WorldWideScience

Sample records for autophagic flux mediates

  1. 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

  2. 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

  3. 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

  4. 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.

  5. 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.

  6. 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.

  7. 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.

  8. 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

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

    Directory of Open Access Journals (Sweden)

    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.

  10. 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.

  11. 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

  12. 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.

  13. 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

  14. 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.

  15. 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.

  16. 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.

  17. 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.

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

    Directory of Open Access Journals (Sweden)

    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.

  19. 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.

  20. 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

  1. 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.

  2. 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

  3. 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.

  4. 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.

  5. 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.

  6. 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.

  7. 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.

  8. 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.

  9. Endosome-mediated autophagy: an unconventional MIIC-driven autophagic pathway operational in dendritic cells.

    Science.gov (United States)

    Kondylis, Vangelis; van Nispen Tot Pannerden, Hezder E; van Dijk, Suzanne; Ten Broeke, Toine; Wubbolts, Richard; Geerts, Willie J; Seinen, Cor; Mutis, Tuna; Heijnen, Harry F G

    2013-06-01

    Activation of TLR signaling has been shown to induce autophagy in antigen-presenting cells (APCs). Using high-resolution microscopy approaches, we show that in LPS-stimulated dendritic cells (DCs), autophagosomes emerge from MHC class II compartments (MIICs) and harbor both the molecular machinery for antigen processing and the autophagosome markers LC3 and ATG16L1. This ENdosome-Mediated Autophagy (ENMA) appears to be the major type of autophagy in DCs, as similar structures were observed upon established autophagy-inducing conditions (nutrient deprivation, rapamycin) and under basal conditions in the presence of bafilomycin A1. Autophagosome formation was not significantly affected in DCs expressing ATG4B (C74A) mutant and atg4b (-/-) bone marrow DCs, but the degradation of the autophagy substrate SQSTM1/p62 was largely impaired. Furthermore, we demonstrate that the previously described DC aggresome-like LPS-induced structures (DALIS) contain vesicular membranes, and in addition to SQSTM1 and ubiquitin, they are positive for LC3. LC3 localization on DALIS is independent of its lipidation. MIIC-driven autophagosomes preferentially engulf the LPS-induced SQSTM1-positive DALIS, which become later degraded in autolysosomes. DALIS-associated membranes also contain ATG16L1, ATG9 and the Q-SNARE VTI1B, suggesting that they may represent (at least in part) a membrane reservoir for autophagosome expansion. We propose that ENMA constitutes an unconventional, APC-specific type of autophagy, which mediates the processing and presentation of cytosolic antigens by MHC class II machinery, and/or the selective clearance of toxic by-products of elevated ROS/RNS production in activated DCs, thereby promoting their survival.

  10. 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.

  11. 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

  12. 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.

  13. 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.

  14. 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.

  15. Seasonality of dipteran-mediated methylmercury flux from ponds.

    Science.gov (United States)

    Chumchal, Matthew M; Drenner, Ray W; Hall, MacGregor N; Polk, D Kirkland; Williams, Edward B; Ortega-Rodriguez, Celeste L; Kennedy, James H

    2018-03-12

    Methylmercury (MeHg) is an aquatic contaminant that can be transferred to terrestrial predators by emergent aquatic insects. We assessed the effects of month and pond permanence on dipteran-mediated MeHg flux (calculated as emergent dipteran biomass × dipteran MeHg concentration) in 10 experimental ponds. Emergent dipterans were collected weekly from permanent ponds with bluegill (Lepomis macrochirus; n = 5) and semipermanent ponds without fish (n = 5) over a 7-mo period (February-August, 2015). We detected a significant effect of month on MeHg flux from 6 dipteran taxa and aggregate MeHg flux, with the highest MeHg flux from herbivorous/detritivorous chironomid midges and predatory midges in March; biting midges, phantom midges and herbivorous/detritivorous orthoclad midges in April; and mosquitoes in August. Aggregate dipteran-mediated MeHg flux peaked in April and then declined throughout the remainder of the summer. We did not detect a significant main effect of pond permanence or a significant month × pond permanence interaction effect on MeHg flux for any of the taxa examined in the present study or for aggregate MeHg flux. Given their ubiquity in aquatic systems and their importance in food webs at the land-water interface, dipterans are important taxa that should not be overlooked as a part of the Hg cycle. Environ Toxicol Chem 2018;9999:1-6. © 2018 SETAC. © 2018 SETAC.

  16. 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

  17. Activation of Autophagic Flux against Xenoestrogen Bisphenol-A-induced Hippocampal Neurodegeneration via AMP kinase (AMPK)/Mammalian Target of Rapamycin (mTOR) Pathways*

    Science.gov (United States)

    Agarwal, Swati; Tiwari, Shashi Kant; Seth, Brashket; Yadav, Anuradha; Singh, Anshuman; Mudawal, Anubha; Chauhan, Lalit Kumar Singh; Gupta, Shailendra Kumar; Choubey, Vinay; Tripathi, Anurag; Kumar, Amit; Ray, Ratan Singh; Shukla, Shubha; Parmar, Devendra; Chaturvedi, Rajnish Kumar

    2015-01-01

    The human health hazards related to persisting use of bisphenol-A (BPA) are well documented. BPA-induced neurotoxicity occurs with the generation of oxidative stress, neurodegeneration, and cognitive dysfunctions. However, the cellular and molecular mechanism(s) of the effects of BPA on autophagy and association with oxidative stress and apoptosis are still elusive. We observed that BPA exposure during the early postnatal period enhanced the expression and the levels of autophagy genes/proteins. BPA treatment in the presence of bafilomycin A1 increased the levels of LC3-II and SQSTM1 and also potentiated GFP-LC3 puncta index in GFP-LC3-transfected hippocampal neural stem cell-derived neurons. BPA-induced generation of reactive oxygen species and apoptosis were mitigated by a pharmacological activator of autophagy (rapamycin). Pharmacological (wortmannin and bafilomycin A1) and genetic (beclin siRNA) inhibition of autophagy aggravated BPA neurotoxicity. Activation of autophagy against BPA resulted in intracellular energy sensor AMP kinase (AMPK) activation, increased phosphorylation of raptor and acetyl-CoA carboxylase, and decreased phosphorylation of ULK1 (Ser-757), and silencing of AMPK exacerbated BPA neurotoxicity. Conversely, BPA exposure down-regulated the mammalian target of rapamycin (mTOR) pathway by phosphorylation of raptor as a transient cell's compensatory mechanism to preserve cellular energy pool. Moreover, silencing of mTOR enhanced autophagy, which further alleviated BPA-induced reactive oxygen species generation and apoptosis. BPA-mediated neurotoxicity also resulted in mitochondrial loss, bioenergetic deficits, and increased PARKIN mitochondrial translocation, suggesting enhanced mitophagy. These results suggest implication of autophagy against BPA-mediated neurodegeneration through involvement of AMPK and mTOR pathways. Hence, autophagy, which arbitrates cell survival and demise during stress conditions, requires further assessment to be

  18. 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...

  19. Attenuation of TNFSF10/TRAIL-induced apoptosis by an autophagic survival pathway involving TRAF2- and RIPK1/RIP1-mediated MAPK8/JNK activation

    Science.gov (United States)

    He, Weiyang; Wang, Qiong; Xu, Jennings; Xu, Xiuling; Padilla, Mabel T.; Ren, Guosheng; Gou, Xin; Lin, Yong

    2012-01-01

    Although it is known that tumor necrosis factor-related apoptosis-inducing ligand (TNFSF10/TRAIL) induces autophagy, the mechanism by which autophagy is activated by TNFSF10 is still elusive. In this report, we show evidence that TRAF2- and RIPK1-mediated MAPK8/JNK activation is required for TNFSF10-induced cytoprotective autophagy. TNFSF10 activated autophagy rapidly in cancer cell lines derived from lung, bladder and prostate tumors. Blocking autophagy with either pharmacological inhibitors or siRNAs targeting the key autophagy factors BECN1/Beclin 1 or ATG7 effectively increased TNFSF10-induced apoptotic cytotoxicity, substantiating a cytoprotective role for TNFSF10-induced autophagy. Blocking MAPK8 but not NFκB effectively blocked autophagy, suggesting that MAPK8 is the main pathway for TNFSF10-induced autophagy. In addition, blocking MAPK8 effectively inhibited degradation of BCL2L1/Bcl-xL and reduction of the autophagy-suppressing BCL2L1–BECN1complex. Knockdown of TRAF2 or RIPK1 effectively suppressed TNFSF10-induced MAPK8 activation and autophagy. Furthermore, suppressing autophagy inhibited expression of antiapoptosis factors BIRC2/cIAP1, BIRC3/cIAP2, XIAP and CFLAR/c-FLIP and increased the formation of TNFSF10-induced death-inducing signaling complex (DISC). These results reveal a critical role for the MAPK8 activation pathway through TRAF2 and RIPK1 for TNFSF10-induced autophagy that blunts apoptosis in cancer cells. Thus, suppression of MAPK8-mediated autophagy could be utilized for sensitizing cancer cells to therapy with TNFSF10. PMID:23051914

  20. 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.

  1. 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.

  2. 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.

  3. 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

  4. 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.

  5. 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.

  6. 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.

  7. Simultaneous coastal measurements of ozone deposition fluxes and iodine-mediated particle emission fluxes with subsequent CCN formation

    Directory of Open Access Journals (Sweden)

    J. D. Whitehead

    2010-01-01

    Full Text Available Here we present the first observations of simultaneous ozone deposition fluxes and ultrafine particle emission fluxes over an extensive infra-littoral zone. Fluxes were measured by the eddy covariance technique at the Station Biologique de Roscoff, on the coast of Brittany, north-west France. This site overlooks a very wide (3 km littoral zone controlled by very deep tides (9.6 m exposing extensive macroalgae beds available for significant iodine mediated photochemical production of ultrafine particles. The aspect at the Station Biologique de Roscoff provides an extensive and relatively flat, uniform fetch within which micrometeorological techniques may be utilized to study links between ozone deposition to macroalgae (and sea water and ultrafine particle production.

    Ozone deposition to seawater at high tide was significantly slower (vd[O3]=0.302±0.095 mm s−1 than low tidal deposition. A statistically significant difference in the deposition velocities to macroalgae at low tide was observed between night time (vd[O3]=1.00±0.10 mm s−1 and daytime (vd[O3]=2.05±0.16 mm s−1 when ultrafine particle formation results in apparent particle emission. Very high emission fluxes of ultrafine particles were observed during daytime periods at low tides ranging from 50 000 particles cm−2 s−1 to greater than 200 000 particles cm−2 s−1 during some of the lowest tides. These emission fluxes exhibited a significant relationship with particle number concentrations comparable with previous observations at another location. Apparent particle growth rates were estimated to be in the range 17–150 nm h−1 for particles in the size range 3–10 nm. Under certain conditions, particle growth may be inferred to continue to greater than 120 nm over tens

  8. 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.

  9. 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.

  10. 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.

  11. Flux

    DEFF Research Database (Denmark)

    Ravn, Ib

    . FLUX betegner en flyden eller strømmen, dvs. dynamik. Forstår man livet som proces og udvikling i stedet for som ting og mekanik, får man et andet billede af det gode liv end det, som den velkendte vestlige mekanicisme lægger op til. Dynamisk forstået indebærer det gode liv den bedst mulige...... kanalisering af den flux eller energi, der strømmer igennem os og giver sig til kende i vore daglige aktiviteter. Skal vores tanker, handlinger, arbejde, samvær og politiske liv organiseres efter stramme og faste regelsæt, uden slinger i valsen? Eller skal de tværtimod forløbe ganske uhindret af regler og bånd...

  12. Sulforaphane-induced autophagy flux prevents prion protein-mediated neurotoxicity through AMPK pathway.

    Science.gov (United States)

    Lee, J-H; Jeong, J-K; Park, S-Y

    2014-10-10

    Prion diseases are neurodegenerative and infectious disorders that involve accumulation of misfolded scrapie prion protein, and which are characterized by spongiform degeneration. Autophagy, a major homeostatic process responsible for the degradation of cytoplasmic components, has garnered attention as the potential target for neurodegenerative diseases such as prion disease. We focused on protective effects of sulforaphane found in cruciferous vegetables on prion-mediated neurotoxicity and the mechanism of sulforaphane related to autophagy. In human neuroblastoma cells, sulforaphane protected prion protein (PrP) (106-126)-mediated neurotoxicity and increased autophagy flux marker microtubule-associated protein 1 light chain 3-II protein levels, following a decrease of p62 protein level. Pharmacological and genetical inhibition of autophagy by 3MA, wortmannin and knockdown of autophagy-related 5 (ATG5) led to block the effect of sulforaphane against PrP (106-126)-induced neurotoxicity. Furthermore we demonstrated that both sulforaphane-induced autophagy and protective effect of sulforaphane against PrP (106-126)-induced neurotoxicity are dependent on the AMP-activated protein kinase (AMPK) signaling. The present results indicated that sulforaphane of cruciferous vegetables enhanced autophagy flux led to the protection effects against prion-mediated neurotoxicity, which was regulated by AMPK signaling pathways in human neuron cells. Our data also suggest that sulforaphane has a potential value as a therapeutic tool in neurodegenerative disease including prion diseases. Copyright © 2014 IBRO. Published by Elsevier Ltd. All rights reserved.

  13. 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

  14. 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.

  15. 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

  16. 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.

  17. 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.

  18. 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

  19. 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.

  20. Tenovin-6 impairs autophagy by inhibiting autophagic flux.

    Science.gov (United States)

    Yuan, Hongfeng; Tan, Brandon; Gao, Shou-Jiang

    2017-02-09

    Tenovin-6 has attracted significant interest because it activates p53 and inhibits sirtuins. It has anti-neoplastic effects on multiple hematopoietic malignancies and solid tumors in both in vitro and in vivo studies. Tenovin-6 was recently shown to impair the autophagy pathway in chronic lymphocytic leukemia cells and pediatric soft tissue sarcoma cells. However, whether tenovin-6 has a general inhibitory effect on autophagy and whether there is any involvement with SIRT1 and p53, both of which are regulators of the autophagy pathway, remain unclear. In this study, we have demonstrated that tenovin-6 increases microtubule-associated protein 1 light chain 3 (LC3-II) level in diverse cell types in a time- and dose-dependent manner. Mechanistically, the increase of LC3-II by tenovin-6 is caused by inhibition of the classical autophagy pathway via impairing lysosomal function without affecting the fusion between autophagosomes and lysosomes. Furthermore, we have revealed that tenovin-6 activation of p53 is cell type dependent, and tenovin-6 inhibition of autophagy is not dependent on its regulatory functions on p53 and SIRT1. Our results have shown that tenovin-6 is a potent autophagy inhibitor, and raised the precaution in interpreting results where tenovin-6 is used as an inhibitor of SIRT1.

  1. 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.

  2. γ-aminobutyric acid (GABA) mediated transmembrane chloride flux with membrane vesicles from rat brain measured by quench flow technique: kinetic homogeneity of ion flux and receptor desensitization

    International Nuclear Information System (INIS)

    Cash, D.J.; Subbarao, K.

    1987-01-01

    Transmembrane chloride flux mediated by the GABA/sub A/ receptor and the desensitization of the receptor were followed using quench flow technique with 36 Cl - and a membrane preparation from rat cerebral cortex. Measurements in short times allowed these two processes to be resolved. In general the ion-flux activity was desensitized in two phases. A fast phase took place in circa 200 ms (100 μM GABA) followed by a slower phase in several seconds. A minority of the membrane preparations did not display the fast phase. It is desirable to be able to separate these two phases of desensitization to facilitate analysis of the responses of the receptor. A short preincubation with GABA removed the fast phase from a subsequent measurement. In the absence of the fast phase the whole ion-flux equilibrium was seen as a single phase. The measurements presented covering a time range of 0.01 seconds to 10 seconds show a single phase of ion flux which can be described by a first order ion influx process and a single first order desensitization process with a halt time of circa 1 s (100 μM GABA). The results imply a single population of vesicles containing a single population of GABA receptor (remaining active) with a single phase of desensitization. An understanding of this homogeneity, and how to ensure it, gives a basis for quantitatively testing the effects of drugs on these responses. Ion flux measurements with quench flow technique are a suitable tool for investigation of the mechanism of action of neurotransmitter receptors from brain. 37 references, 3 figures

  3. 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.

  4. 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.

  5. The absorptive flux of the anti-epileptic drug substance vigabatrin is carrier-mediated across Caco-2 cell monolayers

    DEFF Research Database (Denmark)

    Nøhr, Martha Kampp; Hansen, Steen Honoré; Brodin, Birger

    2014-01-01

    of vigabatrin in Caco-2 cells, a cell culture model of the small intestinal epithelium. The uptake and transepithelial flux of vigabatrin was measured using an LC-MS method for quantification. Transepithelial transport of vigabatrin was shown to be proton-dependent and polarized in the apical-to-basolateral (A...... of the human proton-coupled amino acid transporter (hPAT1) to the apical solution. The present study indicates that the transepithelial A-B flux of vigabatrin is mainly mediated by hPAT1 in Caco-2 cells at dose-relevant concentrations....

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

    Directory of Open Access Journals (Sweden)

    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.

  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. Polyamines as mediators of insulin's action on pyruvate dehydrogenase, 45Ca2+ fluxes, and membrane transport

    International Nuclear Information System (INIS)

    Goldstone, A.D.; Koenig, H.; Lu, C.Y.

    1986-01-01

    Insulin (IN) induces a rapid stimulation of Ca 2+ fluxes and membrane transport in mouse kidney cortex which involves rapid polyamine synthesis. 1.3 nM (IN) induced an early ( 45 Ca 2+ influx and efflux peaked at 1-2 min and returned to basal levels by 5-10 min. The ODC inhibitor α-difluoromethylornithine (DFMO, 5 mM) abolished IN stimulation of PDH, 45 Ca 2+ fluxes and membrane transport, and putrescine (.5 mM) nullified DFMO inhibition. IN (50 mUnits/kg) in rats induced an early ( 2+ fluxes, and membrane transport

  9. 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

    Directory of Open Access Journals (Sweden)

    Niu NK

    2015-03-01

    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 apoptosis and autophagy but inhibits EMT via PI3K/Akt/mTOR, p38 MAPK, and AMPK signaling pathways with involvement of ROS- and sirtuin 1-associated pathways in U-2 OS and MG-63 cells. ALS is a promising anticancer agent in OS treatment and further studies are needed to confirm its efficacy and safety in OS chemotherapy. Keywords: ALS, autophagy, apoptosis, osteosarcoma, PI3K/Akt/mTOR pathway, EMT

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

    Science.gov (United States)

    Katzenell, Sarah

    2016-01-01

    neurons defend against virus infection is poorly understood, but such defense is at least partially mediated by autophagy, an intracellular pathway by which pathogens and other unwanted cargoes are degraded. The study demonstrates and investigates a new autophagic structure that appears to be specific to the interaction between neurotropic herpesviruses and murine primary sensory neurons. This work may therefore have important implications for our understanding of latency and reactivation. PMID:26912623

  11. 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

  12. Quantifying beetle-mediated effects on gas fluxes from dung pats.

    Directory of Open Access Journals (Sweden)

    Atte Penttilä

    Full Text Available Agriculture is one of the largest contributors of the anthropogenic greenhouse gases (GHGs responsible for global warming. Measurements of gas fluxes from dung pats suggest that dung is a source of GHGs, but whether these emissions are modified by arthropods has not been studied. A closed chamber system was used to measure the fluxes of carbon dioxide (CO2, methane (CH4 and nitrous oxide (N2O from dung pats with and without dung beetles on a grass sward. The presence of dung beetles significantly affected the fluxes of GHGs from dung pats. Most importantly, fresh dung pats emitted higher amounts of CO2 and lower amounts of CH4 per day in the presence than absence of beetles. Emissions of N2O showed a distinct peak three weeks after the start of the experiment--a pattern detected only in the presence of beetles. When summed over the main grazing season (June-July, total emissions of CH4 proved significantly lower, and total emissions of N2O significantly higher in the presence than absence of beetles. While clearly conditional on the experimental conditions, the patterns observed here reveal a potential impact of dung beetles on gas fluxes realized at a small spatial scale, and thereby suggest that arthropods may have an overall effect on gas fluxes from agriculture. Dissecting the exact mechanisms behind these effects, mapping out the range of conditions under which they occur, and quantifying effect sizes under variable environmental conditions emerge as key priorities for further research.

  13. Phenomenology of mixed modulus-anomaly mediation in fluxed string compactifications and brane models

    International Nuclear Information System (INIS)

    Choi, Kiwoon; Jeong, Kwang-Sik; Okumura, Ken-ichi

    2005-01-01

    In some string compactifications, for instance the recently proposed KKLT set-up, light moduli are stabilized by nonperturbative effects at supersymmetric AdS vacuum which is lifted to a dS vacuum by supersymmetry breaking uplifting potential. In such models, soft supersymmetry breaking terms are determined by a specific mixed modulus-anomaly mediation in which the two mediations typically give comparable contributions to soft parameters. Similar pattern of soft terms can arise also in brane models to stabilize the radion by nonperturbative effects. We examine some phenomenological consequences of this mixed modulus-anomaly mediation, including the pattern of low energy sparticle spectrum and the possibility of electroweak symmetry breaking. It is noted that adding the anomaly-mediated contributions at M GUT amounts to replacing the messenger scale of the modulus mediation by a mirage messenger scale (m 3/2 /M Pl ) α/2 M GUT where α = m 3/2 /[M 0 ln (M Pl /m 3/2 )] for M 0 denoting the modulus-mediated contribution to the gaugino mass at M GUT . The minimal KKLT set-up predicts α = 1. As a consequence, for α = O(1), the model can lead to a highly distinctive pattern of sparticle masses at TeV scale, particularly when α = 2

  14. 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.

  15. 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.

  16. Concanavalin A/IFN-gamma triggers autophagy-related necrotic hepatocyte death through IRGM1-mediated lysosomal membrane disruption.

    Directory of Open Access Journals (Sweden)

    Chih-Peng Chang

    Full Text Available Interferon-gamma (IFN-γ, a potent Th1 cytokine with multiple biological functions, can induce autophagy to enhance the clearance of the invading microorganism or cause cell death. We have reported that Concanavalin A (Con A can cause autophagic cell death in hepatocytes and induce both T cell-dependent and -independent acute hepatitis in immunocompetent and immunodeficient mice, respectively. Although IFN-γ is known to enhance liver injury in Con A-induced hepatitis, its role in autophagy-related hepatocyte death is not clear. In this study we report that IFN-γ can enhance Con A-induced autophagic flux and cell death in hepatoma cell lines. A necrotic cell death with increased lysosomal membrane permeabilization (LMP is observed in Con A-treated hepatoma cells in the presence of IFN-γ. Cathepsin B and L were released from lysosomes to cause cell death. Furthermore, IFN-γ induces immunity related GTPase family M member 1(IRGM1 translocation to lysosomes and prolongs its activity in Con A-treated hepatoma cells. Knockdown of IRGM1 inhibits the IFN-γ/Con A-induced LMP change and cell death. Furthermore, IFN-γ(-/- mice are resistant to Con A-induced autophagy-associated necrotic hepatocyte death. We conclude that IFN-γ enhances Con A-induced autophagic flux and causes an IRGM1-dependent lysosome-mediated necrotic cell death in hepatocytes.

  17. 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.

  18. Salmon-mediated nutrient flux in selected streams of the Columbia River basin, USA

    Science.gov (United States)

    Kohler, Andre E.; Kusnierz, Paul C.; Copeland, Timothy; Venditti, David A.; Denny, Lytle; Gable, Josh; Lewis, Bert; Kinzer, Ryan; Barnett, Bruce; Wipfli, Mark S.

    2013-01-01

    Salmon provide an important resource subsidy and linkage between marine and land-based ecosystems. This flow of energy and nutrients is not uni-directional (i.e., upstream only); in addition to passive nutrient export via stream flow, juvenile emigrants actively export nutrients from freshwater environments. In some cases, nutrient export can exceed import. We evaluated nutrient fluxes in streams across central Idaho, USA using Chinook salmon (Oncorhynchus tshawytscha) adult escapement and juvenile production data from 1998 to 2008. We found in the majority of stream-years evaluated, adults imported more nutrients than progeny exported; however, in 3% of the years, juveniles exported more nutrients than their parents imported. On average, juvenile emigrants exported 22 ± 3% of the nitrogen and 30 ± 4% of the phosphorus their parents imported. This relationship was density dependent and nonlinear; during periods of low adult abundance juveniles were larger and exported up to 194% and 268% of parental nitrogen and phosphorus inputs, respectively. We highlight minimum escapement thresholds that appear to 1) maintain consistently positive net nutrient flux and 2) reduce the average proportional rate of export across study streams. Our results suggest a state-shift occurs when adult spawner abundance falls below a threshold to a point where the probability of juvenile nutrient exports exceeding adult imports becomes increasingly likely.

  19. U(1)R mediation from the flux compactification in six dimensions

    International Nuclear Information System (INIS)

    Lee, Hyun Min

    2008-01-01

    We consider a supersymmetric completion of codimension-two branes with nonzero tension in a 6D gauged supergravity. As a consequence, we obtain the football solution with 4D Minkowski space as a new supersymmetric background that preserves 4D N = 1 SUSY. In the presence of brane multiplets, we derive the 4D effective supergravity action for the football background and show that the remaining modulus can be stabilized by a bulk non-perturbative correction with brane uplifting potentials at a zero vacuum energy. We find that the U(1) R mediation can be a dominant source of SUSY breaking for a brane scalar with nonzero R charge.

  20. 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.

  1. Dynamic volume changes in astrocytes are an intrinsic phenomenon mediated by bicarbonate ion flux.

    Directory of Open Access Journals (Sweden)

    Clare M Florence

    Full Text Available Astrocytes, the major type of non-neuronal cells in the brain, play an important functional role in extracellular potassium ([K(+](o and pH homeostasis. Pathological brain states that result in [K(+](o and pH dysregulation have been shown to cause astrocyte swelling. However, whether astrocyte volume changes occur under physiological conditions is not known. In this study we used two-photon imaging to visualize real-time astrocyte volume changes in the stratum radiatum of the hippocampus CA1 region. Astrocytes were observed to swell by 19.0±0.9% in response to a small physiological increase in the concentration of [K(+](o (3 mM. Astrocyte swelling was mediated by the influx of bicarbonate (HCO(3- ions as swelling was significantly decreased when the influx of HCO(3- was reduced. We found: 1 in HCO(3- free extracellular solution astrocytes swelled by 5.4±0.7%, 2 when the activity of the sodium-bicarbonate cotransporter (NBC was blocked the astrocytes swelled by 8.3±0.7%, and 3 in the presence of an extracellular carbonic anhydrase (CA inhibitor astrocytes swelled by 11.4±0.6%. Because a significant HCO(3- efflux is known to occur through the γ-amino-butyric acid (GABA channel, we performed a series of experiments to determine if astrocytes were capable of HCO(3- mediated volume shrinkage with GABA channel activation. Astrocytes were found to shrink -7.7±0.5% of control in response to the GABA(A channel agonist muscimol. Astrocyte shrinkage from GABA(A channel activation was significantly decreased to -5.0±0.6% of control in the presence of the membrane-permeant CA inhibitor acetazolamide (ACTZ. These dynamic astrocyte volume changes may represent a previously unappreciated yet fundamental mechanism by which astrocytes regulate physiological brain functioning.

  2. Beaver-mediated lateral hydrologic connectivity, fluvial carbon and nutrient flux, and aquatic ecosystem metabolism

    Science.gov (United States)

    Wegener, Pam; Covino, Tim; Wohl, Ellen

    2017-06-01

    River networks that drain mountain landscapes alternate between narrow and wide valley segments. Within the wide segments, beaver activity can facilitate the development and maintenance of complex, multithread planform. Because the narrow segments have limited ability to retain water, carbon, and nutrients, the wide, multithread segments are likely important locations of retention. We evaluated hydrologic dynamics, nutrient flux, and aquatic ecosystem metabolism along two adjacent segments of a river network in the Rocky Mountains, Colorado: (1) a wide, multithread segment with beaver activity; and, (2) an adjacent (directly upstream) narrow, single-thread segment without beaver activity. We used a mass balance approach to determine the water, carbon, and nutrient source-sink behavior of each river segment across a range of flows. While the single-thread segment was consistently a source of water, carbon, and nitrogen, the beaver impacted multithread segment exhibited variable source-sink dynamics as a function of flow. Specifically, the multithread segment was a sink for water, carbon, and nutrients during high flows, and subsequently became a source as flows decreased. Shifts in river-floodplain hydrologic connectivity across flows related to higher and more variable aquatic ecosystem metabolism rates along the multithread relative to the single-thread segment. Our data suggest that beaver activity in wide valleys can create a physically complex hydrologic environment that can enhance hydrologic and biogeochemical buffering, and promote high rates of aquatic ecosystem metabolism. Given the widespread removal of beaver, determining the cumulative effects of these changes is a critical next step in restoring function in altered river networks.

  3. 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

  4. 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...

  5. 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.

  6. Intracellular zinc flux causes reactive oxygen species mediated mitochondrial dysfunction leading to cell death in Leishmania donovani.

    Directory of Open Access Journals (Sweden)

    Anjali Kumari

    Full Text Available Leishmaniasis caused by Leishmania parasite is a global threat to public health and one of the most neglected tropical diseases. Therefore, the discovery of novel drug targets and effective drug is a major challenge and an important goal. Leishmania is an obligate intracellular parasite that alternates between sand fly and human host. To survive and establish infections, Leishmania parasites scavenge and internalize nutrients from the host. Nevertheless, host cells presents mechanism like nutrient restriction to inhibit microbial growth and control infection. Zinc is crucial for cellular growth and disruption in its homeostasis hinders growth and survival in many cells. However, little is known about the role of zinc in Leishmania growth and survival. In this study, the effect of zinc on the growth and survival of L.donovani was analyzed by both Zinc-depletion and Zinc-supplementation using Zinc-specific chelator N, N, N', N'-tetrakis (2-pyridylmethyl ethylenediamine (TPEN and Zinc Sulfate (ZnSO4. Treatment of parasites with TPEN rather than ZnSO4 had significantly affected the growth in a dose- and time-dependent manner. The pre-treatment of promastigotes with TPEN resulted into reduced host-parasite interaction as indicated by decreased association index. Zn depletion resulted into flux in intracellular labile Zn pool and increased in ROS generation correlated with decreased intracellular total thiol and retention of plasma membrane integrity without phosphatidylserine exposure in TPEN treated promastigotes. We also observed that TPEN-induced Zn depletion resulted into collapse of mitochondrial membrane potential which is associated with increase in cytosolic calcium and cytochrome-c. DNA fragmentation analysis showed increased DNA fragments in Zn-depleted cells. In summary, intracellular Zn depletion in the L. donovani promastigotes led to ROS-mediated caspase-independent mitochondrial dysfunction resulting into apoptosis-like cell death

  7. Intra-slab COH fluid fluxes evidenced by fluid-mediated decarbonation of lawsonite eclogite-facies altered oceanic metabasalts

    Science.gov (United States)

    Vitale Brovarone, Alberto; Chu, Xu; Martin, Laure; Ague, Jay J.; Monié, Patrick; Groppo, Chiara; Martinez, Isabelle; Chaduteau, Carine

    2018-04-01

    The interplay between the processes controlling the mobility of H2O and C-bearing species during subduction zone metamorphism exerts a critical control on plate tectonics and global volatile recycling. Here we present the first study on fresh, carbonate-bearing, lawsonite eclogite-facies metabasalts from Alpine Corsica, France, which reached the critical depths at which important devolatilization reactions occur in subducting slabs. The studied samples indicate that the evolution of oceanic crustal sequences subducted under present-day thermal regimes is dominated by localized fluid-rock interactions that are strongly controlled by the nature and extent of inherited (sub)seafloor hydrothermal processes, and by the possibility of deep fluids to be channelized along inherited or newly-formed discontinuities. Fluid channelization along inherited discontinuities controlled local rehydration and dehydration/decarbonation reactions and the stability of carbonate and silicate minerals at the blueschist-eclogite transition. Fluid-mediated decarbonation was driven by upward, up-temperature fluid flow in the inverted geothermal gradient of a subducting oceanic slab, a process that has not been documented in natural samples to date. We estimate that the observed fluid-rock reactions released 20-60 kg CO2 per m3 of rock (i.e. 0.7-2.1 wt% CO2), which is in line with the values predicted from decarbonation of metabasalts in open systems at these depths. Conversely, the estimated time-integrated fluid fluxes (20-50 t/m2) indicate that the amount of carbon transported by channelized fluid flow within the volcanic part of subducting oceanic plates is potentially much higher than previous numerical estimates, testifying to the percolation of C-bearing fluids resulting from devolatilization/dissolution processes operative in large reservoirs.

  8. 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.

  9. Seasonality of odonate-mediated methylmercury flux from permanent and semipermanent ponds and potential risk to red-winged blackbirds (Agelaius phoeniceus).

    Science.gov (United States)

    Williams, Edward B; Chumchal, Matthew M; Drenner, Ray W; Kennedy, James H

    2017-10-01

    Methylmercury (MeHg) is an aquatic contaminant that can be transferred to terrestrial predators by emergent aquatic insects such as odonates (damselflies and dragonflies). We assessed the effects of month and pond permanence on odonate-mediated MeHg flux (calculated as emergent odonate biomass × MeHg concentration) in 10 experimental ponds and the potential risk to nestling red-winged blackbirds (Agelaius phoeniceus) posed by consuming MeHg-contaminated odonates. Emergent odonates were collected weekly from permanent ponds with bluegill (Lepomis macrochirus; n = 5) and semipermanent ponds without fish (n = 5) over an 8-mo period (January-August 2015). The MeHg flux from damselflies, aeshnid dragonflies, and libellulid dragonflies began in March and peaked in April, May, and June, respectively, and then declined throughout the rest of the summer. Odonate-mediated MeHg flux from semipermanent ponds without fish was greater than that from permanent ponds with fish. Nesting of red-winged blackbirds overlapped with peak odonate emergence and odonate-mediated MeHg flux. Because their diet can be dominated by damselflies and dragonflies, we tested the hypothesis that MeHg-contaminated odonates may pose a health risk to nestling red-winged blackbirds. Concentrations of MeHg in odonates exceeded wildlife values (the minimum odonate MeHg concentrations causing physiologically significant doses in consumers) for nestlings, suggesting that MeHg-contaminated odonates can pose a health risk to nestling red-winged blackbirds. Environ Toxicol Chem 2017;36:2833-2837. © 2017 SETAC. © 2017 SETAC.

  10. 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.

  11. Carbamazepine suppresses calpain-mediated autophagy impairment after ischemia/reperfusion in mouse livers

    Energy Technology Data Exchange (ETDEWEB)

    Kim, Jae-Sung, E-mail: Jae.Kim@surgery.ufl.edu; Wang, Jin-Hee, E-mail: jin-hee.wang@surgery.ufl.edu; Biel, Thomas G., E-mail: Thomas.Biel@surgery.ufl.edu; Kim, Do-Sung, E-mail: do-sung.kim@surgery.med.ufl.edu; Flores-Toro, Joseph A., E-mail: Joseph.Flores-Toro@surgery.ufl.edu; Vijayvargiya, Richa, E-mail: rvijayvargiya@ufl.edu; Zendejas, Ivan, E-mail: ivan.zendejas@surgery.ufl.edu; Behrns, Kevin E., E-mail: Kevin.Behrns@surgery.ufl.edu

    2013-12-15

    Onset of the mitochondrial permeability transition (MPT) plays a causative role in ischemia/reperfusion (I/R) injury. Current therapeutic strategies for reducing reperfusion injury remain disappointing. Autophagy is a lysosome-mediated, catabolic process that timely eliminates abnormal or damaged cellular constituents and organelles such as dysfunctional mitochondria. I/R induces calcium overloading and calpain activation, leading to degradation of key autophagy-related proteins (Atg). Carbamazepine (CBZ), an FDA-approved anticonvulsant drug, has recently been reported to increase autophagy. We investigated the effects of CBZ on hepatic I/R injury. Hepatocytes and livers from male C57BL/6 mice were subjected to simulated in vitro, as well as in vivo I/R, respectively. Cell death, intracellular calcium, calpain activity, changes in autophagy-related proteins (Atg), autophagic flux, MPT and mitochondrial membrane potential after I/R were analyzed in the presence and absence of 20 μM CBZ. CBZ significantly increased hepatocyte viability after reperfusion. Confocal microscopy revealed that CBZ prevented calcium overloading, the onset of the MPT and mitochondrial depolarization. Immunoblotting and fluorometric analysis showed that CBZ blocked calpain activation, depletion of Atg7 and Beclin-1 and loss of autophagic flux after reperfusion. Intravital multiphoton imaging of anesthetized mice demonstrated that CBZ substantially reversed autophagic defects and mitochondrial dysfunction after I/R in vivo. In conclusion, CBZ prevents calcium overloading and calpain activation, which, in turn, suppresses Atg7 and Beclin-1 depletion, defective autophagy, onset of the MPT and cell death after I/R. - Highlights: • A mechanism of carbamazepine (CBZ)-induced cytoprotection in livers is proposed. • Impaired autophagy is a key event contributing to lethal reperfusion injury. • The importance of autophagy is extended and confirmed in an in vivo model. • CBZ is a potential

  12. A PROPOSED PARADIGM FOR SOLAR CYCLE DYNAMICS MEDIATED VIA TURBULENT PUMPING OF MAGNETIC FLUX IN BABCOCK–LEIGHTON-TYPE SOLAR DYNAMOS

    Energy Technology Data Exchange (ETDEWEB)

    Hazra, Soumitra; Nandy, Dibyendu [Department of Physical Sciences, Indian Institute of Science Education and Research, Kolkata (India)

    2016-11-20

    At present, the Babcock–Leighton flux transport solar dynamo models appear to be the most promising models for explaining diverse observational aspects of the sunspot cycle. The success of these flux transport dynamo models is largely dependent upon a single-cell meridional circulation with a deep equatorward component at the base of the Sun’s convection zone. However, recent observations suggest that the meridional flow may in fact be very shallow (confined to the top 10% of the Sun) and more complex than previously thought. Taken together, these observations raise serious concerns on the validity of the flux transport paradigm. By accounting for the turbulent pumping of magnetic flux, as evidenced in magnetohydrodynamic simulations of solar convection, we demonstrate that flux transport dynamo models can generate solar-like magnetic cycles even if the meridional flow is shallow. Solar-like periodic reversals are recovered even when meridional circulation is altogether absent. However, in this case, the solar surface magnetic field dynamics does not extend all the way to the polar regions. Very importantly, our results demonstrate that the Parker–Yoshimura sign rule for dynamo wave propagation can be circumvented in Babcock–Leighton dynamo models by the latitudinal component of turbulent pumping, which can generate equatorward propagating sunspot belts in the absence of a deep, equatorward meridional flow. We also show that variations in turbulent pumping coefficients can modulate the solar cycle amplitude and periodicity. Our results suggest the viability of an alternate magnetic flux transport paradigm—mediated via turbulent pumping—for sustaining solar-stellar dynamo action.

  13. 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.

  14. 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.

  15. 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.

  16. 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...

  17. 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)

  18. 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.

  19. 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.

  20. 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.

  1. 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.

  2. Mediatization

    DEFF Research Database (Denmark)

    Hjarvard, Stig

    2017-01-01

    Mediatization research shares media effects studies' ambition of answering the difficult questions with regard to whether and how media matter and influence contemporary culture and society. The two approaches nevertheless differ fundamentally in that mediatization research seeks answers...... research is concerned with long-term structural changes involving media, culture, and society, i.e. the influences of the media are understood in relation to how media are implicated in social and cultural changes and how these processes come to create new conditions for human communication and interaction....... From the perspective of mediatization research, the most important effect of the media stems from their embeddedness in culture and society....

  3. Spider-mediated flux of PCBs from contaminated sediments to terrestrial ecosystems and potential risks to arachnivorous birds

    Science.gov (United States)

    Walters, D.M.; Mills, M.A.; Fritz, K.M.; Raikow, D.F.

    2010-01-01

    We investigated aquatic insect utilization and PCB exposure in riparian spiders at the Lake Hartwell Superfund site (Clemson, SC). We sampled sediments, adult chironomids, terrestrial insects, riparian spiders (Tetragnathidae, Araneidae, and Mecynogea lemniscata), and upland spiders (Araneidae) along a sediment contamination gradient. Stable isotopes (?13C, ? 15N) indicated that riparian spiders primarily consumed aquatic insects whereas upland spiders consumed terrestrial insects. PCBs in chironomids (mean 1240 ng/g among sites) were 2 orders of magnitude higher than terrestrial insects (15.2 ng/g), similar to differences between riparian (820?2012 ng/g) and upland spiders (30 ng/g). Riparian spider PCBs were positively correlated with sediment concentrations for all taxa (r2 = 0.44?0.87). We calculated spider-based wildlife values (WVs, the minimum spider PCB concentrations causing physiologically significant doses in consumers) to assess exposure risks for arachnivorous birds. Spider concentrations exceeded WVs for most birds at heavily contaminated sites and were ?14-fold higher for the most sensitive species (chickadee nestlings, Poecile spp.). Spiders are abundant and ubiquitous in riparian habitats, where they depend on aquatic insect prey. These traits, along with the high degree of spatial correlation between spider and sediment concentrations we observed, suggest that they are model indicator species for monitoring contaminated sediment sites and assessing risks associated with contaminant flux into terrestrial ecosystems. ?? This article not subject to U.S. Copyright. Published 2009 by the American Chemical Society.

  4. 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

  5. '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.

  6. Toxicity of carboxylated carbon nanotubes in endothelial cells is attenuated by stimulation of the autophagic flux with the release of nanomaterial in autophagic vesicles

    Czech Academy of Sciences Publication Activity Database

    Orecna, M.; De Paoli, S. H.; Janoušková, Olga; Tegegn, T. Z.; Filipová, M.; Bonevich, J. E.; Holada, K.; Simak, J.

    2014-01-01

    Roč. 10, č. 5 (2014), s. 939-948 ISSN 1549-9634 Institutional support: RVO:61389013 Keywords : carbon nanotubes * autophagy * bafilomycin A1 Subject RIV: CD - Macromolecular Chemistry Impact factor: 6.155, year: 2014

  7. 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.

  8. 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

  9. Xenoestrogens at Picomolar to Nanomolar Concentrations Trigger Membrane Estrogen Receptor-α–Mediated Ca2+ Fluxes and Prolactin Release in GH3/B6 Pituitary Tumor Cells

    Science.gov (United States)

    Wozniak, Ann L.; Bulayeva, Nataliya N.; Watson, Cheryl S.

    2005-01-01

    Xenoestrogens (XEs) are widespread in our environment and are known to have deleterious effects in animal (and perhaps human) populations. Acting as inappropriate estrogens, XEs are thought to interfere with endogenous estrogens such as estradiol (E2) to disrupt normal estrogenic signaling. We investigated the effects of E2 versus several XEs representing organochlorine pesticides (dieldrin, endosulfan, o′p′-dichlorodiphenylethylene), plastics manufacturing by-products/detergents (nonylphenol, bisphenol A), a phytoestrogen (coumestrol), and a synthetic estrogen (diethylstilbestrol) on the pituitary tumor cell subline GH3/B6/F10, previously selected for expression of high levels of membrane estrogen receptor-α. Picomolar to nanomolar concentrations of both E2 and XEs caused intracellular Ca2+ changes within 30 sec of administration. Each XE produced a unique temporal pattern of Ca2+ elevation. Removing Ca2+ from the extracellular solution abolished both spontaneous and XE-induced intracellular Ca2+ changes, as did 10 μM nifedipine. This suggests that XEs mediate their actions via voltage-dependent L-type Ca2+ channels in the plasma membrane. None of the Ca2+ fluxes came from intracellular Ca2+ stores. E2 and each XE also caused unique time- and concentration-dependent patterns of prolactin (PRL) secretion that were largely complete within 3 min of administration. PRL secretion was also blocked by nifedipine, demonstrating a correlation between Ca2+ influx and PRL secretion. These data indicate that at very low concentrations, XEs mediate membrane-initiated intracellular Ca2+ increases resulting in PRL secretion via a mechanism similar to that for E2, but with distinct patterns and potencies that could explain their abilities to disrupt endocrine functions. PMID:15811834

  10. 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.

  11. 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

  12. 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.

  13. 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.

  14. Tuning flux: autophagy as a target of heart disease therapy

    Science.gov (United States)

    Xie, Min; Morales, Cyndi R.; Lavandero, Sergio; Hill, Joseph A.

