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Sample records for autophagic flux mediates

  1. An Autophagic Flux Probe that Releases an Internal Control.

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    Kaizuka, Takeshi; Morishita, Hideaki; Hama, Yutaro; Tsukamoto, Satoshi; Matsui, Takahide; Toyota, Yuichiro; Kodama, Akihiko; Ishihara, Tomoaki; Mizushima, Tohru; Mizushima, Noboru

    2016-11-17

    Macroautophagy is an intracellular degradation system that utilizes the autophagosome to deliver cytoplasmic components to the lysosome. Measuring autophagic activity is critically important but remains complicated and challenging. Here, we have developed GFP-LC3-RFP-LC3ΔG, a fluorescent probe to evaluate autophagic flux. This probe is cleaved by endogenous ATG4 proteases into equimolar amounts of GFP-LC3 and RFP-LC3ΔG. GFP-LC3 is degraded by autophagy, while RFP-LC3ΔG remains in the cytosol, serving as an internal control. Thus, autophagic flux can be estimated by calculating the GFP/RFP signal ratio. Using this probe, we re-evaluated previously reported autophagy-modulating compounds, performed a high-throughput screen of an approved drug library, and identified autophagy modulators. Furthermore, we succeeded in measuring both induced and basal autophagic flux in embryos and tissues of zebrafish and mice. The GFP-LC3-RFP-LC3ΔG probe is a simple and quantitative method to evaluate autophagic flux in cultured cells and whole organisms. Copyright © 2016 Elsevier Inc. All rights reserved.

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

    NARCIS (Netherlands)

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

    2015-01-01

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

  3. Doxorubicin Blocks Cardiomyocyte Autophagic Flux by Inhibiting Lysosome Acidification.

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    Li, Dan L; Wang, Zhao V; Ding, Guanqiao; Tan, Wei; Luo, Xiang; Criollo, Alfredo; Xie, Min; Jiang, Nan; May, Herman; Kyrychenko, Viktoriia; Schneider, Jay W; Gillette, Thomas G; Hill, Joseph A

    2016-04-26

    The clinical use of doxorubicin is limited by cardiotoxicity. Histopathological changes include interstitial myocardial fibrosis and the appearance of vacuolated cardiomyocytes. Whereas dysregulation of autophagy in the myocardium has been implicated in a variety of cardiovascular diseases, the role of autophagy in doxorubicin cardiomyopathy remains poorly defined. Most models of doxorubicin cardiotoxicity involve intraperitoneal injection of high-dose drug, which elicits lethargy, anorexia, weight loss, and peritoneal fibrosis, all of which confound the interpretation of autophagy. Given this, we first established a model that provokes modest and progressive cardiotoxicity without constitutional symptoms, reminiscent of the effects seen in patients. We report that doxorubicin blocks cardiomyocyte autophagic flux in vivo and in cardiomyocytes in culture. This block was accompanied by robust accumulation of undegraded autolysosomes. We go on to localize the site of block as a defect in lysosome acidification. To test the functional relevance of doxorubicin-triggered autolysosome accumulation, we studied animals with diminished autophagic activity resulting from haploinsufficiency for Beclin 1. Beclin 1(+/-) mice exposed to doxorubicin were protected in terms of structural and functional changes within the myocardium. Conversely, animals overexpressing Beclin 1 manifested an amplified cardiotoxic response. Doxorubicin blocks autophagic flux in cardiomyocytes by impairing lysosome acidification and lysosomal function. Reducing autophagy initiation protects against doxorubicin cardiotoxicity. © 2016 American Heart Association, Inc.

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

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    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.

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

    International Nuclear Information System (INIS)

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

    2015-01-01

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

  6. In vivo imaging and quantitative monitoring of autophagic flux in tobacco BY-2 cells.

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    Hanamata, Shigeru; Kurusu, Takamitsu; Okada, Masaaki; Suda, Akiko; Kawamura, Koki; Tsukada, Emi; Kuchitsu, Kazuyuki

    2013-01-01

    Autophagy has been shown to play essential roles in the growth, development and survival of eukaryotic cells. However, simple methods for quantification and visualization of autophagic flux remain to be developed in living plant cells. Here, we analyzed the autophagic flux in transgenic tobacco BY-2 cell lines expressing fluorescence-tagged NtATG8a as a marker for autophagosome formation. Under sucrose-starved conditions, the number of punctate signals of YFP-NtATG8a increased, and the fluorescence intensity of the cytoplasm and nucleoplasm decreased. Conversely, these changes were not observed in BY-2 cells expressing a C-terminal glycine deletion mutant of the NtATG8a protein (NtATG8aΔG). To monitor the autophagic flux more easily, we generated a transgenic BY-2 cell line expressing NtATG8a fused to a pH-sensitive fluorescent tag, a tandem fusion of the acid-insensitive RFP and the acid-sensitive YFP. In sucrose-rich conditions, both fluorescent signals were detected in the cytoplasm and only weakly in the vacuole. In contrast, under sucrose-starved conditions, the fluorescence intensity of the cytoplasm decreased, and the RFP signal clearly increased in the vacuole, corresponding to the fusion of the autophagosome to the vacuole and translocation of ATG8 from the cytoplasm to the vacuole. Moreover, we introduce a novel simple easy way to monitor the autophagic flux non-invasively by only measuring the ratio of fluorescence of RFP and YFP in the cell suspension using a fluorescent image analyzer without microscopy. The present in vivo quantitative monitoring system for the autophagic flux offers a powerful tool for determining the physiological functions and molecular mechanisms of plant autophagy induced by environmental stimuli.

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

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    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.

  8. Spastic paraplegia proteins spastizin and spatacsin mediate autophagic lysosome reformation

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    Chang, Jaerak; Lee, Seongju; Blackstone, Craig

    2014-01-01

    Autophagy allows cells to adapt to changes in their environment by coordinating the degradation and recycling of cellular components and organelles to maintain homeostasis. Lysosomes are organelles critical for terminating autophagy via their fusion with mature autophagosomes to generate autolysosomes that degrade autophagic materials; therefore, maintenance of the lysosomal population is essential for autophagy-dependent cellular clearance. Here, we have demonstrated that the two most common...

  9. Spastic paraplegia proteins spastizin and spatacsin mediate autophagic lysosome reformation.

    Science.gov (United States)

    Chang, Jaerak; Lee, Seongju; Blackstone, Craig

    2014-12-01

    Autophagy allows cells to adapt to changes in their environment by coordinating the degradation and recycling of cellular components and organelles to maintain homeostasis. Lysosomes are organelles critical for terminating autophagy via their fusion with mature autophagosomes to generate autolysosomes that degrade autophagic materials; therefore, maintenance of the lysosomal population is essential for autophagy-dependent cellular clearance. Here, we have demonstrated that the two most common autosomal recessive hereditary spastic paraplegia gene products, the SPG15 protein spastizin and the SPG11 protein spatacsin, are pivotal for autophagic lysosome reformation (ALR), a pathway that generates new lysosomes. Lysosomal targeting of spastizin required an intact FYVE domain, which binds phosphatidylinositol 3-phosphate. Loss of spastizin or spatacsin resulted in depletion of free lysosomes, which are competent to fuse with autophagosomes, and an accumulation of autolysosomes, reflecting a failure in ALR. Moreover, spastizin and spatacsin were essential components for the initiation of lysosomal tubulation. Together, these results link dysfunction of the autophagy/lysosomal biogenesis machinery to neurodegeneration.

  10. Intermittent fasting is neuroprotective in focal cerebral ischemia by minimizing autophagic flux disturbance and inhibiting apoptosis.

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    Jeong, Ji Heun; Yu, Kwang Sik; Bak, Dong Ho; Lee, Je Hun; Lee, Nam Seob; Jeong, Young Gil; Kim, Dong Kwan; Kim, Jwa-Jin; Han, Seung-Yun

    2016-11-01

    Previous studies have demonstrated that autophagy induced by caloric restriction (CR) is neuroprotective against cerebral ischemia. However, it has not been determined whether intermittent fasting (IF), a variation of CR, can exert autophagy-related neuroprotection against cerebral ischemia. Therefore, the neuroprotective effect of IF was evaluated over the course of two weeks in a rat model of focal cerebral ischemia, which was induced by middle cerebral artery occlusion and reperfusion (MCAO/R). Specifically, the role of autophagy modulation as a potential underlying mechanism for this phenomenon was investigated. It was demonstrated that IF reduced infarct volume and brain edema, improved neurobehavioral deficits, and rescued neuronal loss after MCAO/R. Furthermore, neuronal apoptosis was decreased by IF in the rat cortex. An increase in the number of autophagosomes (APs) was demonstrated in the cortices of IF-treated rats, using immunofluorescence staining and transmission electron microscopy. Using immunoblots, an IF-induced increase was detected in microtubule-associated protein 1 light chain 3 (LC3)-II, Rab7, and cathepsin D protein levels, which corroborated previous morphological studies. Notably, IF reduced the accumulation of APs and p62, demonstrating that IF attenuated the MCAO/R-induced disturbance of autophagic flux in neurons. The findings of the present study suggest that IF-induced neuroprotection in focal cerebral ischemia is due, at least in part, to the minimization of autophagic flux disturbance and inhibition of apoptosis.

  11. Hydrogen peroxide impairs autophagic flux in a cell model of nonalcoholic fatty liver disease

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    Jiang, Pengtao [National Laboratory of Biomacromolecules, Institute of Biophysics, Chinese Academy of Sciences, 15 Datun Road, Chaoyang District, Beijing 100101 (China); University of Chinese Academy of Sciences, 19 Yuquan Road, Shijingshan District, Beijing 100049 (China); Huang, Zhen [Department of Abdominal Surgical Oncology, Cancer Hospital, Chinese Academy of Medical Sciences, 17 Panjiayuan Nanli, Chaoyang District, Beijing 100021 (China); Zhao, Hong, E-mail: zhaohong9@sina.com [Department of Abdominal Surgical Oncology, Cancer Hospital, Chinese Academy of Medical Sciences, 17 Panjiayuan Nanli, Chaoyang District, Beijing 100021 (China); Wei, Taotao, E-mail: weitt@moon.ibp.ac.cn [National Laboratory of Biomacromolecules, Institute of Biophysics, Chinese Academy of Sciences, 15 Datun Road, Chaoyang District, Beijing 100101 (China)

    2013-04-19

    Highlights: •Free fatty acids exposure induces elevated autophagy. •H{sub 2}O{sub 2} inhibits autophagic flux through impairing the fusion between autophagosomes and lysosomes. •Inhibition of autophagy potentiates H{sub 2}O{sub 2}-induced cell death. -- Abstract: Nonalcoholic fatty liver disease (NAFLD) has become the leading cause of chronic liver disease, but the pathogenesis of NAFLD is not fully clear. The aim of this study was to determine whether autophagy plays a role in the pathogenesis of NAFLD. We found that the levels of autophagy were elevated in hepatoma cells upon exposure to free fatty acids, as confirmed by the increase in the number of autophagosomes. However, exposure of hepatoma cells to H{sub 2}O{sub 2} and TNF-α, two typical “second hit” factors, increased the initiation of autophagy but inhibited the autophagic flux. The inhibition of autophagy sensitized cells to pro-apoptotic stimuli. Taken together, our results suggest that autophagy acts as a protective mechanism in the pathogenesis of NAFLD and that impairment of autophagy might induce more severe lesions of the liver. These findings will be a benefit to the understanding of the pathogenesis of NAFLD and might suggest a strategy for the prevention and cure of NAFLD.

