. However, chronic inflammation is known to play a significant role in the pathophysiology of numerous chronic diseases, such as cardiovascular disease, type 2 diabetes mellitus, and cancer. Thus, the impact of dietary factors on inflammation may provide key insight into mitigating chronic disease risk. Eggs are recognized as a functional food that contain a variety of bioactive compounds that can influence pro- and anti-inflammatory pathways. Interestingly, the effects of egg consumption on inflammation varies across different populations, including those that are classified as healthy, overweight, metabolic syndrome, and type 2 diabetic. The following review will discuss the pro- and anti-inflammatory properties of egg components, with a focus on egg phospholipids, cholesterol, the carotenoids lutein and zeaxanthin, and bioactive proteins. The effects of egg consumption of inflammation across human populations will additionally be presented. Together, these findings have implications for population-specific dietary recommendations and chronic disease risk.

  15. IT Infrastructure Components for Biobanking

    Science.gov (United States)

    Prokosch, H.U.; Beck, A.; Ganslandt, T.; Hummel, M.; Kiehntopf, M.; Sax, U.; Ückert, F.; Semler, S.

    2010-01-01

    Objective Within translational research projects in the recent years large biobanks have been established, mostly supported by homegrown, proprietary software solutions. No general requirements for biobanking IT infrastructures have been published yet. This paper presents an exemplary biobanking IT architecture, a requirements specification for a biorepository management tool and exemplary illustrations of three major types of requirements. Methods We have pursued a comprehensive literature review for biobanking IT solutions and established an interdisciplinary expert panel for creating the requirements specification. The exemplary illustrations were derived from a requirements analysis within two university hospitals. Results The requirements specification comprises a catalog with more than 130 detailed requirements grouped into 3 major categories and 20 subcategories. Special attention is given to multitenancy capabilities in order to support the project-specific definition of varying research and bio-banking contexts, the definition of workflows to track sample processing, sample transportation and sample storage and the automated integration of preanalytic handling and storage robots. Conclusion IT support for biobanking projects can be based on a federated architectural framework comprising primary data sources for clinical annotations, a pseudonymization service, a clinical data warehouse with a flexible and user-friendly query interface and a biorepository management system. Flexibility and scalability of all such components are vital since large medical facilities such as university hospitals will have to support biobanking for varying monocentric and multicentric research scenarios and multiple medical clients. PMID:23616851

  16. Components development in the EU

    International Nuclear Information System (INIS)

    2015-01-01

    In the Euratom Sixth Framework Programme (FP6) an integrated project IP-EUROTRANS (transmutation) is ongoing. One of this project’s objectives is to develop and assess structural materials and heavy liquid metal (HLM) lead–lead-bismuth technologies for transmutation systems, where the HLM is both the spallation material and the core coolant. This involves specification and fabrication of reference materials, their characterisation in HLM and in representative conditions (with and without irradiation environment) in order to provide the data base needed for design purposes (e.g. fuel cladding, in-vessel components, primary vessel, instrumentation, target container, beam window), thermalhydraulics, measurement techniques, large scale integral tests and PTA studies for the MEGAPIE spallation target of FP5. In particular the ongoing R&D for the subcritical reactors XT-ADS, cooled by LBE, and EFIT, cooled by pure lead are: – To provide necessary information for designers, as concerns both T91 and 316L steels in contact with LBE and lead. This R&D is aimed to: • Determine the creep, low cycle fatigue, relaxation (fatigue and creep) fatigue behaviour of T91 and 316L in contact with lead and LBE, both qualitatively and quantitatively; • Characterize their fracture resistance, once again both qualitatively and quantitatively; • Constitute reliable data base over a wide temperature range, attaining 550°C; • Determine the fracture mechanisms of both ferritic–martensitic and austenitic materials in contact with HLMs

  17. Teaching Principal Components Using Correlations.

    Science.gov (United States)

    Westfall, Peter H; Arias, Andrea L; Fulton, Lawrence V

    2017-01-01

    Introducing principal components (PCs) to students is difficult. First, the matrix algebra and mathematical maximization lemmas are daunting, especially for students in the social and behavioral sciences. Second, the standard motivation involving variance maximization subject to unit length constraint does not directly connect to the "variance explained" interpretation. Third, the unit length and uncorrelatedness constraints of the standard motivation do not allow re-scaling or oblique rotations, which are common in practice. Instead, we propose to motivate the subject in terms of optimizing (weighted) average proportions of variance explained in the original variables; this approach may be more intuitive, and hence easier to understand because it links directly to the familiar "R-squared" statistic. It also removes the need for unit length and uncorrelatedness constraints, provides a direct interpretation of "variance explained," and provides a direct answer to the question of whether to use covariance-based or correlation-based PCs. Furthermore, the presentation can be made without matrix algebra or optimization proofs. Modern tools from data science, including heat maps and text mining, provide further help in the interpretation and application of PCs; examples are given. Together, these techniques may be used to revise currently used methods for teaching and learning PCs in the behavioral sciences.