    2013-01-01

    Purpose of review Despite maximum medical and mechanical support therapy, heart failure remains a relentlessly progressive disorder with substantial morbidity and mortality. Autophagy, an evolutionarily conserved process of cellular cannibalization, has been implicated in virtually all forms of cardiovascular disease. Indeed, its role is context dependent, antagonizing or promoting disease depending on the circumstance. Here, we review current understanding of the role of autophagy in the pathogenesis of heart failure and explore this pathway as a target of therapeutic intervention. Recent findings In preclinical models of heart disease, cardiomyocyte autophagic flux is activated; indeed, its role in disease pathogenesis is the subject of intense investigation to define mechanism. Similarly, in failing human heart of a variety of etiologies, cardiomyocyte autophagic activity is upregulated, and therapy, such as with mechanical support systems, elicits declines in autophagy activity. However, when suppression of autophagy is complete, rapid and catastrophic cell death occurs, consistent with a model in which basal autophagic flux is required for proteostasis. Thus, a narrow zone of ‘optimal’ autophagy seems to exist. The challenge moving forward is to tune the stress-triggered autophagic response within that ‘sweet spot’ range for therapeutic benefit. Summary Whereas we have known for some years of the participation of lysosomal mechanisms in heart disease, it is only recently that upstream mechanisms (autophagy) are being explored. The challenge for the future is to dissect the underlying circuitry and titrate the response into an optimal, proteostasis-promoting range in hopes of mitigating the ever-expanding epidemic of heart failure. PMID:21415729

  15. Presenilin 1 mediates the turnover of telencephalin in hippocampal neurons via an autophagic degradative pathway

    NARCIS (Netherlands)

    Esselens, C.; Oorschot, V.; Baert, V.; Raemaekers, T.; Spittaels, K.; Serneels, L.; Zheng, H.; Saftig, P.; Strooper, B. de; Klumperman, J.; Annaert, W.

    2004-01-01

    Presenilin 1 (PS1) interacts with telencephalin (TLN) and the amyloid precursor protein via their transmembrane domain. Here, we demonstrate that TLN is not a substrate for γ-secretase cleavage, but displays a prolonged half-life in PS1⁻/⁻ hippocampal neurons. TLN accumulates in intracellular

  16. 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.

  17. 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.

  18. 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.

  19. 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.

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

    Directory of Open Access Journals (Sweden)

    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.

  1. 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.

  2. Autophagy Mediates Interleukin-1β Secretion in Human Neutrophils

    Directory of Open Access Journals (Sweden)

    Leonardo Iula

    2018-02-01

    Full Text Available Interleukin-1β (IL-1β, a major pro-inflammatory cytokine, is a leaderless cytosolic protein whose secretion does not follow the classical endoplasmic reticulum-to-Golgi pathway, and for which a canonical mechanism of secretion remains to be established. Neutrophils are essential players against bacterial and fungi infections. These cells are rapidly and massively recruited from the circulation into infected tissues and, beyond of displaying an impressive arsenal of toxic weapons effective to kill pathogens, are also an important source of IL-1β in infectious conditions. Here, we analyzed if an unconventional secretory autophagy mechanism is involved in the exportation of IL-1β by these cells. Our findings indicated that inhibition of autophagy with 3-methyladenine and Wortmannin markedly reduced IL-1β secretion induced by LPS + ATP, as did the disruption of the autophagic flux with Bafilomycin A1 and E64d. These compounds did not noticeable affect neutrophil viability ruling out that the effects on IL-1β secretion were due to cell death. Furthermore, VPS34IN-1, a specific autophagy inhibitor, was still able to reduce IL-1β secretion when added after it was synthesized. Moreover, siRNA-mediated knockdown of ATG5 markedly reduced IL-1β secretion in neutrophil-differentiated PLB985 cells. Upon LPS + ATP stimulation, IL-1β was incorporated to an autophagic compartment, as was revealed by its colocalization with LC3B by confocal microscopy. Overlapping of IL-1β-LC3B in a vesicular compartment peaked before IL-1β increased in culture supernatants. On the other hand, stimulation of autophagy by cell starvation augmented the colocalization of IL-1β and LC3B and then promoted neutrophil IL-1β secretion. In addition, specific ELISAs indicated that although both IL-1β and pro-IL-1β are released to culture supernatants upon neutrophil stimulation, autophagy only promotes IL-1β secretion. Furthermore, the serine proteases inhibitor

  3. 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

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

    Directory of Open Access Journals (Sweden)

    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.

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

    Directory of Open Access Journals (Sweden)

    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.

  6. Cathepsin E deficiency impairs autophagic proteolysis in macrophages.

    Directory of Open Access Journals (Sweden)

    Takayuki Tsukuba

    Full Text Available Cathepsin E is an endosomal aspartic proteinase that is predominantly expressed in immune-related cells. Recently, we showed that macrophages derived from cathepsin E-deficient (CatE(-/- mice display accumulation of lysosomal membrane proteins and abnormal membrane trafficking. In this study, we demonstrated that CatE(-/- macrophages exhibit abnormalities in autophagy, a bulk degradation system for aggregated proteins and damaged organelles. CatE(-/- macrophages showed increased accumulation of autophagy marker proteins such as LC3 and p62, and polyubiquitinated proteins. Cathepsin E deficiency also altered autophagy-related signaling pathways such as those mediated by the mammalian target of rapamycin (mTOR, Akt, and extracellular signal-related kinase (ERK. Furthermore, immunofluorescence microscopy analyses showed that LC3-positive vesicles were merged with acidic compartments in wild-type macrophages, but not in CatE(-/- macrophages, indicating inhibition of fusion of autophagosome with lysosomes in CatE(-/- cells. Delayed degradation of LC3 protein was also observed under starvation-induced conditions. Since the autophagy system is involved in the degradation of damaged mitochondria, we examined the accumulation of damaged mitochondria in CatE(-/- macrophages. Several mitochondrial abnormalities such as decreased intracellular ATP levels, depolarized mitochondrial membrane potential, and decreased mitochondrial oxygen consumption were observed. Such mitochondrial dysfunction likely led to the accompanying oxidative stress. In fact, CatE(-/- macrophages showed increased reactive oxygen species (ROS production and up-regulation of oxidized peroxiredoxin-6, but decreased antioxidant glutathione. These results indicate that cathepsin E deficiency causes autophagy impairment concomitantly with increased aberrant mitochondria as well as increased oxidative stress.

  7. 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.

  8. 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.

  9. Water- and plant-mediated responses of ecosystem carbon fluxes to warming and nitrogen addition on the Songnen grassland in northeast China.

    Directory of Open Access Journals (Sweden)

    Li Jiang

    Full Text Available Understanding how grasslands are affected by a long-term increase in temperature is crucial to predict the future impact of global climate change on terrestrial ecosystems. Additionally, it is not clear how the effects of global warming on grassland productivity are going to be altered by increased N deposition and N addition.In-situ canopy CO(2 exchange rates were measured in a meadow steppe subjected to 4-year warming and nitrogen addition treatments. Warming treatment reduced net ecosystem CO(2 exchange (NEE and increased ecosystem respiration (ER; but had no significant impacts on gross ecosystem productivity (GEP. N addition increased NEE, ER and GEP. However, there were no significant interactions between N addition and warming. The variation of NEE during the four experimental years was correlated with soil water content, particularly during early spring, suggesting that water availability is a primary driver of carbon fluxes in the studied semi-arid grassland.Ecosystem carbon fluxes in grassland ecosystems are sensitive to warming and N addition. In the studied water-limited grassland, both warming and N addition influence ecosystem carbon fluxes by affecting water availability, which is the primary driver in many arid and semiarid ecosystems. It remains unknown to what extent the long-term N addition would affect the turn-over of soil organic matter and the C sink size of this grassland.

  10. Transforming Growth Factor TGFβ Increases Levels of Microtubule-Associated Protein MAP1S and Autophagy Flux in Pancreatic Ductal Adenocarcinomas.

    Science.gov (United States)

    Song, Kun; Hu, Wei; Yue, Fei; Zou, Jing; Li, Wenjiao; Chen, Qi; Yao, Qizhi; Sun, Weijia; Liu, Leyuan

    2015-01-01

    Autophagy is a cellular process to regulate the turnover of misfolded/aggregated proteins or dysfunctional organelles such as damaged mitochondria. Microtubule-associated protein MAP1S (originally named C19ORF5) is a widely-distributed homologue of neuronal-specific MAP1A and MAP1B with which autophagy marker light chain 3 (LC3) was originally co-purified. MAP1S bridges autophagic components with microtubules and mitochondria through LC3 and positively regulates autophagy flux from autophagosomal biogenesis to degradation. The MAP1S-mediated autophagy suppresses tumorigenesis as suggested in a mouse liver cancer model and in prostate cancer patients. The TGFβ signaling pathway plays a central role in pancreatic tumorigenesis, and high levels of TGFβ suggest a tumor suppressive function and predict a better survival for some patients with resectable pancreatic ductal adenocarcinoma. In this study, we try to understand the relationship between TGFβ and MAP1S-mediated autophagy in pancreatic ductal adenocarcinoma. We collected the tumor and its adjacent normal tissues from 33 randomly selected patients of pancreatic ductal adenocarcinomas to test the association between TGFβ and autophagy markers MAP1S and LC3. Then we tested the cause and effect relation between TGFβ and autophagy markers in cultured pancreatic cancer cell lines. Here we show that levels of TGFβ and autophagy markers MAP1S and LC3 are dramatically elevated in tumor tissues from patients with pancreatic ductal adenocarcinomas. TGFβ increases levels of MAP1S protein and enhances autophagy flux. TGFβ may suppress the development of pancreatic ductal adenocarcinomas by enhancing MAP1S-mediated autophagy.

  11. Transforming Growth Factor TGFβ Increases Levels of Microtubule-Associated Protein MAP1S and Autophagy Flux in Pancreatic Ductal Adenocarcinomas.

    Directory of Open Access Journals (Sweden)

    Kun Song

    Full Text Available Autophagy is a cellular process to regulate the turnover of misfolded/aggregated proteins or dysfunctional organelles such as damaged mitochondria. Microtubule-associated protein MAP1S (originally named C19ORF5 is a widely-distributed homologue of neuronal-specific MAP1A and MAP1B with which autophagy marker light chain 3 (LC3 was originally co-purified. MAP1S bridges autophagic components with microtubules and mitochondria through LC3 and positively regulates autophagy flux from autophagosomal biogenesis to degradation. The MAP1S-mediated autophagy suppresses tumorigenesis as suggested in a mouse liver cancer model and in prostate cancer patients. The TGFβ signaling pathway plays a central role in pancreatic tumorigenesis, and high levels of TGFβ suggest a tumor suppressive function and predict a better survival for some patients with resectable pancreatic ductal adenocarcinoma. In this study, we try to understand the relationship between TGFβ and MAP1S-mediated autophagy in pancreatic ductal adenocarcinoma.We collected the tumor and its adjacent normal tissues from 33 randomly selected patients of pancreatic ductal adenocarcinomas to test the association between TGFβ and autophagy markers MAP1S and LC3. Then we tested the cause and effect relation between TGFβ and autophagy markers in cultured pancreatic cancer cell lines.Here we show that levels of TGFβ and autophagy markers MAP1S and LC3 are dramatically elevated in tumor tissues from patients with pancreatic ductal adenocarcinomas. TGFβ increases levels of MAP1S protein and enhances autophagy flux.TGFβ may suppress the development of pancreatic ductal adenocarcinomas by enhancing MAP1S-mediated autophagy.

  12. 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.

  13. 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.

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

    Directory of Open Access Journals (Sweden)

    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.

  15. 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.

  16. 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.

  17. 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.

  18. 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.

  19. 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

  20. Macroautophagy and Chaperone-Mediated Autophagy in Heart Failure: The Known and the Unknown

    Directory of Open Access Journals (Sweden)

    Rajeshwary Ghosh

    2018-01-01

    Full Text Available Cardiac diseases including hypertrophic and ischemic cardiomyopathies are increasingly being reported to accumulate misfolded proteins and damaged organelles. These findings have led to an increasing interest in protein degradation pathways, like autophagy, which are essential not only for normal protein turnover but also in the removal of misfolded and damaged proteins. Emerging evidence suggests a previously unprecedented role for autophagic processes in cardiac physiology and pathology. This review focuses on the major types of autophagic processes, the genes and protein complexes involved, and their regulation. It discusses the key similarities and differences between macroautophagy, chaperone-mediated autophagy, and selective mitophagy structures and functions. The genetic models available to study loss and gain of macroautophagy, mitophagy, and CMA are discussed. It defines the markers of autophagic processes, methods for measuring autophagic activities, and their interpretations. This review then summarizes the major studies of autophagy in the heart and their contribution to cardiac pathology. Some reports suggest macroautophagy imparts cardioprotection from heart failure pathology. Meanwhile, other studies find macroautophagy activation may be detrimental in cardiac pathology. An improved understanding of autophagic processes and their regulation may lead to a new genre of treatments for cardiac diseases.

  1. Internal flux dynamics and stray field-mediated coupling in the AC susceptibility response of Nb/Ni thin-film bilayers

    Science.gov (United States)

    Badilla, Juan Pablo; Cornejo, Daniel

    2018-03-01

    The in-phase ac magnetic susceptibility (X‧) of Nb/Ni bilayers was measured using a small in-plane magnetic field (the drive field). The sample’s response changes considerably in the presence of perpendicular stray fields that arise during magnetization reversal of the Ni film. The interplay between stray fields and flux lines inside the superconductor is associated to an enhancement of vortex entrance and exit, suggesting an effective magnetic coupling of the ferromagnetic and superconducting components. As a DC field probes the different configurations of the Ni layer throughout its hysteresis loop, the X‧ signal traces a curve with irreversible features that are analogous to those of well-known magnetoresistance measurements. A modification of the measuring temperature provides access to various kinds of superconductor/ferromagnet interaction.

  2. Acute ethanol exposure-induced autophagy-mediated cardiac injury via activation of the ROS-JNK-Bcl-2 pathway.

    Science.gov (United States)

    Zhu, Zhongxin; Huang, Yewei; Lv, Lingchun; Tao, Youli; Shao, Minglong; Zhao, Congcong; Xue, Mei; Sun, Jia; Niu, Chao; Wang, Yang; Kim, Sunam; Cong, Weitao; Mao, Wei; Jin, Litai

    2018-02-01

    Binge drinking is associated with increased cardiac autophagy, and often triggers heart injury. Given the essential role of autophagy in various cardiac diseases, this study was designed to investigate the role of autophagy in ethanol-induced cardiac injury and the underlying mechanism. Our study showed that ethanol exposure enhanced the levels of LC3-II and LC3-II positive puncta and promoted cardiomyocyte apoptosis in vivo and in vitro. In addition, we found that ethanol induced autophagy and cardiac injury largely via the sequential triggering of reactive oxygen species (ROS) accumulation, activation of c-Jun NH2-terminal kinase (JNK), phosphorylation of Bcl-2, and dissociation of the Beclin 1/Bcl-2 complex. By contrast, inhibition of ethanol-induced autophagic flux with pharmacologic agents in the hearts of mice and cultured cells significantly alleviated ethanol-induced cardiomyocyte apoptosis and heart injury. Elimination of ROS with the antioxidant N-acetyl cysteine (NAC) or inhibition of JNK with the JNK inhibitor SP600125 reduced ethanol-induced autophagy and subsequent autophagy-mediated apoptosis. Moreover, metallothionein (MT), which can scavenge reactive oxygen and nitrogen species, also attenuated ethanol-induced autophagy and cell apoptosis in MT-TG mice. In conclusion, our findings suggest that acute ethanol exposure induced autophagy-mediated heart toxicity and injury mainly through the ROS-JNK-Bcl-2 signaling pathway. © 2017 Wiley Periodicals, Inc.

  3. Impact of elevated levels of CO2 on animal mediated ecosystem function: the modification of sediment nutrient fluxes by burrowing urchins.

    Science.gov (United States)

    Widdicombe, S; Beesley, A; Berge, J A; Dashfield, S L; McNeill, C L; Needham, H R; Øxnevad, S

    2013-08-30

    A mesocosm experiment was conducted to quantify the relationships between the presence and body size of two burrowing heart urchins (Brissopsis lyrifera and Echinocardium cordatum) and rates of sediment nutrient flux. Furthermore, the impact of seawater acidification on these relationships was determined during this 40-day exposure experiment. Using carbon dioxide (CO2) gas, seawater was acidified to pHNBS 7.6, 7.2 or 6.8. Control treatments were maintained in natural seawater (pH≈8.0). Under normocapnic conditions, burrowing urchins were seen to reduce the sediment uptake of nitrite or nitrate whilst enhancing the release of silicate and phosphate. In acidified (hypercapnic) treatments, the biological control of biogeochemical cycles by urchins was significantly affected, probably through the combined impacts of high CO2 on nitrifying bacteria, benthic algae and urchin behaviour. This study highlights the importance of considering biological interactions when predicting the consequences of seawater acidification on ecosystem function. Copyright © 2012 Elsevier Ltd. All rights reserved.

  4. Critical flux determination by flux-stepping

    DEFF Research Database (Denmark)

    Beier, Søren; Jonsson, Gunnar Eigil

    2010-01-01

    In membrane filtration related scientific literature, often step-by-step determined critical fluxes are reported. Using a dynamic microfiltration device, it is shown that critical fluxes determined from two different flux-stepping methods are dependent upon operational parameters such as step......, such values are more or less useless in itself as critical flux predictors, and constant flux verification experiments have to be conducted to check if the determined critical fluxes call predict sustainable flux regimes. However, it is shown that using the step-by-step predicted critical fluxes as start...

  5. 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

  6. 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

  7. 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

  8. 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

  9. 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.

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

    Directory of Open Access Journals (Sweden)

    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.

  11. 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.

  12. 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.

  13. 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.

  14. 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.

  15. 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.

  16. 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.

  17. 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.

  18. 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.

  19. 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.

  20. Na+/H+ Exchanger Regulates Amino Acid-Mediated Autophagy in Intestinal Epithelial Cells

    Directory of Open Access Journals (Sweden)

    Huiying Shi

    2017-08-01

    Full Text Available Background/Aims: Dysfunctional autophagy has been reported to be associated with aberrant intestinal metabolism. Amino acids can regulate autophagic activity in intestinal epithelial cells (IECs. Na+/H+-exchanger 3 (NHE3 has been found to participate in the absorption of amino acids in the intestine, but whether NHE3 is involved in the regulation of autophagy in IECs is unclear. Methods: In the present study, an amino acid starvation-induced autophagic model was established. Then, the effects of alanine and proline with or without the NHE inhibitor 5-(N-ethyl-N-isopropyl amiloride (EIPA were evaluated. Autophagy was examined based on the microtubule-associated light chain 3 (LC3 levels, transmission electron microscopy (TEM, tandem GFP-mCherry-LC3 construct, sequestosome-1 (SQSTM1, P62 mRNA and protein levels, and autophagy-related gene (ATG 5, 7, and 12 expression levels. The autophagic flux was evaluated as the ratio of yellow (autophagosomes to red (autolysosomes LC3 puncta. Results: Following amino acid starvation, we found the LC3-II and ATG expression levels were enhanced in the IEC-18 cells. An increase in the number of autophagic vacuoles was concomitantly observed by TEM and confocal microscopy. Based on the results, supplementation with either alanine or proline depressed autophagy in the IEC-18 cells. Consistent with the elevated LC3-II levels, ATG expression increased upon NHE3 inhibition. Moreover, the mCherry-GFP-LC3 autophagic puncta representing both autophagosomes and autolysosomes per cell increased after EIPA treatment. Conclusions: These results demonstrate that NHE (most likely NHE3 may participate in the amino acid regulation of autophagy in IECs, which would aid in the design of better treatments for intestinal inflammation.

  1. Radon flux measurement methodologies

    International Nuclear Information System (INIS)

    Nielson, K.K.; Rogers, V.C.

    1984-01-01

    Five methods for measuring radon fluxes are evaluated: the accumulator can, a small charcoal sampler, a large-area charcoal sampler, the ''Big Louie'' charcoal sampler, and the charcoal tent sampler. An experimental comparison of the five flux measurement techniques was also conducted. Excellent agreement was obtained between the measured radon fluxes and fluxes predicted from radium and emanation measurements

  2. 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.

  3. Brief Report: Oxidative Stress Mediates Cardiomyocyte Apoptosis in a Human Model of Danon Disease and Heart Failure.

    Science.gov (United States)

    Hashem, Sherin I; Perry, Cynthia N; Bauer, Matthieu; Han, Sangyoon; Clegg, Stacey D; Ouyang, Kunfu; Deacon, Dekker C; Spinharney, Mary; Panopoulos, Athanasia D; Izpisua Belmonte, Juan Carlos; Frazer, Kelly A; Chen, Ju; Gong, Qiuming; Zhou, Zhengfeng; Chi, Neil C; Adler, Eric D

    2015-07-01

    Danon disease is a familial cardiomyopathy associated with impaired autophagy due to mutations in the gene encoding lysosomal-associated membrane protein type 2 (LAMP-2). Emerging evidence has highlighted the importance of autophagy in regulating cardiomyocyte bioenergetics, function, and survival. However, the mechanisms responsible for cellular dysfunction and death in cardiomyocytes with impaired autophagic flux remain unclear. To investigate the molecular mechanisms responsible for Danon disease, we created induced pluripotent stem cells (iPSCs) from two patients with different LAMP-2 mutations. Danon iPSC-derived cardiomyocytes (iPSC-CMs) exhibited impaired autophagic flux and key features of heart failure such as increased cell size, increased expression of natriuretic peptides, and abnormal calcium handling compared to control iPSC-CMs. Additionally, Danon iPSC-CMs demonstrated excessive amounts of mitochondrial oxidative stress and apoptosis. Using the sulfhydryl antioxidant N-acetylcysteine to scavenge free radicals resulted in a significant reduction in apoptotic cell death in Danon iPSC-CMs. In summary, we have modeled Danon disease using human iPSC-CMs from patients with mutations in LAMP-2, allowing us to gain mechanistic insight into the pathogenesis of this disease. We demonstrate that LAMP-2 deficiency leads to an impairment in autophagic flux, which results in excessive oxidative stress, and subsequent cardiomyocyte apoptosis. Scavenging excessive free radicals with antioxidants may be beneficial for patients with Danon disease. In vivo studies will be necessary to validate this new treatment strategy. © 2015 AlphaMed Press.

  4. Clustering of Emerging Flux

    Science.gov (United States)

    Ruzmaikin, A.

    1997-01-01

    Observations show that newly emerging flux tends to appear on the Solar surface at sites where there is flux already. This results in clustering of solar activity. Standard dynamo theories do not predict this effect.

  5. 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

  6. 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.

  7. 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.

  8. 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

  9. 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...

  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. 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.

  14. Substituted 2-hydroxy-N-(arylalkyl)benzamide sensitizes cancer cells to metabolic stress by disrupting actin cytoskeleton and inhibiting autophagic flux

    Czech Academy of Sciences Publication Activity Database

    Pachnikova, G.; Uldrijan, S.; Imramovský, A.; Kryštof, Vladimír; Slaninová, I.

    2016-01-01

    Roč. 37, DEC (2016), s. 70-78 ISSN 0887-2333 Institutional support: RVO:61389030 Keywords : hepatocellular-carcinoma cells * sorafenib * apoptosis * death * maturation * membrane * melanoma * Actin * Autophagy * Melanoma * Metabolic stress * Sorafenib * Substituted 2-hydroxy-N-(arylalkyl)benzamide Subject RIV: CE - Biochemistry Impact factor: 2.866, year: 2016

  15. Compact neutron flux monitor

    International Nuclear Information System (INIS)

    Madhavi, V.; Phatak, P.R.; Bahadur, C.; Bayala, A.K.; Jakati, R.K.; Sathian, V.

    2003-01-01

    Full text: A compact size neutron flux monitor has been developed incorporating standard boards developed for smart radiation monitors. The sensitivity of the monitors is 0.4cps/nV. It has been tested up to 2075 nV flux with standard neutron sources. It shows convincing results even in high flux areas like 6m away from the accelerator in RMC (Parel) for 106/107 nV. These monitors have a focal and remote display, alarm function with potential free contacts for centralized control and additional provision of connectivity via RS485/Ethernet. This paper describes the construction, working and results of the above flux monitor

  16. 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...

  17. 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.

  18. Video Meteor Fluxes

    Science.gov (United States)

    Campbell-Brown, M. D.; Braid, D.

    2011-01-01

    The flux of meteoroids, or number of meteoroids per unit area per unit time, is critical for calibrating models of meteoroid stream formation and for estimating the hazard to spacecraft from shower and sporadic meteors. Although observations of meteors in the millimetre to centimetre size range are common, flux measurements (particularly for sporadic meteors, which make up the majority of meteoroid flux) are less so. It is necessary to know the collecting area and collection time for a given set of observations, and to correct for observing biases and the sensitivity of the system. Previous measurements of sporadic fluxes are summarized in Figure 1; the values are given as a total number of meteoroids striking the earth in one year to a given limiting mass. The Gr n et al. (1985) flux model is included in the figure for reference. Fluxes for sporadic meteoroids impacting the Earth have been calculated for objects in the centimeter size range using Super-Schmidt observations (Hawkins & Upton, 1958); this study used about 300 meteors, and used only the physical area of overlap of the cameras at 90 km to calculate the flux, corrected for angular speed of meteors, since a large angular speed reduces the maximum brightness of the meteor on the film, and radiant elevation, which takes into account the geometric reduction in flux when the meteors are not perpendicular to the horizontal. They bring up corrections for both partial trails (which tends to increase the collecting area) and incomplete overlap at heights other than 90 km (which tends to decrease it) as effects that will affect the flux, but estimated that the two effects cancelled one another. Halliday et al. (1984) calculated the flux of meteorite-dropping fireballs with fragment masses greater than 50 g, over the physical area of sky accessible to the MORP fireball cameras, counting only observations in clear weather. In the micron size range, LDEF measurements of small craters on spacecraft have been used to

  19. 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.

  20. 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.

  1. Solar Magnetic Flux Ropes

    Indian Academy of Sciences (India)

    2016-01-27

    Jan 27, 2016 ... The most probable initial magnetic configuration of a CME is a flux rope consisting of twisted field lines which fill the whole volume of a dark coronal cavity. The flux ropes can be in stable equilibrium in the coronal magnetic field for weeks and even months, but suddenly they lose their stability and erupt with ...

  2. 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.

  3. 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.

  4. 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

  5. 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.

  6. LAMP-2 deficiency leads to hippocampal dysfunction but normal clearance of neuronal substrates of chaperone-mediated autophagy in a mouse model for Danon disease

    OpenAIRE

    Rothaug, Michelle; Stroobants, Stijn; Schweizer, Michaela; Peters, Judith; Zunke, Friederike; Allerding, Mirka; D?Hooge, Rudi; Saftig, Paul; Blanz, Judith

    2015-01-01

    The Lysosomal Associated Membrane Protein type-2 (LAMP-2) is an abundant lysosomal membrane protein with an important role in immunity, macroautophagy (MA) and chaperone-mediated autophagy (CMA). Mutations within the Lamp2 gene cause Danon disease, an X-linked lysosomal storage disorder characterized by (cardio)myopathy and intellectual dysfunction. The pathological hallmark of this disease is an accumulation of glycogen and autophagic vacuoles in cardiac and skeletal muscle that, along with ...

  7. Directed flux motor

    Science.gov (United States)

    Wilson, Andrew (Inventor); Punnoose, Andrew (Inventor); Strausser, Katherine (Inventor); Parikh, Neil (Inventor)

    2011-01-01

    A directed flux motor described utilizes the directed magnetic flux of at least one magnet through ferrous material to drive different planetary gear sets to achieve capabilities in six actuated shafts that are grouped three to a side of the motor. The flux motor also utilizes an interwoven magnet configuration which reduces the overall size of the motor. The motor allows for simple changes to modify the torque to speed ratio of the gearing contained within the motor as well as simple configurations for any number of output shafts up to six. The changes allow for improved manufacturability and reliability within the design.

  8. Autophagic Mechanism in Anti-Cancer Immunity: Its Pros and Cons for Cancer Therapy.

    Science.gov (United States)

    Li, Ying-Ying; Feun, Lynn G; Thongkum, Angkana; Tu, Chiao-Hui; Chen, Shu-Mei; Wangpaichitr, Medhi; Wu, Chunjing; Kuo, Macus T; Savaraj, Niramol

    2017-06-19

    Autophagy, a self-eating machinery, has been reported as an adaptive response to maintain metabolic homeostasis when cancer cells encounter stress. It has been appreciated that autophagy acts as a double-edge sword to decide the fate of cancer cells upon stress factors, molecular subtypes, and microenvironmental conditions. Currently, the majority of evidence support that autophagy in cancer cells is a vital mechanism bringing on resistance to current and prospective treatments, yet whether autophagy affects the anticancer immune response remains unclear and controversial. Accumulated studies have demonstrated that triggering autophagy is able to facilitate anticancer immunity due to an increase in immunogenicity, whereas other studies suggested that autophagy is likely to disarm anticancer immunity mediated by cytotoxic T cells and nature killer (NK) cells. Hence, this contradiction needs to be elucidated. In this review, we discuss the role of autophagy in cancer cells per se and in cancer microenvironment as well as its dual regulatory roles in immune surveillance through modulating presentation of tumor antigens, development of immune cells, and expression of immune checkpoints. We further focus on emerging roles of autophagy induced by current treatments and its impact on anticancer immune response, and illustrate the pros and cons of utilizing autophagy in cancer immunotherapy based on preclinical references.

  9. Aeronet Solar Flux

    Data.gov (United States)

    National Aeronautics and Space Administration — SolRad-Net (Solar Radiation Network) is an established network of ground-based sensors providing high-frequency solar flux measurements in quasi-realtime to the...

  10. Flux in Tallinn

    Index Scriptorium Estoniae

    2004-01-01

    Rahvusvahelise elektroonilise kunsti sümpoosioni ISEA2004 klubiõhtu "Flux in Tallinn" klubis Bon Bon. Eestit esindasid Ropotator, Ars Intel Inc., Urmas Puhkan, Joel Tammik, Taavi Tulev (pseud. Wochtzchee). Klubiõhtu koordinaator Andres Lõo

  11. Determining Reactor Neutrino Flux

    OpenAIRE

    Cao, Jun

    2011-01-01

    Flux is an important source of uncertainties for a reactor neutrino experiment. It is determined from thermal power measurements, reactor core simulation, and knowledge of neutrino spectra of fuel isotopes. Past reactor neutrino experiments have determined the flux to (2-3)% precision. Precision measurements of mixing angle $\\theta_{13}$ by reactor neutrino experiments in the coming years will use near-far detector configurations. Most uncertainties from reactor will be canceled out. Understa...

  12. Theoretical magnetic flux emergence

    OpenAIRE

    MacTaggart, David

    2011-01-01

    Magnetic flux emergence is the subject of how magnetic fields from the solar interior can rise and expand into the atmosphere to produce active regions. It is the link that joins dynamics in the convection zone with dynamics in the atmosphere. In this thesis, we study many aspects of magnetic flux emergence through mathematical modelling and computer simulations. Our primary aim is to understand the key physical processes that lie behind emergence. The first chapter intro...

  13. Flux Emergence (Theory)

    Science.gov (United States)

    Cheung, Mark C. M.; Isobe, Hiroaki

    2014-07-01

    Magnetic flux emergence from the solar convection zone into the overlying atmosphere is the driver of a diverse range of phenomena associated with solar activity. In this article, we introduce theoretical concepts central to the study of flux emergence and discuss how the inclusion of different physical effects (e.g., magnetic buoyancy, magnetoconvection, reconnection, magnetic twist, interaction with ambient field) in models impact the evolution of the emerging field and plasma.

  14. Neutron flux monitoring device

    International Nuclear Information System (INIS)

    Shimazu, Yoichiro.

    1995-01-01

    In a neutron flux monitoring device, there are disposed a neutron flux measuring means for outputting signals in accordance with the intensity of neutron fluxes, a calculation means for calculating a self power density spectrum at a frequency band suitable to an object to be measured based on the output of the neutron flux measuring means, an alarm set value generation means for outputting an alarm set value as a comparative reference, and an alarm judging means for comparing the alarm set value with the outputted value of the calculation means to judge requirement of generating an alarm and generate an alarm in accordance with the result of the judgement. Namely, the time-series of neutron flux signals is put to fourier transformation for a predetermined period of time by the calculation means, and from each of square sums for real number component and imaginary number component for each of the frequencies, a self power density spectrum in the frequency band suitable to the object to be measured is calculated. Then, when the set reference value is exceeded, an alarm is generated. This can reliably prevent generation of erroneous alarm due to neutron flux noises and can accurately generate an alarm at an appropriate time. (N.H.)

  15. Neutron flux monitor

    International Nuclear Information System (INIS)

    Oda, Naotaka.

    1993-01-01

    The device of the present invention greatly saves an analog processing section such as an analog filter and an analog processing circuit. That is, the device of the present invention comprises (1) a neutron flux detection means for detecting neutron fluxed in the reactor, (2) a digital filter means for dividing signals corresponding to the detected neutron fluxes into predetermined frequency band regions, (3) a calculation processing means for applying a calculation processing corresponding to the frequency band regions to the neutron flux detection signals divided by the digital filter means. With such a constitution, since the neutron detection signals are processed by the digital filter means, the accuracy is improved and the change for the property of the filter is facilitated. Further, when a neutron flux level is obtained, a calculation processing corresponding to the frequency band region can be conducted without the analog processing circuit. Accordingly, maintenance and accuracy are improved by greatly decreasing the number of parts. Further, since problems inherent to the analog circuit are solved, neutron fluxes are monitored at high reliability. (I.S.)

  16. 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.

  17. The Open Flux Problem

    International Nuclear Information System (INIS)

    Linker, J. A.; Caplan, R. M.; Downs, C.; Riley, P.; Mikic, Z.; Lionello, R.; Henney, C. J.; Arge, C. N.; Liu, Y.; Derosa, M. L.; Yeates, A.; Owens, M. J.

    2017-01-01

    The heliospheric magnetic field is of pivotal importance in solar and space physics. The field is rooted in the Sun’s photosphere, where it has been observed for many years. Global maps of the solar magnetic field based on full-disk magnetograms are commonly used as boundary conditions for coronal and solar wind models. Two primary observational constraints on the models are (1) the open field regions in the model should approximately correspond to coronal holes (CHs) observed in emission and (2) the magnitude of the open magnetic flux in the model should match that inferred from in situ spacecraft measurements. In this study, we calculate both magnetohydrodynamic and potential field source surface solutions using 14 different magnetic maps produced from five different types of observatory magnetograms, for the time period surrounding 2010 July. We have found that for all of the model/map combinations, models that have CH areas close to observations underestimate the interplanetary magnetic flux, or, conversely, for models to match the interplanetary flux, the modeled open field regions are larger than CHs observed in EUV emission. In an alternative approach, we estimate the open magnetic flux entirely from solar observations by combining automatically detected CHs for Carrington rotation 2098 with observatory synoptic magnetic maps. This approach also underestimates the interplanetary magnetic flux. Our results imply that either typical observatory maps underestimate the Sun’s magnetic flux, or a significant portion of the open magnetic flux is not rooted in regions that are obviously dark in EUV and X-ray emission.

  18. 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.

  19. Human footprints on greenhouse gas fluxes in cryogenic ecosystems

    Science.gov (United States)

    Karelin, D. V.; Goryachkin, S. V.; Zamolodchikov, D. G.; Dolgikh, A. V.; Zazovskaya, E. P.; Shishkov, V. A.; Kraev, G. N.

    2017-12-01

    Various human footprints on the flux of biogenic greenhouse gases from permafrost-affected soils in Arctic and boreal domains in Russia are considered. Tendencies of significant growth or suppression of soil CO2 fluxes change across types of human impact. Overall, the human impacts increase the mean value and variance of local soil CO2 flux. Human footprint on methane exchange between soil and atmosphere is mediated by drainage. However, all the types of human impact suppress the sources and increase sinks of methane to the land ecosystems. N2O flux grew under the considered types of human impact. Based on the results, we suggest that human footprint on soil greenhouse gases fluxes is comparable to the effect of climate change at an annual to decadal timescales.

  20. Soluble organic nutrient fluxes

    Science.gov (United States)

    Robert G. Qualls; Bruce L. Haines; Wayne Swank

    2014-01-01

    Our objectives in this study were (i) compare fluxes of the dissolved organic nutrients dissolved organic carbon (DOC), DON, and dissolved organic phosphorus (DOP) in a clearcut area and an adjacent mature reference area. (ii) determine whether concentrations of dissolved organic nutrients or inorganic nutrients were greater in clearcut areas than in reference areas,...

  1. Radiation flux measuring device

    International Nuclear Information System (INIS)

    Corte, E.; Maitra, P.

    1977-01-01

    A radiation flux measuring device is described which employs a differential pair of transistors, the output of which is maintained constant, connected to a radiation detector. Means connected to the differential pair produce a signal representing the log of the a-c component of the radiation detector, thereby providing a signal representing the true root mean square logarithmic output. 3 claims, 2 figures

  2. Muon and neutrino fluxes

    Science.gov (United States)

    Edwards, P. G.; Protheroe, R. J.

    1985-01-01

    The result of a new calculation of the atmospheric muon and neutrino fluxes and the energy spectrum of muon-neutrinos produced in individual extensive air showers (EAS) initiated by proton and gamma-ray primaries is reported. Also explained is the possibility of detecting atmospheric nu sub mu's due to gamma-rays from these sources.

  3. Flux scaling: Ultimate regime

    Indian Academy of Sciences (India)

    First page Back Continue Last page Overview Graphics. Flux scaling: Ultimate regime. With the Nusselt number and the mixing length scales, we get the Nusselt number and Reynolds number (w'd/ν) scalings: and or. and. scaling expected to occur at extremely high Ra Rayleigh-Benard convection. Get the ultimate regime ...

  4. Peroxisome proliferator-activated receptor-γ agonist 15d-prostaglandin J2 mediates neuronal autophagy after cerebral ischemia-reperfusion injury.

    Directory of Open Access Journals (Sweden)

    Feng Xu

    Full Text Available Peroxisome proliferator-activated receptor-γ (PPAR-γ has recently emerged as potential therapeutic agents for cerebral ischemia-reperfusion (I/R injury because of anti-neuronal apoptotic actions. However, whether PPAR-γ activation mediates neuronal autophagy in such conditions remains unclear. Therefore, in this study, we investigated the role of PPAR-γ agonist 15-PGJ(2 on neuronal autophagy induced by I/R. The expression of autophagic-related protein in ischemic cortex such as LC3-II, Beclin 1, cathepsin-B and LAMP1 increased significantly after cerebral I/R injury. Furthermore, increased punctate LC3 labeling and cathepsin-B staining occurred in neurons. Treatment with PPAR-γ agonist 15d-PGJ(2 decreased not only autophagic-related protein expression in ischemic cortex, but also immunoreactivity of LC3 and cathepsin-B in neurons. Autophagic inhibitor 3-methyladenine (3-MA decreased LC3-II levels, reduced the infarct volume, and mimicked some protective effect of 15d-PGJ(2 against cerebral I/R injury. These results indicate that PPAR-γ agonist 15d-PGJ(2 exerts neuroprotection by inhibiting neuronal autophagy after cerebral I/R injury. Although the molecular mechanisms underlying PPAR-γ agonist in mediating neuronal autophagy remain to be determined, neuronal autophagy may be a new target for PPAR-γ agonist treatment in cerebral I/R injury.

  5. 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.

  6. 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

  7. Anomaly mediation in superstring theory

    Energy Technology Data Exchange (ETDEWEB)

    Conlon, Joseph P. [Rudolf Peierls Center for Theoretical Physics, Oxford (United Kingdom); Balliol College, Oxford (United Kingdom); Goodsell, Mark [Deutsches Elektronen-Synchrotron (DESY), Hamburg (Germany); Palti, Eran [Centre de Physique Theoretique, Ecole Polytechnique, CNRS, Palaiseau (France)

    2010-08-15

    We study anomaly mediated supersymmetry breaking in type IIB string theory and use our results to test the supergravity formula for anomaly mediated gaugino masses. We compute 1-loop gaugino masses for models of D3-branes on orbifold singularities with 3-form fluxes by calculating the annulus correlator of 3-form flux and two gauginos in the zero momentum limit. Consistent with supergravity expectations we find both anomalous and running contributions to 1-loop gaugino masses. For background Neveu-Schwarz H-flux we find an exact match with the supergravity formula. For Ramond-Ramond flux there is an off-shell ambiguity that precludes a full matching. The anomaly mediated gaugino masses, while determined by the infrared spectrum, arise from an explicit sum over UV open string winding modes. We also calculate brane-to-brane tree-level gravity mediated gaugino masses and show that there are two contributions coming from the dilaton and from the twisted modes, which are suppressed by the full T{sup 6} volume and the untwisted T{sup 2} volume respectively. (orig.)

  8. 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.

  9. 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.

  10. 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.

  11. 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.

  12. 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

  13. 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.

  14. 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.

  15. 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.

  16. ULY JUP COSPIN HIGH FLUX TELESCOPE HIGH RES. ION FLUX

    Data.gov (United States)

    National Aeronautics and Space Administration — This data set contains ion flux data recorded by the COSPIN High Flux Telescope (HFT) during the Ulysses Jupiter encounter 1992-Jan-25 to 1992-Feb-18.

  17. Atmospheric lepton fluxes

    Directory of Open Access Journals (Sweden)

    Gaisser Thomas K.

    2015-01-01

    Full Text Available This review of atmospheric muons and neutrinos emphasizes the high energy range relevant for backgrounds to high-energy neutrinos of astrophysical origin. After a brief historical introduction, the main distinguishing features of atmospheric νμ and νe are discussed, along with the implications of the muon charge ratio for the νµ / ν̅µ ratio. Methods to account for effects of the knee in the primary cosmic-ray spectrum and the energy-dependence of hadronic interactions on the neutrino fluxes are discussed and illustrated in the context of recent results from IceCube. A simple numerical/analytic method is proposed for systematic investigation of uncertainties in neutrino fluxes arising from uncertainties in the primary cosmic-ray spectrum/composition and hadronic interactions.

  18. NEUTRON FLUX INTENSITY DETECTION

    Science.gov (United States)

    Russell, J.T.

    1964-04-21

    A method of measuring the instantaneous intensity of neutron flux in the core of a nuclear reactor is described. A target gas capable of being transmuted by neutron bombardment to a product having a resonance absorption line nt a particular microwave frequency is passed through the core of the reactor. Frequency-modulated microwave energy is passed through the target gas and the attenuation of the energy due to the formation of the transmuted product is measured. (AEC)

  19. Physics of magnetic flux ropes

    Science.gov (United States)

    Russell, C. T.; Priest, E. R.; Lee, L. C.

    The present work encompasses papers on the structure, waves, and instabilities of magnetic flux ropes (MFRs), photospheric flux tubes (PFTs), the structure and heating of coronal loops, solar prominences, coronal mass ejections and magnetic clouds, flux ropes in planetary ionospheres, the magnetopause, magnetospheric field-aligned currents and flux tubes, and the magnetotail. Attention is given to the equilibrium of MFRs, resistive instability, magnetic reconnection and turbulence in current sheets, dynamical effects and energy transport in intense flux tubes, waves in solar PFTs, twisted flux ropes in the solar corona, an electrodynamical model of solar flares, filament cooling and condensation in a sheared magnetic field, the magnetopause, the generation of twisted MFRs during magnetic reconnection, ionospheric flux ropes above the South Pole, substorms and MFR structures, evidence for flux ropes in the earth magnetotail, and MFRs in 3D MHD simulations.