  12. Autophagic flux without a block differentiates varicella-zoster virus infection from herpes simplex virus infection.

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    Buckingham, Erin M; Carpenter, John E; Jackson, Wallen; Zerboni, Leigh; Arvin, Ann M; Grose, Charles

    2015-01-06

    Autophagy is a process by which misfolded and damaged proteins are sequestered into autophagosomes, before degradation in and recycling from lysosomes. We have extensively studied the role of autophagy in varicella-zoster virus (VZV) infection, and have observed that vesicular cells are filled with >100 autophagosomes that are easily detectable after immunolabeling for the LC3 protein. To confirm our hypothesis that increased autophagosome formation was not secondary to a block, we examined all conditions of VZV infection as well as carrying out two assessments of autophagic flux. We first investigated autophagy in human skin xenografts in the severe combined immunodeficiency (SCID) mouse model of VZV pathogenesis, and observed that autophagosomes were abundant in infected human skin tissues. We next investigated autophagy following infection with sonically prepared cell-free virus in cultured cells. Under these conditions, autophagy was detected in a majority of infected cells, but was much less than that seen after an infected-cell inoculum. In other words, inoculation with lower-titered cell-free virus did not reflect the level of stress to the VZV-infected cell that was seen after inoculation of human skin in the SCID mouse model or monolayers with higher-titered infected cells. Finally, we investigated VZV-induced autophagic flux by two different methods (radiolabeling proteins and a dual-colored LC3 plasmid); both showed no evidence of a block in autophagy. Overall, therefore, autophagy within a VZV-infected cell was remarkably different from autophagy within an HSV-infected cell, whose genome contains two modifiers of autophagy, ICP34.5 and US11, not present in VZV.

  13. Adipose tissue conditioned media support macrophage lipid-droplet biogenesis by interfering with autophagic flux.

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    Bechor, Sapir; Nachmias, Dikla; Elia, Natalie; Haim, Yulia; Vatarescu, Maayan; Leikin-Frenkel, Alicia; Gericke, Martin; Tarnovscki, Tanya; Las, Guy; Rudich, Assaf

    2017-09-01

    Obesity promotes the biogenesis of adipose tissue (AT) foam cells (FC), which contribute to AT insulin resistance. Autophagy, an evolutionarily-conserved house-keeping process, was implicated in cellular lipid handling by either feeding and/or degrading lipid-droplets (LDs). We hypothesized that beyond phagocytosis of dead adipocytes, AT-FC biogenesis is supported by the AT microenvironment by regulating autophagy. Non-polarized ("M0") RAW264.7 macrophages exposed to AT conditioned media (AT-CM) exhibited a markedly enhanced LDs biogenesis rate compared to control cells (8.3 Vs 0.3 LDs/cells/h, p<0.005). Autophagic flux was decreased by AT-CM, and fluorescently following autophagosomes over time revealed ~20% decline in new autophagic vesicles' formation rate, and 60-70% decrease in autophagosomal growth rate, without marked alternations in the acidic lysosomal compartment. Suppressing autophagy by either targeting autophagosome formation (pharmacologically, with 3-methyladenine or genetically, with Atg12±Atg7-siRNA), decreased the rate of LD formation induced by oleic acid. Conversely, interfering with late autophago-lysosomal function, either pharmacologically with bafilomycin-A1, chloroquine or leupeptin, enhanced LD formation in macrophages without affecting LD degradation rate. Similarly enhanced LD biogenesis rate was induced by siRNA targeting Lamp-1 or the V-ATPase. Collectively, we propose that secreted products from AT interrupt late autophagosome maturation in macrophages, supporting enhanced LDs biogenesis and AT-FC formation, thereby contributing to AT dysfunction in obesity. Copyright © 2017 The Author(s). Published by Elsevier B.V. All rights reserved.

  14. AMPK activation protects cells from oxidative stress-induced senescence via autophagic flux restoration and intracellular NAD(+) elevation.

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    Han, Xiaojuan; Tai, Haoran; Wang, Xiaobo; Wang, Zhe; Zhou, Jiao; Wei, Xiawei; Ding, Yi; Gong, Hui; Mo, Chunfen; Zhang, Jie; Qin, Jianqiong; Ma, Yuanji; Huang, Ning; Xiang, Rong; Xiao, Hengyi

    2016-06-01

    AMPK activation is beneficial for cellular homeostasis and senescence prevention. However, the molecular events involved in AMPK activation are not well defined. In this study, we addressed the mechanism underlying the protective effect of AMPK on oxidative stress-induced senescence. The results showed that AMPK was inactivated in senescent cells. However, pharmacological activation of AMPK by metformin and berberine significantly prevented the development of senescence and, accordingly, inhibition of AMPK by Compound C was accelerated. Importantly, AMPK activation prevented hydrogen peroxide-induced impairment of the autophagic flux in senescent cells, evidenced by the decreased p62 degradation, GFP-RFP-LC3 cancellation, and activity of lysosomal hydrolases. We also found that AMPK activation restored the NAD(+) levels in the senescent cells via a mechanism involving mostly the salvage pathway for NAD(+) synthesis. In addition, the mechanistic relationship of autophagic flux and NAD(+) synthesis and the involvement of mTOR and Sirt1 activities were assessed. In summary, our results suggest that AMPK prevents oxidative stress-induced senescence by improving autophagic flux and NAD(+) homeostasis. This study provides a new insight for exploring the mechanisms of aging, autophagy and NAD(+) homeostasis, and it is also valuable in the development of innovative strategies to combat aging. © 2016 The Authors. Aging Cell published by the Anatomical Society and John Wiley & Sons Ltd.

  15. Acute high-caffeine exposure increases autophagic flux and reduces protein synthesis in C2C12 skeletal myotubes.

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    Hughes, M A; Downs, R M; Webb, G W; Crocker, C L; Kinsey, S T; Baumgarner, Bradley L

    2017-04-01

    Caffeine is a highly catabolic dietary stimulant. High caffeine concentrations (1-10 mM) have previously been shown to inhibit protein synthesis and increase protein degradation in various mammalian cell lines. The purpose of this study was to examine the effect of short-term caffeine exposure on cell signaling pathways that regulate protein metabolism in mammalian skeletal muscle cells. Fully differentiated C2C12 skeletal myotubes either received vehicle (DMSO) or 5 mM caffeine for 6 h. Our analysis revealed that caffeine promoted a 40% increase in autolysosome formation and a 25% increase in autophagic flux. In contrast, caffeine treatment did not significantly increase the expression of the skeletal muscle specific ubiquitin ligases MAFbx and MuRF1 or 20S proteasome activity. Caffeine treatment significantly reduced mTORC1 signaling, total protein synthesis and myotube diameter in a CaMKKβ/AMPK-dependent manner. Further, caffeine promoted a CaMKII-dependent increase in myostatin mRNA expression that did not significantly contribute to the caffeine-dependent reduction in protein synthesis. Our results indicate that short-term caffeine exposure significantly reduced skeletal myotube diameter by increasing autophagic flux and promoting a CaMKKβ/AMPK-dependent reduction in protein synthesis.

  16. Graphene oxide quantum dots disrupt autophagic flux by inhibiting lysosome activity in GC-2 and TM4 cell lines

    International Nuclear Information System (INIS)

    Ji, Xiaoli; Xu, Bo; Yao, Mengmeng; Mao, Zhilei; Zhang, Yuqing; Xu, Guofeng; Tang, Qiusha; Wang, Xinru; Xia, Yankai

    2016-01-01

    Graphene oxide quantum dots (GOQDs) have broad application prospects in many areas including bioimaging, drug delivery, DNA cleavage system, sensors and photocatalyst. Recently, increasing concerns have been raised about their biocompatibility, but studies about the effects of GOQDs on male reproductive system are still lacking. In this work, we explored the effects and molecular mechanisms of GOQDs on GC-2 and TM4 cells. We found autophagosome accumulation in GC-2 and TM4 cells after GOQDs treatment. Both LC3-II/LC3-I ratio and p62 levels increased, and the chloroquine-induced accumulation of LC3-II didn’t enhance in the presence of GOQDs, which indicated that GOQDs blocked autophagic flux. Further studies found that the fusion between autophagosome and lysosome was not inhibited by GOQDs, but the proteolytic capacity of lysosome was weakened and both the expression and activity of cathepsin B reduced. Taken together, these results suggested that GOQDs blocked autophagic flux by decreasing the amount and enzymatic activity of cathepsin B and inhibiting lysosome proteolytic capacity in GC-2 and TM4 cells, which might have a potential hazard to male reproduction.