  18. Fluidics: Basic components and applications

    Science.gov (United States)

    Joyce, J. W.

    1983-08-01

    Since its discovery at Harry Diamond Lab. in 1959, fluidics has gradually been developed into a viable technology. This report describes fluidic components and systems now in use or ready for use in many applications. The fluidic technology provides sensing, computing, and controlling functions with fluid power through interaction of fluid streams. Since fluidics can perform these functions without mechanical moving parts that will wear out, it has the advantages of simplicity and reliability. Other advantages are the low cost, environmental insensitivity, and safety of fluidic systems. Commercial applications of fluidics in the aerospace industry, include medicine, and personal-use items. The first aerospace application in production in the United States was for the thrust-reverser control for a DC-10 airplane. In industry, fluidics has been applied to air-conditioning controls, machine controls, process controls, and production-line controls. One of the first commercial applications of fluidics was for life-support medical equipment. For military use, fluidics has been successfully applied to a fluidic generator to convert pneumatic energy into electrical energy, a fluidic stability augmentation system for helicopters, and a pressure-regulating system for aircraft. Under development are rate sensing circuits for roll rate control of cannon-launched guided projectiles and missiles, and a fluidic capillary pyrometer for continuous temperature measurements in high-temperature process control.

  19. Estimating pure component vapor pressures

    Energy Technology Data Exchange (ETDEWEB)

    Myrdal, P.B.; Yalkowsky, S.H. [Univ. of Arizona, Tucson, AZ (United States). Dept. of Pharmaceutical Sciences

    1994-12-31

    The hazard of exposure to volatile organic compounds is an increasing concern all chemical industries. Recent EPA and FDA guidelines require the environmental assessment of new chemical entities, which includes the determination or estimation of vapor pressure. This work presents a means for the reliable estimation of pure component vapor pressures. The method presented is an extension of the work proposed by Mishra and Yalkowsky. New equations are presented for the heat capacity change upon boiling and the entropy of boiling. The final vapor pressure equation requires only the knowledge of transition temperatures and molecular structure. The equation developed has been successfully applied to 296 organic compounds, giving an overall average absolute error of 0.12 log units (in atm. at 25 C). In addition, the equation is shown to be very accurate in predicting vapor pressure as a function of temperature. However, for many compounds of environmental interest, the boiling point is not known or cannot be determined due to decomposition. In light of this, a new technique has been developed which can be used to estimate ``hypothetical`` boiling points. This enables the estimation of vapor pressure from as little as one transition temperature and molecular structure.

  20. High temperature two component explosive

    Science.gov (United States)

    Mars, James E.; Poole, Donald R.; Schmidt, Eckart W.; Wang, Charles

    1981-01-01

    A two component, high temperature, thermally stable explosive composition comprises a liquid or low melting oxidizer and a liquid or low melting organic fuel. The oxidizer and fuel in admixture are incapable of substantial spontaneous exothermic reaction at temperatures on the order of 475.degree. K. At temperatures on the order of 475.degree. K., the oxidizer and fuel in admixture have an activation energy of at least about 40 kcal/mol. As a result of the high activation energy, the preferred explosive compositions are nondetonable as solids at ambient temperature, and become detonable only when heated beyond the melting point. Preferable oxidizers are selected from alkali or alkaline earth metal nitrates, nitrites, perchlorates, and/or mixtures thereof. Preferred fuels are organic compounds having polar hydrophilic groups. The most preferred fuels are guanidinium nitrate, acetamide and mixtures of the two. Most preferred oxidizers are eutectic mixtures of lithium nitrate, potassium nitrate and sodium nitrate, of sodium nitrite, sodium nitrate and potassium nitrate, and of potassium nitrate, calcium nitrate and sodium nitrate.