  20. Titanium Dioxide Nanoparticles Induce Endoplasmic Reticulum Stress-Mediated Autophagic Cell Death via Mitochondria-Associated Endoplasmic Reticulum Membrane Disruption in Normal Lung Cells

    Science.gov (United States)

    Yu, Kyeong-Nam; Chang, Seung-Hee; Park, Soo Jin; Lim, Joohyun; Lee, Jinkyu; Yoon, Tae-Jong; Kim, Jun-Sung; Cho, Myung-Haing

    2015-01-01

    Nanomaterials are used in diverse fields including food, cosmetic, and medical industries. Titanium dioxide nanoparticles (TiO2-NP) are widely used, but their effects on biological systems and mechanism of toxicity have not been elucidated fully. Here, we report the toxicological mechanism of TiO2-NP in cell organelles. Human bronchial epithelial cells (16HBE14o-) were exposed to 50 and 100 μg/mL TiO2-NP for 24 and 48 h. Our results showed that TiO2-NP induced endoplasmic reticulum (ER) stress in the cells and disrupted the mitochondria-associated endoplasmic reticulum membranes (MAMs) and calcium ion balance, thereby increasing autophagy. In contrast, an inhibitor of ER stress, tauroursodeoxycholic acid (TUDCA), mitigated the cellular toxic response, suggesting that TiO2-NP promoted toxicity via ER stress. This novel mechanism of TiO2-NP toxicity in human bronchial epithelial cells suggests that further exhaustive research on the harmful effects of these nanoparticles in relevant organisms is needed for their safe application. PMID:26121477

  1. Menopause-induced uterine epithelium atrophy results from arachidonic acid/prostaglandin E2 axis inhibition-mediated autophagic cell death

    OpenAIRE

    Shengtao Zhou; Linjie Zhao; Tao Yi; Yuquan Wei; Xia Zhao

    2016-01-01

    Women experience menopause later in life. Menopause is characterized by dramatically decreased circulating estrogen level secondary to loss of ovarian function and atrophic state of genital organs. However, the molecular mechanisms for this process are not fully understood. In this study, we aimed to investigate the potential molecular mechanisms that underlie menopause-induced uterine endometrial atrophy. Our data showed that autophagy was activated in the uterine epithelial cells of both ov...

  2. Influence of the late winter bloom on migrant zooplankton metabolism and its implications on export fluxes

    Science.gov (United States)

    Putzeys, S.; Yebra, L.; Almeida, C.; Bécognée, P.; Hernández-León, S.

    2011-12-01

    Studies on carbon active fluxes due to diel migrants are scarce and critical for carbon flux models and biogeochemical estimates. We studied the temporal variability and vertical distribution of biomass, indices of feeding and respiration of the zooplanktonic community north off the Canary Islands during the end of the late winter bloom, in order to assess vertical carbon fluxes in this area. Biomass distribution during the day presented two dense layers of organisms at 0-200 m and around 500 m, whereas at night, most of the biomass concentrated in the epipelagic layer. The gut pigment flux (0.05-0.18 mgC·m - 2 ·d - 1 ) represented 0.22% of the estimated passive export flux (POC flux) while potential ingestion represented 3.91% of the POC (1.24-3.40 mgC·m - 2 ·d - 1 ). The active respiratory flux (0.50-1.36 mgC·m - 2 ·d - 1 ) was only 1.57% of the POC flux. The total carbon flux mediated by diel migrants (respiration plus potential ingestion) ranged between 3.37 and 9.22% of the POC flux; which is three-fold higher than calculating ingestion fluxes from gut pigments. Our results suggest that the fluxes by diel migrants play a small role in the downward flux of carbon in the open ocean during the post-bloom period.

  3. Reactor flux calculations

    Energy Technology Data Exchange (ETDEWEB)

    Lhuillier, D. [Commissariat à l' Énergie Atomique et aux Énergies Alternatives, Centre de Saclay, IRFU/SPhN, 91191 Gif-sur-Yvette (France)

    2013-02-15

    The status of the prediction of reactor anti-neutrino spectra is presented. The most accurate method is still the conversion of total β spectra of fissionning isotopes as measured at research reactors. Recent re-evaluations of the conversion process led to an increased predicted flux by few percent and were at the origin of the so-called reactor anomaly. The up to date predictions are presented with their main sources of error. Perspectives are given on the complementary ab-initio predictions and upcoming experimental cross-checks of the predicted spectrum shape.

  4. Australian methane fluxes

    International Nuclear Information System (INIS)

    Williams, D.J.

    1990-01-01

    Estimates are provided for the amount of methane emitted annually into the atmosphere in Australia for a variety of sources. The sources considered are coal mining, landfill, motor vehicles, natural gas suply system, rice paddies, bushfires, termites, wetland and animals. This assessment indicates that the major sources of methane are natural or agricultural in nature and therefore offer little scope for reduction. Nevertheless the remainder are not trival and reduction of these fluxes could play a significant part in any Australian action on the greenhouse problem. 19 refs., 7 tabs., 1 fig

  5. [The flux of historiography].

    Science.gov (United States)

    Mazzolini, R G

    2001-01-01

    The author places Grmek's editorial within the flux of the historiographical debate which, since the middle of the 1970s, has concentrated on two major crises due to the end of social science-oriented 'scientific history' and to the 'linguistic turn'. He also argues that Grmek's historiographical work of the 1980s and 1990s was to some extent an alternative to certain observed changes in historical fashion and has achieved greater intelligibility because of its commitment to a rational vision of science and historiography.

  6. Intracellular APP Sorting and Aβ Secretion are Regulated by Src-mediated Phosphorylation of Mint2

    Science.gov (United States)

    Chaufty, Jeremy; Sullivan, Sarah E.; Ho, Angela

    2012-01-01

    Mint adaptor proteins bind to the membrane-bound amyloid precursor protein (APP) and affect the production of pathogenic amyloid-beta (Aβ) peptides related to Alzheimer’s disease (AD). Previous studies have shown that loss of each of the three Mint proteins delays the age-dependent production of amyloid plaques in transgenic mouse models of AD. However, the cellular and molecular mechanisms underlying Mints effect on amyloid production are unclear. Because Aβ generation involves the internalization of membrane-bound APP via endosomes and Mints bind directly to the endocytic motif of APP, we proposed that Mints are involved in APP intracellular trafficking, which in turn, affects Aβ generation. Here, we show that APP endocytosis was attenuated in Mint knockout neurons, revealing a role for Mints in APP trafficking. We also show that the endocytic APP sorting processes are regulated by Src-mediated phosphorylation of Mint2 and that internalized APP is differentially sorted between autophagic and recycling trafficking pathways. A Mint2 phospho-mimetic mutant favored endocytosis of APP along the autophagic sorting pathway leading to increased intracellular Aβ accumulation. Conversely, the Mint2 phospho-resistant mutant increased APP localization to the recycling pathway and back to the cell surface thereby enhancing Aβ42 secretion. These results demonstrate that Src-mediated phosphorylation of Mint2 regulates the APP endocytic sorting pathway, providing a mechanism for regulating Aβ secretion. PMID:22787047

  7. Rottlerin-mediated inhibition of Toxoplasma gondii growth in BeWo trophoblast-like cells.

    Science.gov (United States)

    Ietta, Francesca; Maioli, Emanuela; Daveri, Elena; Gonzaga Oliveira, Juliana; da Silva, Rafaela José; Romagnoli, Roberta; Cresti, Laura; Maria Avanzati, Anna; Paulesu, Luana; Barbosa, Bellisa de Freitas; Gomes, Angelica de Oliveira; Roberto Mineo, José; Ferro, Eloisa Amália Vieira

    2017-04-28

    Autophagy is a crucial and physiological process for cell survival from yeast to mammals, including protozoan parasites. Toxoplasma gondii, an intracellular parasite, typically exploits autophagic machinery of host cell; however host cell upregulates autophagy to combat the infection. Herein we tested the efficacy of Rottlerin, a natural polyphenol with autophagic promoting properties, against Toxoplasma infection on the chorioncarcinoma-derived cell line BeWo. We found that Rottlerin, at sub-toxic doses, induced morphological and biochemical alterations associated with autophagy and decreased Toxoplasma growth in infected cells. Although autophagy was synergically promoted by Toxoplasma infection in combination with Rottlerin treatment, the use of the autophagy inhibitor chloroquine revealed that Rottlerin anti-parasitic effect was largely autophagy-independent and likely mediated by the converging inhibitory effect of Rottlerin and Toxoplasma in host protein translation, mediated by mTOR inhibition and eIF2α phosphorylation. Both events, which on one hand could explain the additive effect on autophagy induction, on the other hand led to inhibition of protein synthesis, thereby depriving Toxoplasma of metabolically essential components for multiplication. We suggest that modulation of the competition between pathogen requirement and host cell defense might be an attractive, novel therapeutic approach against Toxoplasma infection and encourage the development of Rottlerin-based new therapeutic formulations.

  8. Are Quasar Jets Dominated by Poynting Flux?

    Energy Technology Data Exchange (ETDEWEB)

    Sikora, M

    2005-02-02

    The formation of relativistic astrophysical jets is presumably mediated by magnetic fields threading accretion disks and central, rapidly rotating objects. As it is accelerated by magnetic stresses, the jet's kinetic energy flux grows at the expense of its Poynting flux. However, it is unclear how efficient is the conversion from magnetic to kinetic energy and whether there are any observational signatures of this process. We address this issue in the context of jets in quasars. Using data from all spatial scales, we demonstrate that in these objects the conversion from Poynting-flux-dominated to matter-dominated jets is very likely to take place closer to the black hole than the region where most of the Doppler boosted radiation observed in blazars is produced. We briefly discuss the possibility that blazar activity can be induced by global MHD instabilities, e.g., via the production of localized velocity gradients that lead to dissipative events such as shocks or magnetic reconnection, where acceleration of relativistic particles and production of non-thermal flares is taking place.

  9. [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.

  10. 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.

  11. Permanent magnet flux-biased magnetic actuator with flux feedback

    Science.gov (United States)

    Groom, Nelson J. (Inventor)

    1991-01-01

    The invention is a permanent magnet flux-biased magnetic actuator with flux feedback for adjustably suspending an element on a single axis. The magnetic actuator includes a pair of opposing electromagnets and provides bi-directional forces along the single axis to the suspended element. Permanent magnets in flux feedback loops from the opposing electromagnets establish a reference permanent magnet flux-bias to linearize the force characteristics of the electromagnets to extend the linear range of the actuator without the need for continuous bias currents in the electromagnets.

  12. Reactor neutron flux measuring device

    International Nuclear Information System (INIS)

    Okutani, Yasushi; Hayakawa, Toshifumi.

    1994-01-01

    The present invention concerns a device for displaying an approximate neutron flux distribution to recognize the neutron flux distribution of the whole reactor in a short period of time. The device of the present invention displays, the results of measurement for neutron fluxes collected by a data collecting section on every results of the measurements at measuring points situating at horizontally identical positions of the reactor core. In addition, every results of the measurements at the measuring points situating at the identical height in the reactor core are accumulated, and the results of the integration are graphically displayed. With such procedures, the neutron flux distribution in the entire reactor is approximately displayed. Existent devices could not recognize the neutron flux distribution of the entire reactor at a glance and it took much time for the recognition. The device of the present invention can recognize the neutron flux distribution of the entire reactor in a short period of time. (I.S.)

  13. Flux compactifications and generalized geometries

    International Nuclear Information System (INIS)

    Grana, Mariana

    2006-01-01

    Following the lectures given at CERN Winter School 2006, we present a pedagogical overview of flux compactifications and generalized geometries, concentrating on closed string fluxes in type II theories. We start by reviewing the supersymmetric flux configurations with maximally symmetric four-dimensional spaces. We then discuss the no-go theorems (and their evasion) for compactifications with fluxes. We analyse the resulting four-dimensional effective theories for Calabi-Yau and Calabi-Yau orientifold compactifications, concentrating on the flux-induced superpotentials. We discuss the generic mechanism of moduli stabilization and illustrate with two examples: the conifold in IIB and a T 6 /(Z 3 x Z 3 ) torus in IIA. We finish by studying the effective action and flux vacua for generalized geometries in the context of generalized complex geometry

  14. California's Future Carbon Flux

    Science.gov (United States)

    Xu, L.; Pyles, R. D.; Paw U, K.; Gertz, M.

    2008-12-01

    The diversity of the climate and vegetation systems in the state of California provides a unique opportunity to study carton dioxide exchange between the terrestrial biosphere and the atmosphere. In order to accurately calculate the carbon flux, this study couples the sophisticated analytical surface layer model ACASA (Advance Canopy-Atmosphere-Soil Algorithm, developed in the University of California, Davis) with the newest version of mesoscale model WRF (the Weather Research & Forecasting Model, developed by NCAR and several other agencies). As a multilayer, steady state model, ACASA incorporates higher-order representations of vertical temperature variations, CO2 concentration, radiation, wind speed, turbulent statistics, and plant physiology. The WRF-ACASA coupling is designed to identify how multiple environmental factors, in particularly climate variability, population density, and vegetation distribution, impact on future carbon cycle prediction across a wide geographical range such as in California.

  15. LYM2-dependent chitin perception limits molecular flux via plasmodesmata

    Science.gov (United States)

    Faulkner, Christine; Petutschnig, Elena; Benitez-Alfonso, Yoselin; Beck, Martina; Robatzek, Silke; Lipka, Volker; Maule, Andrew J.

    2013-01-01

    Chitin acts as a pathogen-associated molecular pattern from fungal pathogens whose perception triggers a range of defense responses. We show that LYSIN MOTIF DOMAIN-CONTAINING GLYCOSYLPHOSPHATIDYLINOSITOL-ANCHORED PROTEIN 2 (LYM2), the Arabidopsis homolog of a rice chitin receptor-like protein, mediates a reduction in molecular flux via plasmodesmata in the presence of chitin. For this response, lym2-1 mutants are insensitive to the presence of chitin, but not to the flagellin derivative flg22. Surprisingly, the chitin-recognition receptor CHITIN ELCITOR RECEPTOR KINASE 1 (CERK1) is not required for chitin-induced changes to plasmodesmata flux, suggesting that there are at least two chitin-activated response pathways in Arabidopsis and that LYM2 is not required for CERK1-mediated chitin-triggered defense responses, indicating that these pathways are independent. In accordance with a role in the regulation of intercellular flux, LYM2 is resident at the plasma membrane and is enriched at plasmodesmata. Chitin-triggered regulation of molecular flux between cells is required for defense responses against the fungal pathogen Botrytis cinerea, and thus we conclude that the regulation of symplastic continuity and molecular flux between cells is a vital component of chitin-triggered immunity in Arabidopsis. PMID:23674687

  16. Neutron fluxes in test reactors

    Energy Technology Data Exchange (ETDEWEB)

    Youinou, Gilles Jean-Michel [Idaho National Lab. (INL), Idaho Falls, ID (United States)

    2017-01-01

    Communicate the fact that high-power water-cooled test reactors such as the Advanced Test Reactor (ATR), the High Flux Isotope Reactor (HFIR) or the Jules Horowitz Reactor (JHR) cannot provide fast flux levels as high as sodium-cooled fast test reactors. The memo first presents some basics physics considerations about neutron fluxes in test reactors and then uses ATR, HFIR and JHR as an illustration of the performance of modern high-power water-cooled test reactors.

  17. Data Acquisition and Flux Calculations

    DEFF Research Database (Denmark)

    Rebmann, C.; Kolle, O; Heinesch, B

    2012-01-01

    In this chapter, the basic theory and the procedures used to obtain turbulent fluxes of energy, mass, and momentum with the eddy covariance technique will be detailed. This includes a description of data acquisition, pretreatment of high-frequency data and flux calculation.......In this chapter, the basic theory and the procedures used to obtain turbulent fluxes of energy, mass, and momentum with the eddy covariance technique will be detailed. This includes a description of data acquisition, pretreatment of high-frequency data and flux calculation....

  18. Heat Flux Instrumentation Laboratory (HFIL)

    Data.gov (United States)

    Federal Laboratory Consortium — Description: The Heat Flux Instrumentation Laboratory is used to develop advanced, flexible, thin film gauge instrumentation for the Air Force Research Laboratory....

  19. KoFlux: Korean Regional Flux Network in AsiaFlux

    Science.gov (United States)

    Kim, J.

    2002-12-01

    AsiaFlux, the Asian arm of FLUXNET, held the Second International Workshop on Advanced Flux Network and Flux Evaluation in Jeju Island, Korea on 9-11 January 2002. In order to facilitate comprehensive Asia-wide studies of ecosystem fluxes, the meeting launched KoFlux, a new Korean regional network of long-term micrometeorological flux sites. For a successful assessment of carbon exchange between terrestrial ecosystems and the atmosphere, an accurate measurement of surface fluxes of energy and water is one of the prerequisites. During the 7th Global Energy and Water Cycle Experiment (GEWEX) Asian Monsoon Experiment (GAME) held in Nagoya, Japan on 1-2 October 2001, the Implementation Committee of the Coordinated Enhanced Observing Period (CEOP) was established. One of the immediate tasks of CEOP was and is to identify the reference sites to monitor energy and water fluxes over the Asian continent. Subsequently, to advance the regional and global network of these reference sites in the context of both FLUXNET and CEOP, the Korean flux community has re-organized the available resources to establish a new regional network, KoFlux. We have built up domestic network sites (equipped with wind profiler and radiosonde measurements) over deciduous and coniferous forests, urban and rural rice paddies and coastal farmland. As an outreach through collaborations with research groups in Japan, China and Thailand, we also proposed international flux sites at ecologically and climatologically important locations such as a prairie on the Tibetan plateau, tropical forest with mixed and rapid land use change in northern Thailand. Several sites in KoFlux already begun to accumulate interesting data and some highlights are presented at the meeting. The sciences generated by flux networks in other continents have proven the worthiness of a global array of micrometeorological flux towers. It is our intent that the launch of KoFlux would encourage other scientists to initiate and

  20. Mediatized Humanitarianism

    DEFF Research Database (Denmark)

    Vestergaard, Anne

    2014-01-01

    The article investigates the implications of mediatization for the legitimation strategies of humanitarian organizations. Based on a (full population) corpus of ~400 pages of brochure material from 1970 to 2007, the micro-textual processes involved in humanitarian organizations' efforts to legiti......The article investigates the implications of mediatization for the legitimation strategies of humanitarian organizations. Based on a (full population) corpus of ~400 pages of brochure material from 1970 to 2007, the micro-textual processes involved in humanitarian organizations' efforts...... legitimation by accountancy, legitimation by institutionalization, and legitimation by compensation. The analysis relates these changes to a problem of trust associated with mediatization through processes of mediation....

  1. CERT depletion predicts chemotherapy benefit and mediates cytotoxic and polyploid‐specific cancer cell death through autophagy induction

    DEFF Research Database (Denmark)

    Lee, Alvin J. X.; Roylance, Rebecca; Sander, Jil

    2012-01-01

    to the death of CIN cancer cells. Using an integrative functional genomics approach, we find that CERT‐specific multidrug sensitization is associated with enhanced autophagosome–lysosome flux, resulting from the expression of LAMP2 following CERT silencing in colorectal and HER2+ breast cancer cell lines. Live...... cell microscopy analysis revealed that CERT depletion induces LAMP2‐dependent death of polyploid cells following exit from mitosis in the presence of paclitaxel. We find that CERT is relatively over‐expressed in HER2+ breast cancer and CERT protein expression acts as an independent prognostic variable...... and predictor of outcome in adjuvant chemotherapy‐treated patients with primary breast cancer. These data suggest that the induction of LAMP2‐dependent autophagic flux through CERT targeting may provide a rational approach to enhance multidrug sensitization and potentiate the death of polyploid cells following...

  2. From elementary flux modes to elementary flux vectors: Metabolic pathway analysis with arbitrary linear flux constraints

    Science.gov (United States)

    Klamt, Steffen; Gerstl, Matthias P.; Jungreuthmayer, Christian; Mahadevan, Radhakrishnan; Müller, Stefan

    2017-01-01

    Elementary flux modes (EFMs) emerged as a formal concept to describe metabolic pathways and have become an established tool for constraint-based modeling and metabolic network analysis. EFMs are characteristic (support-minimal) vectors of the flux cone that contains all feasible steady-state flux vectors of a given metabolic network. EFMs account for (homogeneous) linear constraints arising from reaction irreversibilities and the assumption of steady state; however, other (inhomogeneous) linear constraints, such as minimal and maximal reaction rates frequently used by other constraint-based techniques (such as flux balance analysis [FBA]), cannot be directly integrated. These additional constraints further restrict the space of feasible flux vectors and turn the flux cone into a general flux polyhedron in which the concept of EFMs is not directly applicable anymore. For this reason, there has been a conceptual gap between EFM-based (pathway) analysis methods and linear optimization (FBA) techniques, as they operate on different geometric objects. One approach to overcome these limitations was proposed ten years ago and is based on the concept of elementary flux vectors (EFVs). Only recently has the community started to recognize the potential of EFVs for metabolic network analysis. In fact, EFVs exactly represent the conceptual development required to generalize the idea of EFMs from flux cones to flux polyhedra. This work aims to present a concise theoretical and practical introduction to EFVs that is accessible to a broad audience. We highlight the close relationship between EFMs and EFVs and demonstrate that almost all applications of EFMs (in flux cones) are possible for EFVs (in flux polyhedra) as well. In fact, certain properties can only be studied with EFVs. Thus, we conclude that EFVs provide a powerful and unifying framework for constraint-based modeling of metabolic networks. PMID:28406903

  3. Squeezing Flux Out of Fat

    DEFF Research Database (Denmark)

    Gonzalez-Franquesa, Alba; Patti, Mary-Elizabeth

    2018-01-01

    Merging transcriptomics or metabolomics data remains insufficient for metabolic flux estimation. Ramirez et al. integrate a genome-scale metabolic model with extracellular flux data to predict and validate metabolic differences between white and brown adipose tissue. This method allows both metab...

  4. Mitophagy confers resistance to siderophore-mediated killing by Pseudomonas aeruginosa.

    Science.gov (United States)

    Kirienko, Natalia V; Ausubel, Frederick M; Ruvkun, Gary

    2015-02-10

    In the arms race of bacterial pathogenesis, bacteria produce an array of toxins and virulence factors that disrupt core host processes. Hosts mitigate the ensuing damage by responding with immune countermeasures. The iron-binding siderophore pyoverdin is a key virulence mediator of the human pathogen Pseudomonas aeruginosa, but its pathogenic mechanism has not been established. Here we demonstrate that pyoverdin enters Caenorhabditis elegans and that it is sufficient to mediate host killing. Moreover, we show that iron chelation disrupts mitochondrial homeostasis and triggers mitophagy both in C. elegans and mammalian cells. Finally, we show that mitophagy provides protection both against the extracellular pathogen P. aeruginosa and to treatment with a xenobiotic chelator, phenanthroline, in C. elegans. Although autophagic machinery has been shown to target intracellular bacteria for degradation (a process known as xenophagy), our report establishes a role for authentic mitochondrial autophagy in the innate immune defense against P. aeruginosa.

  5. Complex Mediation

    DEFF Research Database (Denmark)

    Bødker, Susanne; Andersen, Peter Bøgh

    2005-01-01

    This article has its starting point in a large number of empirical findings regarding computer-mediated work. These empirical findings have challenged our understanding of the role of mediation in such work; on the one hand as an aspect of communication and cooperation at work and on the other hand...... as an aspect of human engagement with instruments of work. On the basis of previous work in activity-theoretical and semiotic human—computer interaction, we propose a model to encompass both of these aspects. In a dialogue with our empirical findings we move on to propose a number of types of mediation...... that have helped to enrich our understanding of mediated work and the design of computer mediation for such work....

  6. Principal Metabolic Flux Mode Analysis.

    Science.gov (United States)

    Bhadra, Sahely; Blomberg, Peter; Castillo, Sandra; Rousu, Juho; Wren, Jonathan

    2018-02-06

    In the analysis of metabolism, two distinct and complementary approaches are frequently used: Principal component analysis (PCA) and stoichiometric flux analysis. PCA is able to capture the main modes of variability in a set of experiments and does not make many prior assumptions about the data, but does not inherently take into account the flux mode structure of metabolism. Stoichiometric flux analysis methods, such as Flux Balance Analysis (FBA) and Elementary Mode Analysis, on the other hand, are able to capture the metabolic flux modes, however, they are primarily designed for the analysis of single samples at a time, and not best suited for exploratory analysis on a large sets of samples. We propose a new methodology for the analysis of metabolism, called Principal Metabolic Flux Mode Analysis (PMFA), which marries the PCA and stoichiometric flux analysis approaches in an elegant regularized optimization framework. In short, the method incorporates a variance maximization objective form PCA coupled with a stoichiometric regularizer, which penalizes projections that are far from any flux modes of the network. For interpretability, we also introduce a sparse variant of PMFA that favours flux modes that contain a small number of reactions. Our experiments demonstrate the versatility and capabilities of our methodology. The proposed method can be applied to genome-scale metabolic network in efficient way as PMFA does not enumerate elementary modes. In addition, the method is more robust on out-of-steady steady-state experimental data than competing flux mode analysis approaches. Matlab software for PMFA and SPMFA and data set used for experiments are available in https://github.com/aalto-ics-kepaco/PMFA. sahely@iitpkd.ac.in, juho.rousu@aalto.fi, Peter.Blomberg@vtt.fi, Sandra.Castillo@vtt.fi. Detailed results are in Supplementary files. Supplementary data are available at https://github.com/aalto-ics-kepaco/PMFA/blob/master/Results.zip.

  7. 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

  8. p53-Mediated Molecular Control of Autophagy in Tumor Cells

    Directory of Open Access Journals (Sweden)

    Maria Mrakovcic

    2018-03-01

    Full Text Available Autophagy is an indispensable mechanism of the eukaryotic cell, facilitating the removal and renewal of cellular components and thereby balancing the cell’s energy consumption and homeostasis. Deregulation of autophagy is now regarded as one of the characteristic key features contributing to the development of tumors. In recent years, the suppression of autophagy in combination with chemotherapeutic treatment has been approached as a novel therapy in cancer treatment. However, depending on the type of cancer and context, interference with the autophagic machinery can either promote or disrupt tumorigenesis. Therefore, disclosure of the major signaling pathways that regulate autophagy and control tumorigenesis is crucial. To date, several tumor suppressor proteins and oncogenes have emerged as eminent regulators of autophagy whose depletion or mutation favor tumor formation. The mammalian cell “janitor” p53 belongs to one of these tumor suppressors that are most commonly mutated in human tumors. Experimental evidence over the last decade convincingly reports that p53 can act as either an activator or an inhibitor of autophagy depending on its subcellular localization and its mode of action. This finding gains particular significance as p53 deficiency or mutant variants of p53 that accumulate in the cytoplasm of tumor cells enable activation of autophagy. Accordingly, we recently identified p53 as a molecular hub that regulates autophagy and apoptosis in histone deacetylase inhibitor-treated uterine sarcoma cells. In light of this novel experimental evidence, in this review, we focus on p53 signaling as a mediator of the autophagic pathway in tumor cells.

  9. Interpreting Flux from Broadband Photometry

    Science.gov (United States)

    Brown, Peter J.; Breeveld, Alice; Roming, Peter W. A.; Siegel, Michael

    2016-10-01

    We discuss the transformation of observed photometry into flux for the creation of spectral energy distributions (SED) and the computation of bolometric luminosities. We do this in the context of supernova studies, particularly as observed with the Swift spacecraft, but the concepts and techniques should be applicable to many other types of sources and wavelength regimes. Traditional methods of converting observed magnitudes to flux densities are not very accurate when applied to UV photometry. Common methods for extinction and the integration of pseudo-bolometric fluxes can also lead to inaccurate results. The sources of inaccuracy, though, also apply to other wavelengths. Because of the complicated nature of translating broadband photometry into monochromatic flux densities, comparison between observed photometry and a spectroscopic model is best done by forward modeling the spectrum into the count rates or magnitudes of the observations. We recommend that integrated flux measurements be made using a spectrum or SED which is consistent with the multi-band photometry rather than converting individual photometric measurements to flux densities, linearly interpolating between the points, and integrating. We also highlight some specific areas where the UV flux can be mischaracterized.

  10. 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.

  11. Complex Mediation

    DEFF Research Database (Denmark)

    Bødker, Susanne; Andersen, Peter Bøgh

    2005-01-01

    This article has its starting point in a large number of empirical findings regarding computer-mediated work. These empirical findings have challenged our understanding of the role of mediation in such work; on the one hand as an aspect of communication and cooperation at work and on the other hand...... as an aspect of human engagement with instruments of work. On the basis of previous work in activity-theoretical and semiotic human—computer interaction, we propose a model to encompass both of these aspects. In a dialogue with our empirical findings we move on to propose a number of types of mediation...

  12. Characterization of the hemocytes in Larvae of Protaetia brevitarsis seulensis: involvement of granulocyte-mediated phagocytosis.

    Directory of Open Access Journals (Sweden)

    Hyojung Kwon

    Full Text Available Hemocytes are key players in the immune response against pathogens in insects. However, the hemocyte types and their functions in the white-spotted flower chafers, Protaetia brevitarsis seulensis (Kolbe, are not known. In this study, we used various microscopes, molecular probes, and flow cytometric analyses to characterize the hemocytes in P. brevitarsis seulensis. The circulating hemocytes were classified based on their size, morphology, and dye-staining properties into six types, including granulocytes, plasmatocytes, oenocytoids, spherulocytes, prohemocytes, and adipohemocytes. The percentages of circulating hemocyte types were as follows: 13% granulocytes, 20% plasmatocytes, 1% oenocytoids, 5% spherulocytes, 17% prohemocytes, and 44% adipohemocytes. Next, we identified the professional phagocytes, granulocytes, which mediate encapsulation and phagocytosis of pathogens. The granulocytes were immunologically or morphologically activated and phagocytosed potentially hazardous substances in vivo. In addition, we showed that the phagocytosis by granulocytes is associated with autophagy, and that the activation of autophagy could be an efficient way to eliminate pathogens in this system. We also observed a high accumulation of autophagic vacuoles in activated granulocytes, which altered their shape and led to autophagic cell death. Finally, the granulocytes underwent mitotic division thus maintaining their number in vivo.

  13. Characterization of the hemocytes in Larvae of Protaetia brevitarsis seulensis: involvement of granulocyte-mediated phagocytosis.

    Science.gov (United States)

    Kwon, Hyojung; Bang, Kyeongrin; Cho, Saeyoull

    2014-01-01

    Hemocytes are key players in the immune response against pathogens in insects. However, the hemocyte types and their functions in the white-spotted flower chafers, Protaetia brevitarsis seulensis (Kolbe), are not known. In this study, we used various microscopes, molecular probes, and flow cytometric analyses to characterize the hemocytes in P. brevitarsis seulensis. The circulating hemocytes were classified based on their size, morphology, and dye-staining properties into six types, including granulocytes, plasmatocytes, oenocytoids, spherulocytes, prohemocytes, and adipohemocytes. The percentages of circulating hemocyte types were as follows: 13% granulocytes, 20% plasmatocytes, 1% oenocytoids, 5% spherulocytes, 17% prohemocytes, and 44% adipohemocytes. Next, we identified the professional phagocytes, granulocytes, which mediate encapsulation and phagocytosis of pathogens. The granulocytes were immunologically or morphologically activated and phagocytosed potentially hazardous substances in vivo. In addition, we showed that the phagocytosis by granulocytes is associated with autophagy, and that the activation of autophagy could be an efficient way to eliminate pathogens in this system. We also observed a high accumulation of autophagic vacuoles in activated granulocytes, which altered their shape and led to autophagic cell death. Finally, the granulocytes underwent mitotic division thus maintaining their number in vivo.

  14. Fluxes, hierarchies, and metastable vacua in supersymmetric field theories

    International Nuclear Information System (INIS)

    Bruemmer, F.

    2008-01-01

    This thesis concerns topics both in low-energy effective field theories from type IIB superstring flux compactifications and in four-dimensional, rigidly supersymmetric gauge theories. We introduce flux compactifications with so-called ''warped throat'' regions, which lead to large hierarchies of scales in the effective four-dimensional theory. The correspondence between a particular such throat and a five-dimensional Randall-Sundrum-like model is established. We shown how certain string-theoretic features of the compactification, such as moduli stabilization by fluxes or the presence of an unstabilized Kaehler modulus, are incorporated in the five-dimensional picture. The KKLT construction for metastable de Sitter vacua is reviewed, as well as some possible modifications involving spontaneous F-term supersymmetry breaking. For KKLT-like models with their hidden sector localized inside a throat, the mediation of supersymmetry breaking to the visible sector is investigated. We review the mechanism of mixed modulus-anomaly mediation, and show that there can be additional equally important gravity-mediated contributions. We finally turn to the ISS model of metastable dynamical supersymmetry breaking in four dimensions, and present a renormalizable extension which generates a large hierarchy naturally. We also recapitulate how the ISS model may be obtained from a type IIB superstring model. (orig.)

  15. Fluxes, hierarchies, and metastable vacua in supersymmetric field theories

    Energy Technology Data Exchange (ETDEWEB)

    Bruemmer, F.

    2008-02-06

    This thesis concerns topics both in low-energy effective field theories from type IIB superstring flux compactifications and in four-dimensional, rigidly supersymmetric gauge theories. We introduce flux compactifications with so-called ''warped throat'' regions, which lead to large hierarchies of scales in the effective four-dimensional theory. The correspondence between a particular such throat and a five-dimensional Randall-Sundrum-like model is established. We shown how certain string-theoretic features of the compactification, such as moduli stabilization by fluxes or the presence of an unstabilized Kaehler modulus, are incorporated in the five-dimensional picture. The KKLT construction for metastable de Sitter vacua is reviewed, as well as some possible modifications involving spontaneous F-term supersymmetry breaking. For KKLT-like models with their hidden sector localized inside a throat, the mediation of supersymmetry breaking to the visible sector is investigated. We review the mechanism of mixed modulus-anomaly mediation, and show that there can be additional equally important gravity-mediated contributions. We finally turn to the ISS model of metastable dynamical supersymmetry breaking in four dimensions, and present a renormalizable extension which generates a large hierarchy naturally. We also recapitulate how the ISS model may be obtained from a type IIB superstring model. (orig.)

  16. Penicillium antifungal protein (PAF) is involved in the apoptotic and autophagic processes of the producer Penicillium chrysogenum.

    Science.gov (United States)

    Kovács, Barbara; Hegedűs, Nikoletta; Bálint, Mihály; Szabó, Zsuzsa; Emri, Tamás; Kiss, Gréta; Antal, Miklós; Pócsi, István; Leiter, Eva

    2014-09-01

    PAF, which is produced by the filamentous fungus Pencicillium chrysogenum, is a small antifungal protein, triggering ROS-mediated apoptotic cell death in Aspergillus nidulans. In this work, we provide information on the function of PAF in the host P. chrysogenum considering that carbon-starving cultures of the Δpaf mutant strain showed significantly reduced apoptosis rates in comparison to the wild-type (wt) strain. Moreover, the addition of PAF to the Δpaf strain resulted in a twofold increase in the apoptosis rate. PAF was also involved in the regulation of the autophagy machinery of this fungus, since several Saccharomyces cerevisiae autophagy-related ortholog genes, e.g. those of atg7, atg22 and tipA, were repressed in the deletion strain. This phenomenon was accompanied by the absence of autophagosomes in the Δpaf strain, even in old hyphae.

  17. Sulforaphane enhances proteasomal and autophagic activities in mice and is a potential therapeutic reagent for Huntington's disease.

    Science.gov (United States)

    Liu, Yanying; Hettinger, Casey L; Zhang, Dong; Rezvani, Khosrow; Wang, Xuejun; Wang, Hongmin

    2014-05-01

    The ubiquitin proteasome system (UPS) is impaired in Huntington's disease, a devastating neurodegenerative disorder. Sulforaphane, a naturally occurring compound, has been shown to stimulate UPS activity in cell cultures. To test whether sulforaphane enhances UPS function in vivo, we treated UPS function reporter mice ubiquitously expressing the green fluorescence protein (GFP) fused to a constitutive degradation signal that promotes its rapid degradation in the conditions of a healthy UPS. The modified GFP is termed GFP UPS reporter (GFPu). We found that both GFPu and ubiquitinated protein levels were significantly reduced and the three peptidase activities of the proteasome were increased in the brain and peripheral tissues of the mice. Interestingly, sulforaphane treatment also enhanced autophagy activity in the brain and the liver. To further examine whether sulforaphane promotes mutant huntingtin (mHtt) degradation, we treated Huntington's disease cells with sulforaphane and found that sulforaphane not only enhanced mHtt degradation but also reduced mHtt cytotoxicity. Sulforaphane-mediated mHtt degradation was mainly through the UPS pathway as the presence of a proteasome inhibitor abolished this effect. Taken together, these data indicate that sulforaphane activates protein degradation machineries in both the brain and peripheral tissues and may be a therapeutic reagent for Huntington's disease and other intractable disorders. Accumulation of mutant huntingtin (mHtt) protein causes Huntington's disease (HD). Sulforaphane (SFN), a naturally occurring compound, increased proteasome and autophagy activities in vivo and enhanced mHtt turnover and cell survival in HD cell models. SFN-mediated mHtt degradation is mainly through the proteasome pathway. These data suggest that SFN can be a therapeutic reagent for treating HD and other intractable disorders. © 2014 International Society for Neurochemistry.

  18. Specification of ROP flux shape

    Energy Technology Data Exchange (ETDEWEB)

    Min, Byung Joo [Korea Atomic Energy Research Institute, Taejon (Korea, Republic of); Gray, A. [Atomic Energy of Canada Ltd., Chalk River, ON (Canada)

    1997-06-01

    The CANDU 9 480/SEU core uses 0.9% SEU (Slightly Enriched Uranium) fuel. The use f SEU fuel enables the reactor to increase the radial power form factor from 0.865, which is typical in current natural uranium CANDU reactors, to 0.97 in the nominal CANDU 9 480/SEU core. The difference is a 12% increase in reactor power. An additional 5% increase can be achieved due to a reduced refuelling ripple. The channel power limits were also increased by 3% for a total reactor power increase of 20%. This report describes the calculation of neutron flux distributions in the CANDU 9 480/SEU core under conditions specified by the C and I engineers. The RFSP code was used to calculate of neutron flux shapes for ROP analysis. Detailed flux values at numerous potential detector sites were calculated for each flux shape. (author). 6 tabs., 70 figs., 4 refs.

  19. Notes on neutron flux measurement

    International Nuclear Information System (INIS)

    Alcala Ruiz, F.

    1984-01-01

    The main purpose of this work is to get an useful guide to carry out topical neutron flux measurements. Although the foil activation technique is used in the majority of the cases, other techniques, such as those based on fission chambers and self-powered neutron detectors, are also shown. Special interest is given to the description and application of corrections on the measurement of relative and absolute induced activities by several types of detectors (scintillators, G-M and gas proportional counters). The thermal arid epithermal neutron fluxes, as determined in this work, are conventional or effective (West cots fluxes), which are extensively used by the reactor experimentalists; however, we also give some expressions where they are related to the integrated neutron fluxes, which are used in neutron calculations. (Author) 16 refs

  20. Conical electromagnetic radiation flux concentrator

    Science.gov (United States)

    Miller, E. R.

    1972-01-01

    Concentrator provides method of concentrating a beam of electromagnetic radiation into a smaller beam, presenting a higher flux density. Smaller beam may be made larger by sending radiation through the device in the reverse direction.

  1. High Flux Isotope Reactor (HFIR)

    Data.gov (United States)

    Federal Laboratory Consortium — The HFIR at Oak Ridge National Laboratory is a light-water cooled and moderated reactor that is the United States’ highest flux reactor-based neutron source. HFIR...

  2. 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.

  3. 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.

  4. 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

  5. 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.

  6. 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.

  7. Flux tubes at finite temperature

    Energy Technology Data Exchange (ETDEWEB)

    Cea, Paolo [INFN, Sezione di Bari,Via G. Amendola 173, I-70126 Bari (Italy); Dipartimento di Fisica dell’Università di Bari,Via G. Amendola 173, I-70126 Bari (Italy); Cosmai, Leonardo [INFN, Sezione di Bari,Via G. Amendola 173, I-70126 Bari (Italy); Cuteri, Francesca; Papa, Alessandro [Dipartimento di Fisica, Università della Calabria & INFN-Cosenza,Ponte Bucci, cubo 31C, I-87036 Rende (Cosenza) (Italy)

    2016-06-07

    The chromoelectric field generated by a static quark-antiquark pair, with its peculiar tube-like shape, can be nicely described, at zero temperature, within the dual superconductor scenario for the QCD confining vacuum. In this work we investigate, by lattice Monte Carlo simulations of the SU(3) pure gauge theory, the fate of chromoelectric flux tubes across the deconfinement transition. We find that, if the distance between the static sources is kept fixed at about 0.76 fm ≃1.6/√σ and the temperature is increased towards and above the deconfinement temperature T{sub c}, the amplitude of the field inside the flux tube gets smaller, while the shape of the flux tube does not vary appreciably across deconfinement. This scenario with flux-tube “evaporation” above T{sub c} has no correspondence in ordinary (type-II) superconductivity, where instead the transition to the phase with normal conductivity is characterized by a divergent fattening of flux tubes as the transition temperature is approached from below. We present also some evidence about the existence of flux-tube structures in the magnetic sector of the theory in the deconfined phase.

  8. Nobiletin attenuates adverse cardiac remodeling after acute myocardial infarction in rats via restoring autophagy flux.

    Science.gov (United States)

    Wu, Xiaoqian; Zheng, Dechong; Qin, Yuyan; Liu, Zumei; Zhang, Guiping; Zhu, Xiaoyan; Zeng, Lihuan; Liang, Zhenye

    2017-10-14

    Our previous study showed that autophagy flux was impaired with sustained heart ischemia, which exacerbated adverse cardiac remodeling after acute myocardial infarction (AMI). Here we investigated whether Nobiletin, a citrus polymethoxylated flavonoids, could restore the autophagy flux and improve cardiac prognosis after AMI. AMI was induced by ligating left anterior descending (LAD) coronary artery in rats. Nobiletin improved the post-infarct cardiac dysfunction significantly and attenuated adverse cardiac remodeling. Meanwhile, Nobiletin protected H9C2 cells against oxygen glucose deprivation (OGD) in vitro. The impaired autophagy flux due to ischemia was ameliorated after Nobiletin treatment by testing the autophagy substrate, LC3BⅡ and P62 protein level both in vivo and in vitro. GFP-mRFP-LC3 adenovirus transfection also supported that Nobiletin restored the impaired autophagy flux. Specifically, the autophagy flux inhibitor, chloroquine, but not 3 MA, alleviated Nobiletin-mediated protection against OGD. Notably, Nobiletin does not affect the activation of classical upstream autophagy signaling pathways. However, Nobiletin increased the lysosome acidation which also supported that Nobiletin accelerated autophagy flux. Taken together, our findings suggested that Nobiletin restored impaired autophagy flux and protected against acute myocardial infarction, suggesting a potential role of autophagy flux in Nobiletin-mediated myocardial protection. Copyright © 2017 Elsevier Inc. All rights reserved.

  9. Particle flux across the mid-European continental margin

    CERN Document Server

    Antia, A N; Peinert, R

    1999-01-01

    Results are presented from particle flux studies using sediment trap and current meter moorings along a transect at the European continental margin at 49 degrees N within the Ocean Margin Exchange (OMEX) project. Two moorings were placed, at the mid- and outer slope in water depths of 1500 and 3660 m, with traps at 600 and 1050 m and at 580, 1440 and 3220 m, respectively. Residual currents at the mid- slope follow the slope contour, whereas seasonal off-slope flow was registered at the outer slope. At 600 m on the slope fluxes are similar to those in the abyssal North Atlantic. The flux of all components (bulk dry weight, particulate organic and inorganic carbon, lithogenic matter and opal) increased with water depth. Highest fluxes were recorded at 1440 m at the outer slope, where off- slope residual currents mediate particle export. The injection of biogenic and lithogenic particles below the depth of winter mixing results in the export of particles from shallower waters. Calculated lateral fluxes of partic...

  10. Phosphorimaging detection and quantitation for isotopic ion flux assays.

    Science.gov (United States)

    Fitch, Richard W; Daly, John W

    2005-07-15

    A 96-well-microplate-based ion flux method utilizing readily available autoradiographic phosphorimaging detection is described. Nicotinic acetylcholine receptor-mediated (22)Na influx in four cultured cell lines provided satisfactory concentration-response data for epibatidine and several other nicotinic agonists. The data were consistent with data obtained using standard 6-well assays. Assays for nicotinic-receptor-mediated (86)Rb efflux produced data similar to data obtained with the (22)Na influx assay. However, assays for (45)Ca influx were not successful, although (45)Ca was readily detected and quantified. Voltage-gated sodium channel-mediated (22)Na influx in a neuroblastoma cell line allowed assay of the effects of such sodium channel activators as batrachotoxin and a pumiliotoxin B/scorpion venom combination. Phosphorimaging detection allows for reliable beta counting of up to 1,200 simultaneous samples with excellent sensitivity and is amenable for application to high-throughput screening.

  11. Mediatized play

    DEFF Research Database (Denmark)

    Johansen, Stine Liv

    Children’s play must nowadays be understood as a mediatized field in society and culture. Media – understood in a very broad sense - holds severe explanatory power in describing and understanding the practice of play, since play happens both with, through and inspired by media of different sorts....... In this presentation the case of ‘playing soccer’ will be outlined through its different mediated manifestations, including soccer games and programs on TV, computer games, magazines, books, YouTube videos and soccer trading cards....