  17. Lysosomotropic cationic drugs induce cytostatic and cytotoxic effects: Role of liposolubility and autophagic flux and antagonism by cholesterol ablation

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    Parks, Alexandre; Marceau, François, E-mail: francois.marceau@crchul.ulaval.ca

    2016-08-15

    Cation trapping in acidic cell compartments determines an antiproliferative effect that has a potential interest in oncology, as shown by clinical data and trials involving chloroquine and hydroxychloroquine. To further characterize the mechanism of this effect, we studied a series of 6 substituted triethylamine (s-Et{sub 3}N) drugs that encompasses a wide range of liposolubility (amiodarone, quinacrine, chloroquine, hydroxychloroquine, lidocaine, and procainamide). Three tumor cell lines and primary human endothelial cells were exploited in proliferation assays (48 h, cell counts). Accumulation of the autophagic effector LC3 II and the apoptotic marker cleaved PARP1 (immunoblots), cytotoxicity, cell cycle analysis and endocytic function were further tested in the p53-null histiocytic lymphoma U937 line. A profound and desynchronized antiproliferative effect was observed in response to all s-Et{sub 3}Ns with essentially no cell type specificity. Predictors of s-Et{sub 3}N potency were liposolubility and the acute accumulation of the autophagic effector LC3 II (6 h-treatments). For each s-Et{sub 3}N, there was an antiproliferative concentration range where cytotoxicity and apoptosis were not triggered in U937 cells (24–48 h-treatments). Quinacrine was the most potent cytostatic drug (1–5 μM). Co-treatment of cells with inhibitors of cholesterol, β-cyclodextrin or lovastatin, partially reversed the antiproliferative effect of each s-Et{sub 3}N. The cytopathology induced by cationic drug accumulation includes a cytostatic effect. Its intensity is cell type- and p53-independent, but predicted by the inhibition of autophagic flux and by the liposolubility of individual drugs and alleviated by cholesterol ablation. The superiority of quinacrine, biomarker value of LC3 II and antagonism by a statin may be clinically relevant. - Highlights: • Cation trapping in acidic cell compartments induces a cytostatic effect. • A series of substituted triethylamines has been

  18. Lysosomotropic cationic drugs induce cytostatic and cytotoxic effects: Role of liposolubility and autophagic flux and antagonism by cholesterol ablation

    International Nuclear Information System (INIS)

    Parks, Alexandre; Marceau, François

    2016-01-01

    Cation trapping in acidic cell compartments determines an antiproliferative effect that has a potential interest in oncology, as shown by clinical data and trials involving chloroquine and hydroxychloroquine. To further characterize the mechanism of this effect, we studied a series of 6 substituted triethylamine (s-Et 3 N) drugs that encompasses a wide range of liposolubility (amiodarone, quinacrine, chloroquine, hydroxychloroquine, lidocaine, and procainamide). Three tumor cell lines and primary human endothelial cells were exploited in proliferation assays (48 h, cell counts). Accumulation of the autophagic effector LC3 II and the apoptotic marker cleaved PARP1 (immunoblots), cytotoxicity, cell cycle analysis and endocytic function were further tested in the p53-null histiocytic lymphoma U937 line. A profound and desynchronized antiproliferative effect was observed in response to all s-Et 3 Ns with essentially no cell type specificity. Predictors of s-Et 3 N potency were liposolubility and the acute accumulation of the autophagic effector LC3 II (6 h-treatments). For each s-Et 3 N, there was an antiproliferative concentration range where cytotoxicity and apoptosis were not triggered in U937 cells (24–48 h-treatments). Quinacrine was the most potent cytostatic drug (1–5 μM). Co-treatment of cells with inhibitors of cholesterol, β-cyclodextrin or lovastatin, partially reversed the antiproliferative effect of each s-Et 3 N. The cytopathology induced by cationic drug accumulation includes a cytostatic effect. Its intensity is cell type- and p53-independent, but predicted by the inhibition of autophagic flux and by the liposolubility of individual drugs and alleviated by cholesterol ablation. The superiority of quinacrine, biomarker value of LC3 II and antagonism by a statin may be clinically relevant. - Highlights: • Cation trapping in acidic cell compartments induces a cytostatic effect. • A series of substituted triethylamines has been studied in 4 cell

  19. Mild hypothermia protects hippocampal neurons against oxygen-glucose deprivation/reperfusion-induced injury by improving lysosomal function and autophagic flux.

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    Zhou, Tianen; Liang, Lian; Liang, Yanran; Yu, Tao; Zeng, Chaotao; Jiang, Longyuan

    2017-09-15

    Mild hypothermia has been proven to be useful to treat brain ischemia/reperfusion injury. However, the underlying mechanisms have not yet been fully elucidated. The present study was undertaken to determine whether mild hypothermia protects hippocampal neurons against oxygen-glucose deprivation/reperfusion(OGD/R)-induced injury via improving lysosomal function and autophagic flux. The results showed that OGD/R induced the occurrence of autophagy, while the acidic environment inside the lysosomes was altered. The autophagic flux assay with RFP-GFP tf-LC3 was impeded in hippocampal neurons after OGD/R. Mild hypothermia recovered the lysosomal acidic fluorescence and the lysosomal marker protein expression of LAMP2, which decreased after OGD/R.Furthermore, we found that mild hypothermia up-regulated autophagic flux and promoted the fusion of autophagosomes and lysosomes in hippocampal neurons following OGD/R injury, but could be reversed by treatment with chloroquine, which acts as a lysosome inhibitor. We also found that mild hypothermia improved mitochondrial autophagy in hippocampal neurons following OGD/R injury. Finally,we found that chloroquine blocked the protective effects of mild hypothermia against OGD/R-induced cell death and injury. Taken together, the present study indicates that mild hypothermia protects hippocampal neurons against OGD/R-induced injury by improving lysosomal function and autophagic flux. Copyright © 2017. Published by Elsevier Inc.

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

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    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.

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

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    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.

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

    International Nuclear Information System (INIS)

    Morissette, Guillaume; Lodge, Robert; Marceau, Francois

    2008-01-01

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

  3. 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.

  4. Skeletal muscle myotubes of the severely obese exhibit altered ubiquitin-proteasome and autophagic/lysosomal proteolytic flux

    Science.gov (United States)

    Bollinger, Lance M.; Powell, Jonathan J. S.; Houmard, Joseph A.; Witczak, Carol A.; Brault, Jeffrey J.

    2015-01-01

    Objective Whole-body protein metabolism is dysregulated with obesity. Our goal was to determine if activity and expression of major protein degradation pathways are compromised specifically in human skeletal muscle with obesity. Methods We utilized primary Human Skeletal Muscle cell (HSkM) cultures since cellular mechanisms can be studied absent of hormones and contractile activity that could independently influence metabolism. HSkM from 10 lean (BMI ≤ 26.0 kg/m2) and 8 severely obese (BMI ≥ 39.0) women were examined basally and when stimulated to atrophy (serum and amino acid starvation). Results HSkM from obese donors had a lower proportion of type I myosin heavy chain and slower flux through the autophagic/lysosomal pathway. During starvation, flux through the ubiquitin-proteasome system diverged according to obesity status, with a decrease in the lean and an increase in HSkM from obese subjects. HSkMC from the obese also displayed elevated proteasome activity despite no difference in proteasome content. Atrophy-related gene expression and myotube area were similar in myotubes derived from lean and obese individuals under basal and starved conditions. Conclusions Our data indicate that muscle cells of the lean and severely obese have innate differences in management of protein degradation, which may explain their metabolic differences. PMID:26010327

  5. 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.

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

    Science.gov (United States)

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

    2018-01-22

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

  7. The reverse-mode NCX1 activity inhibitor KB-R7943 promotes prostate cancer cell death by activating the JNK pathway and blocking autophagic flux.

    Science.gov (United States)

    Long, Zhou; Chen, BaiJun; Liu, Qian; Zhao, Jiang; Yang, ZhenXing; Dong, XingYou; Xia, LiuBin; Huang, ShengQuan; Hu, XiaoYan; Song, Bo; Li, LongKun

    2016-07-05

    We explored the effects of KB-R7943, an inhibitor of reverse-mode NCX1 activity, in prostate cancer (PCa). NCX1 was overexpressed in PCa tissues and cell lines, and higher NCX1 levels were associated higher PCa grades. At concentrations greater than 10 μM, KB-R7943 dose-dependently decreased PC3 and LNCaP cell viability. KB-R7943 also increased cell cycle G1/S phase arrest and induced apoptosis in PC3 cells. KB-R7943 increased autophagosome accumulation in PCa cells as indicated by increases in LC3-II levels and eGFP-LC3 puncta. Combined treatment with chloroquine (CQ) and KB-R7943 decreased P62 and increased LC3-II protein levels in PC3 cells, indicating that KB-R7943 blocked autophagic flux. KB-R7943 induced autophagosome accumulation mainly by downregulating the PI3K/AKT/m-TOR pathway and upregulating the JNK pathway. In xenograft experiments, KB-R7943 inhibited tumor growth. Combined treatment with KB-R7943 and an autophagy inhibitor inhibited growth and increased apoptosis. These results indicate that KB-R7943 promotes cell death in PCa by activating the JNK signaling pathway and blocking autophagic flux.

  8. The Protective Effect of Gangliosides on Lead (Pb)-Induced Neurotoxicity Is Mediated by Autophagic Pathways.

    Science.gov (United States)

    Meng, Hongtao; Wang, Lan; He, Junhong; Wang, Zhufeng

    2016-03-25

    Lead (Pb) is a ubiquitous environmental and industrial pollutant and can affect intelligence development and the learning ability and memory of children. Therefore, necessary measures should be taken to protect the central nervous system (CNS) from Pb toxicity. Gangliosides are sialic acid-containing glycosphingolipids that are constituents of mammalian cell membranes and are more abundantly expressed in the CNS. Studies have shown that gangliosides constitute a useful tool in the attempt to promote functional recovery of CNS and can reverse Pb-induced impairments of synaptic plasticity in rats. However, the detailed mechanisms have yet to be fully understood. In our present study, we tried to investigate the role of gangliosides in Pb-induced injury in hippocampus neurons and to further confirm the detailed mechanism. Our results show that Pb-induced injuries in the spatial reference memory were associated with a reduction of cell viability and cell apoptosis, and treatment with gangliosides markedly ameliorated the Pb-induced injury by inhibition of apoptosis action. Gangliosides further attenuated Pb-induced the abnormal autophagic process by regulation of mTOR pathways. In summary, our study establishes the efficacy of gangliosides as neuroprotective agents and provides a strong rationale for further studies on the underlying mechanisms of their neuroprotective functions.