  12. Mediating Business

    DEFF Research Database (Denmark)

    "Mediating Business" is a study of the expansion of business journalism. Building on evidence from Denmark, Finland, Norway and Sweden, "Mediating Business" is a comparative and multidisciplinary study of one of the major transformations of the mass media and the realm of business - nationally...... and globally. The book explores the history of key innovations and innovators in the business press. It analyzes changes in the discourse of business journalism associated with the growth in business news and the development of new ways of framing business issues and events. Finally, it examines...... the organizational implications of the increased media visibility of business and, in particular, the development of corporate governance and media relations....

  13. Upregulation of BAG3 with apoptotic and autophagic activities in maggot extract‑promoted rat skin wound healing.

    Science.gov (United States)

    Dong, Jian-Li; Dong, Hai-Cao; Yang, Liang; Qiu, Zhe-Wen; Liu, Jia; Li, Hong; Zhong, Li-Xia; Song, Xue; Zhang, Peng; Li, Pei-Nan; Zheng, Lian-Jie

    2018-03-01

    Maggot extract (ME) accelerates rat skin wound healing, however its effect on cell maintenance in wound tissues remains unclear. B‑cell lymphoma (Bcl) 2‑associated athanogene (BAG)3 inhibits apoptosis and promotes autophagy by associating with Bcl‑2 or Beclin 1. Bcl‑2, the downstream effector of signal transducer and activator of transcription 3 signaling, is enhanced in ME‑treated wound tissues, which may reinforce the Bcl‑2 anti‑apoptotic activity and/or cooperate with Beclin 1 to regulate autophagy during wound healing. The present study investigated expression levels of BAG3, Bcl‑2, Beclin 1 and light chain (LC)3 levels in rat skin wound tissues in the presence and absence of ME treatment. The results revealed frequent TUNEL‑negative cell death in the wound tissues in the early three days following injury, irrespective to ME treatment. TUNEL‑positive cells appeared in the wound tissues following 4 days of injury and 150 µg/ml ME efficiently reduced apoptotic rate and enhanced BAG3 and Bcl‑2 expression. Elevated Beclin 1 and LC3 levels and an increased LC3 II ratio were revealed in the ME‑treated tissues during the wound healing. The results of the present study demonstrate the anti‑apoptotic effects of BAG3 and Bcl‑2 in ME‑promoted wound healing. Beclin 1/LC3 mediated autophagy may be favorable in maintaining cell survival in the damaged tissues and ME‑upregulated BAG3 may enhance its activity.

  14. Physics of magnetic flux tubes

    CERN Document Server

    Ryutova, Margarita

    2015-01-01

    This book is the first account of the physics of magnetic flux tubes from their fundamental properties to collective phenomena in an ensembles of flux tubes. The physics of magnetic flux tubes is absolutely vital for understanding fundamental physical processes in the solar atmosphere shaped and governed by magnetic fields. High-resolution and high cadence observations from recent space and  ground-based instruments taken simultaneously at different heights and temperatures not only show the ubiquity of filamentary structure formation but also allow to study how various events are interconnected by system of magnetic flux tubes. The book covers both theory and observations. Theoretical models presented in analytical and phenomenological forms are tailored for practical applications. These are welded with state-of-the-art observations from early decisive ones to the most recent data that open a new phase-space for exploring the Sun and sun-like stars. Concept of magnetic flux tubes is central to various magn...

  15. Flux driven turbulence in tokamaks

    International Nuclear Information System (INIS)

    Garbet, X.; Ghendrih, P.; Ottaviani, M.; Sarazin, Y.; Beyer, P.; Benkadda, S.; Waltz, R.E.

    1999-01-01

    This work deals with tokamak plasma turbulence in the case where fluxes are fixed and profiles are allowed to fluctuate. These systems are intermittent. In particular, radially propagating fronts, are usually observed over a broad range of time and spatial scales. The existence of these fronts provide a way to understand the fast transport events sometimes observed in tokamaks. It is also shown that the confinement scaling law can still be of the gyroBohm type in spite of these large scale transport events. Some departure from the gyroBohm prediction is observed at low flux, i.e. when the gradients are close to the instability threshold. Finally, it is found that the diffusivity is not the same for a turbulence calculated at fixed flux than at fixed temperature gradient, with the same time averaged profile. (author)

  16. Looking for high neutron fluxes

    International Nuclear Information System (INIS)

    Lengeler, Herbert

    1994-01-01

    The neutron is a powerful and versatile probe of both the structure and dynamics of condensed matter. However unlike other techniques such as X-ray, electron or light scattering, its interaction with matter is rather weak. Historically neutron scattering has always been intensity limited and scientists are always looking for more intense sources. These come in two kinds - fission reactors and spallation sources (in which neutrons are released from a target bombardment by beams). Unfortunately the power density of high flux reactors is approaching a technical limit and it will be difficult to achieve a large increase of neutron fluxes above typical present values as represented for example by the high flux reactor at ILL, Grenoble

  17. DISCONNECTING OPEN SOLAR MAGNETIC FLUX

    International Nuclear Information System (INIS)

    DeForest, C. E.; Howard, T. A.; McComas, D. J.

    2012-01-01

    Disconnection of open magnetic flux by reconnection is required to balance the injection of open flux by coronal mass ejections and other eruptive events. Making use of recent advances in heliospheric background subtraction, we have imaged many abrupt disconnection events. These events produce dense plasma clouds whose distinctive shape can now be traced from the corona across the inner solar system via heliospheric imaging. The morphology of each initial event is characteristic of magnetic reconnection across a current sheet, and the newly disconnected flux takes the form of a 'U-'shaped loop that moves outward, accreting coronal and solar wind material. We analyzed one such event on 2008 December 18 as it formed and accelerated at 20 m s –2 to 320 km s –1 , thereafter expanding self-similarly until it exited our field of view 1.2 AU from the Sun. From acceleration and photometric mass estimates we derive the coronal magnetic field strength to be 8 μT, 6 R ☉ above the photosphere, and the entrained flux to be 1.6 × 10 11 Wb (1.6 × 10 19 Mx). We model the feature's propagation by balancing inferred magnetic tension force against accretion drag. This model is consistent with the feature's behavior and accepted solar wind parameters. By counting events over a 36 day window, we estimate a global event rate of 1 day –1 and a global solar minimum unsigned flux disconnection rate of 6 × 10 13 Wb yr –1 (6 × 10 21 Mx yr –1 ) by this mechanism. That rate corresponds to ∼ – 0.2 nT yr –1 change in the radial heliospheric field at 1 AU, indicating that the mechanism is important to the heliospheric flux balance.

  18. The gradiometer flux qubit without an external flux bias

    International Nuclear Information System (INIS)

    Wu, C E; Liu, Y; Chi, C C

    2006-01-01

    We analyse the potential of the gradiometer flux qubit (GFQ), which should be insensitive to flux noise because of the nature of the gradiometer structure. However, to enjoy the benefit of such a design, we must be careful in choosing the initial condition. In the fluxoid quantization condition the flux integer n, which is set to zero in the usual single-loop flux qubit analysis, plays an important role in the GFQ potential. We found that it is impossible to construct a double-well potential if we choose the wrong initial condition. For a qubit application, n must be a small odd integer and the best choice would be n = 1. We also provide a precise and efficient numerical method for calculating the energy spectrum of the arbitrary GFQ potential; this will become useful in designing the circuitry parameters. The state control and read-out schemes are also optimized to a situation where a minimum requirement for using electronics is possible, which reduces noise from instruments directly

  19. 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.

  20. 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.

  1. 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.

  2. 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.

  3. 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

  4. The flux database concerted action

    International Nuclear Information System (INIS)

    Mitchell, N.G.; Donnelly, C.E.

    1999-01-01

    This paper summarizes the background to the UIR action on the development of a flux database for radionuclide transfer in soil-plant systems. The action is discussed in terms of the objectives, the deliverables and the progress achieved so far by the flux database working group. The paper describes the background to the current initiative and outlines specific features of the database and supporting documentation. Particular emphasis is placed on the proforma used for data entry, on the database help file and on the approach adopted to indicate data quality. Refs. 3 (author)

  5. Coupling nitrogen-vacancy centers in diamond to superconducting flux qubits

    DEFF Research Database (Denmark)

    Marcos, D.; Wubs, Martijn; Taylor, J.M.

    2010-01-01

    We propose a method to achieve coherent coupling between nitrogen-vacancy (NV) centers in diamond and superconducting (SC) flux qubits. The resulting coupling can be used to create a coherent interaction between the spin states of distant NV centers mediated by the flux qubit. Furthermore, the ma......, the magnetic coupling can be used to achieve a coherent transfer of quantum information between the flux qubit and an ensemble of NV centers. This enables a long-term memory for a SC quantum processor and possibly an interface between SC qubits and light....

  6. Black branes in flux compactifications

    Energy Technology Data Exchange (ETDEWEB)

    Torroba, Gonzalo; Wang, Huajia

    2013-10-01

    We construct charged black branes in type IIA flux compactifications that are dual to (2 + 1)-dimensional field theories at finite density. The internal space is a general Calabi-Yau manifold with fluxes, with internal dimensions much smaller than the AdS radius. Gauge fields descend from the 3-form RR potential evaluated on harmonic forms of the Calabi-Yau, and Kaluza-Klein modes decouple. Black branes are described by a four-dimensional effective field theory that includes only a few light fields and is valid over a parametrically large range of scales. This effective theory determines the low energy dynamics, stability and thermodynamic properties. Tools from flux compactifications are also used to construct holographic CFTs with no relevant scalar operators, that can lead to symmetric phases of condensed matter systems stable to very low temperatures. The general formalism is illustrated with simple examples such as toroidal compactifications and manifolds with a single size modulus. We initiate the classification of holographic phases of matter described by flux compactifications, which include generalized Reissner-Nordstrom branes, nonsupersymmetric AdS2×R2 and hyperscaling violating solutions.

  7. High flux compact neutron generators

    International Nuclear Information System (INIS)

    Reijonen, J.; Lou, T.-P.; Tolmachoff, B.; Leung, K.-N.; Verbeke, J.; Vujic, J.

    2001-01-01

    Compact high flux neutron generators are developed at the Lawrence Berkeley National Laboratory. The neutron production is based on D-D or D-T reaction. The deuterium or tritium ions are produced from plasma using either a 2 MHz or 13.56 MHz radio frequency (RF) discharge. RF-discharge yields high fraction of atomic species in the beam which enables higher neutron output. In the first tube design, the ion beam is formed using a multiple hole accelerator column. The beam is accelerated to energy of 80 keV by means of a three-electrode extraction system. The ion beam then impinges on a titanium target where either the 2.4 MeV D-D or 14 MeV D-T neutrons are generated. The MCNP computation code has predicted a neutron flux of ∼10 11 n/s for the D-D reaction at beam intensity of 1.5 A at 150 kV. The neutron flux measurements of this tube design will be presented. Recently new compact high flux tubes are being developed which can be used for various applications. These tubes also utilize RF-discharge for plasma generation. The design of these tubes and the first measurements will be discussed in this presentation

  8. Temporal trends in N2O flux dynamics in a Danish wetland – effects of plant-mediated gas transport of N2O and O2 following changes in water level and soil mineral-N availability

    DEFF Research Database (Denmark)

    Jørgensen, Christian Juncher; Struwe, Sten; Elberling, Bo

    2012-01-01

    in subsurface N2O and O2 concentrations, water level (WL), light intensity as well as mineral-N availability. Weekly concentration profiles showed that seasonal variations in N2O concentrations were directly linked to the position of the WL and O2 availability at the capillary fringe above the WL. N2O flux...

  9. Flavour mixings in flux compactifications

    International Nuclear Information System (INIS)

    Buchmuller, Wilfried; Schweizer, Julian

    2017-01-01

    A multiplicity of quark-lepton families can naturally arise as zero-modes in flux compactifications. The flavour structure of quark and lepton mass matrices is then determined by the wave function profiles of the zero-modes. We consider a supersymmetric SO(10) x U(1) model in six dimensions compactified on the orbifold T 2 =Z 2 with Abelian magnetic flux. A bulk 16-plet charged under the U(1) provides the quark-lepton generations whereas two uncharged 10-plets yield two Higgs doublets. Bulk anomaly cancellation requires the presence of additional 16- and 10-plets. The corresponding zero-modes form vectorlike split multiplets that are needed to obtain a successful flavour phenomenology. We analyze the pattern of flavour mixings for the two heaviest families of the Standard Model and discuss possible generalizations to three and more generations.

  10. Flux through a Markov chain

    International Nuclear Information System (INIS)

    Floriani, Elena; Lima, Ricardo; Ourrad, Ouerdia; Spinelli, Lionel

    2016-01-01

    Highlights: • The flux through a Markov chain of a conserved quantity (mass) is studied. • Mass is supplied by an external source and ends in the absorbing states of the chain. • Meaningful for modeling open systems whose dynamics has a Markov property. • The analytical expression of mass distribution is given for a constant source. • The expression of mass distribution is given for periodic or random sources. - Abstract: In this paper we study the flux through a finite Markov chain of a quantity, that we will call mass, which moves through the states of the chain according to the Markov transition probabilities. Mass is supplied by an external source and accumulates in the absorbing states of the chain. We believe that studying how this conserved quantity evolves through the transient (non-absorbing) states of the chain could be useful for the modelization of open systems whose dynamics has a Markov property.

  11. Superconducting flux flow digital circuits

    International Nuclear Information System (INIS)

    Martens, J.S.; Zipperian, T.E.; Hietala, V.M.; Ginley, D.S.; Tigges, C.P.; Phillips, J.M.; Siegal, M.P.

    1993-01-01

    The authors have developed a family of digital logic circuits based on superconducting flux flow transistors that show high speed, reasonable signal levels, large fan-out, and large noise margins. The circuits are made from high-temperature superconductors (HTS) and have been shown to operate at over 90 K. NOR gates have been demonstrated with fan-outs of more than 5 and fully loaded switching times less than a fixture-limited 50 ps. Ring-oscillator data suggest inverter delay times of about 40ps when using a 3-μm linewidths. Simple flip-flops have also been demonstrated showing large noise margins, response times of less than 30 ps, and static power dissipation on the order of 30 nW. Among other uses, this logic family is appropriate as an interface between logic families such as single flux quantum and conventional semiconductor logic

  12. Surface fluxes in heterogeneous landscape

    Energy Technology Data Exchange (ETDEWEB)

    Bay Hasager, C.

    1997-01-01

    The surface fluxes in homogeneous landscapes are calculated by similarity scaling principles. The methodology is well establish. In heterogeneous landscapes with spatial changes in the micro scale range, i e from 100 m to 10 km, advective effects are significant. The present work focus on these effects in an agricultural countryside typical for the midlatitudes. Meteorological and satellite data from a highly heterogeneous landscape in the Rhine Valley, Germany was collected in the large-scale field experiment TRACT (Transport of pollutants over complex terrain) in 1992. Classified satellite images, Landsat TM and ERS SAR, are used as basis for roughness maps. The roughnesses were measured at meteorological masts in the various cover classes and assigned pixel by pixel to the images. The roughness maps are aggregated, i e spatially averaged, into so-called effective roughness lengths. This calculation is performed by a micro scale aggregation model. The model solves the linearized atmospheric flow equations by a numerical (Fast Fourier Transform) method. This model also calculate maps of friction velocity and momentum flux pixel wise in heterogeneous landscapes. It is indicated how the aggregation methodology can be used to calculate the heat fluxes based on the relevant satellite data i e temperature and soil moisture information. (au) 10 tabs., 49 ills., 223 refs.

  13. Neutron flux control systems validation

    International Nuclear Information System (INIS)

    Hascik, R.

    2003-01-01

    In nuclear installations main requirement is to obtain corresponding nuclear safety in all operation conditions. From the nuclear safety point of view is commissioning and start-up after reactor refuelling appropriate period for safety systems verification. In this paper, methodology, performance and results of neutron flux measurements systems validation is presented. Standard neutron flux measuring chains incorporated into the reactor protection and control system are used. Standard neutron flux measuring chain contains detector, preamplifier, wiring to data acquisition unit, data acquisition unit, wiring to display at control room and display at control room. During reactor outage only data acquisition unit and wiring and displaying at reactor control room is verified. It is impossible to verify detector, preamplifier and wiring to data acquisition recording unit during reactor refuelling according to low power. Adjustment and accurate functionality of these chains is confirmed by start-up rate (SUR) measurement during start-up tests after refuelling of the reactors. This measurement has direct impact to nuclear safety and increase operational nuclear safety level. Briefly description of each measuring system is given. Results are illustrated on measurements performed at Bohunice NPP during reactor start-up tests. Main failures and their elimination are described (Authors)

  14. Determination of Energy Fluxes Over Agricultural Surfaces

    Directory of Open Access Journals (Sweden)

    Josefina Argete

    1994-12-01

    Full Text Available An energy budget was conducted over two kinds if surfaces: grass and corn canopy. The net radiative flux and the soil heat flux were directly measured while the latent and sensible heat flux were calculated from the vertical profiles if wet and dry-bulb temperature and wind speed. The crop storage flux was also estimated. Using the gradient or aerodynamic equations, the calculated fluxes when compared to the measured fluxes in the context of an energy budget gave an SEE = 63 Wm-2 over grass and SEE = 81 Wm-2 over corn canopy. The calculated fluxes compared reasonably well with those obtained using the Penman equations.For an energy budget research with limited instrumentation, the aerodynamic method performed satisfactorily in estimating the daytime fluxes, when atmospheric conditions are fully convective, but failed when conditions were stably stratified as during nighttime.

  15. Numerical Simulations of a Flux Rope Ejection

    Indian Academy of Sciences (India)

    2016-01-27

    Jan 27, 2016 ... Coronal mass ejections (CMEs) are the most violent phenomena observed on the Sun. One of the most successful models to explain CMEs is the flux rope ejection model, where a magnetic flux rope is expelled from the solar corona after a long phase along which the flux rope stays in equilibrium while ...

  16. Surface fluxes over natural landscapes using scintillometry

    NARCIS (Netherlands)

    Meijninger, W.M.L.

    2003-01-01

    Motivated by the demand for reliable area-averaged fluxes associated with natural landscapes this thesis investigates a relative new measurement technique known as the scintillation method. For homogeneous areas the surface fluxes can be derived with reasonable accuracy. However, fluxes

  17. Models of Flux Tubes from Constrained Relaxation

    Indian Academy of Sciences (India)

    tribpo

    Equilibria corresponding to the energy extrema while conserving these invariants for parallel flows yield three classes of ... parallel heat flux, due to the boundary condition Β · n = 0, that the total energy, is conserved. In all HR, K, S, and the total mass, ... Zero net current flux tubes are qualitatively similar to the flux tube with ...

  18. Dual PI-3 kinase/mTOR inhibition impairs autophagy flux and induces cell death independent of apoptosis and necroptosis

    Science.gov (United States)

    Button, Robert W.; Vincent, Joseph H.; Strang, Conor J.; Luo, Shouqing

    2016-01-01

    The PI-3 kinase (PI-3K)/mTOR pathway is critical for cell growth and proliferation. Strategies of antagonising this signaling have proven to be detrimental to cell survival. This observation, coupled with the fact many tumours show enhanced growth signaling, has caused dual inhibitors of PI-3K and mTOR to be implicated in cancer treatment, and have thus been studied across various tumour models. Since PI-3K (class-I)/mTOR pathway negatively regulates autophagy, dual inhibitors of PI-3K/mTOR are currently believed to be autophagy activators. However, our present data show that the dual PI-3K/mTOR inhibition (DKI) potently suppresses autophagic flux. We further confirm that inhibition of Vps34/PI3KC3, the class-III PI-3K, causes the blockade to autophagosome-lysosome fusion. Our data suggest that DKI induces cell death independently of apoptosis and necroptosis, whereas autophagy perturbation by DKI may contribute to cell death. Given that autophagy is critical in cellular homeostasis, our study not only clarifies the role of a dual PI-3K/mTOR inhibitor in autophagy, but also suggests that its autophagy inhibition needs to be considered if such an agent is used in cancer chemotherapy. PMID:26814436

  19. Flux of Cadmium through Euphausiids

    International Nuclear Information System (INIS)

    Benayoun, G.; Fowler, S.W.; Oregioni, B.

    1976-01-01

    Flux of the heavy metal cadmium through the euphausiid Meganyctiphanes norvegica was examined. Radiotracer experiments showed that cadmium can be accumulated either directly from water or through the food chain. When comparing equilibrium cadmium concentration factors based on stable element measurements with those obtained from radiotracer experiments, it is evident that exchange between cadmium in the water and that in euphausiid tissue is a relatively slow process, indicating that, in the long term, ingestion of cadmium will probably be the more important route for the accumulation of this metal. Approximately 10% of cadmium ingested by euphausiids was incorporated into internal tissues when the food source was radioactive Artemia. After 1 month cadmium, accumulated directly from water, was found to be most concentrated in the viscera with lesser amounts in eyes, exoskeleton and muscle, respectively. Use of a simple model, based on the assumption that cadmium taken in by the organism must equal cadmium released plus that accumulated in tissue, allowed assessment of the relative importance of various metabolic parameters in controlling the cadmium flux through euphausiids. Fecal pellets, due to their relatively high rate of production and high cadmium content, accounted for 84% of the total cadmium flux through M. norvegica. Comparisons of stable cadmium concentrations in natural euphausiid food and the organism's resultant fecal pellets indicate that the cadmium concentration in ingested material was increased nearly 5-fold during its passage through the euphausiid. From comparisons of all routes by which cadmium can be released from M. norvegica to the water column, it is concluded that fecal pellet deposition represents the principal mechanism effecting the downward vertical transport of cadmium by this species. (author)

  20. Four-collector flux sensor

    International Nuclear Information System (INIS)

    Wiegand, W.J. Jr.; Bullis, R.H.; Mongeon, R.J.

    1980-01-01

    A flowmeter based on ion drift techniques was developed for measuring the rate of flow of a fluid through a given cross-section. Ion collectors are positioned on each side of an immediately adjacent to ion source. When air flows axially through the region in which ions are produced and appropriate electric fields are maintained between the collectors, an electric current flows to each collector due to the net motion of the ions. The electric currents and voltages and other parameters which define the flow are combined in an electric circuit so that the flux of the fluid can be determined. (DN)

  1. Erk regulation of pyruvate dehydrogenase flux through PDK4 modulates cell proliferation

    Science.gov (United States)

    Grassian, Alexandra R.; Metallo, Christian M.; Coloff, Jonathan L.; Stephanopoulos, Gregory; Brugge, Joan S.

    2011-01-01

    Loss of extracellular matrix (ECM) attachment leads to metabolic impairments that limit cellular energy production. Characterization of the metabolic alterations induced by ECM detachment revealed a dramatic decrease in uptake of glucose, glutamine, and pyruvate, and a consequent decrease in flux through glycolysis, the pentose phosphate pathway, and the tricarboxylic acid (TCA) cycle. However, flux through pyruvate dehydrogenase (PDH) is disproportionally decreased, concomitant with increased expression of the PDH inhibitory kinase, PDH kinase 4 (PDK4), and increased carbon secretion. Overexpression of ErbB2 maintains PDH flux by suppressing PDK4 expression in an Erk-dependent manner, and Erk signaling also regulates PDH flux in ECM-attached cells. Additionally, epidermal growth factor (EGF), a potent inducer of Erk, positively regulates PDH flux through decreased PDK4 expression. Furthermore, overexpression of PDK4 in ECM-detached cells suppresses the ErbB2-mediated rescue of ATP levels, and in attached cells, PDK4 overexpression decreases PDH flux, de novo lipogenesis, and cell proliferation. Mining of microarray data from human tumor data sets revealed that PDK4 mRNA is commonly down-regulated in tumors compared with their tissues of origin. These results identify a novel mechanism by which ECM attachment, growth factors, and oncogenes modulate the metabolic fate of glucose by controlling PDK4 expression and PDH flux to influence proliferation. PMID:21852536

  2. Tokamak disruption heat flux simulator

    International Nuclear Information System (INIS)

    Langhoff, M.; Hess, G.; Gahl, J.; Ingram, R.

    1990-01-01

    A coaxial plasma gun system, operating in the deflagration mode, has been built and fired at the University of New Mexico. This system, powered by a 100 kJ capacitor bank, was designed to give a variable pulse length of approximately 50-100 us. The gun is intended to deliver to a target an energy deposition density of 1 kJ per cm 2 via impact with a deuterium plasma possessing a highly directed energy. This system should simulate on the target, over an area of approximately 10 cm 2 , the heat flux of a tokamak plasma disruption on plasma facing components. Current diagnostics for the system are rather rudimentary but sufficient for determination of plasma pulse characteristics and energy transfer to target. Electrical measurements include bank voltage measured via resistive voltage dividers, and bank current measured via Rogowski coil. The shape of the plasma, its position relative to the target area, and the final impact area, is determined via open-shutter photography and the use of witness plates. Total energy deposited onto targets will be determined through simple calorimetry and careful target mass measurements. Preliminary results describing the ablation of carbon targets exposed to disruption like heat fluxes will be presented as well as a description of the experimental apparatus

  3. Neutron flux enhancement at LASREF

    International Nuclear Information System (INIS)

    Sommer, W.F.; Ferguson, P.D.; Wechsler, M.S.

    1991-01-01

    The accelerator at the Los Alamos Meson Physics Facility produces a 1-mA beam of protons at an energy of 800 MeV. Since 1985, the Los Alamos Spallation Radiation Effects Facility (LASREF) has made use of the neutron flux that is generated as the incident protons interact with the nuclei in targets and a copper beam stop. A variety of basic and applied experiments in radiation damage and radiation effects have been completed. Recent studies indicate that the flux at LASREF can be increased by at least a factor of ten from the present level of about 5 E+17 m -2 s -1 . This requires changing the beam-stop material from Cu to W and optimizing the geometry of the beam-target interaction region. These studies are motivated by the need for a large volume, high energy, and high intensity neutron source in the development of materials for advanced energy concepts such as fusion reactors. 18 refs., 7 figs., 2 tabs

  4. 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.

  5. 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

  6. Carbon dioxide, water vapour and energy fluxes over a semi ...

    Indian Academy of Sciences (India)

    42

    vapour fluxes in Mangrove ecosystems, Sundarbans (India). The above observations are. 57 .... with the help of PAR. 115 sensor. Soil heat flux plates were used for the measurement of soil heat flux. ..... where Rn is net radiation, G is the soil heat flux, H is sensible heat flux and LE is the latent. 233 heat flux. 234. We have ...

  7. Pyrolytic graphite gauge for measuring heat flux

    Science.gov (United States)

    Bunker, Robert C. (Inventor); Ewing, Mark E. (Inventor); Shipley, John L. (Inventor)

    2002-01-01

    A gauge for measuring heat flux, especially heat flux encountered in a high temperature environment, is provided. The gauge includes at least one thermocouple and an anisotropic pyrolytic graphite body that covers at least part of, and optionally encases the thermocouple. Heat flux is incident on the anisotropic pyrolytic graphite body by arranging the gauge so that the gauge surface on which convective and radiative fluxes are incident is perpendicular to the basal planes of the pyrolytic graphite. The conductivity of the pyrolytic graphite permits energy, transferred into the pyrolytic graphite body in the form of heat flux on the incident (or facing) surface, to be quickly distributed through the entire pyrolytic graphite body, resulting in small substantially instantaneous temperature gradients. Temperature changes to the body can thereby be measured by the thermocouple, and reduced to quantify the heat flux incident to the body.

  8. Local rectification of heat flux

    Science.gov (United States)

    Pons, M.; Cui, Y. Y.; Ruschhaupt, A.; Simón, M. A.; Muga, J. G.

    2017-09-01

    We present a chain-of-atoms model where heat is rectified, with different fluxes from the hot to the cold baths located at the chain boundaries when the temperature bias is reversed. The chain is homogeneous except for boundary effects and a local modification of the interactions at one site, the “impurity”. The rectification mechanism is due here to the localized impurity, the only asymmetrical element of the structure, apart from the externally imposed temperature bias, and does not rely on putting in contact different materials or other known mechanisms such as grading or long-range interactions. The effect survives if all interaction forces are linear except the ones for the impurity.

  9. Nuclear transmutation by flux compression

    International Nuclear Information System (INIS)

    Seifritz, W.

    2001-01-01

    A new idea for the transmutation of minor actinides, long (and even short) lived fission products is presented. It is based an the property of neutron flux compression in nuclear (fast and/or thermal) reactors possessing spatially non-stationary critical masses. An advantage factor for the burn-up fluence of the elements to be transmuted in the order of magnitude of 100 and more is obtainable compared with the classical way of transmutation. Three typical examples of such transmuters (a subcritical ringreactor with a rotating reflector, a sub-critical ring reactor with a rotating spallation source, the socalled ''pulsed energy amplifier'', and a fast burn-wave reactor) are presented and analysed with regard to this purpose. (orig.) [de

  10. Insects, infestations and nutrient fluxes

    Science.gov (United States)

    Michalzik, B.

    2012-04-01

    Forest ecosystems are characterized by a high temporal and spatial variability in the vertical transfer of energy and matter within the canopy and the soil compartment. The mechanisms and controlling factors behind canopy processes and system-internal transfer dynamics are imperfectly understood at the moment. Seasonal flux diversities and inhomogeneities in throughfall composition have been reported from coniferous and deciduous forests, and in most cases leaf leaching has been considered as principle driver for differences in the amount and quality of nutrients and organic compounds (Tukey and Morgan 1963). Since herbivorous insects and the processes they initiate received less attention in past times, ecologists now emphasize the need for linking biological processes occurring in different ecosystem strata to explain rates and variability of nutrient cycling (Bardgett et al. 1998, Wardle et al. 2004). Consequently, herbivore insects in the canopies of forests are increasingly identified to play an important role for the (re)cycling and availability of nutrients, or, more generally, for the functioning of ecosystems not only in outbreak situations but also at endemic (non-outbreak) density levels (Stadler et al. 2001, Hunter et al. 2003). Before, little attention was paid to insect herbivores when quantifying element and energy fluxes through ecosystems, although the numerous and different functions insects fulfill in ecosystems (e.g. as pollinators, herbivores or detritivores) were unanimously recognized (Schowalter 2000). Amongst the reasons for this restraint was the argument that the total biomass of insects tends to be relatively low compared to the biomass of trees or the pool of soil organic matter (Ohmart et al. 1983). A second argument which was put forward to justify the inferior role of insects in nutrient cycling were the supposed low defoliation losses between 5-10% of the annual leaf biomass, or net primary production, due to insect herbivory under

  11. Structure of Energetic Particle Mediated Shocks Revisited

    Energy Technology Data Exchange (ETDEWEB)

    Mostafavi, P.; Zank, G. P. [Department of Space Science, University of Alabama in Huntsville, Huntsville, AL 35899 (United States); Webb, G. M. [Center for Space Plasma and Aeronomic Research (CSPAR), University of Alabama in Huntsville, Huntsville, AL 35899 (United States)

    2017-05-20

    The structure of collisionless shock waves is often modified by the presence of energetic particles that are not equilibrated with the thermal plasma (such as pickup ions [PUIs] and solar energetic particles [SEPs]). This is relevant to the inner and outer heliosphere and the Very Local Interstellar Medium (VLISM), where observations of shock waves (e.g., in the inner heliosphere) show that both the magnetic field and thermal gas pressure are less than the energetic particle component pressures. Voyager 2 observations revealed that the heliospheric termination shock (HTS) is very broad and mediated by energetic particles. PUIs and SEPs contribute both a collisionless heat flux and a higher-order viscosity. We show that the incorporation of both effects can completely determine the structure of collisionless shocks mediated by energetic ions. Since the reduced form of the PUI-mediated plasma model is structurally identical to the classical cosmic ray two-fluid model, we note that the presence of viscosity, at least formally, eliminates the need for a gas sub-shock in the classical two-fluid model, including in that regime where three are possible. By considering parameters upstream of the HTS, we show that the thermal gas remains relatively cold and the shock is mediated by PUIs. We determine the structure of the weak interstellar shock observed by Voyager 1 . We consider the inclusion of the thermal heat flux and viscosity to address the most general form of an energetic particle-thermal plasma two-fluid model.

  12. Structure of Energetic Particle Mediated Shocks Revisited

    Science.gov (United States)

    Mostafavi, P.; Zank, G. P.; Webb, G. M.

    2017-05-01

    The structure of collisionless shock waves is often modified by the presence of energetic particles that are not equilibrated with the thermal plasma (such as pickup ions [PUIs] and solar energetic particles [SEPs]). This is relevant to the inner and outer heliosphere and the Very Local Interstellar Medium (VLISM), where observations of shock waves (e.g., in the inner heliosphere) show that both the magnetic field and thermal gas pressure are less than the energetic particle component pressures. Voyager 2 observations revealed that the heliospheric termination shock (HTS) is very broad and mediated by energetic particles. PUIs and SEPs contribute both a collisionless heat flux and a higher-order viscosity. We show that the incorporation of both effects can completely determine the structure of collisionless shocks mediated by energetic ions. Since the reduced form of the PUI-mediated plasma model is structurally identical to the classical cosmic ray two-fluid model, we note that the presence of viscosity, at least formally, eliminates the need for a gas sub-shock in the classical two-fluid model, including in that regime where three are possible. By considering parameters upstream of the HTS, we show that the thermal gas remains relatively cold and the shock is mediated by PUIs. We determine the structure of the weak interstellar shock observed by Voyager 1. We consider the inclusion of the thermal heat flux and viscosity to address the most general form of an energetic particle-thermal plasma two-fluid model.

  13. Heat Flux Inhibition by Whistlers: Experimental Confirmation

    International Nuclear Information System (INIS)

    Eichler, D.

    2002-01-01

    Heat flux in weakly magnetized collisionless plasma is, according to theoretical predictions, limited by whistler turbulence that is generated by heat flux instabilities near threshold. Observations of solar wind electrons by Gary and coworkers appear to confirm the limit on heat flux as being roughly the product of the magnetic energy density and the electron thermal velocity, in agreement with prediction (Pistinner and Eichler 1998)

  14. Dimensional reduction of a generalized flux problem

    International Nuclear Information System (INIS)

    Moroz, A.

    1992-01-01

    In this paper, a generalized flux problem with Abelian and non-Abelian fluxes is considered. In the Abelian case we shall show that the generalized flux problem for tight-binding models of noninteracting electrons on either 2n- or (2n + 1)-dimensional lattice can always be reduced to an n-dimensional hopping problem. A residual freedom in this reduction enables one to identify equivalence classes of hopping Hamiltonians which have the same spectrum. In the non-Abelian case, the reduction is not possible in general unless the flux tensor factorizes into an Abelian one times are element of the corresponding algebra

  15. Self-organization in magnetic flux ropes

    Science.gov (United States)

    Lukin, Vyacheslav S.

    2014-06-01

    This cross-disciplinary special issue on 'Self-organization in magnetic flux ropes' follows in the footsteps of another collection of manuscripts dedicated to the subject of magnetic flux ropes, a volume on 'Physics of magnetic flux ropes' published in the American Geophysical Union's Geophysical Monograph Series in 1990 [1]. Twenty-four years later, this special issue, composed of invited original contributions highlighting ongoing research on the physics of magnetic flux ropes in astrophysical, space and laboratory plasmas, can be considered an update on our state of understanding of this fundamental constituent of any magnetized plasma. Furthermore, by inviting contributions from research groups focused on the study of the origins and properties of magnetic flux ropes in a variety of different environments, we have attempted to underline both the diversity of and the commonalities among magnetic flux ropes throughout the solar system and, indeed, the universe. So, what is a magnetic flux rope? The answer will undoubtedly depend on whom you ask. A flux rope can be as narrow as a few Larmor radii and as wide as the Sun (see, e.g., the contributions by Heli Hietala et al and by Angelous Vourlidas). As described below by Ward Manchester IV et al , they can stretch from the Sun to the Earth in the form of interplanetary coronal mass ejections. Or, as in the Swarthmore Spheromak Experiment described by David Schaffner et al , they can fit into a meter-long laboratory device tended by college students. They can be helical and line-tied (see, e.g., Walter Gekelman et al or J Sears et al ), or toroidal and periodic (see, e.g., John O'Bryan et al or Philippa Browning et al ). They can form in the low plasma beta environment of the solar corona (Tibor Török et al ), the order unity beta plasmas of the solar wind (Stefan Eriksson et al ) and the plasma pressure dominated stellar convection zones (Nicholas Nelson and Mark Miesch). In this special issue, Setthivoine You

  16. Surface Flux Modeling for Air Quality Applications

    Directory of Open Access Journals (Sweden)

    Limei Ran

    2011-08-01

    Full Text Available For many gasses and aerosols, dry deposition is an important sink of atmospheric mass. Dry deposition fluxes are also important sources of pollutants to terrestrial and aquatic ecosystems. The surface fluxes of some gases, such as ammonia, mercury, and certain volatile organic compounds, can be upward into the air as well as downward to the surface and therefore should be modeled as bi-directional fluxes. Model parameterizations of dry deposition in air quality models have been represented by simple electrical resistance analogs for almost 30 years. Uncertainties in surface flux modeling in global to mesoscale models are being slowly reduced as more field measurements provide constraints on parameterizations. However, at the same time, more chemical species are being added to surface flux models as air quality models are expanded to include more complex chemistry and are being applied to a wider array of environmental issues. Since surface flux measurements of many of these chemicals are still lacking, resistances are usually parameterized using simple scaling by water or lipid solubility and reactivity. Advances in recent years have included bi-directional flux algorithms that require a shift from pre-computation of deposition velocities to fully integrated surface flux calculations within air quality models. Improved modeling of the stomatal component of chemical surface fluxes has resulted from improved evapotranspiration modeling in land surface models and closer integration between meteorology and air quality models. Satellite-derived land use characterization and vegetation products and indices are improving model representation of spatial and temporal variations in surface flux processes. This review describes the current state of chemical dry deposition modeling, recent progress in bi-directional flux modeling, synergistic model development research with field measurements, and coupling with meteorological land surface models.

  17. Sensorless Direct Flux Vector Control of Synchronous Reluctance Motors Including Standstill, MTPA and Flux Weakening

    OpenAIRE

    Yousefi-Talouki, Arzhang; Pescetto, Paolo; Pellegrino, Gian-Mario Luigi

    2017-01-01

    This paper proposes a sensorless direct flux vector control scheme for synchronous reluctance motor drives. Torque is controlled at constant switching frequency, via the closed loop regulation of the stator flux linkage vector and of the current component in quadrature with it, using the stator flux oriented reference frame. A hybrid flux and position observer combines back-electromotive force integration with pulsating voltage injection around zero speed. Around zero speed, the position obse...

  18. Estimation of Throughfall and Stemflow Bacterial Flux in a Subtropical Oak-Cedar Forest

    Science.gov (United States)

    Bittar, Thais B.; Pound, Preston; Whitetree, Ansley; Moore, L. Dean; Van Stan, John T.

    2018-02-01

    Transport pathways of microbes between ecosystem spheres (atmosphere, phyllosphere, and pedosphere) represent major fluxes in nutrient cycles and have the potential to affect microbially mediated biogeochemical processes. Novel data on bacterial fluxes from the phyllosphere to the pedosphere during rainfall via throughfall (rain dripping from/through the canopy) and stemflow (rain funneled down tree stems) are reported. Bacterial concentrations were quantified using flow cytometry and validated with quantitative polymerase chain reaction assays in rainfall samples from an oak-cedar forest in coastal Georgia (southeastern U.S.). Bacteria concentrations (cells mL-1) and storm-normalized fluxes (cells m-2 h-1, cells m-2 mm-1) were greater for cedar versus oak. Total bacterial flux was 1.5 × 1016 cells ha-1 yr-1. These previously unexamined bacterial fluxes are interpreted in the context of major elemental pools and fluxes in forests and could represent inoculum-level sources of bacteria (if alive), and organic matter and inorganic solute inputs (if lysed) to soils.

  19. Flux compactifications, gauge algebras and De Sitter

    NARCIS (Netherlands)

    Dibitetto, Giuseppe; Linares, Roman; Roest, Diederik

    2010-01-01

    The introduction of (non-)geometric fluxes allows for N = 1 moduli stabilisation in a De Sitter vacuum. The aim of this Letter is to assess to what extent this is true in N = 4 compactifications. First we identify the correct gauge algebra in terms of gauge and (non-)geometric fluxes. We then show

  20. Neutron flux measurement by mobile detectors

    International Nuclear Information System (INIS)

    Verchain, M.

    1987-01-01

    Various incore instrumentation systems and their technological evolution are first reviewed. Then, for 1300 MWe PWR nuclear power plant, temperature and neutron flux measurement are described. Mobile fission chambers, with their large measuring range and accurate location allow a good knowledge of the core. Other incore measures are possible because of flux detector thimble tubes inserted in the reactor core [fr

  1. Fast flux module detection using matroid theory.

    Science.gov (United States)

    Reimers, Arne C; Bruggeman, Frank J; Olivier, Brett G; Stougie, Leen

    2015-05-01

    Flux balance analysis (FBA) is one of the most often applied methods on genome-scale metabolic networks. Although FBA uniquely determines the optimal yield, the pathway that achieves this is usually not unique. The analysis of the optimal-yield flux space has been an open challenge. Flux variability analysis is only capturing some properties of the flux space, while elementary mode analysis is intractable due to the enormous number of elementary modes. However, it has been found by Kelk et al. (2012) that the space of optimal-yield fluxes decomposes into flux modules. These decompositions allow a much easier but still comprehensive analysis of the optimal-yield flux space. Using the mathematical definition of module introduced by Müller and Bockmayr (2013b), we discovered useful connections to matroid theory, through which efficient algorithms enable us to compute the decomposition into modules in a few seconds for genome-scale networks. Using that every module can be represented by one reaction that represents its function, in this article, we also present a method that uses this decomposition to visualize the interplay of modules. We expect the new method to replace flux variability analysis in the pipelines for metabolic networks.

  2. EL-2 reactor: Thermal neutron flux distribution

    International Nuclear Information System (INIS)

    Rousseau, A.; Genthon, J.P.

    1958-01-01

    The flux distribution of thermal neutrons in EL-2 reactor is studied. The reactor core and lattices are described as well as the experimental reactor facilities, in particular, the experimental channels and special facilities. The measurement shows that the thermal neutron flux increases in the central channel when enriched uranium is used in place of natural uranium. However the thermal neutron flux is not perturbed in the other reactor channels by the fuel modification. The macroscopic flux distribution is measured according the radial positioning of fuel rods. The longitudinal neutron flux distribution in a fuel rod is also measured and shows no difference between enriched and natural uranium fuel rods. In addition, measurements of the flux distribution have been effectuated for rods containing other material as steel or aluminium. The neutron flux distribution is also studied in all the experimental channels as well as in the thermal column. The determination of the distribution of the thermal neutron flux in all experimental facilities, the thermal column and the fuel channels has been made with a heavy water level of 1825 mm and is given for an operating power of 1000 kW. (M.P.)

  3. Increased heat fluxes near a forest edge

    NARCIS (Netherlands)

    Klaassen, W; van Breugel, PB; Moors, EJ; Nieveen, JP

    2002-01-01

    Observations of sensible and latent heat flux above forest downwind of a forest edge show these fluxes to be larger than the available energy over the forest. The enhancement averages to 56 W m(-2), or 16% of the net radiation, at fetches less than 400 m, equivalent to fetch to height ratios less

  4. Increased heat fluxes near a forest edge

    NARCIS (Netherlands)

    Klaassen, W.; Breugel, van P.B.; Moors, E.J.; Nieveen, J.P.

    2002-01-01

    Observations of sensible and latent heat flux above forest downwind of a forest edge show these fluxes to be larger than the available energy over the forest. The enhancement averages to 56 W mm2, or 16 f the net radiation, at fetches less than 400 m, equivalent to fetch to height ratios less than

  5. Initiation of CMEs by Magnetic Flux Emergence

    Indian Academy of Sciences (India)

    The initiation of solar Coronal Mass Ejections (CMEs) is studied in the framework of numerical magnetohydrodynamics (MHD). The initial CME model includes a magnetic flux rope in spherical, axisymmetric geometry. The initial configuration consists of a magnetic flux rope embedded in a gravitationally stratified solar ...