  9. The Protective Effect of Gangliosides on Lead (Pb-Induced Neurotoxicity Is Mediated by Autophagic Pathways

    Directory of Open Access Journals (Sweden)

    Hongtao Meng

    2016-03-01

    Full Text Available Lead (Pb is a ubiquitous environmental and industrial pollutant and can affect intelligence development and the learning ability and memory of children. Therefore, necessary measures should be taken to protect the central nervous system (CNS from Pb toxicity. Gangliosides are sialic acid-containing glycosphingolipids that are constituents of mammalian cell membranes and are more abundantly expressed in the CNS. Studies have shown that gangliosides constitute a useful tool in the attempt to promote functional recovery of CNS and can reverse Pb-induced impairments of synaptic plasticity in rats. However, the detailed mechanisms have yet to be fully understood. In our present study, we tried to investigate the role of gangliosides in Pb-induced injury in hippocampus neurons and to further confirm the detailed mechanism. Our results show that Pb-induced injuries in the spatial reference memory were associated with a reduction of cell viability and cell apoptosis, and treatment with gangliosides markedly ameliorated the Pb-induced injury by inhibition of apoptosis action. Gangliosides further attenuated Pb-induced the abnormal autophagic process by regulation of mTOR pathways. In summary, our study establishes the efficacy of gangliosides as neuroprotective agents and provides a strong rationale for further studies on the underlying mechanisms of their neuroprotective functions.

  10. The Ketone Body, β-Hydroxybutyrate Stimulates the Autophagic Flux and Prevents Neuronal Death Induced by Glucose Deprivation in Cortical Cultured Neurons.

    Science.gov (United States)

    Camberos-Luna, Lucy; Gerónimo-Olvera, Cristian; Montiel, Teresa; Rincon-Heredia, Ruth; Massieu, Lourdes

    2016-03-01

    Glucose is the major energy substrate in brain, however, during ketogenesis induced by starvation or prolonged hypoglycemia, the ketone bodies (KB), acetoacetate and β-hydroxybutyrate (BHB) can substitute for glucose. KB improve neuronal survival in diverse injury models, but the mechanisms by which KB prevent neuronal damage are still not well understood. In the present study we have investigated whether protection by the D isomer of BHB (D-BHB) against neuronal death induced by glucose deprivation (GD), is related to autophagy. Autophagy is a lysosomal-dependent degradation process activated during nutritional stress, which leads to the digestion of damaged proteins and organelles providing energy for cell survival. Results show that autophagy is activated in cortical cultured neurons during GD, as indicated by the increase in the levels of the lipidated form of the microtubule associated protein light chain 3 (LC3-II), and the number of autophagic vesicles. At early phases of glucose reintroduction (GR), the levels of p62 declined suggesting that the degradation of the autophagolysosomal content takes place at this time. In cultures exposed to GD and GR in the presence of D-BHB, the levels of LC3-II and p62 rapidly declined and remained low during GR, suggesting that the KB stimulates the autophagic flux preventing autophagosome accumulation and improving neuronal survival.

  11. Tetherin Suppresses Type I Interferon Signaling by Targeting MAVS for NDP52-Mediated Selective Autophagic Degradation in Human Cells.

    Science.gov (United States)

    Jin, Shouheng; Tian, Shuo; Luo, Man; Xie, Weihong; Liu, Tao; Duan, Tianhao; Wu, Yaoxing; Cui, Jun

    2017-10-19

    Tetherin (BST2/CD317) is an interferon-inducible antiviral factor known for its ability to block the release of enveloped viruses from infected cells. Yet its role in type I interferon (IFN) signaling remains poorly defined. Here, we demonstrate that Tetherin is a negative regulator of RIG-I like receptor (RLR)-mediated type I IFN signaling by targeting MAVS. The induction of Tetherin by type I IFN accelerates MAVS degradation via ubiquitin-dependent selective autophagy in human cells. Moreover, Tetherin recruits E3 ubiquitin ligase MARCH8 to catalyze K27-linked ubiquitin chains on MAVS at lysine 7, which serves as a recognition signal for NDP52-dependent autophagic degradation. Taken together, our findings reveal a negative feedback loop of RLR signaling generated by Tetherin-MARCH8-MAVS-NDP52 axis and provide insights into a better understanding of the crosstalk between selective autophagy and optimal deactivation of type I IFN signaling. Copyright © 2017 Elsevier Inc. All rights reserved.

  12. U(1) mediation of flux supersymmetry breaking

    Science.gov (United States)

    Grimm, Thomas W.; Klemm, Albrecht

    2008-10-01

    We study the mediation of supersymmetry breaking triggered by background fluxes in Type II string compactifications with Script N = 1 supersymmetry. The mediation arises due to an U(1) vector multiplet coupling to both a hidden supersymmetry breaking flux sector and a visible D-brane sector. The required internal manifolds can be constructed by non-Kähler resolutions of singular Calabi-Yau manifolds. The effective action encoding the U(1) coupling is then determined in terms of the global topological properties of the internal space. We investigate suitable local geometries for the hidden and visible sector in detail. This includes a systematic study of orientifold symmetries of del Pezzo surfaces realized in compact geometries after geometric transition. We construct compact examples admitting the key properties to realize flux supersymmetry breaking and U(1) mediation. Their toric realization allows us to analyze the geometry of curve classes and confirm the topological connection between the hidden and visible sector.

  13. U(1) mediation of flux supersymmetry breaking

    International Nuclear Information System (INIS)

    Grimm, Thomas W.; Klemm, Albrecht

    2008-01-01

    We study the mediation of supersymmetry breaking triggered by background fluxes in Type II string compactifications with N = 1 supersymmetry. The mediation arises due to an U(1) vector multiplet coupling to both a hidden supersymmetry breaking flux sector and a visible D-brane sector. The required internal manifolds can be constructed by non-Kaehler resolutions of singular Calabi-Yau manifolds. The effective action encoding the U(1) coupling is then determined in terms of the global topological properties of the internal space. We investigate suitable local geometries for the hidden and visible sector in detail. This includes a systematic study of orientifold symmetries of del Pezzo surfaces realized in compact geometries after geometric transition. We construct compact examples admitting the key properties to realize flux supersymmetry breaking and U(1) mediation. Their toric realization allows us to analyze the geometry of curve classes and confirm the topological connection between the hidden and visible sector.

  14. Honokiol induces autophagic cell death in malignant glioma through reactive oxygen species-mediated regulation of the p53/PI3K/Akt/mTOR signaling pathway

    Energy Technology Data Exchange (ETDEWEB)

    Lin, Chien-Ju [Graduate Institute of Medical Sciences, Taipei Medical University, Taipei, Taiwan (China); Comprehensive Cancer Center, Taipei Medical University, Taipei, Taiwan (China); Chen, Ta-Liang [Anesthetics and Toxicology Research Center, Taipei Medical University Hospital, Taipei, Taiwan (China); Department of Anesthesiology, Taipei Medical University Hospital, Taipei, Taiwan (China); Tseng, Yuan-Yun [Department of Neurosurgery, Shuang-Ho Hospital, Taipei Medical University, Taipei, Taiwan (China); Wu, Gong-Jhe [Department of Anesthesiology, Shin Kong Wu Ho-Su Memorial Hospital, Taipei, Taiwan (China); Hsieh, Ming-Hui [Anesthetics and Toxicology Research Center, Taipei Medical University Hospital, Taipei, Taiwan (China); Department of Anesthesiology, Taipei Medical University Hospital, Taipei, Taiwan (China); Lin, Yung-Wei [Brain Disease Research Center, Taipei Medical University Wan-Fang Hospital, Taipei, Taiwan (China); Chen, Ruei-Ming, E-mail: rmchen@tmu.edu.tw [Graduate Institute of Medical Sciences, Taipei Medical University, Taipei, Taiwan (China); Anesthetics and Toxicology Research Center, Taipei Medical University Hospital, Taipei, Taiwan (China); Brain Disease Research Center, Taipei Medical University Wan-Fang Hospital, Taipei, Taiwan (China); Comprehensive Cancer Center, Taipei Medical University, Taipei, Taiwan (China)

    2016-08-01

    Honokiol, an active constituent extracted from the bark of Magnolia officinalis, possesses anticancer effects. Apoptosis is classified as type I programmed cell death, while autophagy is type II programmed cell death. We previously proved that honokiol induces cell cycle arrest and apoptosis of U87 MG glioma cells. Subsequently in this study, we evaluated the effect of honokiol on autophagy of glioma cells and examined the molecular mechanisms. Administration of honokiol to mice with an intracranial glioma increased expressions of cleaved caspase 3 and light chain 3 (LC3)-II. Exposure of U87 MG cells to honokiol also induced autophagy in concentration- and time-dependent manners. Results from the addition of 3-methyladenine, an autophagy inhibitor, and rapamycin, an autophagy inducer confirmed that honokiol-induced autophagy contributed to cell death. Honokiol decreased protein levels of PI3K, phosphorylated (p)-Akt, and p-mammalian target of rapamycin (mTOR) in vitro and in vivo. Pretreatment with a p53 inhibitor or transfection with p53 small interfering (si)RNA suppressed honokiol-induced autophagy by reversing downregulation of p-Akt and p-mTOR expressions. In addition, honokiol caused generation of reactive oxygen species (ROS), which was suppressed by the antioxidant, vitamin C. Vitamin C also inhibited honokiol-induced autophagic and apoptotic cell death. Concurrently, honokiol-induced alterations in levels of p-p53, p53, p-Akt, and p-mTOR were attenuated following vitamin C administration. Taken together, our data indicated that honokiol induced ROS-mediated autophagic cell death through regulating the p53/PI3K/Akt/mTOR signaling pathway. - Highlights: • Exposure of mice with intracranial gliomas to honokiol induces cell apoptosis and autophagy. • Honokiol triggers autophagy of human glioma cells via the PISK/AKT/mTOR signaling pathway. • P53 induces autophagy via regulating the AKT/mTOR pathway in honokiol-treated glioma cells. • ROS participates

  15. Oxygen-Glucose-Deprivation/Reoxygenation-Induced Autophagic Cell Death Depends on JNK-Mediated Phosphorylation of Bcl-2

    Directory of Open Access Journals (Sweden)

    Jin Fan

    2016-03-01

    Full Text Available Background/Aims: The purpose of this study was to investigate the role of autophagy in oxygen-glucose-deprivation/reoxygenation (OGD/R injury in rat neurons. Methods and results: Cortical neurons were isolated from Sprague-Dawley rats and identified by immunofluorescence. The cortical neurons were randomly assigned to one of four groups: control group (I, experimental group (OGD/R group, II, JNK inhibitor pretreatment group (III and JNK inhibitor pretreatment + OGD/R group (IV. Neuronal cell viability significantly decreased after 6h and 12h of reoxygenation in Group IV (P P Conclusion: The regulation of the JNK/Bcl-2/Beclin-1 signaling pathway may be one of the mechanisms underlying the OGD/R-induced autophagic cell death of neurons.