  6. Heat flux viscosity in collisional magnetized plasmas

    Energy Technology Data Exchange (ETDEWEB)

    Liu, C., E-mail: cliu@pppl.gov [Princeton University, Princeton, New Jersey 08544 (United States); Fox, W. [Princeton Plasma Physics Laboratory, Princeton, New Jersey 08543 (United States); Bhattacharjee, A. [Princeton University, Princeton, New Jersey 08544 (United States); Princeton Plasma Physics Laboratory, Princeton, New Jersey 08543 (United States)

    2015-05-15

    Momentum transport in collisional magnetized plasmas due to gradients in the heat flux, a “heat flux viscosity,” is demonstrated. Even though no net particle flux is associated with a heat flux, in a plasma there can still be momentum transport owing to the velocity dependence of the Coulomb collision frequency, analogous to the thermal force. This heat-flux viscosity may play an important role in numerous plasma environments, in particular, in strongly driven high-energy-density plasma, where strong heat flux can dominate over ordinary plasma flows. The heat flux viscosity can influence the dynamics of the magnetic field in plasmas through the generalized Ohm's law and may therefore play an important role as a dissipation mechanism allowing magnetic field line reconnection. The heat flux viscosity is calculated directly using the finite-difference method of Epperlein and Haines [Phys. Fluids 29, 1029 (1986)], which is shown to be more accurate than Braginskii's method [S. I. Braginskii, Rev. Plasma Phys. 1, 205 (1965)], and confirmed with one-dimensional collisional particle-in-cell simulations. The resulting transport coefficients are tabulated for ease of application.

  7. Anthropogenic heat flux estimation from space

    NARCIS (Netherlands)

    Chrysoulakis, Nektarios; Marconcini, Mattia; Gastellu-Etchegorry, Jean Philippe; Grimmond, C.S.B.; Feigenwinter, Christian; Lindberg, Fredrik; Frate, Del Fabio; Klostermann, Judith; Mitraka, Zina; Esch, Thomas; Landier, Lucas; Gabey, Andy; Parlow, Eberhard; Olofson, Frans

    2016-01-01

    H2020-Space project URBANFLUXES (URBan ANthrpogenic heat FLUX from Earth observation Satellites) investigates the potential of Copernicus Sentinels to retrieve anthropogenic heat flux, as a key component of the Urban Energy Budget (UEB). URBANFLUXES advances the current knowledge of the impacts

  8. ANthropogenic heat FLUX estimation from Space

    NARCIS (Netherlands)

    Chrysoulakis, Nektarios; Marconcini, Mattia; Gastellu-Etchegorry, Jean Philippe; Grimmong, C.S.B.; Feigenwinter, Christian; Lindberg, Fredrik; Frate, Del Fabio; Klostermann, Judith; Mi, Zina; Esch, Thomas; Landier, Lucas; Gabey, Andy; Parlow, Eberhard; Olofson, Frans

    2017-01-01

    The H2020-Space project URBANFLUXES (URBan ANthrpogenic heat FLUX from Earth observation Satellites) investigates the potential of Copernicus Sentinels to retrieve anthropogenic heat flux, as a key component of the Urban Energy Budget (UEB). URBANFLUXES advances the current knowledge of the

  9. Optical magnetic flux generation in superconductor

    Indian Academy of Sciences (India)

    Abstract. The generation of the magnetic flux quanta inside the superconductors is studied as a new effect to destroy ... Ultrafast phenomena; femtosecond laser; optical magnetic flux generation. PACS Nos 85.25. .... [8] M Tonouchi, M Tani, Z Wang, K Sakai, S Tomozawa, M Hangyo, Y Murakami and S. Nakashima, Jpn. J.

  10. Multi-circular flux motor

    Energy Technology Data Exchange (ETDEWEB)

    El-Kharashi, Eyhab Aly, E-mail: EyhabElkharahi@hotmail.com [Faculty of Engineering, Electrical Power and Machines Department, Ain Shams University, 1 El-Sarayat Street, Abdou Basha Square, Abbassia 11517, Cairo (Egypt)

    2011-11-15

    Highlights: {yields} The paper uses the multi-circular rotor in the switched reluctance motor to increase its output torque and its efficiency. {yields} Finite element is used to model the new SRM accurately. {yields} The Matlab/Simulink is used to dynamically model the new SRM. {yields} The paper compares the torque capability of the multi-circular rotor SRM. {yields} The new SRM produces approximately double the torque of its equivalent conventional SRM. - Abstract: The paper introduces a new type of electrical machines which has significantly high output torque. The toothed-rotor in the conventional electrical machine is replaced by a multi-circular rotor to increase the saliency and to shorten the flux loops consequently the output torque increases. The paper presents the design steps of this new type of electrical machine and also examines its performance. In addition, the paper compares the percentage increase in output torque from the proposed new electric machine to its equivalent conventional motor. Then the paper proceeds to discuss the relation between the switching on angle and the maximum speed, the torque ripples, and the efficiency.

  11. Crystal growth of emerald by flux method

    International Nuclear Information System (INIS)

    Inoue, Mikio; Narita, Eiichi; Okabe, Taijiro; Morishita, Toshihiko.

    1979-01-01

    Emerald crystals have been formed in two binary fluxes of Li 2 O-MoO 2 and Li 2 O-V 2 O 5 using the slow cooling method and the temperature gradient method under various conditions. In the flux of Li 2 O-MoO 3 carried out in the range of 2 -- 5 of molar ratios (MoO 3 /Li 2 O), emerald was crystallized in the temperature range from 750 to 950 0 C, and the suitable crystallization conditions were found to be the molar ratio of 3 -- 4 and the temperature about 900 0 C. In the flux of Li 2 O-V 2 O 5 carried out in the range of 1.7 -- 5 of molar ratios (V 2 O 5 /Li 2 O), emerald was crystallized in the temperature range from 900 to 1150 0 . The suitable crystals were obtained at the molar ratio of 3 and the temperature range of 1000 -- 1100 0 C. The crystallization temperature rised with an increase in the molar ratio of the both fluxes. The emeralds grown in two binary fluxes were transparent green, having the density of 2.68, the refractive index of 1.56, and the two distinct bands in the visible spectrum at 430 and 600nm. The emerald grown in Li 2 O-V 2 O 5 flux was more bluish green than that grown in Li 2 O-MoO 3 flux. The size of the spontaneously nucleated emerald grown in the former flux was larger than the latter, when crystallized by the slow cooling method. As for the solubility of beryl in the two fluxes, Li 2 O-V 2 O 5 flux was superior to Li 2 O-MoO 3 flux whose small solubility of SiO 2 caused an experimental problem to the temperature gradient method. The suitability of the two fluxes for the crystal growth of emerald by the flux method was discussed from the view point of various properties of above-mentioned two fluxes. (author)

  12. Heat Flux Distribution of Antarctica Unveiled

    Science.gov (United States)

    Martos, Yasmina M.; Catalán, Manuel; Jordan, Tom A.; Golynsky, Alexander; Golynsky, Dmitry; Eagles, Graeme; Vaughan, David G.

    2017-11-01

    Antarctica is the largest reservoir of ice on Earth. Understanding its ice sheet dynamics is crucial to unraveling past global climate change and making robust climatic and sea level predictions. Of the basic parameters that shape and control ice flow, the most poorly known is geothermal heat flux. Direct observations of heat flux are difficult to obtain in Antarctica, and until now continent-wide heat flux maps have only been derived from low-resolution satellite magnetic and seismological data. We present a high-resolution heat flux map and associated uncertainty derived from spectral analysis of the most advanced continental compilation of airborne magnetic data. Small-scale spatial variability and features consistent with known geology are better reproduced than in previous models, between 36% and 50%. Our high-resolution heat flux map and its uncertainty distribution provide an important new boundary condition to be used in studies on future subglacial hydrology, ice sheet dynamics, and sea level change.

  13. Flux Modulation in the Electrodynamic Loudspeaker

    DEFF Research Database (Denmark)

    Halvorsen, Morten; Tinggaard, Carsten; Agerkvist, Finn T.

    2015-01-01

    This paper discusses the effect of flux modulation in the electrodynamic loudspeaker with main focus on the effect on the force factor. A measurement setup to measure the AC flux modulation with static voice coil is explained and the measurements shows good consistency with FEA simulations....... Measurements of the generated AC flux modulation shows, that eddy currents are the main source to magnetic losses in form of phase lag and amplitude changes. Use of a copper cap shows a decrease in flux modulation amplitude at the expense of increased power losses. Finally, simulations show...... that there is a high dependency between the generated AC flux modulation from the voice coil and the AC force factor change....

  14. Spacecraft-produced neutron fluxes on Skylab

    Science.gov (United States)

    Quist, T. C.; Furst, M.; Burnett, D. S.; Baum, J. H.; Peacock, C. L., Jr.; Perry, D. G.

    1977-01-01

    Estimates of neutron fluxes in different energy ranges are reported for the Skylab spacecraft. Detectors composed of uranium, thorium, and bismuth foils with mica as a fission track recorder, as well as boron foils with cellulose acetate as an alpha-particle recorder, were deployed at different positions in the Orbital Workshop. It was found that the Skylab neutron flux was dominated by high energy (greater than 1 MeV) contributions and that there was no significant time variation in the fluxes. Firm upper limits of 7-15 neutrons/sq cm-sec, depending on the detector location in the spacecraft, were established for fluxes above 1 MeV. Below 1 MeV, the neutron fluxes were about an order of magnitude lower. The neutrons are interpreted as originating from the interactions of leakage protons from the radiation belt with the spacecraft.

  15. OpenFLUX: efficient modelling software for 13C-based metabolic flux analysis

    Directory of Open Access Journals (Sweden)

    Nielsen Lars K

    2009-05-01

    Full Text Available Abstract Background The quantitative analysis of metabolic fluxes, i.e., in vivo activities of intracellular enzymes and pathways, provides key information on biological systems in systems biology and metabolic engineering. It is based on a comprehensive approach combining (i tracer cultivation on 13C substrates, (ii 13C labelling analysis by mass spectrometry and (iii mathematical modelling for experimental design, data processing, flux calculation and statistics. Whereas the cultivation and the analytical part is fairly advanced, a lack of appropriate modelling software solutions for all modelling aspects in flux studies is limiting the application of metabolic flux analysis. Results We have developed OpenFLUX as a user friendly, yet flexible software application for small and large scale 13C metabolic flux analysis. The application is based on the new Elementary Metabolite Unit (EMU framework, significantly enhancing computation speed for flux calculation. From simple notation of metabolic reaction networks defined in a spreadsheet, the OpenFLUX parser automatically generates MATLAB-readable metabolite and isotopomer balances, thus strongly facilitating model creation. The model can be used to perform experimental design, parameter estimation and sensitivity analysis either using the built-in gradient-based search or Monte Carlo algorithms or in user-defined algorithms. Exemplified for a microbial flux study with 71 reactions, 8 free flux parameters and mass isotopomer distribution of 10 metabolites, OpenFLUX allowed to automatically compile the EMU-based model from an Excel file containing metabolic reactions and carbon transfer mechanisms, showing it's user-friendliness. It reliably reproduced the published data and optimum flux distributions for the network under study were found quickly ( Conclusion We have developed a fast, accurate application to perform steady-state 13C metabolic flux analysis. OpenFLUX will strongly facilitate and

  16. Soil nitrogen gas fluxes during woody legume encroachment: Does encroachment increase gaseous losses?

    Science.gov (United States)

    Soper, F.; Groffman, P. M.; Sparks, J. P.

    2014-12-01

    Expansion of nitrogen (N2)-fixing trees is a major driver of ecosystem N enrichment in semi-arid grasslands. During this process, fluxes of N trace gases from soils are likely mediated by interactions between changing soil N availability and primary abiotic biogeochemical drivers in arid systems, namely temperature and wetting/re-wetting dynamics. We investigated the effects of encroachment, season and rainfall dynamics on total reactive N flux (NO, NOy, NH3, N2O) in a sub-tropical, semi-arid Texan savanna encroached by N-fixing Prosopis glandulosa over two years. We compared unencroached upland grasslands and non-fixing woody clusters with continuous Prosopis cover over uplands, intermediate drainages, and playa lowlands. We also quantified denitrification potential of intact soil cores to determine whether N2 could contribute significantly to soil N flux. Substantial soil N enrichment in upland Prosopis groves did not elevate N fluxes above those in remnant grasslands, though lower (moister) landscape positions did exhibit higher total emissions. Along with temperature, soil-wetting dynamics explained the greatest portion of variation in emissions and interacted with vegetation type. Timing and quantity of most recent soil wetting and interval to previous wetting were significant predictors, highlighting the importance of dynamics not captured by soil moisture measurements alone. As with other arid systems, rainfall events after dry periods can stimulate pulse emissions of >400 ug NO-N m-2 h-1. At realistic soil O2 concentrations, N2 fluxes fell below the detection limit of the Nitrogen-Free Atmospheric Recirculation Method system (~11 ug N m-2 h-1). However, applying plausible N2O:N2 flux ratios likely constrains the flux to much lower levels under field conditions. We conclude that encroachment does not increase N fluxes from upland savannas, but that interactions with rainfall and landscape position are important determinants of total emissions.

  17. Activation of retinal glial (Müller cells by extracellular ATP induces pronounced increases in extracellular H+ flux.

    Directory of Open Access Journals (Sweden)

    Boriana K Tchernookova

    Full Text Available Small alterations in extracellular acidity are potentially important modulators of neuronal signaling within the vertebrate retina. Here we report a novel extracellular acidification mechanism mediated by glial cells in the retina. Using self-referencing H+-selective microelectrodes to measure extracellular H+ fluxes, we show that activation of retinal Müller (glial cells of the tiger salamander by micromolar concentrations of extracellular ATP induces a pronounced extracellular H+ flux independent of bicarbonate transport. ADP, UTP and the non-hydrolyzable analog ATPγs at micromolar concentrations were also potent stimulators of extracellular H+ fluxes, but adenosine was not. The extracellular H+ fluxes induced by ATP were mimicked by the P2Y1 agonist MRS 2365 and were significantly reduced by the P2 receptor blockers suramin and PPADS, suggesting activation of P2Y receptors. Bath-applied ATP induced an intracellular rise in calcium in Müller cells; both the calcium rise and the extracellular H+ fluxes were significantly attenuated when calcium re-loading into the endoplasmic reticulum was inhibited by thapsigargin and when the PLC-IP3 signaling pathway was disrupted with 2-APB and U73122. The anion transport inhibitor DIDS also markedly reduced the ATP-induced increase in H+ flux while SITS had no effect. ATP-induced H+ fluxes were also observed from Müller cells isolated from human, rat, monkey, skate and lamprey retinae, suggesting a highly evolutionarily conserved mechanism of potential general importance. Extracellular ATP also induced significant increases in extracellular H+ flux at the level of both the outer and inner plexiform layers in retinal slices of tiger salamander which was significantly reduced by suramin and PPADS. We suggest that the novel H+ flux mediated by ATP-activation of Müller cells and of other glia as well may be a key mechanism modulating neuronal signaling in the vertebrate retina and throughout the brain.

  18. Neutron flux enhancement in the NRAD reactor

    International Nuclear Information System (INIS)

    Weeks, A.A.; Heidel, C.C.; Imel, G.R.

    1988-01-01

    In 1987 a series of experiments were conducted at the NRAD reactor facility at Argonne National Laboratory - West (ANL-W) to investigate the possibility of increasing the thermal neutron content at the end of the reactor's east beam tube through the use of hydrogenous flux traps. It was desired to increase the thermal flux for a series of experiments to be performed in the east radiography cell, in which the enhanced flux was required in a relatively small volume. Hence, it was feasible to attempt to focus the cross section of the beam to a smaller area. Two flux traps were constructed from unborated polypropylene and tested to determine their effectiveness. Both traps were open to the entire cross-sectional area of the neutron beam (as it emerges from the wall and enters the beam room). The sides then converged such that at the end of the trap the beam would be 'focused' to a greater intensity. The differences in the two flux traps were primarily in length, and hence angle to the beam as the inlet and outlet cross-sectional areas were held constant. The experiments have contributed to the design of a flux trap in which a thermal flux of nearly 10 9 was obtained, with an enhancement of 6.61

  19. CO2 flux geothermometer for geothermal exploration

    Science.gov (United States)

    Harvey, M. C.; Rowland, J. V.; Chiodini, G.; Rissmann, C. F.; Bloomberg, S.; Fridriksson, T.; Oladottir, A. A.

    2017-09-01

    A new geothermometer (TCO2 Flux) is proposed based on soil diffuse CO2 flux and shallow temperature measurements made on areas of steam heated, thermally altered ground above active geothermal systems. This CO2 flux geothermometer is based on a previously reported CO2 geothermometer that was designed for use with fumarole analysis. The new geothermometer provides a valuable additional exploration tool for estimating subsurface temperatures in high-temperature geothermal systems. Mean TCO2 Flux estimates fall within the range of deep drill hole temperatures at Wairakei (New Zealand), Tauhara (New Zealand), Rotokawa (New Zealand), Ohaaki (New Zealand), Reykjanes (Iceland) and Copahue (Argentina). The spatial distribution of geothermometry estimates is consistent with the location of major upflow zones previously reported at the Wairakei and Rotokawa geothermal systems. TCO2 Flux was also evaluated at White Island (New Zealand) and Reporoa (New Zealand), where limited sub-surface data exists. Mode TCO2 Flux at White Island is high (320 °C), the highest of the systems considered in this study. However, the geothermometer relies on mineral-water equilibrium in neutral pH reservoir fluids, and would not be reliable in such an active and acidic environment. Mean TCO2 Flux at Reporoa (310 °C) is high, which indicates Reporoa has a separate upflow from the nearby Waiotapu geothermal system; an outflow from Waiotapu would not be expected to have such high temperature.

  20. Poynting flux dominated jets challenged by their photospheric emission

    Energy Technology Data Exchange (ETDEWEB)

    Bégué, Damien [The Oskar Klein Centre for Cosmoparticle Physics, AlbaNova, SE-106 91 Stockholm (Sweden); Department of Physics, KTH Royal Institute of Technology, AlbaNova, University Center, SE-106 91 Stockholm (Sweden)

    2015-12-17

    One of the key open question for gamma-ray bursts (GRBs) jets, is the magnetization of the outflow. Here we consider the photospheric emission of Poynting flux dominated outflows, when the dynamics is mediated by magnetic reconnection. We show that thermal three-particle processes, responsible for the thermalization of the plasma, become inefficient far below the photosphere. Conservation of the total photon number above this radius, combined with Compton scattering below the photosphere enforces kinetic equilibrium between electrons and photons. This, in turn, leads to an increase in the observed photon temperature, which reaches ≳ 8 MeV (observed energy) when decoupling the plasma at the photosphere. This result is weakly dependent on the free model parameters. The predicted peak energy is more than an order of magnitude higher than the observed peak energy of most GRBs, which puts strong constraints on the magnetization of these outflows.

  1. Eddy Correlation Flux Measurement System (ECOR) Handbook

    Energy Technology Data Exchange (ETDEWEB)

    Cook, DR

    2011-01-31

    The eddy correlation (ECOR) flux measurement system provides in situ, half-hour measurements of the surface turbulent fluxes of momentum, sensible heat, latent heat, and carbon dioxide (CO2) (and methane at one Southern Great Plains extended facility (SGP EF) and the North Slope of Alaska Central Facility (NSA CF). The fluxes are obtained with the eddy covariance technique, which involves correlation of the vertical wind component with the horizontal wind component, the air temperature, the water vapor density, and the CO2 concentration.

  2. Magnetic refrigeration using flux compression in superconductors

    International Nuclear Information System (INIS)

    Israelsson, U.E.; Strayer, D.M.; Jackson, H.W.; Petrac, D.

    1990-01-01

    The feasibility of using flux compression in high-temperature superconductors to produce the large time-varying magnetic fields required in a field cycled magnetic refrigerator operating between 20 K and 4 K is presently investigated. This paper describes the refrigerator concept and lists limitations and advantages in comparison with conventional refrigeration techniques. The maximum fields obtainable by flux compression in high-temperature superconductor materials, as presently prepared, are too low to serve in such a refrigerator. However, reports exist of critical current values that are near usable levels for flux pumps in refrigerator applications. 9 refs

  3. Evolution of magnetic flux ropes associated with flux transfer events and interplanetary magnetic clouds

    International Nuclear Information System (INIS)

    Wei, C.Q.; Lee, L.C.; Wang, S.; Akasofu, S.I.

    1991-01-01

    Spacecraft observations suggest that flux transfer events and interplanetary magnetic clouds may be associated with magnetic flux ropes which are magnetic flux tubes containing helical magnetic field lines. In the magnetic flux ropes, the azimuthal magnetic field (B θ ) is superposed on the axial field (B z ). In this paper the time evolution of a localized magnetic flux rope is studied. A two-dimensional compressible magnetohydrodynamic simulation code with a cylindrical symmetry is developed to study the wave modes associated with the evolution of flux ropes. It is found that in the initial phase both the fast magnetosonic wave and the Alfven wave are developed in the flux rope. After this initial phase, the Alfven wave becomes the dominant wave mode for the evolution of the magnetic flux rope and the radial expansion velocity of the flux rope is found to be negligible. Numerical results further show that even for a large initial azimuthal component of the magnetic field (B θ ≅ 1-4 B z ) the propagation velocity along the axial direction of the flux rope remains to be the Alfven velocity. Diagnoses show that after the initial phase the transverse kinetic energy equals the transverse magnetic energy, which is characteristic of the Alfven mode. It is also found that the localized magnetic flux rope tends to evolve into two separate magnetic ropes propagating in opposite directions. The simulation results are used to study the evolution of magnetic flux ropes associated with flux transfer events observed at the Earth's dayside magnetopause and magnetic clouds in the interplanetary space

  4. Accuracy of surface heat fluxes from observations of operational satellites

    Digital Repository Service at National Institute of Oceanography (India)

    Pankajakshan, T.; Sugimori, Y.

    Uncertainties in the flux estimates, resulting from the use of bulk method and remotely sensed data are worked out and are presented for individual and total fluxes. These uncertainties in satellite derived fluxes are further compared...

  5. Nordic Mediation Reseach

    DEFF Research Database (Denmark)

    A presentation of 12 studies on mediation from researchers from Denmark, Finland, Norway and Sweden.......A presentation of 12 studies on mediation from researchers from Denmark, Finland, Norway and Sweden....

  6. Tetrakis-amido high flux membranes

    Science.gov (United States)

    McCray, S.B.

    1989-10-24

    Composite RO membranes of a microporous polymeric support and a polyamide reaction product of a tetrakis-aminomethyl compound and a polyacylhalide are disclosed, said membranes exhibiting high flux and good chlorine resistance.

  7. 400 Area/Fast Flux Test Facility

    Data.gov (United States)

    Federal Laboratory Consortium — The 400 Area at Hanford is home primarily to the Fast Flux Test Facility (FFTF), a DOE-owned, formerly operating, 400-megawatt (thermal) liquid-metal (sodium)-cooled...

  8. Pulse power applications of flux compression generators

    International Nuclear Information System (INIS)

    Fowler, C.M.; Caird, R.S.; Erickson, D.J.; Freeman, B.L.

    1981-01-01

    Characteristics are presented for two different types of explosive driven flux compression generators and a megavolt pulse transformer. Status reports are given for rail gun and plasma focus programs for which the generators serve as power sources

  9. Rotating flux compressor for energy conversion

    International Nuclear Information System (INIS)

    Chowdhuri, P.; Linton, T.W.; Phillips, J.A.

    1983-01-01

    The rotating flux compressor (RFC) converts rotational kinetic energy into an electrical output pulse which would have higher energy than the electrical energy initially stored in the compressor. An RFC has been designed in which wedge-shaped rotor blades pass through the air gaps between successive turns of a solenoid, the stator. Magnetic flux is generated by pulsing the stator solenoids when the inductance is a maximum, i.e., when the flux fills the stator-solenoid volume. Connecting the solenoid across a load conserves the flux which is compressed within the small volume surrounding the stator periphery when the rotor blades cut into the free space between the stator plates, creating a minimum-inductance condition. The unique features of this design are: (1) no electrical connections (brushes) to the rotor; (2) no conventional windings; and (3) no maintenance. The device has been tested up to 5000 rpm of rotor speed

  10. Modelling drug flux through microporated skin.

    Science.gov (United States)

    Rzhevskiy, Alexey S; Guy, Richard H; Anissimov, Yuri G

    2016-11-10

    A simple mathematical equation has been developed to predict drug flux through microporated skin. The theoretical model is based on an approach applied previously to water evaporation through leaf stomata. Pore density, pore radius and drug molecular weight are key model parameters. The predictions of the model were compared with results derived from a simple, intuitive method using porated area alone to estimate the flux enhancement. It is shown that the new approach predicts significantly higher fluxes than the intuitive analysis, with transport being proportional to the total pore perimeter rather than area as intuitively anticipated. Predicted fluxes were in good general agreement with experimental data on drug delivery from the literature, and were quantitatively closer to the measured values than those derived from the intuitive, area-based approach. Copyright © 2016 Elsevier B.V. All rights reserved.

  11. Flux Tube Dynamics in the Dual Superconductor

    International Nuclear Information System (INIS)

    Lampert, M.; Svetitsky, B.

    1999-01-01

    We have studied plasma oscillations in a flux tube created in a dual superconductor. The theory contains an Abelian gauge field coupled magnetically to a Higgs field that confines electric charge via the dual Meissner effect. Starting from a static flux tube configuration, with electric charges at either end, we release a fluid of electric charges in the system that accelerate and screen the electric field. The weakening of the electric field allows the flux tube to collapse, and the inertia of the charges forces it open again. We investigate both Type I and Type II superconductors, with plasma frequencies both above and below the threshold for radiation into the Higgs vacuum. (The parameters appropriate to QCD are in the Type II regime; the plasma frequency depends on the mass taken for the fluid constituents.) The coupling of the plasma oscillations to the Higgs field making up the flux tube is the main new feature in our work

  12. CO2 fluxes near a forest edge

    DEFF Research Database (Denmark)

    Sogachev, Andrey; Leclerc, Monique Y.; Zhang, Gensheng

    2008-01-01

    the concentration and flux fields against those of a uniform forested surface. We use an atmospheric boundary layer two-equation closure model that accounts for the flow dynamics and vertical divergence of CO2 sources/sinks within a plant canopy. This paper characterizes the spatial variation of CO2 fluxes...... as a function of both sources/sinks distribution and the vertical structure of the canopy. Results suggest that the ground source plays a major role in the formation of wave-like vertical CO2 flux behavior downwind of a forest edge, despite the fact that the contribution of foliage sources/sinks changes...... monotonously. Such a variation is caused by scalar advection in the trunk space and reveals itself as a decrease or increase in vertical fluxes over the forest relative to carbon dioxide exchange of the underlying forest. The effect was more pronounced in model forests where the leaf area is concentrated...

  13. Magnetic flux generator for balanced membrane loudspeaker

    DEFF Research Database (Denmark)

    Rehder, Jörg; Rombach, Pirmin; Hansen, Ole

    2002-01-01

    This paper reports the development of a magnetic flux generator with an application in a hearing aid loudspeaker produced in microsystem technology (MST). The technology plans for two different designs for the magnetic flux generator utilizing a softmagnetic substrate or electroplated NiCoFe as c......CoFe as core material are presented and the production and characterization of four different mono- and double-layer planar coil types are reported....

  14. Stochastic flux analysis of chemical reaction networks.

    Science.gov (United States)

    Kahramanoğulları, Ozan; Lynch, James F

    2013-12-07

    Chemical reaction networks provide an abstraction scheme for a broad range of models in biology and ecology. The two common means for simulating these networks are the deterministic and the stochastic approaches. The traditional deterministic approach, based on differential equations, enjoys a rich set of analysis techniques, including a treatment of reaction fluxes. However, the discrete stochastic simulations, which provide advantages in some cases, lack a quantitative treatment of network fluxes. We describe a method for flux analysis of chemical reaction networks, where flux is given by the flow of species between reactions in stochastic simulations of the network. Extending discrete event simulation algorithms, our method constructs several data structures, and thereby reveals a variety of statistics about resource creation and consumption during the simulation. We use these structures to quantify the causal interdependence and relative importance of the reactions at arbitrary time intervals with respect to the network fluxes. This allows us to construct reduced networks that have the same flux-behavior, and compare these networks, also with respect to their time series. We demonstrate our approach on an extended example based on a published ODE model of the same network, that is, Rho GTP-binding proteins, and on other models from biology and ecology. We provide a fully stochastic treatment of flux analysis. As in deterministic analysis, our method delivers the network behavior in terms of species transformations. Moreover, our stochastic analysis can be applied, not only at steady state, but at arbitrary time intervals, and used to identify the flow of specific species between specific reactions. Our cases study of Rho GTP-binding proteins reveals the role played by the cyclic reverse fluxes in tuning the behavior of this network.

  15. Determination flux in the Reactor JEN-1

    International Nuclear Information System (INIS)

    Manas Diaz, L.; Montes Ponce de leon, J.

    1960-01-01

    This report summarized several irradiations that have been made to determine the neutron flux distributions in the core of the JEN-1 reactor. Gold foils of 380 μ gr and Mn-Ni (12% de Ni) of 30 mg have been employed. the epithermal flux has been determined by mean of the Cd radio. The resonance integral values given by Macklin and Pomerance have been used. (Author) 9 refs

  16. Flux at a point in MCNP

    International Nuclear Information System (INIS)

    Cashwell, E.D.; Schrandt, R.G.

    1980-01-01

    The current state of the art of calculating flux at a point with MCNP is discussed. Various techniques are touched upon, but the main emphasis is on the fast improved version of the once-more-collided flux estimator, which has been modified to treat neutrons thermalized by the free gas model. The method is tested on several problems on interest and the results are presented

  17. Controlling fluxes for microbial metabolic engineering

    OpenAIRE

    Sachdeva, Gairik

    2014-01-01

    This thesis presents novel synthetic biology tools and design principles usable for microbial metabolic engineering. Controlling metabolic fluxes is essential for biological manufacturing of fuels, materials, and high value chemicals. Insulating the flow of metabolites is a successful natural strategy for metabolic flux regulation. Recently, approaches using scaffolds, both in vitro and in vivo, to spatially co-localize enzymes have reported significant gains in product yields. RNA is suitabl...

  18. Mold Flux Crystallization and Mold Thermal Behavior

    Science.gov (United States)

    Peterson, Elizabeth Irene

    Mold flux plays a small but critical role in the continuous casting of steel. The carbon-coated powder is added at the top of the water-cooled copper mold, over time it melts and infiltrates the gap between the copper mold and the solidifying steel strand. Mold powders serve five primary functions: (1) chemical insulation, (2) thermal insulation, (3) lubrication between the steel strand and mold, (4) absorption of inclusions, and (5) promotion of even heat flux. All five functions are critical to slab casting, but surface defect prevention is primarily controlled through even heat flux. Glassy fluxes have high heat transfer and result in a thicker steel shell. Steels with large volumetric shrinkage on cooling must have a crystalline flux to reduce the radiative heat transfer and avoid the formation of cracks in the shell. Crystallinity plays a critical role in steel shell formation, therefore it is important to study the thermal conditions that promote each phase and its morphology. Laboratory tests were performed to generate continuous cooling transformation (CCT) and time-temperature-transformation (TTT) diagrams. Continuous cooling transformation tests were performed in an instrumented eight cell step chill mold. Results showed that cuspidine was the only phase formed in conventional fluxes and all observed structures were dendritic. An isothermal tin bath quench method was also developed to isothermally age glassy samples. Isothermal tests yielded different microstructures and different phases than those observed by continuous cooling. Comparison of aged tests with industrial flux films indicates similar faceted structures along the mold wall, suggesting that mold flux first solidifies as a glass along the mold wall, but the elevated temperature devitrifies the glassy structure forming crystals that cannot form by continuous cooling.

  19. mediation: R Package for Causal Mediation Analysis

    Directory of Open Access Journals (Sweden)

    Dustin Tingley

    2014-09-01

    Full Text Available In this paper, we describe the R package mediation for conducting causal mediation analysis in applied empirical research. In many scientific disciplines, the goal of researchers is not only estimating causal effects of a treatment but also understanding the process in which the treatment causally affects the outcome. Causal mediation analysis is frequently used to assess potential causal mechanisms. The mediation package implements a comprehensive suite of statistical tools for conducting such an analysis. The package is organized into two distinct approaches. Using the model-based approach, researchers can estimate causal mediation effects and conduct sensitivity analysis under the standard research design. Furthermore, the design-based approach provides several analysis tools that are applicable under different experimental designs. This approach requires weaker assumptions than the model-based approach. We also implement a statistical method for dealing with multiple (causally dependent mediators, which are often encountered in practice. Finally, the package also offers a methodology for assessing causal mediation in the presence of treatment noncompliance, a common problem in randomized trials.

  20. Bidirectional solar wind electron heat flux events

    International Nuclear Information System (INIS)

    Gosling, J.T.; Baker, D.N.; Bame, S.J.; Feldman, W.C.; Zwickl, R.D.; Smith, E.J.

    1987-01-01

    Normally the approx. >80-eV electrons which carry the solar wind electron heat flux are collimated along the interplanetary magnetic field (IMF) in the direction pointing outward away from the sun. Occasionally, however, collimated fluxes of approx. >80-eV electrons are observed traveling both parallel and antiparallel to the IMF. Here we present the results of a survey of such bidirectional electron heat flux events as observed with the plasma and magnetic field experiments aboard ISEE 3 at times when the spacecraft was not magnetically connected to the earth's bow shock. The onset of a bidirectional electron heat flux at ISEE 3 usually signals spacecraft entry into a distinct solar wind plasma and field entity, most often characterized by anomalously low proton and electron temperatures, a strong, smoothly varying magnetic field, a low plasma beta, and a high total pressure. Significant field rotations often occur at the beginning and/or end of bidirectional heat flux events, and, at times, the large field rotations characteristic of ''magnetic clouds'' are present. Approximately half of all bidirectional heat flux events are associated with and follow interplanetary shocks, while the other events have no obvious shock associations

  1. 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

  2. Bayesian Mediation Analysis

    Science.gov (United States)

    Yuan, Ying; MacKinnon, David P.

    2009-01-01

    In this article, we propose Bayesian analysis of mediation effects. Compared with conventional frequentist mediation analysis, the Bayesian approach has several advantages. First, it allows researchers to incorporate prior information into the mediation analysis, thus potentially improving the efficiency of estimates. Second, under the Bayesian…

  3. Turbulent fluxes by "Conditional Eddy Sampling"

    Science.gov (United States)

    Siebicke, Lukas

    2015-04-01

    Turbulent flux measurements are key to understanding ecosystem scale energy and matter exchange, including atmospheric trace gases. While the eddy covariance approach has evolved as an invaluable tool to quantify fluxes of e.g. CO2 and H2O continuously, it is limited to very few atmospheric constituents for which sufficiently fast analyzers exist. High instrument cost, lack of field-readiness or high power consumption (e.g. many recent laser-based systems requiring strong vacuum) further impair application to other tracers. Alternative micrometeorological approaches such as conditional sampling might overcome major limitations. Although the idea of eddy accumulation has already been proposed by Desjardin in 1972 (Desjardin, 1977), at the time it could not be realized for trace gases. Major simplifications by Businger and Oncley (1990) lead to it's widespread application as 'Relaxed Eddy Accumulation' (REA). However, those simplifications (flux gradient similarity with constant flow rate sampling irrespective of vertical wind velocity and introduction of a deadband around zero vertical wind velocity) have degraded eddy accumulation to an indirect method, introducing issues of scalar similarity and often lack of suitable scalar flux proxies. Here we present a real implementation of a true eddy accumulation system according to the original concept. Key to our approach, which we call 'Conditional Eddy Sampling' (CES), is the mathematical formulation of conditional sampling in it's true form of a direct eddy flux measurement paired with a performant real implementation. Dedicated hardware controlled by near-real-time software allows full signal recovery at 10 or 20 Hz, very fast valve switching, instant vertical wind velocity proportional flow rate control, virtually no deadband and adaptive power management. Demonstrated system performance often exceeds requirements for flux measurements by orders of magnitude. The system's exceptionally low power consumption is ideal

  4. PKA/KIN-1 mediates innate immune responses to bacterial pathogens in Caenorhabditis elegans.

    Science.gov (United States)

    Xiao, Yi; Liu, Fang; Zhao, Pei-Ji; Zou, Cheng-Gang; Zhang, Ke-Qin

    2017-11-01

    The genetically tractable organism Caenorhabditis elegans is a powerful model animal for the study of host innate immunity. Although the intestine and the epidermis of C. elegans that is in contact with pathogens are likely to function as sites for the immune function, recent studies indicate that the nervous system could control innate immunity in C. elegans. In this report, we demonstrated that protein kinase A (PKA)/KIN-1 in the neurons contributes to resistance against Salmonella enterica infection in C. elegans. Microarray analysis revealed that PKA/KIN-1 regulates the expression of a set of antimicrobial effectors in the non-neuron tissues, which are required for innate immune responses to S. enterica. Furthermore, PKA/KIN-1 regulated the expression of lysosomal genes during S. enterica infection. Our results suggest that the lysosomal signaling molecules are involved in autophagy by controlling autophagic flux, rather than formation of autophagosomes. As autophagy is crucial for host defense against S. enterica infection in a metazoan, the lysosomal pathway also acts as a downstream effector of the PKA/KIN-1 signaling for innate immunity. Our data indicate that the PKA pathway contributes to innate immunity in C. elegans by signaling from the nervous system to periphery tissues to protect the host against pathogens.

  5. A finite element calculation of flux pumping

    Science.gov (United States)

    Campbell, A. M.

    2017-12-01

    A flux pump is not only a fascinating example of the power of Faraday’s concept of flux lines, but also an attractive way of powering superconducting magnets without large electronic power supplies. However it is not possible to do this in HTS by driving a part of the superconductor normal, it must be done by exceeding the local critical density. The picture of a magnet pulling flux lines through the material is attractive, but as there is no direct contact between flux lines in the magnet and vortices, unless the gap between them is comparable to the coherence length, the process must be explicable in terms of classical electromagnetism and a nonlinear V-I characteristic. In this paper a simple 2D model of a flux pump is used to determine the pumping behaviour from first principles and the geometry. It is analysed with finite element software using the A formulation and FlexPDE. A thin magnet is passed across one or more superconductors connected to a load, which is a large rectangular loop. This means that the self and mutual inductances can be calculated explicitly. A wide strip, a narrow strip and two conductors are considered. Also an analytic circuit model is analysed. In all cases the critical state model is used, so the flux flow resistivity and dynamic resistivity are not directly involved, although an effective resistivity appears when J c is exceeded. In most of the cases considered here is a large gap between the theory and the experiments. In particular the maximum flux transferred to the load area is always less than the flux of the magnet. Also once the threshold needed for pumping is exceeded the flux in the load saturates within a few cycles. However the analytic circuit model allows a simple modification to allow for the large reduction in I c when the magnet is over a conductor. This not only changes the direction of the pumped flux but leads to much more effective pumping.

  6. General gauge mediation

    International Nuclear Information System (INIS)

    Meade, Patrick; Seiberg, Nathan; Shih, David

    2009-01-01

    We give a general definition of gauge mediated supersymmetry breaking which encompasses all the known gauge mediation models. In particular, it includes both models with messengers as well as direct mediation models. A formalism for computing the soft terms in the generic model is presented. Such a formalism is necessary in strongly-coupled direct mediation models where perturbation theory cannot be used. It allows us to identify features of the entire class of gauge mediation models and to distinguish them from specific signatures of various subclasses. (author)

  7. Estimating surface fluxes using eddy covariance and numerical ogive optimization

    DEFF Research Database (Denmark)

    Sievers, J.; Papakyriakou, T.; Larsen, Søren Ejling

    2015-01-01

    Estimating representative surface fluxes using eddy covariance leads invariably to questions concerning inclusion or exclusion of low-frequency flux contributions. For studies where fluxes are linked to local physical parameters and up-scaled through numerical modelling efforts, low......-frequency contributions interfere with our ability to isolate local biogeochemical processes of interest, as represented by turbulent fluxes. No method currently exists to disentangle low-frequency contributions on flux estimates. Here, we present a novel comprehensive numerical scheme to identify and separate out low......-frequency contributions to vertical turbulent surface fluxes. For high flux rates (|Sensible heat flux| > 40Wm-2, |latent heat flux|> 20Wm-2 and |CO2 flux|> 100 mmolm-2 d-1/ we found that the average relative difference between fluxes estimated by ogive optimization and the conventional method was low (5–20 %) suggesting...

  8. A model for heliospheric flux-ropes

    Science.gov (United States)

    Nieves-Chinchilla, T.; Linton, M.; Vourlidas, A.; Hidalgo, M. A. U.

    2017-12-01

    This work is presents an analytical flux-rope model, which explores different levels of complexity starting from a circular-cylindrical geometry. The framework of this series of models was established by Nieves-Chinchilla et al. 2016 with the circular-cylindrical analytical flux rope model. The model attempts to describe the magnetic flux rope topology with distorted cross-section as a possible consequence of the interaction with the solar wind. In this model, the flux rope is completely described in a non-orthogonal geometry. The Maxwell equations are solved using tensor calculus consistent with the geometry chosen, invariance along the axial direction, and with the assumption of no radial current density. The model is generalized in terms of the radial and azimuthal dependence of the poloidal current density component and axial current density component. The misalignment between current density and magnetic field is studied in detail for several example profiles of the axial and poloidal current density components. This theoretical analysis provides a map of the force distribution inside of the flux-rope. For reconstruction of the heliospheric flux-ropes, the circular-cylindrical reconstruction technique has been adapted to the new geometry and applied to in situ ICMEs with a flux-rope entrained and tested with cases with clear in situ signatures of distortion. The model adds a piece in the puzzle of the physical-analytical representation of these magnetic structures that should be evaluated with the ultimate goal of reconciling in-situ reconstructions with imaging 3D remote sensing CME reconstructions. Other effects such as axial curvature and/or expansion could be incorporated in the future to fully understand the magnetic structure.

  9. Production flux of sea spray aerosol

    Energy Technology Data Exchange (ETDEWEB)

    de Leeuw, G.; Lewis, E.; Andreas, E. L.; Anguelova, M. D.; Fairall, C. W.; O’Dowd, C.; Schulz, M.; Schwartz, S. E.

    2011-05-07

    Knowledge of the size- and composition-dependent production flux of primary sea spray aerosol (SSA) particles and its dependence on environmental variables is required for modeling cloud microphysical properties and aerosol radiative influences, interpreting measurements of particulate matter in coastal areas and its relation to air quality, and evaluating rates of uptake and reactions of gases in sea spray drops. This review examines recent research pertinent to SSA production flux, which deals mainly with production of particles with r{sub 80} (equilibrium radius at 80% relative humidity) less than 1 {micro}m and as small as 0.01 {micro}m. Production of sea spray particles and its dependence on controlling factors has been investigated in laboratory studies that have examined the dependences on water temperature, salinity, and the presence of organics and in field measurements with micrometeorological techniques that use newly developed fast optical particle sizers. Extensive measurements show that water-insoluble organic matter contributes substantially to the composition of SSA particles with r{sub 80} < 0.25 {micro}m and, in locations with high biological activity, can be the dominant constituent. Order-of-magnitude variation remains in estimates of the size-dependent production flux per white area, the quantity central to formulations of the production flux based on the whitecap method. This variation indicates that the production flux may depend on quantities such as the volume flux of air bubbles to the surface that are not accounted for in current models. Variation in estimates of the whitecap fraction as a function of wind speed contributes additional, comparable uncertainty to production flux estimates.

  10. Derivative processes for modelling metabolic fluxes

    Science.gov (United States)

    Žurauskienė, Justina; Kirk, Paul; Thorne, Thomas; Pinney, John; Stumpf, Michael

    2014-01-01

    Motivation: One of the challenging questions in modelling biological systems is to characterize the functional forms of the processes that control and orchestrate molecular and cellular phenotypes. Recently proposed methods for the analysis of metabolic pathways, for example, dynamic flux estimation, can only provide estimates of the underlying fluxes at discrete time points but fail to capture the complete temporal behaviour. To describe the dynamic variation of the fluxes, we additionally require the assumption of specific functional forms that can capture the temporal behaviour. However, it also remains unclear how to address the noise which might be present in experimentally measured metabolite concentrations. Results: Here we propose a novel approach to modelling metabolic fluxes: derivative processes that are based on multiple-output Gaussian processes (MGPs), which are a flexible non-parametric Bayesian modelling technique. The main advantages that follow from MGPs approach include the natural non-parametric representation of the fluxes and ability to impute the missing data in between the measurements. Our derivative process approach allows us to model changes in metabolite derivative concentrations and to characterize the temporal behaviour of metabolic fluxes from time course data. Because the derivative of a Gaussian process is itself a Gaussian process, we can readily link metabolite concentrations to metabolic fluxes and vice versa. Here we discuss how this can be implemented in an MGP framework and illustrate its application to simple models, including nitrogen metabolism in Escherichia coli. Availability and implementation: R code is available from the authors upon request. Contact: j.norkunaite@imperial.ac.uk; m.stumpf@imperial.ac.uk Supplementary information: Supplementary data are available at Bioinformatics online. PMID:24578401

  11. mTOR Hyperactivation by Ablation of Tuberous Sclerosis Complex 2 in the Mouse Heart Induces Cardiac Dysfunction with the Increased Number of Small Mitochondria Mediated through the Down-Regulation of Autophagy.

    Directory of Open Access Journals (Sweden)

    Manabu Taneike

    Full Text Available Mammalian target of rapamycin complex 1 (mTORC1 is a key regulator of cell growth, proliferation and metabolism. mTORC1 regulates protein synthesis positively and autophagy negatively. Autophagy is a major system to manage bulk degradation and recycling of cytoplasmic components and organelles. Tuberous sclerosis complex (TSC 1 and 2 form a heterodimeric complex and inactivate Ras homolog enriched in brain, resulting in inhibition of mTORC1. Here, we investigated the effects of hyperactivation of mTORC1 on cardiac function and structure using cardiac-specific TSC2-deficient (TSC2-/- mice. TSC2-/- mice were born normally at the expected Mendelian ratio. However, the median life span of TSC2-/- mice was approximately 10 months and significantly shorter than that of control mice. TSC2-/- mice showed cardiac dysfunction and cardiomyocyte hypertrophy without considerable fibrosis, cell infiltration or apoptotic cardiomyocyte death. Ultrastructural analysis of TSC2-/- hearts revealed misalignment, aggregation and a decrease in the size and an increase in the number of mitochondria, but the mitochondrial function was maintained. Autophagic flux was inhibited, while the phosphorylation level of S6 or eukaryotic initiation factor 4E -binding protein 1, downstream of mTORC1, was increased. The upregulation of autophagic flux by trehalose treatment attenuated the cardiac phenotypes such as cardiac dysfunction and structural abnormalities of mitochondria in TSC2-/- hearts. The results suggest that autophagy via the TSC2-mTORC1 signaling pathway plays an important role in maintenance of cardiac function and mitochondrial quantity and size in the heart and could be a therapeutic target to maintain mitochondrial homeostasis in failing hearts.

  12. Measuring Convective Mass Fluxes Over Tropical Oceans

    Science.gov (United States)

    Raymond, David

    2017-04-01

    Deep convection forms the upward branches of all large-scale circulations in the tropics. Understanding what controls the form and intensity of vertical convective mass fluxes is thus key to understanding tropical weather and climate. These mass fluxes and the corresponding conditions supporting them have been measured by recent field programs (TPARC/TCS08, PREDICT, HS3) in tropical disturbances considered to be possible tropical storm precursors. In reality, this encompasses most strong convection in the tropics. The measurements were made with arrays of dropsondes deployed from high altitude. In some cases Doppler radar provided additional measurements. The results are in some ways surprising. Three factors were found to control the mass flux profiles, the strength of total surface heat fluxes, the column-integrated relative humidity, and the low to mid-tropospheric moist convective instability. The first two act as expected, with larger heat fluxes and higher humidity producing more precipitation and stronger lower tropospheric mass fluxes. However, unexpectedly, smaller (but still positive) convective instability produces more precipitation as well as more bottom-heavy convective mass flux profiles. Furthermore, the column humidity and the convective instability are anti-correlated, at least in the presence of strong convection. On spatial scales of a few hundred kilometers, the virtual temperature structure appears to be in dynamic balance with the pattern of potential vorticity. Since potential vorticity typically evolves on longer time scales than convection, the potential vorticity pattern plus the surface heat fluxes then become the immediate controlling factors for average convective properties. All measurements so far have taken place in regions with relatively flat sea surface temperature (SST) distributions. We are currently seeking funding for a measurement program in the tropical east Pacific, a region that exhibits strong SST gradients and

  13. Turbulent Fogwater Flux Measurements Above A Forest

    Science.gov (United States)

    Burkard, R.; Eugster, W.; Buetzberger, P.; Siegwolf, R.

    Many forest ecosystems in elevated regions receive a significant fraction of their wa- ter and nutrient input by the interception of fogwater. Recently, several studies have demonstrated the suitability of the eddy covariance technique for the direct measure- ment of turbulent liquid water fluxes. Since summer 2001 a fogwater flux measure- ment equipment has been running at a montane site above a mixed forest canopy in Switzerland. The measurement equipment consists of a high-speed size-resolving droplet spectrometer and a three-dimensional ultrasonic anemometer. The chemical composition of the fogwater was determined from samples collected with a modified Caltech active strand collector. The deposition of nutrients by fog (occult deposition) was calculated by multiplying the total fogwater flux (total of measured turbulent and calculated gravitational flux) during each fog event by the ionic concentrations found in the collected fogwater. Several uncertainties still exist as far as the accuracy of the measurements is con- cerned. Although there is no universal statistical approach for testing the quality of the liquid water flux data directly, results of independent data quality checks of the two time series involved in the flux computation and accordingly the two instruments (ultrasonic anemometer and the droplet spectrometer) are presented. Within the measurement period, over 80 fog events with a duration longer than 2.5 hours were analyzed. An enormous physical and chemical heterogeneity among these fog events was found. We assume that some of this heterogeneity is due to the fact that fog or cloud droplets are not conservative entities: the turbulent flux of fog droplets, which can be referred to as the liquid water flux, is affected by phase change processes and coagulation. The measured coexistence of upward fluxes of small fog droplets (di- ameter < 10 µm) with the downward transport of larger droplets indicates the influ- ence of such processes. With the

  14. Neutron flux measurement utilizing Campbell technique

    International Nuclear Information System (INIS)

    Kropik, M.

    2000-01-01

    Application of the Campbell technique for the neutron flux measurement is described in the contribution. This technique utilizes the AC component (noise) of a neutron chamber signal rather than a usually used DC component. The Campbell theorem, originally discovered to describe noise behaviour of valves, explains that the root mean square of the AC component of the chamber signal is proportional to the neutron flux (reactor power). The quadratic dependence of the reactor power on the root mean square value usually permits to accomplish the whole current power range of the neutron flux measurement by only one channel. Further advantage of the Campbell technique is that large pulses of the response to neutrons are favoured over small pulses of the response to gamma rays in the ratio of their mean square charge transfer and thus, the Campbell technique provides an excellent gamma rays discrimination in the current operational range of a neutron chamber. The neutron flux measurement channel using state of the art components was designed and put into operation. Its linearity, accuracy, dynamic range, time response and gamma discrimination were tested on the VR-1 nuclear reactor in Prague, and behaviour under high neutron flux (accident conditions) was tested on the TRIGA nuclear reactor in Vienna. (author)

  15. CO2 flux from Javanese mud volcanism

    Science.gov (United States)

    Burton, M. R.; Arzilli, F.; Chiarugi, A.; Marliyani, G. I.; Anggara, F.; Harijoko, A.

    2017-01-01

    Abstract Studying the quantity and origin of CO2 emitted by back‐arc mud volcanoes is critical to correctly model fluid‐dynamical, thermodynamical, and geochemical processes that drive their activity and to constrain their role in the global geochemical carbon cycle. We measured CO2 fluxes of the Bledug Kuwu mud volcano on the Kendeng Fold and thrust belt in the back arc of Central Java, Indonesia, using scanning remote sensing absorption spectroscopy. The data show that the expelled gas is rich in CO2 with a volume fraction of at least 16 vol %. A lower limit CO2 flux of 1.4 kg s−1 (117 t d−1) was determined, in line with the CO2 flux from the Javanese mud volcano LUSI. Extrapolating these results to mud volcanism from the whole of Java suggests an order of magnitude total CO2 flux of 3 kt d−1, comparable with the expected back‐arc efflux of magmatic CO2. After discussing geochemical, geological, and geophysical evidence we conclude that the source of CO2 observed at Bledug Kuwu is likely a mixture of thermogenic, biogenic, and magmatic CO2, with faulting controlling potential pathways for magmatic fluids. This study further demonstrates the merit of man‐portable active remote sensing instruments for probing natural gas releases, enabling bottom‐up quantification of CO2 fluxes. PMID:28944134

  16. CO2 flux from Javanese mud volcanism

    Science.gov (United States)

    Queißer, M.; Burton, M. R.; Arzilli, F.; Chiarugi, A.; Marliyani, G. I.; Anggara, F.; Harijoko, A.

    2017-06-01

    Studying the quantity and origin of CO2 emitted by back-arc mud volcanoes is critical to correctly model fluid-dynamical, thermodynamical, and geochemical processes that drive their activity and to constrain their role in the global geochemical carbon cycle. We measured CO2 fluxes of the Bledug Kuwu mud volcano on the Kendeng Fold and thrust belt in the back arc of Central Java, Indonesia, using scanning remote sensing absorption spectroscopy. The data show that the expelled gas is rich in CO2 with a volume fraction of at least 16 vol %. A lower limit CO2 flux of 1.4 kg s-1 (117 t d-1) was determined, in line with the CO2 flux from the Javanese mud volcano LUSI. Extrapolating these results to mud volcanism from the whole of Java suggests an order of magnitude total CO2 flux of 3 kt d-1, comparable with the expected back-arc efflux of magmatic CO2. After discussing geochemical, geological, and geophysical evidence we conclude that the source of CO2 observed at Bledug Kuwu is likely a mixture of thermogenic, biogenic, and magmatic CO2, with faulting controlling potential pathways for magmatic fluids. This study further demonstrates the merit of man-portable active remote sensing instruments for probing natural gas releases, enabling bottom-up quantification of CO2 fluxes.

  17. Neutron flux enhancement in the NRAD reactor

    International Nuclear Information System (INIS)

    Weeks, A.A.; Heidel, C.C.; Imel, G.R.

    1988-01-01

    In 1987 a series of experiments were conducted at the NRAD reactor facility at Argonne National Laboratory - West (ANL-W) to investigate the possibility of increasing the thermal neutron content at the end of the reactor's east beam tube through the use of hydrogenous flux traps. It was desired to increase the thermal flux for a series of experiments to be performed in the east radiography cell, in which the enhanced flux was required in a relatively small volume. Hence, it was feasible to attempt to focus the cross section of the beam to a smaller area. Two flux traps were constructed from unborated polypropylene and tested to determine their effectiveness. Both traps were open to the entire cross-sectional area of the neutron beam (as it emerges from the wall and enters the beam room). The sides then converged such that at the end of the trap the beam would be 'focused' to a greater intensity. The differences in the two flux traps were primarily in length, and hence angle to the beam as the inlet and outlet cross-sectional areas were held constant. It should be noted that merely placing a slab of polypropylene in the beam will not yield significant multiplication as neutrons are primarily scattered away

  18. The Flux Database Concerted Action (invited paper)

    International Nuclear Information System (INIS)

    Mitchell, N.G.; Donnelly, C.E.

    2000-01-01

    The background to the IUR action on the development of a flux database for radionuclide transfer in soil-plant systems is summarised. The action is discussed in terms of the objectives, the deliverables and the progress achieved by the flux database working group. The paper describes the background to the current initiative, outlines specific features of the database and supporting documentation, and presents findings from the working group's activities. The aim of the IUR flux database working group is to bring together researchers to collate data from current experimental studies investigating aspects of radionuclide transfer in soil-plant systems. The database will incorporate parameters describing the time-dependent transfer of radionuclides between soil, plant and animal compartments. Work under the EC Concerted Action considers soil-plant interactions. This initiative has become known as the radionuclide flux database. It is emphasised that the word flux is used in this case simply to indicate the flow of radionuclides between compartments in time. (author)

  19. About Merging Threshold and Critical Flux Concepts into a Single One: The Boundary Flux

    Directory of Open Access Journals (Sweden)

    Marco Stoller

    2014-01-01

    Full Text Available In the last decades much effort was put in understanding fouling phenomena on membranes. One successful approach to describe fouling issues on membranes is the critical flux theory. The possibility to measure a maximum value of the permeate flux for a given system without incurring in fouling issues was a breakthrough in membrane process design. However, in many cases critical fluxes were found to be very low, lower than the economic feasibility of the process. The knowledge of the critical flux value must be therefore considered as a good starting point for process design. In the last years, a new concept was introduced, the threshold flux, which defines the maximum permeate flow rate characterized by a low constant fouling rate regime. This concept, more than the critical flux, is a new practical tool for membrane process designers. In this paper a brief review on critical and threshold flux will be reported and analyzed. And since the concepts share many common aspects, merged into a new concept, called the boundary flux, the validation will occur by the analysis of previously collected data by the authors, during the treatment of olive vegetation wastewater by ultrafiltration and nanofiltration membranes.

  20. Eddy covariance based methane flux in Sundarbans mangroves, India

    Indian Academy of Sciences (India)

    Eddy covariance based methane flux in Sundarbans mangroves, India ... Eddy covariance; mangrove forests; methane flux; Sundarbans. ... In order to quantify the methane flux in mangroves, an eddy covariance flux tower was recently erected in the largest unpolluted and undisturbed mangrove ecosystem in Sundarbans ...

  1. Fluxes of nitrogen in Chaliyar River Estuary, India

    Digital Repository Service at National Institute of Oceanography (India)

    Xavier, J.K.; Joseph, T.; Paimpillii, J.S.

    the instantaneous nutrient fluxes. The net fluxes are the algebraic sums of the instantaneous fluxes over the tidal cycle sampled divided by the number of observations in the tidal cycle. Net fluxes for all the stations with its cross sectional averages for each...

  2. Generating energy dependent neutron flux maps for effective ...

    African Journals Online (AJOL)

    For activation analysis and irradiation scheme of miniature neutron source reactor, designers or engineers usually require information on thermal neutron flux levels and other energy group flux levels (such as fast, resonance and epithermal). A methodology for readily generating such flux maps and flux profiles for any ...

  3. Non-geometric fluxes and mixed-symmetry potentials

    NARCIS (Netherlands)

    Bergshoeff, E.A.; Penas, V.A.; Riccioni, F.; Risoli, S.

    2015-01-01

    We discuss the relation between generalised fluxes and mixed-symmetry potentials. We refer to the fluxes that cannot be described even locally in the framework of supergravity as ‘non-geometric’. We first consider the NS fluxes, and point out that the non-geometric R flux is dual to a mixed-symmetry

  4. Neutron-diffraction investigations of flux-lines in superconductors

    Energy Technology Data Exchange (ETDEWEB)

    Forgan, E.M. [Birmingham Univ. (United Kingdom); Lee, S.L. [Saint Andrews Univ. (United Kingdom); McKPaul, D. [Warwick Univ., Coventry (United Kingdom); Mook, H.A. [Oak Ridge National Lab., TN (United States); Cubitt, R. [Institut Max von Laue - Paul Langevin (ILL), 38 - Grenoble (France)

    1997-04-01

    SANS has proved an extremely useful tool for investigating flux-line structures within the bulk of superconductors. With high-T{sub c} materials, the scattered intensities are weak, but careful measurements are giving important new information about flux lattices, flux pinning and flux-lattice melting. (author). 10 refs.

  5. Standardized Automated CO2/H2O Flux Systems for Individual Research Groups and Flux Networks

    Science.gov (United States)

    Burba, George; Begashaw, Israel; Fratini, Gerardo; Griessbaum, Frank; Kathilankal, James; Xu, Liukang; Franz, Daniela; Joseph, Everette; Larmanou, Eric; Miller, Scott; Papale, Dario; Sabbatini, Simone; Sachs, Torsten; Sakai, Ricardo; McDermitt, Dayle

    2017-04-01

    In recent years, spatial and temporal flux data coverage improved significantly, and on multiple scales, from a single station to continental networks, due to standardization, automation, and management of data collection, and better handling of the extensive amounts of generated data. With more stations and networks, larger data flows from each station, and smaller operating budgets, modern tools are required to effectively and efficiently handle the entire process. Such tools are needed to maximize time dedicated to authoring publications and answering research questions, and to minimize time and expenses spent on data acquisition, processing, and quality control. Thus, these tools should produce standardized verifiable datasets and provide a way to cross-share the standardized data with external collaborators to leverage available funding, promote data analyses and publications. LI-COR gas analyzers are widely used in past and present flux networks such as AmeriFlux, ICOS, AsiaFlux, OzFlux, NEON, CarboEurope, and FluxNet-Canada, etc. These analyzers have gone through several major improvements over the past 30 years. However, in 2016, a three-prong development was completed to create an automated flux system which can accept multiple sonic anemometer and datalogger models, compute final and complete fluxes on-site, merge final fluxes with supporting weather soil and radiation data, monitor station outputs and send automated alerts to researchers, and allow secure sharing and cross-sharing of the station and data access. Two types of these research systems were developed: open-path (LI-7500RS) and enclosed-path (LI-7200RS). Key developments included: • Improvement of gas analyzer performance • Standardization and automation of final flux calculations onsite, and in real-time • Seamless integration with latest site management and data sharing tools In terms of the gas analyzer performance, the RS analyzers are based on established LI-7500/A and LI-7200

  6. Characterization of ion fluxes and heat fluxes for PMI relevant conditions on Proto-MPEX

    Science.gov (United States)

    Beers, Clyde; Shaw, Guinevere; Biewer, Theodore; Rapp, Juergen

    2016-10-01

    Plasma characterization, in particular, particle flux and electron and ion temperature distributions nearest to an exposed target, are critical to quantifying Plasma Surface Interaction (PSI). In the Proto-Material Plasma Exposure eXperiment (Proto-MPEX), the ion fluxes and heat fluxes are derived from double Langmuir Probes (DLP) and Thomson Scattering in front of the target assuming Bohm conditions at the sheath entrance. Power fluxes derived from ne and Te measurements are compared to heat fluxes measured with IR thermography. The comparison will allow conclusions on the sheath heat transmission coefficient to be made experimentally. Different experimental conditions (low and high density plasmas (0.5 - 6 x 1019 m-3) with different magnetic configuration are compared. This work was supported by the U.S. D.O.E. contract DE-AC05-00OR22725.

  7. Automated flux chamber for investigating gas flux at water-air interfaces.

    Science.gov (United States)

    Duc, Nguyen Thanh; Silverstein, Samuel; Lundmark, Lars; Reyier, Henrik; Crill, Patrick; Bastviken, David

    2013-01-15

    Aquatic ecosystems are major sources of greenhouse gases (GHG). Representative measurements of GHG fluxes from aquatic ecosystems to the atmosphere are vital for quantitative understanding of relationships between biogeochemistry and climate. Fluxes occur at high temporal variability at diel or longer scales, which are not captured by traditional short-term deployments (often in the order of 30 min) of floating flux chambers. High temporal frequency measurements are necessary but also extremely labor intensive if manual flux chamber based methods are used. Therefore, we designed an inexpensive and easily mobile automated flux chamber (AFC) for extended deployments. The AFC was designed to measure in situ accumulation of gas in the chamber and also to collect gas samples in an array of sample bottles for subsequent analysis in the laboratory, providing two independent ways of CH(4) concentration measurements. We here present the AFC design and function together with data from initial laboratory tests and from a field deployment.

  8. Freezing E3-brane instantons with fluxes

    Energy Technology Data Exchange (ETDEWEB)

    Bianchi, M.; Martucci, L. [Dipartimento di Fisica, Universita di Roma Tor Vergata (Italy); I.N.F.N., Sezione di Roma Tor Vergata (Italy); Collinucci, A. [Theory Group, Physics Department, CERN, Geneva (Switzerland); Physique Theorique et Mathematique Universite Libre de Bruxelles (Belgium)

    2012-07-15

    E3-instantons that generate non-perturbative superpotentials in IIB N = 1 compactifications have a much more frequent occurrence than currently believed. Worldvolume fluxes will typically lift the E3-brane geometric moduli and their fermionic superpartners, leaving only the two required universal fermionic zero-modes. We consistently incorporate SL(2,Z) monodromies and world-volume fluxes in the effective theory of the E3-brane fermions and study the resulting zero modes spectrum, highlighting the relation between F-theory and perturbative IIB results. This leads us to a IIB derivation of the index for generation of superpotential terms, which reproduces and generalizes available results. Furthermore, we show how E3 worldvolume fluxes can be explicitly constructed in a one-modulus compactification, such that the instanton has exactly two fermonic zero-modes. This construction is readily applicable to numerous scenarios. (Copyright copyright 2012 WILEY-VCH Verlag GmbH and Co. KGaA, Weinheim)

  9. Heat-Flux Gage thermophosphor system

    Energy Technology Data Exchange (ETDEWEB)

    Tobin, K.W.

    1991-08-01

    This document describes the installation, hardware requirements, and application of the Heat-Flux Gage (Version 1.0) software package developed by the Oak Ridge National Laboratory, Applied Technology Division. The developed software is a single component of a thermographic phosphor-based temperature and heat-flux measurement system. The heat-flux transducer was developed by EG G Energy Measurements Systems and consists of a 1- by 1-in. polymethylpentene sheet coated on the front and back with a repeating thermographic phosphor pattern. The phosphor chosen for this application is gadolinium oxysulphide doped with terbium. This compound has a sensitive temperature response from 10 to 65.6{degree}C (50--150{degree}F) for the 415- and 490-nm spectral emission lines. 3 refs., 17 figs.

  10. Comic ray flux anisotropies caused by astrospheres

    Science.gov (United States)

    Scherer, K.; Strauss, R. D.; Ferreira, S. E. S.; Fichtner, H.

    2016-09-01

    Huge astrospheres or stellar wind bubbles influence the propagation of cosmic rays at energies up to the TeV range and can act as small-scale sinks decreasing the cosmic ray flux. We model such a sink (in 2D) by a sphere of radius 10 pc embedded within a sphere of a radius of 1 kpc. The cosmic ray flux is calculated by means of backward stochastic differential equations from an observer, which is located at r0, to the outer boundary. It turns out that such small-scale sinks can influence the cosmic ray flux at the observer's location by a few permille (i.e. a few 0.1%), which is in the range of the observations by IceCube, Milagro and other large area telescopes.

  11. From Hubble's NGSL to Absolute Fluxes

    Science.gov (United States)

    Heap, Sara R.; Lindler, Don

    2012-01-01

    Hubble's Next Generation Spectral Library (NGSL) consists of R-l000 spectra of 374 stars of assorted temperature, gravity, and metallicity. Each spectrum covers the wavelength range, 0.18-1.00 microns. The library can be viewed and/or downloaded from the website, http://archive.stsci.edu/prepds/stisngsll. Stars in the NGSL are now being used as absolute flux standards at ground-based observatories. However, the uncertainty in the absolute flux is about 2%, which does not meet the requirements of dark-energy surveys. We are therefore developing an observing procedure that should yield fluxes with uncertainties less than 1 % and will take part in an HST proposal to observe up to 15 stars using this new procedure.

  12. The FLUKA atmospheric neutrino flux calculation

    CERN Document Server

    Battistoni, G.; Montaruli, T.; Sala, P.R.

    2003-01-01

    The 3-dimensional (3-D) calculation of the atmospheric neutrino flux by means of the FLUKA Monte Carlo model is here described in all details, starting from the latest data on primary cosmic ray spectra. The importance of a 3-D calculation and of its consequences have been already debated in a previous paper. Here instead the focus is on the absolute flux. We stress the relevant aspects of the hadronic interaction model of FLUKA in the atmospheric neutrino flux calculation. This model is constructed and maintained so to provide a high degree of accuracy in the description of particle production. The accuracy achieved in the comparison with data from accelerators and cross checked with data on particle production in atmosphere certifies the reliability of shower calculation in atmosphere. The results presented here can be already used for analysis by current experiments on atmospheric neutrinos. However they represent an intermediate step towards a final release, since this calculation does not yet include the...

  13. MHD energy fluxes for late type dwarfs

    Science.gov (United States)

    Rosner, R.; Musielak, Z. E.

    1987-01-01

    The efficiency of MHD wave generation by turbulent motions in stratified stellar atmospheres with embedded uniform magnetic fields is calculated. In contradiction with previous results, it is shown that there is no significant increase in the efficiency of wave generation because of the presence of magnetic fields, at least within the theory's limits of applicability. It is shown that MHD energy fluxes for late-type stars are less than those obtained for acoustic waves in a magnetic-field-free atmosphere, and do not vary enough for a given spectral type in order to explain observed UV and X-ray fluxes. Thus, the results show that MHD energy fluxes obtained if stellar surface magnetic fields are uniform cannot explain the observed stellar coronal emissions.

  14. Color magnetic flux tubes in dense QCD

    International Nuclear Information System (INIS)

    Eto, Minoru; Nitta, Muneto

    2009-01-01

    QCD is expected to be in the color-flavor locking phase in high baryon density, which exhibits color superconductivity. The most fundamental topological objects in the color superconductor are non-Abelian vortices which are topologically stable color magnetic flux tubes. We present numerical solutions of the color magnetic flux tube for diverse choices of the coupling constants based on the Ginzburg-Landau Lagrangian. We also analytically study its asymptotic profiles and find that they are different from the case of usual superconductors. We propose the width of color magnetic fluxes and find that it is larger than naive expectation of the Compton wavelength of the massive gluon when the gluon mass is larger than the scalar mass.

  15. Real Time Flux Control in PM Motors

    Energy Technology Data Exchange (ETDEWEB)

    Otaduy, P.J.

    2005-09-27

    Significant research at the Oak Ridge National Laboratory (ORNL) Power Electronics and Electric Machinery Research Center (PEEMRC) is being conducted to develop ways to increase (1) torque, (2) speed range, and (3) efficiency of traction electric motors for hybrid electric vehicles (HEV) within existing current and voltage bounds. Current is limited by the inverter semiconductor devices' capability and voltage is limited by the stator wire insulation's ability to withstand the maximum back-electromotive force (emf), which occurs at the upper end of the speed range. One research track has been to explore ways to control the path and magnitude of magnetic flux while the motor is operating. The phrase, real time flux control (RTFC), refers to this mode of operation in which system parameters are changed while the motor is operating to improve its performance and speed range. RTFC has potential to meet an increased torque demand by introducing additional flux through the main air gap from an external source. It can augment the speed range by diverting flux away from the main air gap to reduce back-emf at high speeds. Conventional RTFC technology is known as vector control [1]. Vector control decomposes the stator current into two components; one that produces torque and a second that opposes (weakens) the magnetic field generated by the rotor, thereby requiring more overall stator current and reducing the efficiency. Efficiency can be improved by selecting a RTFC method that reduces the back-emf without increasing the average current. This favors methods that use pulse currents or very low currents to achieve field weakening. Foremost in ORNL's effort to develop flux control is the work of J. S. Hsu. Early research [2,3] introduced direct control of air-gap flux in permanent magnet (PM) machines and demonstrated it with a flux-controlled generator. The configuration eliminates the problem of demagnetization because it diverts all the flux from the

  16. Open string wavefunctions in flux compactifications

    CERN Document Server

    Cámara, Pablo G

    2009-01-01

    We consider compactifications of type I supergravity on manifolds with SU(3) structure, in the presence of RR fluxes and magnetized D9-branes, and analyze the generalized Dirac and Laplace-Beltrami operators associated to the D9-brane worldvolume fields. These compactifications are T-dual to standard type IIB toroidal orientifolds with NSNS and RR 3-form fluxes and D3/D7 branes. By using techniques of representation theory and harmonic analysis, the spectrum of open string wavefunctions can be computed for Lie groups and their quotients, as we illustrate with explicit twisted tori examples. We find a correspondence between irreducible unitary representations of the Kaloper-Myers algebra and families of Kaluza-Klein excitations. We perform the computation of 2- and 3-point couplings for matter fields in the above flux compactifications, and compare our results with those of 4d effective supergravity.

  17. U-dual fluxes and Generalized Geometry

    CERN Document Server

    Aldazabal, G; Camara, Pablo G; Grana, M

    2010-01-01

    We perform a systematic analysis of generic string flux compactifications, making use of Exceptional Generalized Geometry (EGG) as an organizing principle. In particular, we establish the precise map between fluxes, gaugings of maximal 4d supergravity and EGG, identifying the complete set of gaugings that admit an uplift to 10d heterotic or type IIB supegravity backgrounds. Our results reveal a rich structure, involving new deformations of 10d supergravity backgrounds, such as the RR counterparts of the $\\beta$-deformation. These new deformations are expected to provide the natural extension of the $\\beta$-deformation to full-fledged F-theory backgrounds. Our analysis also provides some clues on the 10d origin of some of the particularly less understood gaugings of 4d supergravity. Finally, we derive the explicit expression for the effective superpotential in arbitrary N = 1 heterotic or type IIB orientifold compactifications, for all the allowed fluxes.

  18. Hamiltonian boundary term and quasilocal energy flux

    International Nuclear Information System (INIS)

    Chen, C.-M.; Nester, James M.; Tung, R.-S.

    2005-01-01

    The Hamiltonian for a gravitating region includes a boundary term which determines not only the quasilocal values but also, via the boundary variation principle, the boundary conditions. Using our covariant Hamiltonian formalism, we found four particular quasilocal energy-momentum boundary term expressions; each corresponds to a physically distinct and geometrically clear boundary condition. Here, from a consideration of the asymptotics, we show how a fundamental Hamiltonian identity naturally leads to the associated quasilocal energy flux expressions. For electromagnetism one of the four is distinguished: the only one which is gauge invariant; it gives the familiar energy density and Poynting flux. For Einstein's general relativity two different boundary condition choices correspond to quasilocal expressions which asymptotically give the ADM energy, the Trautman-Bondi energy and, moreover, an associated energy flux (both outgoing and incoming). Again there is a distinguished expression: the one which is covariant

  19. Evaluating Energy Flux in Vibrofluidized Granular Bed

    Directory of Open Access Journals (Sweden)

    N. A. Sheikh

    2013-01-01

    Full Text Available Granular flows require sustained input of energy for fluidization. A level of fluidization depends on the amount of heat flux provided to the flow. In general, the dissipation of the grains upon interaction balances the heat inputs and the resultant flow patterns can be described using hydrodynamic models. However, with the increase in packing fraction, the heat fluxes prediction of the cell increases. Here, a comparison is made for the proposed theoretical models against the MD simulations data. It is observed that the variation of packing fraction in the granular cell influences the heat flux at the base. For the elastic grain-base interaction, the predictions vary appreciably compared to MD simulations, suggesting the need to accurately model the velocity distribution of grains for averaging.

  20. Warped Kähler potentials and fluxes

    International Nuclear Information System (INIS)

    Martucci, Luca

    2017-01-01

    The four-dimensional effective theory for type IIB warped flux compactifications proposed in https://www.doi.org/10.1007/JHEP03(2015)067 is completed by taking into account the backreaction of the Kähler moduli on the three-form fluxes. The only required modification consists in a flux-dependent contribution to the chiral fields parametrising the Kähler moduli. The resulting supersymmetric effective theory satisfies the no-scale condition and consistently combines previous partial results present in the literature. Similar results hold for M-theory warped compactifications on Calabi-Yau fourfolds, whose effective field theory and Kähler potential are also discussed.

  1. Type IIB flux compactifications on twistor bundles

    Energy Technology Data Exchange (ETDEWEB)

    Imaanpur, Ali, E-mail: aimaanpu@modares.ac.ir

    2014-02-05

    We construct a U(1) bundle over N(1,1), usually considered as an SO(3) bundle on CP{sup 2}, and show that type IIB supergravity can be consistently compactified over it. With the five form flux turned on, there is a solution for which the metric becomes Einstein. We further turn on 3-form fluxes and show that there is a one parameter family of solutions. In particular, there is a limiting solution of large 3-form fluxes for which two U(1) fiber directions of the metric shrink to zero size. We also discuss compactifications over N(1,1) to AdS{sub 3}. All solutions turn out to be non-supersymmetric.

  2. Enumerating Flux Vacua With Enhanced Symmetries

    Energy Technology Data Exchange (ETDEWEB)

    DeWolfe, O.

    2004-11-12

    We study properties of flux vacua in type IIB string theory in several simple but illustrative models. We initiate the study of the relative frequencies of vacua with vanishing superpotential W = 0 and with certain discrete symmetries. For the models we investigate we also compute the overall rate of growth of the number of vacua as a function of the D3-brane charge associated to the fluxes, and the distribution of vacua on the moduli space. The latter two questions can also be addressed by the statistical theory developed by Ashok, Denef and Douglas, and our results are in good agreement with their predictions. Analysis of the first two questions requires methods which are more number-theoretic in nature. We develop some elementary techniques of this type, which are based on arithmetic properties of the periods of the compactification geometry at the points in moduli space where the flux vacua are located.

  3. Atmosphere–Surface Fluxes of CO2 using Spectral Techniques

    DEFF Research Database (Denmark)

    Sørensen, Lise Lotte; Larsen, Søren Ejling

    2010-01-01

    Different flux estimation techniques are compared here in order to evaluate air–sea exchange measurement methods used on moving platforms. Techniques using power spectra and cospectra to estimate fluxes are presented and applied to measurements of wind speed and sensible heat, latent heat and CO2...... fluxes. Momentum and scalar fluxes are calculated from the dissipation technique utilizing the inertial subrange of the power spectra and from estimation of the cospectral amplitude, and both flux estimates are compared to covariance derived fluxes. It is shown how even data having a poor signal......-to-noise ratio can be used for flux estimations....

  4. Software applications for flux balance analysis.

    Science.gov (United States)

    Lakshmanan, Meiyappan; Koh, Geoffrey; Chung, Bevan K S; Lee, Dong-Yup

    2014-01-01

    Flux balance analysis (FBA) is a widely used computational method for characterizing and engineering intrinsic cellular metabolism. The increasing number of its successful applications and growing popularity are possibly attributable to the availability of specific software tools for FBA. Each tool has its unique features and limitations with respect to operational environment, user-interface and supported analysis algorithms. Presented herein is an in-depth evaluation of currently available FBA applications, focusing mainly on usability, functionality, graphical representation and inter-operability. Overall, most of the applications are able to perform basic features of model creation and FBA simulation. COBRA toolbox, OptFlux and FASIMU are versatile to support advanced in silico algorithms to identify environmental and genetic targets for strain design. SurreyFBA, WEbcoli, Acorn, FAME, GEMSiRV and MetaFluxNet are the distinct tools which provide the user friendly interfaces in model handling. In terms of software architecture, FBA-SimVis and OptFlux have the flexible environments as they enable the plug-in/add-on feature to aid prospective functional extensions. Notably, an increasing trend towards the implementation of more tailored e-services such as central model repository and assistance to collaborative efforts was observed among the web-based applications with the help of advanced web-technologies. Furthermore, most recent applications such as the Model SEED, FAME, MetaFlux and MicrobesFlux have even included several routines to facilitate the reconstruction of genome-scale metabolic models. Finally, a brief discussion on the future directions of FBA applications was made for the benefit of potential tool developers.

  5. Can Polar Fields Explain Missing Open Flux?

    Science.gov (United States)

    Linker, J.; Downs, C.; Caplan, R. M.; Riley, P.; Mikic, Z.; Lionello, R.

    2017-12-01

    The "open" magnetic field is the portion of the Sun's magnetic field that extends out into the heliosphere and becomes the interplanetary magnetic field (IMF). Both the IMF and the Sun's magnetic field in the photosphere have been measured for many years. In the standard paradigm of coronal structure, the open magnetic field originates primarily in coronal holes. The regions that are magnetically closed trap the coronal plasma and give rise to the streamer belt. This basic picture is qualitatively reproduced by models of coronal structure using photospheric magnetic fields as input. If this paradigm is correct, there are two primary observational constraints on the models: (1) The open field regions in the model should approximately correspond to coronal holes observed in emission, and (2) the magnitude of the open magnetic flux in the model should match that inferred from in situ spacecraft measurements. Linker et al. (2017, ApJ, submitted) investigated the July 2010 time period for a range of observatory maps and both PFSS and MHD models. We found that all of the model/map combinations underestimated the interplanetary magnetic flux, unless the modeled open field regions were larger than observed coronal holes. An estimate of the open magnetic flux made entirely from solar observations (combining detected coronal hole boundaries with observatory synoptic magnetic maps) also underestimated the interplanetary magnetic flux. The magnetic field near the Sun's poles is poorly observed and may not be well represented in observatory maps. In this paper, we explore whether an underestimate of the polar magnetic flux during this time period could account for the overall underestimate of open magnetic flux. Research supported by NASA, AFOSR, and NSF.

  6. Eddy Correlation Flux Measurement System Handbook

    Energy Technology Data Exchange (ETDEWEB)

    Cook, D. R. [Argonne National Lab. (ANL), Argonne, IL (United States)

    2016-01-01

    The eddy correlation (ECOR) flux measurement system provides in situ, half-hour measurements of the surface turbulent fluxes of momentum, sensible heat, latent heat, and carbon dioxide (CO2) (and methane at one Southern Great Plains extended facility (SGP EF) and the North Slope of Alaska Central Facility (NSA CF). The fluxes are obtained with the eddy covariance technique, which involves correlation of the vertical wind component with the horizontal wind component, the air temperature, the water vapor density, and the CO2 concentration. The instruments used are: • a fast-response, three-dimensional (3D) wind sensor (sonic anemometer) to obtain the orthogonal wind components and the speed of sound (SOS) (used to derive the air temperature) • an open-path infrared gas analyzer (IRGA) to obtain the water vapor density and the CO2 concentration, and • an open-path infrared gas analyzer (IRGA) to obtain methane density and methane flux at one SGP EF and at the NSA CF. The ECOR systems are deployed at the locations where other methods for surface flux measurements (e.g., energy balance Bowen ratio [EBBR] systems) are difficult to employ, primarily at the north edge of a field of crops. A Surface Energy Balance System (SEBS) has been installed collocated with each deployed ECOR system in SGP, NSA, Tropical Western Pacific (TWP), ARM Mobile Facility 1 (AMF1), and ARM Mobile Facility 2 (AMF2). The surface energy balance system consists of upwelling and downwelling solar and infrared radiometers within one net radiometer, a wetness sensor, and soil measurements. The SEBS measurements allow the comparison of ECOR sensible and latent heat fluxes with the energy balance determined from the SEBS and provide information on wetting of the sensors for data quality purposes. The SEBS at one SGP and one NSA site also support upwelling and downwelling PAR measurements to qualify those two locations as Ameriflux sites.

  7. Wet Deposition Flux of Reactive Organic Carbon

    Science.gov (United States)

    Safieddine, S.; Heald, C. L.

    2016-12-01

    Reactive organic carbon (ROC) is the sum of non-methane volatile organic compounds (NMVOCs) and primary and secondary organic aerosols (OA). ROC plays a key role in driving the chemistry of the atmosphere, affecting the hydroxyl radical concentrations, methane lifetime, ozone formation, heterogeneous chemical reactions, and cloud formation, thereby impacting human health and climate. Uncertainties on the lifecycle of ROC in the atmosphere remain large. In part this can be attributed to the large uncertainties associated with the wet deposition fluxes. Little is known about the global magnitude of wet deposition as a sink of both gas and particle phase organic carbon, making this an important area for research and sensitivity testing in order to better understand the global ROC budget. In this study, we simulate the wet deposition fluxes of the reactive organic carbon of the troposphere using a global chemistry transport model, GEOS-Chem. We start by showing the current modeled global distribution of ROC wet deposition fluxes and investigate the sensitivity of these fluxes to variability in Henry's law solubility constants and spatial resolution. The average carbon oxidation state (OSc) is a useful metric that depicts the degree of oxidation of atmospheric reactive carbon. Here, we present for the first time the simulated gas and particle phase OSc of the global troposphere. We compare the OSc in the wet deposited reactive carbon flux and the dry deposited reactive carbon flux to the OSc of atmospheric ROC to gain insight into the degree of oxidation in deposited material and, more generally, the aging of organic material in the troposphere.

  8. Depicting CH4 fluxes and drivers dynamics

    Science.gov (United States)

    Dengel, S.; Billesbach, D. P.; Hughes, H.; Humphreys, E.; Lee, J.; Noormets, A.; Verfaillie, J. G.

    2016-12-01

    Since the advancement in CH4 eddy covariance flux measurements, monitoring of CH4 emissions is becoming more widespread. Since CH4 fluxes are not as predictable or as easily interpretable as CO2 fluxes, understanding their emission patterns often still challenging. As these are spatially (ecosystem and latitudinal) and temporal very divers and often event based, a better understanding or interpretation of results is required. An improvement in understanding does also increase the reliability of gap-filling methods as annual greenhouse gas budgets rely on high quality data. There are generalised additive models (Wood 2001) that can easily be applied to sites, models where a relationship between the response variable, in this case CH4 and explanatory variables (drivers) is established. Relevant for CH4flux dynamics are the smoothing function that is applied, where each predictor variable is separated into sections and a polynomial function fitted. On the one hand such models are rarely used as they are difficult to interpret since no parameter values are retuned. On the other hand, such models are very good for prediction and explanatory analysis in estimating the functional nature of a response. Applying such models to CH4 eddy flux data does improve our understanding of the dynamics of CH4 emissions and the respective meteorological drivers. Furthermore, such models combined with tree models (interactions between the explanatory variables), can visualise precise dynamics and easily applied to individual sites. These models are simple tools in understanding of these complex fluxes, as they can include a variety of drivers, and their relevance tested by the model. Model input variables should be as independent as possible (avoiding cross-correlation), avoiding redundant inputs, as models should follow the principle of parsimony of being simple but not too simple. Wood SN (2001). mgcv: GAMs and generalized ridge regression for R. R news.

  9. Flexible Mediation Analysis With Multiple Mediators.

    Science.gov (United States)

    Steen, Johan; Loeys, Tom; Moerkerke, Beatrijs; Vansteelandt, Stijn

    2017-07-15

    The advent of counterfactual-based mediation analysis has triggered enormous progress on how, and under what assumptions, one may disentangle path-specific effects upon combining arbitrary (possibly nonlinear) models for mediator and outcome. However, current developments have largely focused on single mediators because required identification assumptions prohibit simple extensions to settings with multiple mediators that may depend on one another. In this article, we propose a procedure for obtaining fine-grained decompositions that may still be recovered from observed data in such complex settings. We first show that existing analytical approaches target specific instances of a more general set of decompositions and may therefore fail to provide a comprehensive assessment of the processes that underpin cause-effect relationships between exposure and outcome. We then outline conditions for obtaining the remaining set of decompositions. Because the number of targeted decompositions increases rapidly with the number of mediators, we introduce natural effects models along with estimation methods that allow for flexible and parsimonious modeling. Our procedure can easily be implemented using off-the-shelf software and is illustrated using a reanalysis of the World Health Organization's Large Analysis and Review of European Housing and Health Status (WHO-LARES) study on the effect of mold exposure on mental health (2002-2003). © The Author(s) 2017. Published by Oxford University Press on behalf of the Johns Hopkins Bloomberg School of Public Health. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.

  10. Diffusive flux of energy in binary mixtures

    International Nuclear Information System (INIS)

    Sampaio, R.S.

    1976-04-01

    The diffusive flux of energy j tilde is studied through the reduced diffusive flux of energy K tilde, which obeys equations of the form: sim(delta K tilde/delta grad rho sub(α))= sim(delta K tilde/delta grad theta)=0. By a representation theorem, herein proved, is obtained a general representation for K tilde which is simplified, for the case of binary mixtures, using the principle of objectivity. Some consequences of this representation are discussed such as the symmetry of the partial stresses T 1 tilde and T 2 tilde and the difference between the normal stresses [pt

  11. Observation of a Coulomb flux tube

    Science.gov (United States)

    Greensite, Jeff; Chung, Kristian

    2018-03-01

    In Coulomb gauge there is a longitudinal color electric field associated with a static quark-antiquark pair. We have measured the spatial distribution of this field, and find that it falls off exponentially with transverse distance from a line joining the two quarks. In other words there is a Coulomb flux tube, with a width that is somewhat smaller than that of the minimal energy flux tube associated with the asymptotic string tension. A confinement criterion for gauge theories with matter fields is also proposed.

  12. Atmospheric electron flux at airplane altitude

    International Nuclear Information System (INIS)

    Enomoto, R.; Chiba, J.; Ogawa, K.; Sumiyoshi, T.; Takasaki, F.; Kifune, T.; Matsubara, Y.; Nishimura, J.

    1991-01-01

    We have developed a new detector to systematically measure the cosmic-ray electron flux at airplane altitudes. We loaded a lead-glass-based electron telescope onto a commercial cargo airplane. The first experiment was carried out using the air route between Narita (Japan) and Sydney (Australia); during this flight we measured the electron flux at various altitudes and latitudes. The thresholds of the electron energies were 1, 2, and 4 GeV. The results agree with a simple estimation using one-dimensional shower theory. A comparison with a Monte Carlo calculation was made

  13. Growth of zircaloy 4 under neutron flux

    International Nuclear Information System (INIS)

    Morize, P.; Baicry, J.; Morlot, G.; Sciers, P.; Lehmann, D.