  16. Autophagic pathways and metabolic stress.

    Science.gov (United States)

    Kaushik, S; Singh, R; Cuervo, A M

    2010-10-01

    Autophagy is an essential intracellular process that mediates degradation of intracellular proteins and organelles in lysosomes. Autophagy was initially identified for its role as alternative source of energy when nutrients are scarce but, in recent years, a previously unknown role for this degradative pathway in the cellular response to stress has gained considerable attention. In this review, we focus on the novel findings linking autophagic function with metabolic stress resulting either from proteins or lipids. Proper autophagic activity is required in the cellular defense against proteotoxicity arising in the cytosol and also in the endoplasmic reticulum, where a vast amount of proteins are synthesized and folded. In addition, autophagy contributes to mobilization of intracellular lipid stores and may be central to lipid metabolism in certain cellular conditions. In this review, we focus on the interrelation between autophagy and different types of metabolic stress, specifically the stress resulting from the presence of misbehaving proteins within the cytosol or in the endoplasmic reticulum and the stress following a lipogenic challenge. We also comment on the consequences that chronic exposure to these metabolic stressors could have on autophagic function and on how this effect may underlie the basis of some common metabolic disorders. © 2010 Blackwell Publishing Ltd.

  17. Autophagic cell death: Loch Ness monster or endangered species?

    Science.gov (United States)

    Shen, Han-Ming; Codogno, Patrice

    2011-05-01

    The concept of autophagic cell death was first established based on observations of increased autophagic markers in dying cells. The major limitation of such a morphology-based definition of autophagic cell death is that it fails to establish the functional role of autophagy in the cell death process, and thus contributes to the confusion in the literature regarding the role of autophagy in cell death and cell survival. Here we propose to define autophagic cell death as a modality of non-apoptotic or necrotic programmed cell death in which autophagy serves as a cell death mechanism, upon meeting the following set of criteria: (i) cell death occurs without the involvement of apoptosis; (ii) there is an increase of autophagic flux, and not just an increase of the autophagic markers, in the dying cells; and (iii) suppression of autophagy via both pharmacological inhibitors and genetic approaches is able to rescue or prevent cell death. In light of this new definition, we will discuss some of the common problems and difficulties in the study of autophagic cell death and also revisit some well-reported cases of autophagic cell death, aiming to achieve a better understanding of whether autophagy is a real killer, an accomplice or just an innocent bystander in the course of cell death. At present, the physiological relevance of autophagic cell death is mainly observed in lower eukaryotes and invertebrates such as Dictyostelium discoideum and Drosophila melanogaster. We believe that such a clear definition of autophagic cell death will help us study and understand the physiological or pathological relevance of autophagic cell death in mammals.

  18. 4-Acetylantroquinonol B suppresses autophagic flux and improves cisplatin sensitivity in highly aggressive epithelial cancer through the PI3K/Akt/mTOR/p70S6K signaling pathway

    Energy Technology Data Exchange (ETDEWEB)

    Liu, Mingche [Graduate Institute of Biomedical Materials and Tissue Engineering, College of biomedical engineering, Taipei Medical University, Taipei, Taiwan (China); Department of Urology, Taipei Medical University Hospital, Taipei, Taiwan (China); Department of Urology, School of Medicine, college of Medicine, Taipei Medical University, Taipei, Taiwan (China); Bamodu, Oluwaseun Adebayo [Department of Hematology and Oncology, Cancer Center, Taipei Medical University-Shuang Ho Hospital, New Taipei City, Taiwan (China); Department of Medical Research & Education, Taipei Medical University-Shuang Ho Hospital, New Taipei City, Taiwan (China); Huang, Wen-Chien [Institute of Traditional Medicine, School of Medicine, National Yang Ming University, Taipei, Taiwan (China); Department of Surgery, Division of Thoracic Surgery, MacKay Memorial Hospital, Taipei, Taiwan (China); Zucha, Muhammad Ary [Graduate Institute of Medical Sciences, Taipei Medical University, Taipei, Taiwan (China); Lin, Yen-Kuang [Biostatistics and Research Consultation Center, Taipei Medical University, Taipei 11031, Taiwan (China); Wu, Alexander T.H. [The Ph.D. Program for Translational Medicine, College of Medical Science and Technology, Taipei Medical University, Taipei, Taiwan (China); Huang, Chun-Chih [Center for General Education, National Taitung University, Taitung, Taiwan (China); Lee, Wei-Hwa [Department of Pathology, Taipei Medical University-Shuang Ho Hospital, Taipei, Taiwan (China); Yuan, Chiou-Chung [Obstetrics and Gynecology Department, Taipei Medical University-Shuang Ho Hospital, Taipei, Taiwan (China); Hsiao, M. [Genomics Research Center, Academia Sinica, Taipei, Taiwan (China); Deng, Li [Beijing Bioprocess Key Laboratory, College of Life Science and Technology, Beijing University of Chemical Technology, Beijing (China); Amoy-BUCT Industrial Bio-technovation Institute, Amoy (China); and others

    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. - Highlights: • Atg-5 is overexpressed in ovarian cancer and silencing Atg-5 induces apoptosis. • 4-AAQB suppresses autophagy and PI3K/Akt/mTOR pathway. • 4-AAQB + cisplatin synergistically suppresses ovarian cancer via

  19. 4-Acetylantroquinonol B suppresses autophagic flux and improves cisplatin sensitivity in highly aggressive epithelial cancer through the PI3K/Akt/mTOR/p70S6K signaling pathway

    International Nuclear Information System (INIS)

    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

    2017-01-01

    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. - Highlights: • Atg-5 is overexpressed in ovarian cancer and silencing Atg-5 induces apoptosis. • 4-AAQB suppresses autophagy and PI3K/Akt/mTOR pathway. • 4-AAQB + cisplatin synergistically suppresses ovarian cancer via

  20. 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.

  1. Tetrandrine, an Activator of Autophagy, Induces Autophagic Cell Death via PKC-α Inhibition and mTOR-Dependent Mechanisms

    Directory of Open Access Journals (Sweden)

    Vincent Kam Wai Wong

    2017-06-01

    Full Text Available Emerging evidence suggests the therapeutic role of autophagic modulators in cancer therapy. This study aims to identify novel traditional Chinese medicinal herbs as potential anti-tumor agents through autophagic induction, which finally lead to autophagy mediated-cell death in apoptosis-resistant cancer cells. Using bioactivity-guided purification, we identified tetrandrine (Tet from herbal plant, Radix stephaniae tetrandrae, as an inducer of autophagy. Across a number of cancer cell lines, we found that breast cancer cells treated with tetrandrine show an increase autophagic flux and formation of autophagosomes. In addition, tetrandrine induces cell death in a panel of apoptosis-resistant cell lines that are deficient for caspase 3, caspase 7, caspase 3 and 7, or Bax-Bak respectively. We also showed that tetrandrine-induced cell death is independent of necrotic cell death. Mechanistically, tetrandrine induces autophagy that depends on mTOR inactivation. Furthermore, tetrandrine induces autophagy in a calcium/calmodulin-dependent protein kinase kinase-β (CaMKK-β, 5′ AMP-activated protein kinase (AMPK independent manner. Finally, by kinase profiling against 300 WT kinases and computational molecular docking analysis, we showed that tetrandrine is a novel PKC-α inhibitor, which lead to autophagic induction through PKC-α inactivation. This study provides detailed insights into the novel cytotoxic mechanism of an anti-tumor compound originated from the herbal plant, which may be useful in promoting autophagy mediated- cell death in cancer cell that is resistant to apoptosis.

  2. The Autophagic Machinery in Enterovirus Infection.

    Science.gov (United States)

    Lai, Jeffrey K F; Sam, I-Ching; Chan, Yoke Fun

    2016-01-27

    The Enterovirus genus of the Picornaviridae family comprises many important human pathogens, including polioviruses, rhinovirus, enterovirus A71, and enterovirus D68. They cause a wide variety of diseases, ranging from mild to severe life-threatening diseases. Currently, no effective vaccine is available against enteroviruses except for poliovirus. Enteroviruses subvert the autophagic machinery to benefit their assembly, maturation, and exit from host. Some enteroviruses spread between cells via a process described as autophagosome-mediated exit without lysis (AWOL). The early and late phases of autophagy are regulated through various lipids and their metabolizing enzymes. Some of these lipids and enzymes are specifically regulated by enteroviruses. In the present review, we summarize the current understanding of the regulation of autophagic machinery by enteroviruses, and provide updates on recent developments in this field.

  3. 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...

  4. 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

  5. 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.

  6. Recovery of aquatic insect-mediated methylmercury flux from ponds following drying disturbance.

    Science.gov (United States)

    Chumchal, Matthew M; Drenner, Ray W; Greenhill, Frank M; Kennedy, James H; Courville, Ashlyn E; Gober, Charlie A A; Lossau, Luke O

    2017-08-01

    Small ponds exist across a permanence gradient, and pond permanence is hypothesized to be a primary determinant of insect community structure and insect-mediated methylmercury (MeHg) flux from ponds to the surrounding terrestrial landscape. The present study describes the first experiment examining the recovery of insect-mediated MeHg flux following a drying disturbance that converted permanent ponds with insectivorous fish to semipermanent ponds without fish. Floating emergence traps were used to collect emergent insects for 10 wk in the spring and summer from 5 ponds with fish (permanent) and 5 ponds that were drained to remove fish, dried, and refilled with water (semipermanent). During the 73-d period after semipermanent ponds were refilled, total MeHg flux from semipermanent ponds was not significantly different than total MeHg flux from permanent ponds, indicating that insect-mediated MeHg flux had rapidly recovered in semipermanent ponds following the drying disturbance. Methylmercury fluxes from dragonflies (Odonata: Anisoptera) and phantom midges (Diptera: Chaoboridae) were significantly greater from newly refilled semipermanent ponds than permanent ponds, but the MeHg fluxes from the other 8 emergent insect taxa did not differ between treatments. The present study demonstrates the impact of drying disturbance and the effect of community structure on the cross-system transport of contaminants from aquatic to terrestrial ecosystems. Environ Toxicol Chem 2017;36:1986-1990. © 2017 SETAC. © 2017 SETAC.