    1982-06-01

    Between 300 and 385 0 C, and under neutron fluxes between 0.5 and 2.10 14 n/cm 2 /s, the growth of zircaloy tubes is nil in the plane perpendicular to the axis, and can be represented by the equation: Δl/l=4.6610 -14 (phit)sup(0.49) in the axial direction. In the area investigated, neither the irradiation temperature nor the instantaneous flux has any effect on the metallurgical state (relieved or recrystallized) [fr

  14. Dual neutron flux/temperature measurement sensor

    Science.gov (United States)

    Mihalczo, John T.; Simpson, Marc L.; McElhaney, Stephanie A.

    1994-01-01

    Simultaneous measurement of neutron flux and temperature is provided by a single sensor which includes a phosphor mixture having two principal constituents. The first constituent is a neutron sensitive 6LiF and the second is a rare-earth activated Y203 thermophosphor. The mixture is coated on the end of a fiber optic, while the opposite end of the fiber optic is coupled to a light detector. The detected light scintillations are quantified for neutron flux determination, and the decay is measured for temperature determination.

  15. Gravitational effects on planetary neutron flux spectra

    Science.gov (United States)

    Feldman, W. C.; Drake, D. M.; O'Dell, R. D.; Brinkley, F. W., Jr.; Anderson, R. C.

    1989-01-01

    The effects of gravity on the planetary neutron flux spectra for planet Mars, and the lifetime of the neutron, were investigated using a modified one-dimensional diffusion accelerated neutral-particle transport code, coupled with a multigroup cross-section library tailored specifically for Mars. The results showed the presence of a qualitatively new feature in planetary neutron leakage spectra in the form of a component of returning neutrons with kinetic energies less than the gravitational binding energy (0.132 eV for Mars). The net effect is an enhancement in flux at the lowest energies that is largest at and above the outermost layer of planetary matter.

  16. Flux pinning characteristics of YBCO coated conductor

    International Nuclear Information System (INIS)

    Matsushita, T.; Watanabe, T.; Fukumoto, Y.; Yamauchi, K.; Kiuchi, M.; Otabe, E.S.; Kiss, T.; Watanabe, T.; Miyata, S.; Ibi, A.; Muroga, T.; Yamada, Y.; Shiohara, Y.

    2005-01-01

    Flux pinning properties of PLD-processed YBCO coated conductors deposited on IBAD substrate are investigated. The thickness of YBCO layer is changed in the range of 0.27-1.0 μm. The thickness dependence of critical current density, n-value and irreversibility field are measured in a wide range of magnetic field. The results are compared with the theoretical flux creep-flow model. It is found that these pinning properties are strongly influenced by the thickness as well as the pinning strength. Optimum condition for high field application of this superconductor is discussed

  17. Planck intermediate results - LII. Planet flux densities

    DEFF Research Database (Denmark)

    Akrami, Y.; Ashdown, M.; Aumont, J.

    2017-01-01

    Measurements of flux density are described for five planets, Mars, Jupiter, Saturn, Uranus, and Neptune, across the six Planck High Frequency Instrument frequency bands (100–857 GHz) and these are then compared with models and existing data. In our analysis, we have also included estimates of the...... experiments. In particular, we observe that the flux densities measured by Planck HFI and WMAP agree to within 2%. These results allow experiments operating in the mm-wavelength range to cross-calibrate against Planck and improve models of radiative transport used in planetary science....

  18. ROCK1 is associated with Alzheimer’s disease-specific plaques, as well as enhances autophagosome formation but not autophagic Aβ clearance

    Directory of Open Access Journals (Sweden)

    Yong-Bo Hu

    2016-11-01

    Full Text Available Alzheimer’s disease (AD is the most prevalent form of late-life dementia in the population, characterised by amyloid plaque formation and increased tau deposition, which is modulated by Rho-associated coiled-coil kinase 1 (ROCK1. In this study, we further analyse whether ROCK1 regulates the metabolism of amyloid precursor protein (APP. We show that ROCK1 is colocalised with mature Aβ plaques in patients with AD, in that ROCK1 enhances the amyloidogenic pathway, and that ROCK1 mediated autophagy enhances the intracellular buildup of Aβ in a cell model of AD, (confirmed by increased ROCK1 and decreased Beclin 1 protein levels, with neuronal autophagosome accumulation in prefrontal cortex of AD APP/PS1 mouse model. In vitro over-expression of ROCK1 leads to a decrease in Aβ secretion and an increase in the expression of autophagy-related molecules. ROCK1 interacts with Beclin1, an autophagy initiator, and enhances the intracellular accumulation of Aβ. Reciprocally, overexpression of APP/Aβ promotes ROCK1 expression. Our data suggest ROCK1 participates in regulating Aβ secretion, APP shedding and autophagosome accumulation, and that ROCK1, rather than other kinases, is more likely to be a targetable enzyme for AD therapy.

  19. Pirarubicin induces an autophagic cytoprotective response through suppression of the mammalian target of rapamycin signaling pathway in human bladder cancer cells

    International Nuclear Information System (INIS)

    Li, Kuiqing; Chen, Xu; Liu, Cheng; Gu, Peng; Li, Zhuohang; Wu, Shaoxu; Xu, Kewei; Lin, Tianxin; Huang, Jian

    2015-01-01

    Pirarubicin is widely used in intravesical chemotherapy for bladder cancer, but its efficacy is limited due to drug resistance; the mechanism has not been well studied. Emerging evidence shows that autophagy can be a novel target for cancer therapy. This study aimed to investigate the role of autophagy in pirarubicin-treated bladder cancer cells. Bladder cancer cells EJ and J82 were treated with pirarubicin, siRNA, 3-methyladenine or hydroxychloroquine. Cell proliferation and apoptosis were tested by cell survival assay and flow cytometric analysis, respectively. Autophagy was evaluated by immunoblotting before and after the treatments. The phosphorylated mammalian target of rapamycin, serine/threonine kinase p70 S6 kinase, and eukaryotic translation initiation factor 4E binding protein 1 were also investigated by immunoblotting. We found that pirarubicin could induce autophagy in bladder cancer cells. Inhibition of autophagy by 3-methyladenine, hydroxychloroquine or knockdown of autophagy related gene 3 significantly increased apoptosis in pirarubicin-treated bladder cancer cells. Pirarubicin-induced autophagy was mediated via the mTOR/p70S6K/4E-BP1 signaling pathway. In conclusion, autophagy induced by pirarubicin plays a cytoprotective role in bladder cancer cells, suggesting that inhibition of autophagy may improve efficacy over traditional pirarubicin chemotherapy in bladder cancer patients. - Highlights: • Pirarubicin induced autophagy in bladder cancer cells. • Inhibition of autophagy enhanced pirarubicin-induced apoptosis. • Pirarubicin induced autophagy through inhibition of mTOR signaling pathway

  20. Pirarubicin induces an autophagic cytoprotective response through suppression of the mammalian target of rapamycin signaling pathway in human bladder cancer cells

    Energy Technology Data Exchange (ETDEWEB)

    Li, Kuiqing; Chen, Xu [Department of Urology, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Guangzhou 510120 (China); Guangdong Provincial Key Laboratory of Malignant Tumor Epigenetics and Gene Regulation, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Guangzhou 510120 (China); Liu, Cheng [Department of Urology, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Guangzhou 510120 (China); Gu, Peng; Li, Zhuohang; Wu, Shaoxu [Department of Urology, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Guangzhou 510120 (China); Guangdong Provincial Key Laboratory of Malignant Tumor Epigenetics and Gene Regulation, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Guangzhou 510120 (China); Xu, Kewei [Department of Urology, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Guangzhou 510120 (China); Lin, Tianxin, E-mail: tianxinl@sina.com [Department of Urology, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Guangzhou 510120 (China); Guangdong Provincial Key Laboratory of Malignant Tumor Epigenetics and Gene Regulation, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Guangzhou 510120 (China); Huang, Jian, E-mail: urolhj@sina.com [Department of Urology, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Guangzhou 510120 (China)

    2015-05-01

    Pirarubicin is widely used in intravesical chemotherapy for bladder cancer, but its efficacy is limited due to drug resistance; the mechanism has not been well studied. Emerging evidence shows that autophagy can be a novel target for cancer therapy. This study aimed to investigate the role of autophagy in pirarubicin-treated bladder cancer cells. Bladder cancer cells EJ and J82 were treated with pirarubicin, siRNA, 3-methyladenine or hydroxychloroquine. Cell proliferation and apoptosis were tested by cell survival assay and flow cytometric analysis, respectively. Autophagy was evaluated by immunoblotting before and after the treatments. The phosphorylated mammalian target of rapamycin, serine/threonine kinase p70 S6 kinase, and eukaryotic translation initiation factor 4E binding protein 1 were also investigated by immunoblotting. We found that pirarubicin could induce autophagy in bladder cancer cells. Inhibition of autophagy by 3-methyladenine, hydroxychloroquine or knockdown of autophagy related gene 3 significantly increased apoptosis in pirarubicin-treated bladder cancer cells. Pirarubicin-induced autophagy was mediated via the mTOR/p70S6K/4E-BP1 signaling pathway. In conclusion, autophagy induced by pirarubicin plays a cytoprotective role in bladder cancer cells, suggesting that inhibition of autophagy may improve efficacy over traditional pirarubicin chemotherapy in bladder cancer patients. - Highlights: • Pirarubicin induced autophagy in bladder cancer cells. • Inhibition of autophagy enhanced pirarubicin-induced apoptosis. • Pirarubicin induced autophagy through inhibition of mTOR signaling pathway.

  1. Flux pinning and flux flow studies in superconductors using flux flow noise techniques. Progress report, April 1-December 30, 1979

    International Nuclear Information System (INIS)

    Joiner, W.C.H.

    1979-12-01

    Flux flow noise power spectra were investigated, and information obtained through such spectra is applied to describe flux flow and pinning in situations where volume pinning force data is also available. In one case, the application of noise data to PB 80 In 20 samples after recovery and after high temperature annealing is discussed. This work is consistent with a recent model for flux flow noise generation. In the second case we discuss experiments designed to change the fluxoid transit path length, which according to the model should affect both the noise amplitude and the parameter α specifying the longest subpulse times in terms of the average transit time, tau/sub c/. Transient flux flow voltages when a current is switched on after field cycling a Pb 60 In 40 sample have been discovered. Noise spectra have been measured during the transient. These observations are discussed along with a simple model which fits the data. A surprising result is that the transient decay times increase with the applied current. Other characteristics of Pb 60 In 40 after cold working are also discussed

  2. Immunologically mediated oral diseases

    OpenAIRE

    Jimson, Sudha; Balachader, N.; Anita, N.; Babu, R.

    2015-01-01

    Immune mediated diseases of oral cavity are uncommon. The lesions may be self-limiting and undergo remission spontaneously. Among the immune mediated oral lesions the most important are lichen planus, pemphigus, erythema multiformi, epidermolysis bullosa, systemic lupus erythematosis. Cellular and humoral mediated immunity play a major role directed against epithelial and connective tissue in chronic and recurrent patterns. Confirmatory diagnosis can be made by biopsy, direct and indirect imm...

  3. Applied mediation analyses

    DEFF Research Database (Denmark)

    Lange, Theis; Hansen, Kim Wadt; Sørensen, Rikke

    2017-01-01

    In recent years, mediation analysis has emerged as a powerful tool to disentangle causal pathways from an exposure/treatment to clinically relevant outcomes. Mediation analysis has been applied in scientific fields as diverse as labour market relations and randomized clinical trials of heart...... disease treatments. In parallel to these applications, the underlying mathematical theory and computer tools have been refined. This combined review and tutorial will introduce the reader to modern mediation analysis including: the mathematical framework; required assumptions; and software implementation...

  4. An Overview of Flux Pumps for HTS Coils

    OpenAIRE

    Coombs, Timothy Arthur; Geng, Jianzhao; Fu, L; Matsuda, K

    2016-01-01

    High-Tc superconducting (HTS) flux pumps are capable of injecting flux into closed HTS magnets without electrical contact. It is becoming a promising alternative of current source in powering HTS coils. This paper reviews the recent progress in flux pumps for HTS coil magnets. Different types of HTS flux pumps are introduced. The physics of these flux pumps are explained and comparisons are made. J. Geng would like to acknowledge Cambridge Trust for offering Cambridge International Scholar...

  5. Implementing general gauge mediation

    International Nuclear Information System (INIS)

    Carpenter, Linda M.; Dine, Michael; Festuccia, Guido; Mason, John D.

    2009-01-01

    Recently there has been much progress in building models of gauge mediation, often with predictions different than those of minimal gauge mediation. Meade, Seiberg, and Shih have characterized the most general spectrum which can arise in gauge-mediated models. We discuss some of the challenges of building models of general gauge mediation, especially the problem of messenger parity and issues connected with R symmetry breaking and CP violation. We build a variety of viable, weakly coupled models which exhibit some or all of the possible low energy parameters.

  6. The Schizosaccharomyces pombe Mediator

    DEFF Research Database (Denmark)

    Venturi, Michela

    , Schizosaccharomyces pombe and mammalian Mediator. In our study, we have taken the S. pombe Mediator into consideration and characterized genetically and biochemically two subunits already know in S. cerevisiae, Med9 and Med11, but still not identified in the S. pombe Mediator. Genetic analysis has shown that med9...... complex, but our results did not exclude it completely either. Our attempts to demonstrate the presence of these two subunits in the Mediator complex remain inconclusive primarily due to the lack of proper expression of the tagged versions of the proteins. However, we have paved a way to further...

  7. Integrated passive flux measurement in groundwater: design and performance of iFLUX samplers

    Science.gov (United States)

    Verreydt, Goedele; Razaei, Meisam; Meire, Patrick; Van Keer, Ilse; Bronders, Jan; Seuntjens, Piet

    2017-04-01

    The monitoring and management of soil and groundwater is a challenge. Current methods for the determination of movement or flux of pollution in groundwater use no direct measurements but only simulations based on concentration measurements and Darcy velocity estimations. This entails large uncertainties which cause remediation failures and higher costs for contaminated site owners. On top of that, the lack of useful data makes it difficult to get approval for a risk-based management approach which completely avoids costly remedial actions. The iFLUX technology is a key development of Dr. Goedele Verreydt at the University of Antwerp and VITO. It is supported by the passive flux measurement technology as invented by Prof. Mike Annable and his team at the University of Florida. The iFLUX technology includes an in situ measurement device for capturing dynamic groundwater quality and quantity, the iFLUX sampler, and an associated interpretation and visualization method. The iFLUX sampler is a modular passive sampler that provides simultaneous in situ point determinations of a time-averaged target compound mass flux and water flux. The sampler is typically installed in a monitoring well where it intercepts the groundwater flow and captures the compounds of interest. The sampler consists of permeable cartridges which are each packed with a specific sorbent matrix. The sorbent matrix of the water flux cartridge is impregnated with known amounts of water soluble resident tracers. These tracers are leached from the matrix at rates proportional to the groundwater flux. The measurements of the contaminants and the remaining resident tracer are used to determine groundwater and target compound fluxes. Exposure times range from 1 week to 6 months, depending on the expected concentration and groundwater flow velocity. The iFLUX sampler technology has been validated and tested at several field projects. Currently, 4 cartridges are tested and available: 1 waterflux cartridge to

  8. A flux footprint analysis to understand ecosystem fluxes in an intensively managed landscape

    Science.gov (United States)

    Hernandez Rodriguez, L. C.; Goodwell, A. E.; Kumar, P.

    2017-12-01

    Flux tower studies in agricultural sites have mainly been done at plot scale, where the footprint of the instruments is small such that the data reveals the behaviour of the nearby crop on which the study is focused. In the Midwestern United States, the agricultural ecosystem and its associated drainage, evapotranspiration, and nutrient dynamics are dominant influences on interactions between the soil, land, and atmosphere. In this study, we address large-scale ecohydrologic fluxes and states in an intensively managed landscape based on data from a 25m high eddy covariance flux tower. We show the calculated upwind distance and flux footprint for a flux tower located in Central Illinois as part of the Intensively Managed Landscapes Critical Zone Observatory (IMLCZO). In addition, we calculate the daily energy balance during the summer of 2016 from the flux tower measurements and compare with the modelled energy balance from a representative corn crop located in the flux tower footprint using the Multi-Layer Canopy model, MLCan. The changes in flux footprint over the course of hours, days, and the growing season have significant implications for the measured fluxes of carbon and energy at the flux tower. We use MLCan to simulate these fluxes under land covers of corn and soybeans. Our results demonstrate how the instrument heights impact the footprint of the captured eddy covariance fluxes, and we explore the implication for hydrological analysis. The convective turbulent atmosphere during the daytime shows a wide footprint of more than 10 km2, which reaches 3km length for the 90% contribution, where buoyancy is the dominant mechanism driving turbulence. In contrast, the stable atmosphere during the night-time shows a narrower footprint that goes beyond 8km2 and grows in the direction of the prevalent wind, which exceeds 4 km in length. This study improves our understanding of agricultural ecosystem behaviour in terms of the magnitude and variability of fluxes and

  9. Apparatus for measuring low thermal fluxes

    International Nuclear Information System (INIS)

    Aranovitch, R.; Warnery, M.

    1972-01-01

    Device for the measurement of slight wall heat fluxes, made up of a metallic contact plate combined with a shaft; temperature measurement elements are spaced along the shaft which is kept at a cold adjustable reference temperature lower than that of the walls; heat insulation is provided for the exposed part of the plate and for the shaft [fr

  10. Terrestrial water fluxes dominated by transpiration: Comment

    Science.gov (United States)

    Daniel R. Schlaepfer; Brent E. Ewers; Bryan N. Shuman; David G. Williams; John M. Frank; William J. Massman; William K. Lauenroth

    2014-01-01

    The fraction of evapotranspiration (ET) attributed to plant transpiration (T) is an important source of uncertainty in terrestrial water fluxes and land surface modeling (Lawrence et al. 2007, Miralles et al. 2011). Jasechko et al. (2013) used stable oxygen and hydrogen isotope ratios from 73 large lakes to investigate the relative roles of evaporation (E) and T in ET...

  11. EUV mirror based absolute incident flux detector

    Science.gov (United States)

    Berger, Kurt W.

    2004-03-23

    A device for the in-situ monitoring of EUV radiation flux includes an integrated reflective multilayer stack. This device operates on the principle that a finite amount of in-band EUV radiation is transmitted through the entire multilayer stack. This device offers improvements over existing vacuum photo-detector devices since its calibration does not change with surface contamination.

  12. Solitary wave propagation in solar flux tubes

    International Nuclear Information System (INIS)

    Erdelyi, Robert; Fedun, Viktor

    2006-01-01

    The aim of the present work is to investigate the excitation, time-dependent dynamic evolution, and interaction of nonlinear propagating (i.e., solitary) waves on vertical cylindrical magnetic flux tubes in compressible solar atmospheric plasma. The axisymmetric flux tube has a field strength of 1000 G at its footpoint, which is typical for photospheric regions. Nonlinear waves that develop into solitary waves are excited by a footpoint driver. The propagation of the nonlinear signal is investigated by solving numerically a set of fully nonlinear 2.0D magnetohydrodynamic (MHD) equations in cylindrical coordinates. For the initial conditions, axisymmetric solutions of the linear dispersion relation for wave modes in a magnetic flux tube are applied. In the present case, we focus on the sausage mode only. The dispersion relation is solved numerically for a range of plasma parameters. The equilibrium state is perturbed by a Gaussian at the flux tube footpoint. Two solitary solutions are found by solving the full nonlinear MHD equations. First, the nonlinear wave propagation with external sound speed is investigated. Next, the solitary wave propagating close to the tube speed, also found in the numerical solution, is studied. In contrast to previous analytical and numerical works, here no approximations were made to find the solitary solutions. A natural application of the present study may be spicule formation in the low chromosphere. Future possible improvements in modeling and the relevance of the photospheric chromospheric transition region coupling by spicules is suggested

  13. Annual Cycles of Surface Shortwave Radiative Fluxes

    Science.gov (United States)

    Wilber, Anne C.; Smith, G. Louis; Gupta, Shashi K.; Stackhouse, Paul W.

    2006-01-01

    The annual cycles of surface shortwave flux are investigated using the 8-yr dataset of the surface radiation budget (SRB) components for the period July 1983-June 1991. These components include the downward, upward, and net shortwave radiant fluxes at the earth's surface. The seasonal cycles are quantified in terms of principal components that describe the temporal variations and empirical orthogonal functions (EOFs) that describe the spatial patterns. The major part of the variation is simply due to the variation of the insolation at the top of the atmosphere, especially for the first term, which describes 92.4% of the variance for the downward shortwave flux. However, for the second term, which describes 4.1% of the variance, the effect of clouds is quite important and the effect of clouds dominates the third term, which describes 2.4% of the variance. To a large degree the second and third terms are due to the response of clouds to the annual cycle of solar forcing. For net shortwave flux at the surface, similar variances are described by each term. The regional values of the EOFs are related to climate classes, thereby defining the range of annual cycles of shortwave radiation for each climate class.

  14. Optimal flux patterns in cellular metabolic networks

    Energy Technology Data Exchange (ETDEWEB)

    Almaas, E

    2007-01-20

    The availability of whole-cell level metabolic networks of high quality has made it possible to develop a predictive understanding of bacterial metabolism. Using the optimization framework of flux balance analysis, I investigate metabolic response and activity patterns to variations in the availability of nutrient and chemical factors such as oxygen and ammonia by simulating 30,000 random cellular environments. The distribution of reaction fluxes is heavy-tailed for the bacteria H. pylori and E. coli, and the eukaryote S. cerevisiae. While the majority of flux balance investigations have relied on implementations of the simplex method, it is necessary to use interior-point optimization algorithms to adequately characterize the full range of activity patterns on metabolic networks. The interior-point activity pattern is bimodal for E. coli and S. cerevisiae, suggesting that most metabolic reaction are either in frequent use or are rarely active. The trimodal activity pattern of H. pylori indicates that a group of its metabolic reactions (20%) are active in approximately half of the simulated environments. Constructing the high-flux backbone of the network for every environment, there is a clear trend that the more frequently a reaction is active, the more likely it is a part of the backbone. Finally, I briefly discuss the predicted activity patterns of the central-carbon metabolic pathways for the sample of random environments.

  15. Predicting flux decline of reverse osmosis membranes

    NARCIS (Netherlands)

    Schippers, J.C.; Hanemaayer, J.H.; Smolders, C.A.; Kostense, A.

    1981-01-01

    A mathematical model predicting flux decline of reverse osmosis membranes due to colloidal fouling has been verified. This mathema- tical model is based on the theory of cake or gel filtration and the Modified Fouling Index (MFI). Research was conducted using artificial colloidal solutions and a

  16. Self-powered neutron flux detector assembly

    International Nuclear Information System (INIS)

    Allan, C.J.; McIntyre, I.L.

    1980-01-01

    A self-powered neutron flux detector has both the central emitter electrode and its surrounding collector electrode made of inconel 600. The lead cables may also be made of inconel. Other nickel alloys, or iron, nickel, titamium, chromium, zirconium or their alloys may also be used for the electrodes

  17. Radiation linewidth of flux-flow oscillators

    DEFF Research Database (Denmark)

    Koshelets, V.P.; Dmitriev, P.N.; Ermakov, A.B.

    2001-01-01

    (applied magnetic field) are taken. A profile of the FFO radiation line is measured in different regimes of FFO operation and compared to the theoretical models. A Lorentzian shape of the FFO line is observed both at Fiske steps (FSs) in the resonant regime and on the flux-flow step (FFS) at high voltages...

  18. SLC positron source flux concentrator modulator

    International Nuclear Information System (INIS)

    de Lamare, J.; Kulikov, A.; Cassel, R.; Nesterov, V.

    1991-06-01

    The modulator for the SLC e+ source flux concentrator provides 16 kA in a 5 μs sinusoidal half wave current for a pure inductive load, at 120 Hz. The modulator incorporates 10 EEV CX1622 thyratrons in a switching network. It provides reliable operation with acceptable thyratron lifetime. 3 refs., 3 figs., 1 tab

  19. AVERAGE FLUXES FROM HETEROGENEOUS VEGETATED REGIONS

    NARCIS (Netherlands)

    KLAASSEN, W

    Using a surface-layer model, fluxes of heat and momentum have been calculated for flat regions with regularly spaced step changes in surface roughness and stomatal resistance. The distance between successive step changes is limited to 10 km in order to fill the gap between micro-meteorological

  20. Models of Flux Tubes from Constrained Relaxation

    Indian Academy of Sciences (India)

    tribpo

    J. Astrophys. Astr. (2000) 21, 299 302. Models of Flux Tubes from Constrained Relaxation. Α. Mangalam* & V. Krishan†, Indian Institute of Astrophysics, Koramangala,. Bangalore 560 034, India. *e mail: mangalam @ iiap. ernet. in. † e mail: vinod@iiap.ernet.in. Abstract. We study the relaxation of a compressible plasma to ...

  1. Optical magnetic flux generation in superconductor

    Indian Academy of Sciences (India)

    Abstract. The generation of the magnetic flux quanta inside the superconductors is studied as a new effect to destroy superconductivity using femtosecond (fs) laser. The vortices are successfully generated in the YBa2Cu3O7−δ thin film striplines by the fs laser. It is revealed that the vortex distribution in the strip reflects the fs ...

  2. Physicochemical Flux and Phytoplankton diversity in Shagari ...

    African Journals Online (AJOL)

    USER

    2007-03-20

    Mar 20, 2007 ... Physicochemical Flux and Phytoplankton diversity in Shagari Reservoir,Sokoto, Nigeria. *1I.M. Magami, 1T. Adamu and 2A.A. Aliero. 1Zoology Unit, Department of Biological Sciences, Usmanu Danfodiyo University, Sokoto, Nigeria. 2Botany Unit, Department of Biological Sciences, Usmanu Danfodiyo ...

  3. Examining gas flux responses to restoration

    Science.gov (United States)

    Wetlands play an important role in the flux of gases such as carbon dioxide, methane, and nitrous oxide. Wetland ecosystems are characterized by slow decomposition and, often, high productivity, making them net sinks of carbon dioxide. However, under some conditions, such as ti...

  4. Modelling radiocesium fluxes in forest ecosystems

    International Nuclear Information System (INIS)

    Shaw, G.; Kliashtorin, A.; Mamikhin, S.; Shcheglov, A.; Rafferty, B.; Dvornik, A.; Zhuchenko, T.; Kuchma, N.

    1996-01-01

    Monitoring of radiocesium inventories and fluxes has been carried out in forest ecosystems in Ukraine, Belarus and Ireland to determine distributions and rates of migration. This information has been used to construct and calibrate mathematical models which are being used to predict the likely longevity of contamination of forests and forest products such as timber following the Chernobyl accident

  5. MAGNETIC FLUX CANCELLATION IN ELLERMAN BOMBS

    Energy Technology Data Exchange (ETDEWEB)

    Reid, A.; Mathioudakis, M.; Nelson, C. J.; Henriques, V. [Astrophysics Research Centre, School of Mathematics and Physics, Queen’s University Belfast, BT7 1NN, Northern Ireland (United Kingdom); Doyle, J. G. [Armagh Observatory, College Hill, Armagh, BT61 9DG (United Kingdom); Scullion, E. [Trinity College Dublin, College Green, Dublin 2 (Ireland); Ray, T., E-mail: areid29@qub.ac.uk [Dublin Institute for Advanced Studies, 31 Fitzwilliam Place, Dublin 2 (Ireland)

    2016-06-01

    Ellerman Bombs (EBs) are often found to be co-spatial with bipolar photospheric magnetic fields. We use H α imaging spectroscopy along with Fe i 6302.5 Å spectropolarimetry from the Swedish 1 m Solar Telescope (SST), combined with data from the Solar Dynamic Observatory , to study EBs and the evolution of the local magnetic fields at EB locations. EBs are found via an EB detection and tracking algorithm. Using NICOLE inversions of the spectropolarimetric data, we find that, on average, (3.43 ± 0.49) × 10{sup 24} erg of stored magnetic energy disappears from the bipolar region during EB burning. The inversions also show flux cancellation rates of 10{sup 14}–10{sup 15} Mx s{sup −1} and temperature enhancements of 200 K at the detection footpoints. We investigate the near-simultaneous flaring of EBs due to co-temporal flux emergence from a sunspot, which shows a decrease in transverse velocity when interacting with an existing, stationary area of opposite polarity magnetic flux, resulting in the formation of the EBs. We also show that these EBs can be fueled further by additional, faster moving, negative magnetic flux regions.

  6. Demystifying Electric Flux and Gauss's Law

    Science.gov (United States)

    McManus, Jeff

    2017-01-01

    Many physics students have experienced the difficulty of internalizing concepts in electrostatics. After studying concrete, measurable details in mechanics, they are challenged by abstract ideas such as electric fields, flux, Gauss's law, and electric potential. There are a few well-known hands-on activities that help students get experience with…

  7. Autophagy mediates cell cycle response by regulating nucleocytoplasmic transport of PAX6 in limbal stem cells under ultraviolet-A stress.

    Directory of Open Access Journals (Sweden)

    Maria Laggner

    Full Text Available Limbal stem cells (LSC account for homeostasis and regeneration of corneal epithelium. Solar ultraviolet A (UVA is the major source causing oxidative damage in the ocular surface. Autophagy, a lysosomal degradation mechanism, is essential for physiologic function and stress defense of stem cells. PAX6, a master transcription factor governing corneal homeostasis by regulating cell cycle and cell fate of LSC, responds to oxidative stress by nucleocytoplasmic shuttling. Impaired autophagy and deregulated PAX6 have been reported in oxidative stress-related ocular surface disorders. We hypothesize a functional role for autophagy and PAX6 in LSC's stress response to UVA. Therefore, human LSC colonies were irradiated with a sub-lethal dose of UVA and autophagic activity and intracellular reactive oxygen species (ROS were measured by CYTO-ID assay and CM-H2DCFDA live staining, respectively. Following UVA irradiation, the percentage of autophagic cells significantly increased in LSC colonies while intracellular ROS levels remained unaffected. siRNA-mediated knockdown (KD of ATG7 abolished UVA-induced autophagy and led to an excessive accumulation of ROS. Upon UVA exposure, LSCs displayed nuclear-to-cytoplasmic translocation of PAX6, while ATG7KD or antioxidant pretreatment largely attenuated the intracellular trafficking event. Immunofluorescence showing downregulation of proliferative marker PCNA and induction of cell cycle regulator p21 indicates cell cycle arrest in UVA-irradiated LSC. Abolishing autophagy, adenoviral-assisted restoration of nuclear PAX6 or antioxidant pretreatment abrogated the UVA-induced cell cycle arrest. Adenoviral expression of an ectopic PAX gene, PAX7, did not affect UVA cell cycle response. Furthermore, knocking down PAX6 attenuated the cell cycle progression of irradiated ATG7KD LSC by de-repressing p21 expression. Collectively, our data suggest a crosstalk between autophagy and PAX6 in regulating cell cycle response of

  8. What controls sediment flux in dryland channels?

    Science.gov (United States)

    Michaelides, K.; Singer, M. B.

    2010-12-01

    Theories for the development of longitudinal and grain size profiles in perennial fluvial systems are well developed, allowing for generalization of sediment flux and sorting in these fluvial systems over decadal to millennial time scales under different forcings (e.g., sediment supply, climate changes, etc). However, such theoretical frameworks are inadequate for understanding sediment flux in dryland channels subject to spatially and temporally discontinuous streamflow, where transport capacity is usually much lower than sediment supply. In such fluvial systems, channel beds are poorly sorted with weak vertical layering, poorly defined bar forms, minimal downstream fining, and straight longitudinal profiles. Previous work in dryland channels has documented sediment flux at higher rates than their humid counterparts once significant channel flow develops, pulsations in bed material transport under constant discharge, and oscillations in dryland channel width that govern longitudinal patterns in erosion and deposition. These factors point to less well appreciated controls on sediment flux in dryland valley floors that invite further study. This paper investigates the relative roles of hydrology, bed material grain size, and channel width on sediment flux rates in the Rambla de Nogalte in southeastern Spain. Topographic valley cross sections and hillslope and channel particle sizes were collected from an ephemeral-river reach. Longitudinal grain-size variation on the hillslopes and on the channel bed were analysed in order to determine the relationship between hillslope supply characteristics and channel grain-size distribution and longitudinal changes. Local fractional estimates of bed-material transport in the channel were calculated using a range of channel discharge scenarios in order to examine the effect of channel hydrology on sediment transport. Numerical modelling was conducted to investigate runoff connectivity from hillslopes to channel and to examine the

  9. The Solar-flux Third Granulation Signature

    Science.gov (United States)

    Gray, David F.; Oostra, Benjamin

    2018-01-01

    The velocity shifts of spectral lines as a function of line strength, so-called the third signature of granulation, are investigated using three published solar-flux atlases. We use flux atlases because we wish to treat the Sun as a star, against which stellar observations can be compared and judged. The atlases are critiqued and compared to the lower-resolution observations taken with the Elginfield stellar spectrograph. Third-signature plots are constructed for the 6020–6340 Å region. No dependence on excitation potential or wavelength is found over this wavelength span. The shape of the plots from the three solar atlases is essentially the same, with rms line-core velocity differences of 30–35 m s‑1. High-resolution atlas data are degraded to the level of the Elginfield spectrograph and compared to direct observations taken with that spectrograph. The line-core velocities show good agreement, with rms differences of 38 m s‑1. A new standard curve is derived and compared with the previously published one. Only small differences in shape are found, but a significant (+97 m s‑1) change in the zero point is indicated. The bisector of the Fe I 6253 line is mapped onto the third-signature plots and flux deficits are derived, which measure the granule/lane flux imbalance. The lower spectral resolution lowers the flux deficit area slightly and moves the peak of the deficit 0.3–0.5 km s‑1 toward higher velocities. These differences, while significant, are not large compared to measurement errors for stellar data.

  10. Flux trapping and shielding in irreversible superconductors

    International Nuclear Information System (INIS)

    Frankel, D.J.

    1978-05-01

    Flux trappings and shielding experiments were carried out on Pb, Nb, Pb-Bi, Nb-Sn, and Nb-Ti samples of various shapes. Movable Hall probes were used to measure fields near or inside the samples as a function of position and of applied field. The trapping of transverse multipole magnetic fields in tubular samples was accomplished by cooling the samples in an applied field and then smoothly reducing the applied field to zero. Transverse quadrupole and sextupole fields with gradients of over 2000 G/cm were trapped with typical fidelity to the original impressed field of a few percent. Transverse dipole fields of up to 17 kG were also trapped with similar fidelity. Shielding experiments were carried out by cooling the samples in zero field and then gradually applying an external field. Flux trapping and shielding abilities were found to be limited by two factors, the pinning strength of the material, and the susceptibility of a sample to flux jumping. The trapping and shielding behavior of flat disk samples in axial fields and thin-walled tubular samples in transverse fields was modeled. The models, which were based on the concept of the critical state, allowed a connection to be made between the pinning strength and critical current level, and the flux trapping and shielding abilities. Adiabatic and dynamic stability theories are discussed and applied to the materials tested. Good qualitative, but limited quantitative agreement was obtained between the predictions of the theoretical stability criteria and the observed flux jumping behavior

  11. How Giant Magnetospheres Maintain Their Magnetic Flux.

    Science.gov (United States)

    Rymer, A. M.

    2017-12-01

    Magnetic flux lost from a planet must be returned [Maxwell's first law, there are no magnetic monopoles (div(B) = 0)], and the dominant mechanism by which this is achieved is still to be determined. Here we compare a mechanism for magnetic flux return via small-scale plasma circulation. The existence of bi-modal superposed electron distributions at Jupiter and Saturn was a surprise to Voyager researchers [e.g. Sittler et al., 1983] that remains something of a mystery to this day. Electrons are virtually massless and are expected to rapidly thermalize to a single distribution. Observations by the Cassini spacecraft at Saturn have elucidated on the source of the hot electron component - small scale isolated flux tubes (commonly referred to as `injection events') that bubble planetward, returning magnetic flux that had been convected outward by centrifugal forces or stripped away during magnetospheric reconfigurations, such as substorms [Rymer et al., 2008]. Saturn is an ideal place to study injection events; relatively quiescent, aligned magnetic and geographic spins axes and a nice fast rotation rate in comparison to plasma drift speeds. The other magnetospheric laboratories in our solar system (Jupiter, Uranus and Neptune) will be more challenging. In this presentation we describe predictions for how plasma injection will be manifest as a function of magnetic field strength, topology and planetary spin rate and its importance in conservation of magnetic flux globally. Sittler, E. C., Jr., K. W. Ogilvie, and J. D. Scudder, 1983. Survey of low-energy plasma electrons in Saturn's magnetosphere: Voyager 1 and 2, J. Geophys. Res., 88, 8847- 8870. Rymer, A. M., Mauk, B. H. , Hill, T. W., Paranicas, C., Mitchell, D. G., Coates, A. J., Young, D. T. , 2008. Electron circulation in Saturn's magnetosphere. J. Geophys. Res.113, A01201.

  12. Comparison between Evapotranspiration Fluxes Assessment Methods

    Science.gov (United States)

    Casola, A.; Longobardi, A.; Villani, P.

    2009-11-01

    Knowledge of hydrological processes acting in the water balance is determinant for a rational water resources management plan. Among these, the water losses as vapour, in the form of evapotranspiration, play an important role in the water balance and the heat transfers between the land surface and the atmosphere. Mass and energy interactions between soil, atmosphere and vegetation, in fact, influence all hydrological processes modificating rainfall interception, infiltration, evapotraspiration, surface runoff and groundwater recharge.A numbers of methods have been developed in scientific literature for modelling evapotranspiration. They can be divided in three main groups: i) traditional meteorological models, ii) energy fluxes balance models, considering interaction between vegetation and the atmosphere, and iii) remote sensing based models. The present analysis preliminary performs a study of fluxes directions and an evaluation of energy balance closure in a typical Mediterranean short vegetation area, using data series recorded from an eddy covariance station, located in the Campania region, Southern Italy. The analysis was performed on different seasons of the year with the aim to assess climatic forcing features impact on fluxes balance, to evaluate the smaller imbalance and to highlight influencing factors and sampling errors on balance closure. The present study also concerns evapotranspiration fluxes assessment at the point scale. Evapotranspiration is evaluated both from empirical relationships (Penmann-Montheit, Penmann F AO, Prestley&Taylor) calibrated with measured energy fluxes at mentioned experimental site, and from measured latent heat data scaled by the latent heat of vaporization. These results are compared with traditional and reliable well known models at the plot scale (Coutagne, Turc, Thorthwaite).

  13. Laccase/Mediator Systems

    NARCIS (Netherlands)

    Hilgers, Roelant; Vincken, Jean Paul; Gruppen, Harry; Kabel, Mirjam A.

    2018-01-01

    Laccase-mediator systems (LMS) have been widely studied for their capacity to oxidize the nonphenolic subunits of lignin (70-90% of the polymer). The phenolic subunits (10-30% of the polymer), which can also be oxidized without mediators, have received considerably less attention. Consequently, it

  14. The influence of cattle grazing on methane fluxes and engaged microbial communities in alpine forest soils.

    Science.gov (United States)

    Mutschlechner, Mira; Praeg, Nadine; Illmer, Paul

    2018-05-01

    Recent dynamics and uncertainties in global methane budgets necessitate a dissemination of current knowledge on the controls of sources and sinks of atmospheric methane. Forest soils are considered to be efficient methane sinks; however, as they are microbially mediated they are sensitive to anthropogenic influences and tend to switch from being sinks to being methane sources. With regard to global changes in land use, the present study aimed at (i) investigating the influence of grazing on flux rates of methane in forest soils, (ii) deducing possible (a)biotic factors regulating these fluxes, and (iii) gaining an insight into the complex interactions between methane-cycling microorganisms and ecosystem functioning. Here we show that extensive grazing significantly mitigated the soil's sink strength for atmospheric methane through alterations of both microbial activity and community composition. In situ flux measurements revealed that all native, non-grazed areas were net methane consumers, while the adjacent, grazed areas were net methane producers. Whereas neither parent material nor soil properties including moisture and organic matter showed any correlation to the ascertained fluxes, significantly higher archaeal abundances at the grazed study sites indicated that small inputs of methanogens associated with cattle grazing may be sufficient to sustainably increase methane emissions.

  15. Suberoylanilide hydroxamic acid sensitizes neuroblastoma to paclitaxel by inhibiting thioredoxin-related protein 14-mediated autophagy.

    Science.gov (United States)

    Zhen, Zijun; Yang, Kaibin; Ye, Litong; You, Zhiyao; Chen, Rirong; Liu, Ying; He, Youjian

    2017-07-01

    Paclitaxel is not as effective for neuroblastoma as most of the front-line chemotherapeutics due to drug resistance. This study explored the regulatory mechanism of paclitaxel-associated autophagy and potential solutions to paclitaxel resistance in neuroblastoma. The formation of autophagic vesicles was detected by scanning transmission electron microscopy and flow cytometry. The autophagy-associated proteins were assessed by western blot. Autophagy was induced and the autophagy-associated proteins LC3-I, LC3-II, Beclin 1, and thioredoxin-related protein 14 (TRP14), were found to be upregulated in neuroblastoma cells that were exposed to paclitaxel. The inhibition of Beclin 1 or TRP14 by siRNA increased the sensitivity of the tumor cells to paclitaxel. In addition, Beclin 1-mediated autophagy was regulated by TRP14. Furthermore, the TRP14 inhibitor suberoylanilide hydroxamic acid (SAHA) downregulated paclitaxel-induced autophagy and enhanced the anticancer effects of paclitaxel in normal control cancer cells but not in cells with upregulated Beclin 1 and TRP14 expression. Our findings showed that paclitaxel-induced autophagy in neuroblastoma cells was regulated by TRP14 and that SAHA could sensitize neuroblastoma cells to paclitaxel by specifically inhibiting TRP14. © 2017 The Authors. Cancer Science published by John Wiley & Sons Australia, Ltd on behalf of Japanese Cancer Association.

  16. Gradient-driven flux-tube simulations of ion temperature gradient turbulence close to the non-linear threshold

    Energy Technology Data Exchange (ETDEWEB)

    Peeters, A. G.; Rath, F.; Buchholz, R.; Grosshauser, S. R.; Strintzi, D.; Weikl, A. [Physics Department, University of Bayreuth, Universitätsstrasse 30, Bayreuth (Germany); Camenen, Y. [Aix Marseille Univ, CNRS, PIIM, UMR 7345, Marseille (France); Candy, J. [General Atomics, PO Box 85608, San Diego, California 92186-5608 (United States); Casson, F. J. [CCFE, Culham Science Centre, Abingdon OX14 3DB, Oxon (United Kingdom); Hornsby, W. A. [Max Planck Institut für Plasmaphysik, Boltzmannstrasse 2 85748 Garching (Germany)

    2016-08-15

    It is shown that Ion Temperature Gradient turbulence close to the threshold exhibits a long time behaviour, with smaller heat fluxes at later times. This reduction is connected with the slow growth of long wave length zonal flows, and consequently, the numerical dissipation on these flows must be sufficiently small. Close to the nonlinear threshold for turbulence generation, a relatively small dissipation can maintain a turbulent state with a sizeable heat flux, through the damping of the zonal flow. Lowering the dissipation causes the turbulence, for temperature gradients close to the threshold, to be subdued. The heat flux then does not go smoothly to zero when the threshold is approached from above. Rather, a finite minimum heat flux is obtained below which no fully developed turbulent state exists. The threshold value of the temperature gradient length at which this finite heat flux is obtained is up to 30% larger compared with the threshold value obtained by extrapolating the heat flux to zero, and the cyclone base case is found to be nonlinearly stable. Transport is subdued when a fully developed staircase structure in the E × B shearing rate forms. Just above the threshold, an incomplete staircase develops, and transport is mediated by avalanche structures which propagate through the marginally stable regions.

  17. Music, radio and mediatization

    DEFF Research Database (Denmark)

    Michelsen, Morten; Krogh, Mads

    2016-01-01

    Mediatization has become a key concept for understanding the relations between media and other cultural and social fields. Contributing to the discussions related to the concept of mediatization, this article discusses how practices of radio and music(al life) influence each other. We follow Deacon......’s and Stanyer’s advice to supplement the concept of mediatization with ‘a series of additional concepts at lower levels of abstraction’ and suggest, in this respect, the notion of heterogeneous milieus of music–radio. Hereby, we turn away from the all-encompassing perspectives related to the concept...... of mediatization where media as such seem to be ascribed agency. Instead, we consider historical accounts of music–radio in order to address the complex nonlinearity of concrete processes of mediatization as they take place in the multiple meetings between a decentred notion of radio and musical life....

  18. Arctigenin inhibits the activation of the mTOR pathway, resulting in autophagic cell death and decreased ER expression in ER-positive human breast cancer cells.