  7. Voltage-gated calcium flux mediates Escherichia coli mechanosensation.

    Science.gov (United States)

    Bruni, Giancarlo N; Weekley, R Andrew; Dodd, Benjamin J T; Kralj, Joel M

    2017-08-29

    Electrically excitable cells harness voltage-coupled calcium influx to transmit intracellular signals, typically studied in neurons and cardiomyocytes. Despite intense study in higher organisms, investigations of voltage and calcium signaling in bacteria have lagged due to their small size and a lack of sensitive tools. Only recently were bacteria shown to modulate their membrane potential on the timescale of seconds, and little is known about the downstream effects from this modulation. In this paper, we report on the effects of electrophysiology in individual bacteria. A genetically encoded calcium sensor expressed in Escherichia coli revealed calcium transients in single cells. A fusion sensor that simultaneously reports voltage and calcium indicated that calcium influx is induced by voltage depolarizations, similar to metazoan action potentials. Cytoplasmic calcium levels and transients increased upon mechanical stimulation with a hydrogel, and single cells altered protein concentrations dependent on the mechanical environment. Blocking voltage and calcium flux altered mechanically induced changes in protein concentration, while inducing calcium flux reproduced these changes. Thus, voltage and calcium relay a bacterial sense of touch and alter cellular lifestyle. Although the calcium effectors remain unknown, these data open a host of new questions about E. coli , including the identity of the underlying molecular players, as well as other signals conveyed by voltage and calcium. These data also provide evidence that dynamic voltage and calcium exists as a signaling modality in the oldest domain of life, and therefore studying electrophysiology beyond canonical electrically excitable cells could yield exciting new findings.

  8. 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.

  9. Bacteroides fragilis Enterotoxin Induces Formation of Autophagosomes in Endothelial Cells but Interferes with Fusion with Lysosomes for Complete Autophagic Flux through a Mitogen-Activated Protein Kinase-, AP-1-, and C/EBP Homologous Protein-Dependent Pathway.

    Science.gov (United States)

    Ko, Su Hyuk; Jeon, Jong Ik; Myung, Hyun Soo; Kim, Young-Jeon; Kim, Jung Mogg

    2017-10-01

    Bacteroides fragilis enterotoxin (BFT), a virulence factor of enterotoxigenic B. fragilis (ETBF), plays an essential role in mucosal inflammation. Although autophagy contributes to the pathogenesis of diverse infectious diseases, little is known about autophagy in ETBF infection. This study was conducted to investigate the role of BFT in the autophagic process in endothelial cells (ECs). Stimulation of human umbilical vein ECs (HUVECs) with BFT increased light chain 3 protein II (LC3-II) conversion from LC3-I and protein expression of p62, Atg5, and Atg12. In addition, BFT-exposed ECs showed increased indices of autophagosomal fusion with lysosomes such as LC3-lysosome-associated protein 2 (LAMP2) colocalization and the percentage of red vesicles monitored by the expression of dual-tagged LC3B. BFT also upregulated expression of C/EBP homologous protein (CHOP), and inhibition of CHOP significantly increased indices of autophagosomal fusion with lysosomes. BFT activated an AP-1 transcription factor, in which suppression of AP-1 activity significantly downregulated CHOP and augmented autophagosomal fusion with lysosomes. Furthermore, suppression of Jun N-terminal protein kinase (JNK) mitogen-activated protein kinase (MAPK) significantly inhibited the AP-1 and CHOP signals, leading to an increase in autophagosomal fusion with lysosomes in BFT-stimulated ECs. These results suggest that BFT induced accumulation of autophagosomes in ECs, but activation of a signaling pathway involving JNK, AP-1, and CHOP may interfere with complete autophagy. Copyright © 2017 American Society for Microbiology.

  10. 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

  11. HBV subgenotypes F1b and F4 replication induces an incomplete autophagic process in hepatocytes: Role of BCP and preCore mutations.

    Science.gov (United States)

    Elizalde, María Mercedes; Pérez, Paula Soledad; Sevic, Ina; Grasso, Daniel; Ropolo, Alejandro; Barbini, Luciana; Campos, Rodolfo Héctor; Vaccaro, María Inés; Flichman, Diego Martín

    2018-01-01

    Hepatitis B virus (HBV) genotypes and mutants have been associated with differences in clinical and virological characteristics. Autophagy is a cellular process that degrades long-lived proteins and damaged organelles. Viruses have evolved mechanisms to alter this process to survive in host cells. In this work, we studied the modulation of autophagy by the replication of HBV subgenotypes F1b and F4, and the naturally occurring mutants BCP and preCore. HBV subgenotypes F1b and F4 replication induced accumulation of autophagosomes in hepatoma cells. However, no autophagic protein degradation was observed, indicating a blockage of autophagic flux at later stages. This inhibition of autophagy flux might be due to an impairment of lysosomal acidification in hepatoma cells. Moreover, HBV-mediated autophagy modulation was independent of the viral subgenotypes and enhanced in viruses with BCP and preCore naturally occurring mutations. These results contribute to understand the mechanisms by which different HBV variants contribute to the pathogenesis of HBV infections. In addition, this study is the first to describe the role that two highly prevalent naturally occurring mutations exert on the modulation of HBV-induced autophagy.

  12. 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.

  13. 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.

  14. 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...

  15. 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.

  16. 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

  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

    2018-01-01

    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.

    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.

  19. Low shear stress induces vascular eNOS uncoupling via autophagy-mediated eNOS phosphorylation.

    Science.gov (United States)

    Zhang, Jun-Xia; Qu, Xin-Liang; Chu, Peng; Xie, Du-Jiang; Zhu, Lin-Lin; Chao, Yue-Lin; Li, Li; Zhang, Jun-Jie; Chen, Shao-Liang

    2018-05-01

    Uncoupled endothelial nitric oxide synthase (eNOS) produces O 2 - instead of nitric oxide (NO). Earlier, we reported rapamycin, an autophagy inducer and inhibitor of cellular proliferation, attenuated low shear stress (SS) induced O 2 - production. Nevertheless, it is unclear whether autophagy plays a critical role in the regulation of eNOS uncoupling. Therefore, this study aimed to investigate the modulation of autophagy on eNOS uncoupling induced by low SS exposure. We found that low SS induced endothelial O 2 - burst, which was accompanied by reduced NO release. Furthermore, inhibition of eNOS by L-NAME conspicuously attenuated low SS-induced O 2 - releasing, indicating eNOS uncoupling. Autophagy markers such as LC3 II/I ratio, amount of Beclin1, as well as ULK1/Atg1 were increased during low SS exposure, whereas autophagic degradation of p62/SQSTM1 was markedly reduced, implying impaired autophagic flux. Interestingly, low SS-induced NO reduction could be reversed by rapamycin, WYE-354 or ATG5 overexpression vector via restoration of autophagic flux, but not by N-acetylcysteine or apocynin. eNOS uncoupling might be ascribed to autophagic flux blockade because phosphorylation of eNOS Thr495 by low SS or PMA stimulation was also regulated by autophagy. In contrast, eNOS acetylation was not found to be regulated by low SS and autophagy. Notably, although low SS had no influence on eNOS Ser1177 phosphorylation, whereas boosted eNOS Ser1177 phosphorylation by rapamycin were in favor of the eNOS recoupling through restoration of autophagic flux. Taken together, we reported a novel mechanism for regulation of eNOS uncoupling by low SS via autophagy-mediated eNOS phosphorylation, which is implicated in geometrical nature of atherogenesis. Copyright © 2018 Elsevier B.V. All rights reserved.

  20. 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.

  1. 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....

  2. 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.

  3. Coronary atherosclerosis: Significance of autophagic armour.

    Science.gov (United States)

    Arora, Mansi; Kaul, Deepak

    2012-09-26

    Autophagy is a lysosomal degradation pathway of cellular components such as organelles and long-lived proteins. Though a protective role for autophagy has been established in various patho-physiologic conditions such as cancer, neurodegeneration, aging and heart failure, a growing body of evidence now reveals a protective role for autophagy in atherosclerosis, mainly by removing oxidatively damaged organelles and proteins and also by promoting cholesterol egress from the lipid-laden cells. Recent studies by Razani et al and Liao et al unravel novel pathways that might be involved in autophagic protection and in this commentary we highlight the importance of autophagy in atherosclerosis in the light of these two recent papers.

  4. Methods for assessing autophagy and autophagic cell death.

    Science.gov (United States)

    Tasdemir, Ezgi; Galluzzi, Lorenzo; Maiuri, M Chiara; Criollo, Alfredo; Vitale, Ilio; Hangen, Emilie; Modjtahedi, Nazanine; Kroemer, Guido

    2008-01-01

    Autophagic (or type 2) cell death is characterized by the massive accumulation of autophagic vacuoles (autophagosomes) in the cytoplasm of cells that lack signs of apoptosis (type 1 cell death). Here we detail and critically assess a series of methods to promote and inhibit autophagy via pharmacological and genetic manipulations. We also review the techniques currently available to detect autophagy, including transmission electron microscopy, half-life assessments of long-lived proteins, detection of LC3 maturation/aggregation, fluorescence microscopy, and colocalization of mitochondrion- or endoplasmic reticulum-specific markers with lysosomal proteins. Massive autophagic vacuolization may cause cellular stress and represent a frustrated attempt of adaptation. In this case, cell death occurs with (or in spite of) autophagy. When cell death occurs through autophagy, on the contrary, the inhibition of the autophagic process should prevent cellular demise. Accordingly, we describe a strategy for discriminating cell death with autophagy from cell death through autophagy.

  5. A novel compound DT-010 protects against doxorubicin-induced cardiotoxicity in zebrafish and H9c2 cells by inhibiting reactive oxygen species-mediated apoptotic and autophagic pathways.

    Science.gov (United States)

    Tang, Fan; Zhou, Xinhua; Wang, Liang; Shan, Luchen; Li, Chuwen; Zhou, Hefeng; Lee, Simon Ming-Yuen; Hoi, Maggie Pui-Man

    2018-02-05

    Doxorubicin (Dox) is an effective anti-cancer agent but limited by its cardiotoxicity, thus the search for pharmacological agents for enhancing anti-cancer activities and protecting against cardiotoxicity has been a subject of great interest. We have previously reported the synergistic anti-cancer effects of a novel compound DT-010. In the present study, we further investigated the cardioprotective effects of DT-010 in zebrafish embryos in vivo and the molecular underlying mechanisms in H9c2 cardiomyocytes in vitro. We showed that DT-010 prevented the Dox-induced morphological distortions in the zebrafish heart and the associated cardiac impairments, and especially improved ventricular functions. By using H9c2 cells model, we showed that DT-010 directly inhibited the generation of reactive oxygen species by Dox and protected cell death and cellular damage. We further observed that DT-010 protected against Dox-induced myocardiopathy via inhibiting downstream molecular pathways in response to oxidative stress, including reactive oxygen species-mediated MAPK signaling pathways ERK and JNK, and apoptotic pathways involving the activation of caspase 3, caspase 7, and PARP signaling. Recent studies also suggest the importance of alterations in cardiac autophagy in Dox cardiotoxicity. We further showed that DT-010 could inhibit the induction of autophagosomes formation by Dox via regulating the upstream Akt/AMPK/mTOR signaling. Since Dox-induced cardiotoxicity is multifactorial, our results suggest that multi-functional agent such as DT-010 might be an effective therapeutic agent for combating cardiotoxicity associated with chemotherapeutic agents such as Dox. Copyright © 2017 Elsevier B.V. All rights reserved.