    Science.gov (United States)

    Maxwell, Thressi; Lee, Kyu Shik; Kim, Soyoung; Nam, Kyung-Soo

    2018-04-01

    Arctigenin, a member of the Asteraceae family, is a biologically active lignan that is consumed worldwide due to its several health benefits. However, its use may pose a problem for patients with estrogen receptor (ER)α-positive breast cancer, since studies have shown that arctigenin is a phytoestrogen that exerts a proliferative effect by binding to the ER. Thus, in this study, we examined the effect of arctigenin on ERα-positive MCF-7 human breast cancer cells to determine whether the consumption of arctigenin is safe for patients with breast cancer. First, we found that arctigenin inhibited the viability of the MCF-7 cells, and colony formation assay confirmed that this effect was cytotoxic rather than cytostatic. The cytotoxic effects were not mediated by cell cycle arrest, apoptosis, or necroptosis, despite DNA damage, as indicated by poly(ADP-ribose) polymerase (PARP) cleavage and phosphorylated H2A.X. An increase in lipidated LC3, a marker of autophagosome formation, was observed, indicating that autophagy was induced by arctigenin, which was found to be triggered by the inhibition of the mechanistic target of rapamycin (mTOR) pathway. We then examined the effects of arctigenin on ERα expression and determined whether it affects the sensitivity of the cells to tamoxifen, as tamoxifen is commonly used against hormone-responsive cancers and is known to act via the ERα. We found that treatment with arctigenin effectively downregulated ERα expression, which was found to be a consequence of the inhibition of the mTOR pathway. However, treatment with arctigenin in combination with tamoxifen did not affect the sensitivity of the cells to tamoxifen, but instead, exerted a synergistic effect. On the whole, our data indicate that the phytoestrogen, arctigenin, mainly targeted the mTOR pathway in ERα-positive MCF-7 human breast cancer cells, leading to autophagy-induced cell death and the downregulation of ERα expression. Furthermore, the synergistic effects

  19. The induction of autophagy against mitochondria-mediated apoptosis in lung cancer cells by a ruthenium (II) imidazole complex

    Science.gov (United States)

    Peng, Fa; Jie, Xinming; Dongye, Guangzhi; Cai, Kangrong; Feng, Ruibing; Li, Baojun; Zeng, Qingwang; Lun, Kaiyi; Chen, Jincan; Xu, Bilian

    2016-01-01

    In the present study, it was found that the ruthenium (II) imidazole complex [Ru(Im)4(dppz)]2+ (Ru1) could induce significant growth inhibition and apoptosis in A549 and NCI-H460 cells. Apart from the induction of apoptosis, it was reported for the first time that Ru1 induced an autophagic response in A549 and NCI-H460 cells as evidenced by the formation of autophagosomes, acidic vesicular organelles (AVOs), and the up-regulation of LC3-II. Furthermore, scavenging of reactive oxygen species (ROS) by antioxidant NAC or Tiron inhibited the release of cytochrome c, caspase-3 activity, and eventually rescued cancer cells from Ru1-mediated apoptosis, suggesting that Ru1 inducing apoptosis was partially caspase 3-dependent by triggering ROS-mediated mitochondrial dysfunction in A549 and NCI-H460 cells. Further study indicated that the extracellular signal-regulated kinase (ERK) signaling pathway was involved in Ru1-induced autophagy in A549 and NCI-H460 cells. Moreover, blocking autophagy using pharmacological inhibitors 3-methyladenine (3-MA) and chloroquine (CQ) enhanced Ru1-induced apoptosis, indicating the cytoprotective role of autophagy in Ru1-treated A549 and NCI-H460 cells. Finally, the in vivo mice bearing A549 xenografts, Ru1 dosed at 10 or 20 mg/kg significantly inhibited tumor growth. PMID:27811372

  20. Flux quantisation in superconductivity rings and the mixed state

    International Nuclear Information System (INIS)

    Gough, C.E.

    1992-01-01

    This lecture introduces the concept of the macroscopic superconducting wave function and describes how this accounts for the Meissner Effect and flux quantisation. The experimental confirmation of flux quantisation in LTC, HTC and hybrid LTC/HTC rings will be briefly discussed. Flux quantisation in the superconducting mixed state leads to the formation of the Abrikosov flux in line lattice. Experiments confirming the flux line lattice in HTC superconductors by magnetic decoration and recent low angle neutron diffraction will be described. An extension of the mixed state model to granular superconductors with giant flux lines will also be briefly considered. (orig.)

  1. The limitation and modification of flux-limited diffusion theory

    International Nuclear Information System (INIS)

    Liu Chengan; Huang Wenkai

    1986-01-01

    The limitation of various typical flux-limited diffusion theory and advantages of asymptotic diffusion theory with time absorption constant are analyzed and compared. The conclusions are as following: Though the flux-limited problem in neutron diffusion theory are theoretically solved by derived flux-limited diffusion equation, it's going too far to limit flux due to the inappropriate assumption in deriving flux-limited diffusion equation. The asymptotic diffusion theory with time absorption constant has eliminated the above-mentioned limitation, and it is more accurate than flux-limited diffusion theory in describing neutron transport problem

  2. Inverse modeling of the terrestrial carbon flux in China with flux covariance among inverted regions

    Science.gov (United States)

    Wang, H.; Jiang, F.; Chen, J. M.; Ju, W.; Wang, H.

    2011-12-01

    Quantitative understanding of the role of ocean and terrestrial biosphere in the global carbon cycle, their response and feedback to climate change is required for the future projection of the global climate. China has the largest amount of anthropogenic CO2 emission, diverse terrestrial ecosystems and an unprecedented rate of urbanization. Thus information on spatial and temporal distributions of the terrestrial carbon flux in China is of great importance in understanding the global carbon cycle. We developed a nested inversion with focus in China. Based on Transcom 22 regions for the globe, we divide China and its neighboring countries into 17 regions, making 39 regions in total for the globe. A Bayesian synthesis inversion is made to estimate the terrestrial carbon flux based on GlobalView CO2 data. In the inversion, GEOS-Chem is used as the transport model to develop the transport matrix. A terrestrial ecosystem model named BEPS is used to produce the prior surface flux to constrain the inversion. However, the sparseness of available observation stations in Asia poses a challenge to the inversion for the 17 small regions. To obtain additional constraint on the inversion, a prior flux covariance matrix is constructed using the BEPS model through analyzing the correlation in the net carbon flux among regions under variable climate conditions. The use of the covariance among different regions in the inversion effectively extends the information content of CO2 observations to more regions. The carbon flux over the 39 land and ocean regions are inverted for the period from 2004 to 2009. In order to investigate the impact of introducing the covariance matrix with non-zero off-diagonal values to the inversion, the inverted terrestrial carbon flux over China is evaluated against ChinaFlux eddy-covariance observations after applying an upscaling methodology.

  3. Sensors for Metering Heat Flux Area Density and Metrological Equipment for the Heat Flux Density Measurement

    Science.gov (United States)

    Doronin, D. O.

    2018-04-01

    The demand in measuring and studies of heat conduction of various media is very urgent now. This article considers the problem of heat conduction monitoring and measurement in various media and materials in any industries and branches of science as well as metrological support of the heat flux measurement equipment. The main study objects are both the sensors manufactured and facilities onto which these sensors will be installed: different cladding structures of the buildings, awnings, rocket fairings, boiler units, internal combustion engines. The Company develops and manufactures different types of heat flux sensors: thermocouple, thin-film, heterogeneous gradient as well as metrological equipment for the gauging calibration of the heat flux density measurement. The calibration shall be performed using both referencing method in the unit and by fixed setting of the heat flux in the unit. To manufacture heterogeneous heat flux gradient sensors (HHFGS) the Company developed and designed a number of units: diffusion welding unit, HHFGS cutting unit. Rather good quality HHFGS prototypes were obtained. At this stage the factory tests on the equipment for the heat flux density measurement equipment are planned. A high-sensitivity heat flux sensor was produced, now it is tested at the Construction Physics Research Institute (Moscow). It became possible to create thin-film heat flux sensors with the sensitivity not worse than that of the sensors manufactured by Captec Company (France). The Company has sufficient premises to supply the market with a wide range of sensors, to master new sensor manufacture technologies which will enable their application range.

  4. Nitric oxide fluxes from an agricultural soil using a flux-gradient method

    Science.gov (United States)

    Taylor, N. M.; Wagner-Riddle, C.; Thurtell, G. W.; Beauchamp, E. G.

    1999-05-01

    Soil emission of nitric oxide may be a significant source of NOx in rural areas. Agricultural practices may enhance these emissions by addition of nitrogen fertilizers. A system that enables continuous measurement of NO fluxes from agricultural surfaces using the flux-gradient method was developed. Hourly differences in NO concentrations in air sampled at two intake heights (0.6 and 1 m) were determined using a chemiluminescence analyzer. Eddy diffusivities were determined using wind profiles (cup anemometers), and stability corrections calculated using a 5 cm path sonic anemometer. Fast switching of sampling between air intake heights (every 30 s) and determination of concentration values at a frequency of 2 Hz minimized the errors due to fluctuations in background concentration. Low travel times for air samples in the tubing (˜8 s) were estimated to result in small errors in flux values (chemical reactions. The overall resolution of the system was estimated as ˜1 ng N m-2s-1. NO fluxes from a bare soil were measured quasi-continuously from January to June 1995 at Elora, Canada, comprising a total of 1833 hourly values. Daily NO fluxes before nitrogen fertilization were small, increasing after nitrogen fertilizer was added (>10 ng N m-2 s-1). Monthly NO fluxes estimated were similar to those observed in previous studies. The designed system could be easily modified to measure NOx and NO fluxes by using an additional chemiluminescence analyzer. The system also could be adapted to measure fluxes sequentially from various plots, enabling testing of agricultural practices on NO emissions.

  5. Effect of chamber enclosure time on soil respiration flux: A comparison of linear and non-linear flux calculation methods

    DEFF Research Database (Denmark)

    Kandel, Tanka P; Lærke, Poul Erik; Elsgaard, Lars

    2016-01-01

    -deployment fluxes by linear regression techniques. Thus, usually the cumulative flux curve becomes downward concave due to the decreased gas diffusion rate. Non-linear models based on biophysical theory usually fit to such curvatures and may reduce the underestimation of fluxes. In this study, we examined...... the effect of increasing chamber enclosure time on SR flux rates calculated using a linear, an exponential and a revised Hutchinson and Mosier model (HMR). Soil respiration rates were measured with a closed chamber in combination with an infrared gas analyzer. During SR flux measurements the chamber......) to obtain a range of fluxes with different shapes of flux curves. The linear method provided more stable flux results during short enclosure times (few min) but underestimated initial fluxes by 15–300% after 45 min deployment time. Non-linear models reduced the underestimation as average underestimation...

  6. Regional nitrous oxide flux in Amazon basin

    International Nuclear Information System (INIS)

    Felippe, Monica Tais Siqueira D'Amelio

    2010-01-01

    Nitrous oxide (N 2 O) is the third most important anthropogenic greenhouse gas. Globally, the main sources of N 2 O are nitrification and denitrification in soils. About two thirds of the soil emissions occur in the tropics and approximately 20% originate in wet rain forest ecosystems, like the Amazon forest. The work presented here involves aircraft vertical profiles of N 2 O from the surface to 4 km over two sites in the Eastern and Central Amazon: Tapajos National Forest (2000-2009) and Cuieiras Biologic Reserve (2004-2007), and the estimation of N 2 O fluxes for regions upwind of these sites using two methods: Column Integration Technique and Inversion Model - FLEXPART. To our knowledge, these regional scale N 2 O measurements in Amazonia are unique and represent a new approach to looking regional scale emissions. For the both methods, the fluxes upwind of Cuieiras Biologic Reserve exhibited little seasonality, and the annual mean was 1.9 ±1.6 mgN 2 Om -2 day -1 for the Column Integration Technique and 2.3±0.9 mgN 2 Om -2 day -1 for Inversion Model - FLEXPART. For fluxes upwind of Tapajos Nacional Forest, the Inversion Model - FLEXPART presented about half (0.9±1.7 mgN 2 Om -2 day -1 ) of the Column Integration Technique (2.0±1.1 mgN 2 Om -2 day -1 ) for the same period (2004-2008). One reason could be because the inversion model does not consider anthropic activities, once it had a good representation for less impacted area. Both regions presented similar emission during wet season. By Column Integration Technique, fluxes upwind Tapajos Nacional Forest were similar for dry and wet seasons. The dry season N 2 O fluxes exhibit significant correlations with CO fluxes, indicating a larger than expected source of N 2 O from biomass burning. The average CO:N 2 O ratio for all 38 profiles sampled during the dry season was 82±69 mol CO:molN 2 O and suggests a larger biomass burning contribution to the global N 2 O budget than previously reported. (author)

  7. Gauge fluxes in F-theory compactifications

    Energy Technology Data Exchange (ETDEWEB)

    Lin, Ling

    2016-07-13

    In this thesis, we study the geometry and physics of gauge fluxes in F-theory compactifications to four dimensions. Motivated by the phenomenological requirement of chiral matter in realistic model building scenarios, we develop methods for a systematic analysis of primary vertical G{sub 4}-fluxes on torus-fibred Calabi-Yau fourfolds. In particular, we extend the well-known description of fluxes on elliptic fibrations with sections to the more general set-up of genus-one fibrations with multi-sections. The latter are known to give rise to discrete abelian symmetries in F-theory. We test our proposal for constructing fluxes in such geometries on an explicit model with SU(5) x Z{sub 2} symmetry, which is connected to an ordinary elliptic fibration with SU(5) x U(1) symmetry by a conifold transition. With our methods we systematically verify anomaly cancellation and tadpole matching in both models. Along the way, we find a novel way of understanding anomaly cancellation in 4D F-theory in purely geometric terms. This observation is further strengthened by a similar analysis of an SU(3) x SU(2) x U(1){sup 2} model. The obvious connection of this particular model with the Standard Model is then investigated in a more phenomenologically motivated survey. There, we will first provide possible matchings of the geometric spectrum with the Standard Model states, which highlights the role of the additional U(1) factor as a selection rule. In a second step, we then utilise our novel methods on flux computations to set up a search algorithm for semi-realistic chiral spectra in our Standard- Model-like fibrations over specific base manifolds B. As a demonstration, we scan over three choices P{sup 3}, Bl{sub 1}P{sup 3} and Bl{sub 2}P{sup 3} for the base. As a result we find a consistent flux that gives the chiral Standard Model spectrum with a vector-like triplet exotic, which may be lifted by a Higgs mechanism.

  8. Effects of quartz on crystallization behavior of mold fluxes and microstructural characteristics of flux film.

    Science.gov (United States)

    Lei, Liu; Xiuli, Han; Mingduo, Li; Di, Zhang

    2018-01-01

    Mold fluxes are mainly prepared using cement clinker, quartz, wollastonite, borax, fluorite, soda ash and other mineral materials. Quartz, as one of the most common and essential materials, was chosen for this study to analyze itseffects on crystallization temperature, critical cooling rate, crystal incubation time, crystallization ratio and phases of flux film. We used the research methods of process mineralogy with the application of the single hot thermocouple technique, heat flux simulator, polarizing microscope, X-ray diffraction, etc. Results: By increasing the quartz content from 16 mass% to 24 mass%, the crystallization temperature, critical cooling rate and crystallization ratio of flux film decreased, and the crystal incubation time was extended. Meanwhile, the mineralogical structure of the flux film changed, with a large amount of wollastonite precipitation and a significant decrease in the cuspidine content until it reached zero. This showed a steady decline in the heat transfer control capacity of the flux film. The reason for the results above is that, by increasing the quartz content, the silicon-oxygen tetrahedron network structure promoted a rise in viscosity and restrained ion migration, inhibiting crystal nucleation and growth, leading to the weakening of the crystallization and a decline in the crystallization ratio.

  9. Comparison between elementary flux modes analysis and 13C-metabolic fluxes measured in bacterial and plant cells.

    Science.gov (United States)

    Beurton-Aimar, Marie; Beauvoit, Bertrand; Monier, Antoine; Vallée, François; Dieuaide-Noubhani, Martine; Colombié, Sophie

    2011-06-20

    (13)C metabolic flux analysis is one of the pertinent ways to compare two or more physiological states. From a more theoretical standpoint, the structural properties of metabolic networks can be analysed to explore feasible metabolic behaviours and to define the boundaries of steady state flux distributions. Elementary flux mode analysis is one of the most efficient methods for performing this analysis. In this context, recent approaches have tended to compare experimental flux measurements with topological network analysis. Metabolic networks describing the main pathways of central carbon metabolism were set up for a bacteria species (Corynebacterium glutamicum) and a plant species (Brassica napus) for which experimental flux maps were available. The structural properties of each network were then studied using the concept of elementary flux modes. To do this, coefficients of flux efficiency were calculated for each reaction within the networks by using selected sets of elementary flux modes. Then the relative differences - reflecting the change of substrate i.e. a sugar source for C. glutamicum and a nitrogen source for B. napus - of both flux efficiency and flux measured experimentally were compared. For both organisms, there is a clear relationship between these parameters, thus indicating that the network structure described by the elementary flux modes had captured a significant part of the metabolic activity in both biological systems. In B. napus, the extension of the elementary flux mode analysis to an enlarged metabolic network still resulted in a clear relationship between the change in the coefficients and that of the measured fluxes. Nevertheless, the limitations of the method to fit some particular fluxes are discussed. This consistency between EFM analysis and experimental flux measurements, validated on two metabolic systems allows us to conclude that elementary flux mode analysis could be a useful tool to complement (13)C metabolic flux analysis

  10. General resonance mediation

    International Nuclear Information System (INIS)

    McGarrie, Moritz

    2012-07-01

    We extend the framework of general gauge mediation to cases where the mediating fields have a nontrivial spectral function, as might arise from strong dynamics. We demonstrate through examples that this setup describes a broad class of possible models of gauge mediated supersymmetry breaking. A main emphasis is to give general formulas for cross sections for σ(visible → hidden) in these resonance models. We will also give formulas for soft masses, A-terms and demonstrate the framework with a holographic setup.

  11. Axionic Mirage Mediation

    International Nuclear Information System (INIS)

    Nakamura, Shuntaro; Okumura, Ken-ichi; Yamaguchi, Masahiro

    2008-01-01

    In this talk, we propose a model of mirage mediation, in which Peccei-Quinn symmetry is incorporated. In this axionic mirage mediation, it is shown that the Peccei-Quinn symmetry breaking scale is dynamically determined around 10 10 GeV to 10 12 GeV due to the supersymmetry breaking effects. The problems in the original mirage mediation such as the μ-problem and the moduli problem can be solved simultaneouly. Furthermore, in our model the axino, which is the superpartner of the axion, is the lightest sparticle.

  12. Linking genes to ecosystem trace gas fluxes in a large-scale model system

    Science.gov (United States)

    Meredith, L. K.; Cueva, A.; Volkmann, T. H. M.; Sengupta, A.; Troch, P. A.

    2017-12-01

    Soil microorganisms mediate biogeochemical cycles through biosphere-atmosphere gas exchange with significant impact on atmospheric trace gas composition. Improving process-based understanding of these microbial populations and linking their genomic potential to the ecosystem-scale is a challenge, particularly in soil systems, which are heterogeneous in biodiversity, chemistry, and structure. In oligotrophic systems, such as the Landscape Evolution Observatory (LEO) at Biosphere 2, atmospheric trace gas scavenging may supply critical metabolic needs to microbial communities, thereby promoting tight linkages between microbial genomics and trace gas utilization. This large-scale model system of three initially homogenous and highly instrumented hillslopes facilitates high temporal resolution characterization of subsurface trace gas fluxes at hundreds of sampling points, making LEO an ideal location to study microbe-mediated trace gas fluxes from the gene to ecosystem scales. Specifically, we focus on the metabolism of ubiquitous atmospheric reduced trace gases hydrogen (H2), carbon monoxide (CO), and methane (CH4), which may have wide-reaching impacts on microbial community establishment, survival, and function. Additionally, microbial activity on LEO may facilitate weathering of the basalt matrix, which can be studied with trace gas measurements of carbonyl sulfide (COS/OCS) and carbon dioxide (O-isotopes in CO2), and presents an additional opportunity for gene to ecosystem study. This work will present initial measurements of this suite of trace gases to characterize soil microbial metabolic activity, as well as links between spatial and temporal variability of microbe-mediated trace gas fluxes in LEO and their relation to genomic-based characterization of microbial community structure (phylogenetic amplicons) and genetic potential (metagenomics). Results from the LEO model system will help build understanding of the importance of atmospheric inputs to

  13. Polyarene mediators for mediated redox flow battery

    Energy Technology Data Exchange (ETDEWEB)

    Delnick, Frank M.; Ingersoll, David; Liang, Chengdu

    2018-01-02

    The fundamental charge storage mechanisms in a number of currently studied high energy redox couples are based on intercalation, conversion, or displacement reactions. With exception to certain metal-air chemistries, most often the active redox materials are stored physically in the electrochemical cell stack thereby lowering the practical gravimetric and volumetric energy density as a tradeoff to achieve reasonable power density. In a general embodiment, a mediated redox flow battery includes a series of secondary organic molecules that form highly reduced anionic radicals as reaction mediator pairs for the reduction and oxidation of primary high capacity redox species ex situ from the electrochemical cell stack. Arenes are reduced to stable anionic radicals that in turn reduce a primary anode to the charged state. The primary anode is then discharged using a second lower potential (more positive) arene. Compatible separators and solvents are also disclosed herein.

  14. Lepton fluxes from atmospheric charm revisited

    International Nuclear Information System (INIS)

    Garzelli, M.V.; Moch, S.; Sigl, G.

    2015-07-01

    We update predictions for lepton fluxes from the hadroproduction of charm quarks in the scattering of primary cosmic rays with the Earth's atmosphere. The calculation of charm-pair hadroproduction applies the latest results from perturbative QCD through next-to-next-to-leading order and modern parton distributions, together with estimates on various sources of uncertainties. Our predictions for the lepton fluxes turn out to be compatible, within the uncertainty band, with recent results in the literature. However, by taking into account contributions neglected in previous works, our total uncertainties are much larger. The predictions are crucial for the interpretation of results from neutrino experiments like IceCube, when disentangling signals of neutrinos of astrophysical origin from the atmospheric background.

  15. Observations on fluxes near anti-branes

    Energy Technology Data Exchange (ETDEWEB)

    Cohen-Maldonado, Diego [Institute of Physics, University of Amsterdam, Science Park,Postbus 94485, Amsterdam, 1090 GL The (Netherlands); Diaz, Juan; Riet, Thomas Van [Instituut voor Theoretische Fysica, K.University Leuven,Celestijnenlaan 200D, Leuven, B-3001 (Belgium); Vercnocke, Bert [Institute of Physics, University of Amsterdam, Science Park,Postbus 94485, Amsterdam, 1090 GL The (Netherlands)

    2016-01-20

    We revisit necessary conditions for gluing local (anti-)D3 throats into flux throats with opposite charge. These consistency conditions typically reveal singularities in the 3-form fluxes whose meaning is being debated. In this note we prove, under well-motivated assumptions, that unphysical singularities can potentially be avoided when the anti-branes polarise into spherical NS5 branes, with a specific radius. If a consistent solution can then indeed be found, our analysis seems to suggests a rather large correction to the radius of the polarization sphere compared to the probe result. We furthermore comment on the gluing conditions at finite temperature and point out that one specific assumption of a recent no-go theorem can be broken if anti-branes are indeed to polarise into spherical NS5 branes at zero temperature.

  16. Earth-like sand fluxes on Mars.

    Science.gov (United States)

    Bridges, N T; Ayoub, F; Avouac, J-P; Leprince, S; Lucas, A; Mattson, S

    2012-05-09

    Strong and sustained winds on Mars have been considered rare, on the basis of surface meteorology measurements and global circulation models, raising the question of whether the abundant dunes and evidence for wind erosion seen on the planet are a current process. Recent studies showed sand activity, but could not determine whether entire dunes were moving--implying large sand fluxes--or whether more localized and surficial changes had occurred. Here we present measurements of the migration rate of sand ripples and dune lee fronts at the Nili Patera dune field. We show that the dunes are near steady state, with their entire volumes composed of mobile sand. The dunes have unexpectedly high sand fluxes, similar, for example, to those in Victoria Valley, Antarctica, implying that rates of landscape modification on Mars and Earth are similar.

  17. Helium cosmic ray flux measurements at Mars

    International Nuclear Information System (INIS)

    Lee, Kerry; Pinsky, Lawrence; Andersen, Vic; Zeitlin, Cary; Cleghorn, Tim; Cucinotta, Frank; Saganti, Premkumar; Atwell, William; Turner, Ron

    2006-01-01

    The helium energy spectrum in Martian orbit has been observed by the MARIE charged particle spectrometer aboard the 2001 Mars Odyssey spacecraft. The orbital data were taken from March 13, 2002 to October 28, 2003, at which time a very intense Solar Particle Event caused a loss of communication between the instrument and the spacecraft. The silicon detector stack in MARIE is optimized for the detection of protons and helium in the energy range below 100MeV/n, which typically includes almost all of the flux during SPEs. This also makes MARIE an efficient detector for GCR helium in the energy range of 50-150MeV/n. We will present the first fully normalized flux results from MARIE, using helium ions in this energy range

  18. Reduced TCA Flux in Diabetic Myotubes

    DEFF Research Database (Denmark)

    Gaster, Michael

    2012-01-01

    The diabetic phenotype is complex, requiring elucidation of key initiating defects. Diabetic myotubes express a primary reduced tricarboxylic acid (TCA) cycle flux but at present it is unclear in which part of the TCA cycle the defect is localised. In order to localise the defect we studied ATP...... production in isolated mitochondria from substrates entering the TCA cycle at various points. ATP production was measured by luminescence with or without concomitant ATP utilisation by hexokinase in mitochondria isolated from myotubes established from eight lean and eight type 2 diabetic subjects. The ATP......, there was no significant difference between groups. These results show that the primary reduced TCA cycle flux in diabetic myotubes is not explained by defects in specific part of the TCA cycle but rather results from a general downregulation of the TCA cycle....

  19. Anthropogenic methane ebullition and continuous flux measurement

    Science.gov (United States)

    Alshboul, Zeyad

    2017-04-01

    Keywords: Methane, Wastewater, Effluent, Anaerobic treatment. Municipal wastewater treatment plants (WWTPs) have shown to emit significant amount of methane during treatment processes. While most of studies cover only in-plant diffusive methane flux, magnitude and sources of methane ebullition have not well assessed. Moreover, the reported results of methane emissions from WWTPs are based on low spatial and temporal resolution. Using a continuous measurement approach of methane flux rate for effluent system and secondary clarifier treatment process at one WWTP in Southwest Germany, our results show that high percentage of methane is emitted by ebullition during the anaerobic treatment (clarification pond) with high spatial and temporal variability. Our measurements revealed that no ebullition is occur at the effluent system. The observed high contribution of methane ebullition to the total in-plant methane emission, emphasizes the need for considering in-plant methane emission by ebullition as well as the spatial and temporal variability of these emissions.

  20. Flux Limiter Lattice Boltzmann for Compressible Flows

    International Nuclear Information System (INIS)

    Chen Feng; Li Yingjun; Xu Aiguo; Zhang Guangcai

    2011-01-01

    In this paper, a new flux limiter scheme with the splitting technique is successfully incorporated into a multiple-relaxation-time lattice Boltzmann (LB) model for shacked compressible flows. The proposed flux limiter scheme is efficient in decreasing the artificial oscillations and numerical diffusion around the interface. Due to the kinetic nature, some interface problems being difficult to handle at the macroscopic level can be modeled more naturally through the LB method. Numerical simulations for the Richtmyer-Meshkov instability show that with the new model the computed interfaces are smoother and more consistent with physical analysis. The growth rates of bubble and spike present a satisfying agreement with the theoretical predictions and other numerical simulations. (electromagnetism, optics, acoustics, heat transfer, classical mechanics, and fluid dynamics)

  1. Flux qubit to a transmission line

    Energy Technology Data Exchange (ETDEWEB)

    Haeberlein, Max; Baust, Alexander; Zhong, Ling; Gross, Rudolf [Walther-Meissner-Institut, Bayerische Akademie der Wissenschaften, Garching (Germany); Physik-Department, TU Muenchen, Garching (Germany); Nanosystems Initiative Munich (NIM), Muenchen (Germany); Anderson, Gustav; Wang, Lujun; Eder, Peter; Fischer, Michael; Goetz, Jan; Xie, Edwar; Schwarz, Manuel; Wulschner, Karl Friedrich; Deppe, Frank; Fedorov, Kirill; Huebl, Hans; Menzel, Edwin [Walther-Meissner-Institut, Bayerische Akademie der Wissenschaften, Garching (Germany); Physik-Department, TU Muenchen, Garching (Germany); Marx, Achim [Walther-Meissner-Institut, Bayerische Akademie der Wissenschaften, Garching (Germany)

    2015-07-01

    Within the last decade, superconducting qubits coupled to microwave resonators have been extensively studied within the framework of quantum electrodynamics. Ultimately, quantum computing seems within reach in such architectures. However, error correction schemes are necessary to achieve the required fidelity in multi-qubit operations, drastically increasing the number of qubits involved. In this work, we couple a flux qubit to a transmission line where it interacts with itinerant microwave photons granting access to all-optical quantum computing. In this approach, travelling photons generate entanglement between two waveguides, containing the qubit information. In this presentation, we show experimental data on flux qubits coupled to transmission lines. Furthermore, we will discuss entanglement generation between two separate paths.

  2. Chiral charge flux and electroweak baryogenesis

    Energy Technology Data Exchange (ETDEWEB)

    Funakubo, Koichi [Saga Univ. (Japan). Dept. of Physics; Kakuto, Akira; Otsuki, Shoichiro; Takenaga, Kazunori; Toyoda, Fumihiko

    1995-06-01

    By treating CP-violating interaction of the electroweak bubble wall as a perturbative term, chiral charge flux through the bubble wall is estimated. It is found that the absolute value of the flux F{sub Q} has a sharp peak at m{sub 0} - a - T with F{sub Q}/(uT{sup 3}) - 10{sup -3}(Q{sub L}-Q{sub R}){Delta}{theta}. Here m{sub 0} is the fermion mass, 1/a is the wall thickness, T is the temperature at which the bubbles are growing, u is the wall velocity, Q{sub L(R)} is the chiral charge of the relevant left (right)-handed fermion and {Delta}{theta} is the measure of CP violation. (author).

  3. Noninvasive microelectrode ion flux estimation technique (MIFE) for the study of the regulation of root membrane transport by cyclic nucleotides

    KAUST Repository

    Ordoñez, Natalia Maria

    2013-09-03

    Changes in ion permeability and subsequently intracellular ion concentrations play a crucial role in intracellular and intercellular communication and, as such, confer a broad array of developmental and adaptive responses in plants. These changes are mediated by the activity of plasma-membrane based transport proteins many of which are controlled by cyclic nucleotides and/or other signaling molecules. The MIFE technique for noninvasive microelectrode ion flux measuring allows concurrent quantification of net fluxes of several ions with high spatial (μm range) and temporal (ca. 5 s) resolution, making it a powerful tool to study various aspects of downstream signaling events in plant cells. This chapter details basic protocols enabling the application of the MIFE technique to study regulation of root membrane transport in general and cyclic nucleotide mediated transport in particular. © Springer Science+Business Media New York 2013.

  4. Attenuation of particulate organic carbon flux in the Scotia Sea, Southern Ocean, is controlled by zooplankton fecal pellets

    Science.gov (United States)

    Cavan, E. L.; Le Moigne, F. A. C.; Poulton, A. J.; Tarling, G. A.; Ward, P.; Daniels, C. J.; Fragoso, G. M.; Sanders, R. J.

    2015-02-01

    The Southern Ocean (SO) is an important CO2 reservoir, some of which enters via the production, sinking, and remineralization of organic matter. Recent work suggests that the fraction of production that sinks is inversely related to production in the SO, a suggestion that we confirm from 20 stations in the Scotia Sea. The efficiency with which exported material is transferred to depth (transfer efficiency) is believed to be low in high-latitude systems. However, our estimates of transfer efficiency are bimodal, with stations in the seasonal ice zone showing intense losses and others displaying increases in flux with depth. Zooplankton fecal pellets dominated the organic carbon flux and at stations with transfer efficiency >100% fecal pellets were brown, indicative of fresh phytodetritus. We suggest that active flux mediated by zooplankton vertical migration and the presence of sea ice regulates the transfer of organic carbon into the oceans interior in the Southern Ocean.

  5. Data system for automatic flux mapping applications

    International Nuclear Information System (INIS)

    Oates, R.M.; Neuner, J.A.; Couch, R.D. Jr.; Kasinoff, A.M.

    1982-01-01

    This patent discloses interface circuitry for coupling the data from neutron flux detectors in a reactor core to microprocessors. This circuitry minimizes the microprocessor time required to accept data and provides a technique for measuring variable frequency data from the in-core detectors within a minimum amount of hardware and with crystal-controlled accuracy. A frequency link is employed to transmit data with good isolation, and the information is measured using a programmable timer

  6. 2 π gaseous flux proportional detector

    International Nuclear Information System (INIS)

    Guevara, E.A.; Costello, E.D.; Di Carlo, R.O.

    1986-01-01

    A counting system has been developed in order to measure carbon-14 samples obtained in the course of a study of a plasmapheresis treatment for diabetic children. The system is based on the use of a 2π gaseous flux proportional detector especially designed for the stated purpose. The detector is described and experiment results are given, determining the characteristic parameters which set up the working conditions. (Author) [es

  7. Periods of High Intensity Solar Proton Flux

    Science.gov (United States)

    Xapsos, Michael A.; Stauffer, Craig A.; Jordan, Thomas M.; Adams, James H.; Dietrich, William F.

    2012-01-01

    Analysis is presented for times during a space mission that specified solar proton flux levels are exceeded. This includes both total time and continuous time periods during missions. Results for the solar maximum and solar minimum phases of the solar cycle are presented and compared for a broad range of proton energies and shielding levels. This type of approach is more amenable to reliability analysis for spacecraft systems and instrumentation than standard statistical models.

  8. The cosmic ray muon flux at WIPP

    Energy Technology Data Exchange (ETDEWEB)

    Esch, E.-I. [Los Alamos National Laboratory, LANSCE-3, MS H855, Los Alamos, NM 87545 (United States) and II. Physikalisches Institut, Justus Liebig Univeritaet Giessen, Giessen (Germany)]. E-mail: ernst@lanl.gov; Bowles, T.J [Los Alamos National Laboratory, LANSCE-3, MS H855, Los Alamos, NM 87545 (United States); Hime, A. [Los Alamos National Laboratory, LANSCE-3, MS H855, Los Alamos, NM 87545 (United States); Pichlmaier, A. [Los Alamos National Laboratory, LANSCE-3, MS H855, Los Alamos, NM 87545 (United States); Reifarth, R. [Los Alamos National Laboratory, LANSCE-3, MS H855, Los Alamos, NM 87545 (United States); Wollnik, H. [II. Physikalisches Institut, Justus Liebig Univeritaet Giessen, Giessen (Germany)

    2005-02-11

    In this work, a measurement of the muon intensity at the Waste Isolation Pilot Plant (WIPP) near Carlsbad, NM, USA is presented. WIPP is a salt mine with a depth of 655m. The vertical muon flux was measured with a two panel scintillator coincidence setup to {phi}{sub vert}=(3.10{sub -0.07}{sup +0.05})10{sup -7}s{sup -1}cm{sup -}2sr{sup -1}.

  9. Axial flux permanent magnet brushless machines

    CERN Document Server

    Gieras, Jacek F; Kamper, Maarten J

    2008-01-01

    Axial Flux Permanent Magnet (AFPM) brushless machines are modern electrical machines with a lot of advantages over their conventional counterparts. They are being increasingly used in consumer electronics, public life, instrumentation and automation system, clinical engineering, industrial electromechanical drives, automobile manufacturing industry, electric and hybrid electric vehicles, marine vessels and toys. They are also used in more electric aircrafts and many other applications on larger scale. New applications have also emerged in distributed generation systems (wind turbine generators

  10. FAST FLUX TEST FACILITY DRIVER FUEL MEETING

    Energy Technology Data Exchange (ETDEWEB)

    None,

    1966-06-01

    The Pacific Northwest Laboratory has convened this meeting to enlist the best talents of our laboratories and industry in soliciting factual, technical information pertinent to the Pacific Northwest's Laboratory's evaluation of the potential fuel systems for the Fast Flux Test Facility. The particular factors emphasized for these fuel systems are those associated with safety, ability to meet testing objectives, and economics. The proceedings includes twenty-three presentations, along with a transcript of the discussion following each, as well as a summary discussion.

  11. Greenhouse gas flux dynamics in wetlands

    Energy Technology Data Exchange (ETDEWEB)

    Silvola, J.; Alm, J.; Saarnio, S. [Joensuu Univ. (Finland). Dept. of Biology; Martikainen, P.J. [National Public Health Inst., Kuopio (Finland). Dept. of Environmental Microbiology

    1996-12-31

    Two important greenhouse gases, CO{sub 2} and CH{sub 4}, are closely connected to the carbon cycling of wetlands. Although virgin wetlands are mostly carbon accumulating ecosystems, major proportion of the CO{sub 2} bound annually in photosynthesis is released back to the atmosphere. Main portion of the carbon cycling in wetlands is quite fast while a small proportion of carbon diffusing from soil is released from organic matter, which may be ten thousand years old. Methane is formed in the anaerobic layers of wetlands, from where it is released gradually to the atmosphere. The decomposition in anaerobic conditions is very slow, which means that usually only a few percent of the annual carbon cycling takes place as methane. Research on CO{sub 2} fluxes of different virgin and managed peatlands was the main topic of this project during the first phase of SILMU. The measurements were made during two seasons in varying conditions in c. 30 study sites. In the second phase of SILMU the research topics were the spatial and temporal variation of CO{sub 2} and CH{sub 4} fluxes, the relationships between vegetation and gas fluxes as well as carbon balance studies in wetlands at some intensive sites

  12. Small scale magnetic flux-averaged magnetohydrodynamics

    International Nuclear Information System (INIS)

    Pfirsch, D.; Sudan, R.N.

    1994-01-01

    By relaxing exact magnetic flux conservation below a scale λ a system of flux-averaged magnetohydrodynamic equations are derived from Hamilton's principle with modified constraints. An energy principle can be derived from the linearized averaged system because the total system energy is conserved. This energy principle is employed to treat the resistive tearing instability and the exact growth rate is recovered when λ is identified with the resistive skin depth. A necessary and sufficient stability criteria of the tearing instability with line tying at the ends for solar coronal loops is also obtained. The method is extended to both spatial and temporal averaging in Hamilton's principle. The resulting system of equations not only allows flux reconnection but introduces irreversibility for appropriate choice of the averaging function. Except for boundary contributions which are modified by the time averaging process total energy and momentum are conserved over times much longer than the averaging time τ but not for less than τ. These modified boundary contributions correspond to the existence, also, of damped waves and shock waves in this theory. Time and space averaging is applied to electron magnetohydrodynamics and in one-dimensional geometry predicts solitons and shocks in different limits

  13. Kubo Resistivity of magnetic flux ropes

    Science.gov (United States)

    Gekelman, Walter; Dehaas, Tim; Pribyl, Pat; Vincena, Stephen; van Compernolle, Bart; Sydora, Rick; Tang, Shawn Wenjie

    2017-10-01

    Magnetic flux ropes are bundles of twisted magnetic fields and their associated current. They are common on the surface of the sun (and presumably all other stars) and are observed to have a large range of sizes and lifetimes. They can become unstable and resulting in coronal mass ejections that can travel to earth and indeed, have been observed by satellites. Two side by side flux ropes are generated in the LAPD device at UCLA. Using a series of novel diagnostics the following key quantities, B, u, Vp, n, Te have been measured at more than 48,000 spatial locations and 7,000 time steps. Every term in Ohm's law is also evaluated across and along the local magnetic field and the plasma resistivity derived and it is shown that Ohms law is non-local. The electron distribution function parallel and antiparallel to the background magnetic field was measured and found to be a drifting Kappa function. The Kubo AC conductivity at the flux rope rotation frequency, a 3X3 tensor, was evaluated using velocity correlations and will be presented. This yields meaningful results for the global resistivity. Frequency spectra and the presence of time domain structures may offer a clue to the enhanced resistivity. Work supported by the Department of Energy and National Science Foundation.

  14. High heat flux device of thermonuclear device

    International Nuclear Information System (INIS)

    Tachikawa, Nobuo.

    1994-01-01

    The present invention provides an equipments for high heat flux device (divertor) of a thermonuclear device, which absorbs thermal deformation during operation, has a high installation accuracy, and sufficiently withstands for thermal stresses. Namely, a heat sink member is joined to a structural base. Armour tiles are joined on the heat sink member. Cooling pipes are disposed between the heat sink member and the armour tiles. With such a constitution, the heat sink member using a highly heat conductive material having ductility, such as oxygen free copper, the cooling pipes using a material having excellent high temperature resistance and excellent elongation, such as aluminum-dispersed reinforced copper, and the armour tiles are completely joined on the structural base. Therefore, when thermal deformation tends to cause in the high heat flux device such as a divertor, cooling pipes cause no plastic deformation because of their high temperature resistance, but the heat sink member such as a oxygen free copper causes plastic deformation to absorb thermal deformation. As a result, the high heat flux device such as a divertor causes no deformation. (I.S.)

  15. Burnout heat flux in natural flow boiling

    International Nuclear Information System (INIS)

    Helal, M.M.; Darwish, M.A.; Mahmoud, S.I.

    1978-01-01

    Twenty runs of experiments were conducted to determine the critical heat flux for natural flow boiling with water flowing upwards through annuli of centrally heated stainless steel tube. The test section has concentric heated tube of 14mm diameter and heated lengthes of 15 and 25 cm. The outside surface of the annulus was formed by various glass tubes of 17.25, 20 and 25.9mm diameter. System pressure is atmospheric. Inlet subcooling varied from 18 to 5 0 C. Obtained critical heat flux varied from 24.46 to 62.9 watts/cm 2 . A number of parameters having dominant influence on the critical heat flux and hydrodynamic instability (flow and pressure oscillations) preceeding the burnout have been studied. These parameters are mass flow rate, mass velocity, throttling, channel geometry (diameters ratio, length to diameter ratio, and test section length), and inlet subcooling. Flow regimes before and at the moments of burnout were observed, discussed, and compared with the existing physical model of burnout

  16. GALILEO PROBE NET FLUX RADIOMETER DATA V1.0

    Data.gov (United States)

    National Aeronautics and Space Administration — The Galileo Probe Net Flux Radiometer (NFR) measured net and upward radiation fluxes in Jupiter's atmosphere between about 0.44 bars and 14 bars, using five spectral...

  17. NAMMA SENEGAL RADIOSONDE AND TOWER FLUX DATA V1

    Data.gov (United States)

    National Aeronautics and Space Administration — The NAMMA Senegal Radiosonde and Tower Flux data includes measurements of humidity, wind speed/direction and velocity. Additionally, the flux data includes...

  18. Advanced Tethersonde for High-Speed Flux Measurements Project

    Data.gov (United States)

    National Aeronautics and Space Administration — Flux measurements of trace gases and other quantities, such as latent heat, are of great importance in scientific field research. One typical flux measurement setup...

  19. Advanced Tethersonde for High-Speed Flux Measurements, Phase I

    Data.gov (United States)

    National Aeronautics and Space Administration — Flux measurements of trace gases and other quantities, such as latent heat, are of great importance in scientific field research. One typical flux measurement setup...

  20. Physics of magnetic flux ropes. Geophysical Monograph, No. 58

    International Nuclear Information System (INIS)

    Russell, C.T.; Priest, E.R.; Lee, L.C.

    1990-01-01

    The present work encompasses papers on the structure, waves, and instabilities of magnetic flux ropes (MFRs), photospheric flux tubes (PFTs), the structure and heating of coronal loops, solar prominences, coronal mass ejections and magnetic clouds, flux ropes in planetary ionospheres, the magnetopause, magnetospheric field-aligned currents and flux tubes, and the magnetotail. Attention is given to the equilibrium of MFRs, resistive instability, magnetic reconnection and turbulence in current sheets, dynamical effects and energy transport in intense flux tubes, waves in solar PFTs, twisted flux ropes in the solar corona, an electrodynamical model of solar flares, filament cooling and condensation in a sheared magnetic field, the magnetopause, the generation of twisted MFRs during magnetic reconnection, ionospheric flux ropes above the South Pole, substorms and MFR structures, evidence for flux ropes in the earth magnetotail, and MFRs in 3D MHD simulations