  6. 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

  7. 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

  8. 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

  9. Quantifying Beetle-Mediated Effects on Gas Fluxes from Dung Pats

    Science.gov (United States)

    Penttilä, Atte; Slade, Eleanor M.; Simojoki, Asko; Riutta, Terhi; Minkkinen, Kari; Roslin, Tomas

    2013-01-01

    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. PMID:23940758

  10. The different roles of selective autophagic protein degradation in mammalian cells.

    Science.gov (United States)

    Wang, Da-wei; Peng, Zhen-ju; Ren, Guang-fang; Wang, Guang-xin

    2015-11-10

    Autophagy is an intracellular pathway for bulk protein degradation and the removal of damaged organelles by lysosomes. Autophagy was previously thought to be unselective; however, studies have increasingly confirmed that autophagy-mediated protein degradation is highly regulated. Abnormal autophagic protein degradation has been associated with multiple human diseases such as cancer, neurological disability and cardiovascular disease; therefore, further elucidation of protein degradation by autophagy may be beneficial for protein-based clinical therapies. Macroautophagy and chaperone-mediated autophagy (CMA) can both participate in selective protein degradation in mammalian cells, but the process is quite different in each case. Here, we summarize the various types of macroautophagy and CMA involved in determining protein degradation. For this summary, we divide the autophagic protein degradation pathways into four categories: the post-translational modification dependent and independent CMA pathways and the ubiquitin dependent and independent macroautophagy pathways, and describe how some non-canonical pathways and modifications such as phosphorylation, acetylation and arginylation can influence protein degradation by the autophagy lysosome system (ALS). Finally, we comment on why autophagy can serve as either diagnostics or therapeutic targets in different human diseases.

  11. 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.

  12. 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.

  13. Dislocation-mediated trapping of deuterium in tungsten under high-flux high-temperature exposures

    Science.gov (United States)

    Bakaeva, A.; Terentyev, D.; De Temmerman, G.; Lambrinou, K.; Morgan, T. W.; Dubinko, A.; Grigorev, P.; Verbeken, K.; Noterdaeme, J. M.

    2016-10-01

    The effect of severe plastic deformation on the deuterium retention in tungsten exposed to high-flux low-energy plasma (flux ∼1024 m-2 s-1, energy ∼50 eV and fluence up to 5 × 1025 D/m2) was studied experimentally in a wide temperature range (460-1000 K) relevant for application in ITER. The desorption spectra in both reference and plastically-deformed samples were deconvoluted into three contributions associated with the detrapping from dislocations, deuterium-vacancy clusters and pores. As the exposure temperature increases, the positions of the release peaks in the plastically-deformed material remain in the same temperature range but the peak amplitudes are altered as compared to the reference material. The desorption peak attributed to the release from pores (i.e. cavities and bubbles) was suppressed in the plastically deformed samples for the low-temperature exposures, but became dominant for exposures above 700 K. The observed strong modulation of the deuterium storage in "shallow" and "deep" traps, as well as the reduction of the integral retention above 700 K, suggest that the dislocation network changes its role from "trapping sites" to "diffusion channels" above a certain temperature. The major experimental observations of the present work are in line with recent computational assessment based on atomistic and mean field theory calculations available in literature.

  14. Dislocation-mediated trapping of deuterium in tungsten under high-flux high-temperature exposures

    Energy Technology Data Exchange (ETDEWEB)

    Bakaeva, A. [SCK-CEN, Nuclear Materials Science Institute, Boeretang 200, 2400, Mol (Belgium); Department of Applied Physics, Ghent University, St. Pietersnieuwstraat 41, 9000, Ghent (Belgium); Terentyev, D., E-mail: dterenty@sckcen.be [SCK-CEN, Nuclear Materials Science Institute, Boeretang 200, 2400, Mol (Belgium); De Temmerman, G. [ITER Organization, Route de Vinon-sur-Verdon, CS 90 046, 13067, St Paul Lez Durance Cedex (France); Lambrinou, K. [SCK-CEN, Nuclear Materials Science Institute, Boeretang 200, 2400, Mol (Belgium); Morgan, T.W. [FOM Institute DIFFER, De Zaale 20, 5612 AJ, Eindhoven (Netherlands); Dubinko, A.; Grigorev, P. [SCK-CEN, Nuclear Materials Science Institute, Boeretang 200, 2400, Mol (Belgium); Department of Applied Physics, Ghent University, St. Pietersnieuwstraat 41, 9000, Ghent (Belgium); Verbeken, K. [Department of Materials Science and Engineerin, Ghent University, St. Pietersnieuwstraat 41, 9000, Ghent (Belgium); Noterdaeme, J.M. [Department of Applied Physics, Ghent University, St. Pietersnieuwstraat 41, 9000, Ghent (Belgium)

    2016-10-15

    The effect of severe plastic deformation on the deuterium retention in tungsten exposed to high-flux low-energy plasma (flux ∼10{sup 24} m{sup −2} s{sup −1}, energy ∼50 eV and fluence up to 5 × 10{sup 25} D/m{sup 2}) was studied experimentally in a wide temperature range (460–1000 K) relevant for application in ITER. The desorption spectra in both reference and plastically-deformed samples were deconvoluted into three contributions associated with the detrapping from dislocations, deuterium-vacancy clusters and pores. As the exposure temperature increases, the positions of the release peaks in the plastically-deformed material remain in the same temperature range but the peak amplitudes are altered as compared to the reference material. The desorption peak attributed to the release from pores (i.e. cavities and bubbles) was suppressed in the plastically deformed samples for the low-temperature exposures, but became dominant for exposures above 700 K. The observed strong modulation of the deuterium storage in “shallow” and “deep” traps, as well as the reduction of the integral retention above 700 K, suggest that the dislocation network changes its role from “trapping sites” to “diffusion channels” above a certain temperature. The major experimental observations of the present work are in line with recent computational assessment based on atomistic and mean field theory calculations available in literature.

  15. 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.

  16. PF-4708671, a specific inhibitor of p70 ribosomal S6 kinase 1, activates Nrf2 by promoting p62-dependent autophagic degradation of Keap1

    Energy Technology Data Exchange (ETDEWEB)

    Park, Jeong Su [Severance Biomedical Science Institute (Korea, Republic of); Yonsei Biomedical Research Institute, Yonsei University College of Medicine, 50 Yonsei-ro, Seodaemun-gu, Seoul 120-752 (Korea, Republic of); Kang, Dong Hoon [Department of Life Science and Ewha Research Center for Systems Biology (Korea, Republic of); The Research Center for Cell Homeostasis, Ewha Womans University, Seoul 127-750 (Korea, Republic of); Lee, Da Hyun [Severance Biomedical Science Institute (Korea, Republic of); Yonsei Biomedical Research Institute, Yonsei University College of Medicine, 50 Yonsei-ro, Seodaemun-gu, Seoul 120-752 (Korea, Republic of); Bae, Soo Han, E-mail: soohanbae@yuhs.ac [Severance Biomedical Science Institute (Korea, Republic of); Yonsei Biomedical Research Institute, Yonsei University College of Medicine, 50 Yonsei-ro, Seodaemun-gu, Seoul 120-752 (Korea, Republic of)

    2015-10-23

    p70 ribosomal S6 kinase 1 (S6K1) is an important serine/threonine kinase and downstream target of the mechanistic target of rapamycin complex 1 (mTORC1) signaling pathway. PF-4708671 is a specific inhibitor of S6K1, and prevents S6K1-mediated phosphorylation of the S6 protein. PF-4708671 treatment often leads to apoptotic cell death. However, the protective mechanism against PF-4708671-induced cell death has not been elucidated. The nuclear factor erythroid 2-related factor 2 (Nrf2)-Kelch-like ECH-associated protein 1 (Keap1) pathway is essential for protecting cells against oxidative stress. p62, an adaptor protein in the autophagic process, enhances Nrf2 activation through the impairment of Keap1 activity. In this study, we showed that PF-4708671 induces autophagic Keap1 degradation-mediated Nrf2 activation in p62-dependent manner. Furthermore, p62-dependent Nrf2 activation plays a crucial role in protecting cells from PF-4708671-mediated apoptosis. - Highlights: • PF-4708671, a S6K1-specific inhibitor, prevents S6K1-mediated S6 phosphorylation. • However, PF-4708671 treatment often leads to apoptotic cell death. • Protective mechanism against PF-4708671-induced cell death remains to be elucidated. • PF-4708671 induced p62-dependent, autophagic Keap1 degradation-mediated Nrf2 activation. • p62-dependent Nrf2 activation protects cells from PF-4708671-mediated apoptosis.

  17. Interplay of pathogenic forms of human tau with different autophagic pathways.

    Science.gov (United States)

    Caballero, Benjamin; Wang, Yipeng; Diaz, Antonio; Tasset, Inmaculada; Juste, Yves Robert; Stiller, Barbara; Mandelkow, Eva-Maria; Mandelkow, Eckhard; Cuervo, Ana Maria

    2018-02-01

    Loss of neuronal proteostasis, a common feature of the aging brain, is accelerated in neurodegenerative disorders, including different types of tauopathies. Aberrant turnover of tau, a microtubule-stabilizing protein, contributes to its accumulation and subsequent toxicity in tauopathy patients' brains. A direct toxic effect of pathogenic forms of tau on the proteolytic systems that normally contribute to their turnover has been proposed. In this study, we analyzed the contribution of three different types of autophagy, macroautophagy, chaperone-mediated autophagy, and endosomal microautophagy to the degradation of tau protein variants and tau mutations associated with this age-related disease. We have found that the pathogenic P301L mutation inhibits degradation of tau by any of the three autophagic pathways, whereas the risk-associated tau mutation A152T reroutes tau for degradation through a different autophagy pathway. We also found defective autophagic degradation of tau when using mutations that mimic common posttranslational modifications in tau or known to promote its aggregation. Interestingly, although most mutations markedly reduced degradation of tau through autophagy, the step of this process preferentially affected varies depending on the type of tau mutation. Overall, our studies unveil a complex interplay between the multiple modifications of tau and selective forms of autophagy that may determine its physiological degradation and its faulty clearance in the disease context. © 2017 The Authors. Aging Cell published by the Anatomical Society and John Wiley & Sons Ltd.

  18. 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.

  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. T315 Decreases Acute Myeloid Leukemia Cell Viability through a Combination of Apoptosis Induction and Autophagic Cell Death

    Directory of Open Access Journals (Sweden)

    Chang-Fang Chiu

    2016-08-01

    Full Text Available T315, an integrin-linked kinase (ILK inhibitor, has been shown to suppress the proliferation of breast cancer, stomach cancer and chronic lymphocytic leukemia cells. Here we demonstrate that T315 decreases cell viability of acute myeloid leukemia (AML cell lines (HL-60 and THP-1 and primary leukemia cells from AML patients in a dose-responsive manner. Normal human bone marrow cells are less sensitive than leukemia cells to T315. T315 down regulates protein kinase B (Akt and p-Akt and induces caspase activation, poly-ADP-ribose polymerase (PARP cleavage, apoptosis and autophagy through an ILK-independent manner. Interestingly, pretreatment with autophagy inhibitors rescues cells from apoptosis and concomitant PARP cleavage, which implicates a key role of autophagic cell death in T315-mediated cytotoxicity. T315 also demonstrates efficacy in vivo, suppressing the growth of THP-1 xenograft tumors in athymic nude mice when administered intraperitoneally. This study shows that autophagic cell death and apoptosis cooperatively contribute to the anticancer activity of T315 in AML cells. In conclusion, the complementary roles of apoptotic and autophagic cell death should be considered in the future assessment of the translational value of T315 in AML therapy.

  1. Single-nitrogen-vacancy-center quantum memory for a superconducting flux qubit mediated by a ferromagnet

    Science.gov (United States)

    Lai, Yen-Yu; Lin, Guin-Dar; Twamley, Jason; Goan, Hsi-Sheng

    2018-05-01

    We propose a quantum memory scheme to transfer and store the quantum state of a superconducting flux qubit (FQ) into the electron spin of a single nitrogen-vacancy (NV) center in diamond via yttrium iron garnet (YIG), a ferromagnet. Unlike an ensemble of NV centers, the YIG moderator can enhance the effective FQ-NV-center coupling strength without introducing additional appreciable decoherence. We derive the effective interaction between the FQ and the NV center by tracing out the degrees of freedom of the collective mode of the YIG spins. We demonstrate the transfer, storage, and retrieval procedures, taking into account the effects of spontaneous decay and pure dephasing. Using realistic experimental parameters for the FQ, NV center and YIG, we find that a combined transfer, storage, and retrieval fidelity higher than 0.9, with a long storage time of 10 ms, can be achieved. This hybrid system not only acts as a promising quantum memory, but also provides an example of enhanced coupling between various systems through collective degrees of freedom.

  2. 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.

  3. 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.

  4. 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

  5. Curcumin induces autophagic cell death in Spodoptera frugiperda cells.

    Science.gov (United States)

    Veeran, Sethuraman; Shu, Benshui; Cui, Gaofeng; Fu, Shengjiao; Zhong, Guohua

    2017-06-01

    The increasing interest in the role of autophagy (type II cell death) in the regulation of insect toxicology has propelled study of investigating autophagic cell death pathways. Turmeric, the rhizome of the herb Curcuma longa (Mañjaḷ in Tamil, India and Jiānghuáng in Chinese) have been traditionally used for the pest control either alone or combination with other botanical pesticides. However, the mechanisms by which Curcuma longa or curcumin exerts cytotoxicity in pests are not well understood. In this study, we investigated the potency of Curcuma longa (curcumin) as a natural pesticide employing Sf9 insect line. Autophagy induction effect of curcumin on Spodoptera frugiperda (Sf9) cells was investigated using various techniques including cell proliferation assay, morphology analysis with inverted phase contrast microscope and Transmission Electron Microscope (TEM) analysis. Autophagy was evaluated using the fluorescent dye monodansylcadaverine (MDC). Cell death measurement was examined using 3-(4,5-Dimethylthiazol-2-yl)-2,5-Diphenyltetrazolium Bromide (MTT) within the concentrations of 5-15μg/mL. Curcumin inhibited the growth of the Sf9 cells and induced autophagic cell death in a time and dose dependent manner. Staining the cells with MDC showed the presence of autophagic vacuoles while increased in a dose and time dependent manner. At the ultrastructural level transmission electron microscopy, cells revealed massive autophagy vacuole accumulation and absence of chromatin condensation. Protein expression levels of ATG8-I and ATG8-II, well-established markers of autophagy related protein were elevated in a time dependent manner after curcumin treatment. The present study proves that curcumin induces autophagic cell death in Sf9 insect cell line and this is the first report of cytotoxic effect of curcumin in insect cells and that will be utilized as natural pesticides in future. Copyright © 2017. Published by Elsevier Inc.

  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. Augmenting brain metabolism to increase macro- and chaperone-mediated autophagy for decreasing neuronal proteotoxicity and aging.

    Science.gov (United States)

    Loos, Ben; Klionsky, Daniel J; Wong, Esther

    2017-09-01

    Accumulation of toxic protein aggregates in the nerve cells is a hallmark of neuronal diseases and brain aging. Mechanisms to enhance neuronal surveillance to improve neuronal proteostasis have a direct impact on promoting neuronal health and forestalling age-related decline in brain function. Autophagy is a lysosomal degradative pathway pivotal for neuronal protein quality control. Different types of autophagic mechanisms participate in protein handling in neurons. Macroautophagy targets misfolded and aggregated proteins in autophagic vesicles to the lysosomes for destruction, while chaperone-mediated autophagy (CMA) degrades specific soluble cytosolic proteins delivered to the lysosomes by chaperones. Dysfunctions in macroautophagy and CMA contribute to proteo- and neuro-toxicity associated with neurodegeneration and aging. Thus, augmenting or preserving both autophagic mechanisms pose significant benefits in delaying physiological and pathological neuronal demises. Recently, life-style interventions that modulate metabolite ketone bodies, energy intake by caloric restriction and energy expenditure by exercise have shown to enhance both autophagy and brain health. However, to what extent these interventions affect neuronal autophagy to promote brain fitness remains largely unclear. Here, we review the functional connections of how macroautophagy and CMA are affected by ketone bodies, caloric restriction and exercise in the context of neurodegeneration. A concomitant assessment of yeast Saccharomyces cerevisiae is performed to reveal the conserved nature of such autophagic responses to substrate perturbations. In doing so, we provide novel insights and integrated evidence for a potential adjuvant therapeutic strategy to intervene in the neuronal decline in neurodegenerative diseases by controlling both macroautophagy and CMA fluxes favorably. Copyright © 2017 Elsevier Ltd. All rights reserved.

  9. Lipidation of BmAtg8 is required for autophagic degradation of p62 bodies containing ubiquitinated proteins in the silkworm, Bombyx mori.

    Science.gov (United States)

    Ji, Ming-Ming; Lee, Jae Man; Mon, Hiroaki; Iiyama, Kazuhiro; Tatsuke, Tsuneyuki; Morokuma, Daisuke; Hino, Masato; Yamashita, Mami; Hirata, Kazuma; Kusakabe, Takahiro

    2017-10-01

    p62/Sequestosome-1 (p62/SQSTM1, hereafter referred to as p62) is a major adaptor that allows ubiquitinated proteins to be degraded by autophagy, and Atg8 homologs are required for p62-mediated autophagic degradation, but their relationship is still not understood in Lepidopteran insects. Here it is clearly demonstrated that the silkworm homolog of mammalian p62, Bombyx mori p62 (Bmp62), forms p62 bodies depending on its Phox and Bem1p (PB1) and ubiquitin-associated (UBA) domains. These two domains are associated with Bmp62 binding to ubiquitinated proteins to form the p62 bodies, and the UBA domain is essential for the binding, but Bmp62 still self-associates without the PB1 or UBA domain. The p62 bodies in Bombyx cells are enclosed by BmAtg9-containing membranes and degraded via autophagy. It is revealed that the interaction between the Bmp62 AIM motif and BmAtg8 is critical for the autophagic degradation of the p62 bodies. Intriguingly, we further demonstrate that lipidation of BmAtg8 is required for the Bmp62-mediated complete degradation of p62 bodies by autophagy. Our results should be useful in future studies of the autophagic mechanism in Lepidopteran insects. Copyright © 2017 Elsevier Ltd. All rights reserved.

  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. 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.

  12. 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

  13. 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.

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

    International Nuclear Information System (INIS)

    Hazra, Soumitra; Nandy, Dibyendu

    2016-01-01

    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.

  15. HAMLET (human alpha-lactalbumin made lethal to tumor cells) triggers autophagic tumor cell death.

    Science.gov (United States)

    Aits, Sonja; Gustafsson, Lotta; Hallgren, Oskar; Brest, Patrick; Gustafsson, Mattias; Trulsson, Maria; Mossberg, Ann-Kristin; Simon, Hans-Uwe; Mograbi, Baharia; Svanborg, Catharina

    2009-03-01

    HAMLET, a complex of partially unfolded alpha-lactalbumin and oleic acid, kills a wide range of tumor cells. Here we propose that HAMLET causes macroautophagy in tumor cells and that this contributes to their death. Cell death was accompanied by mitochondrial damage and a reduction in the level of active mTOR and HAMLET triggered extensive cytoplasmic vacuolization and the formation of double-membrane-enclosed vesicles typical of macroautophagy. In addition, HAMLET caused a change from uniform (LC3-I) to granular (LC3-II) staining in LC3-GFP-transfected cells reflecting LC3 translocation during macroautophagy, and this was blocked by the macroautophagy inhibitor 3-methyladenine. HAMLET also caused accumulation of LC3-II detected by Western blot when lysosomal degradation was inhibited suggesting that HAMLET caused an increase in autophagic flux. To determine if macroautophagy contributed to cell death, we used RNA interference against Beclin-1 and Atg5. Suppression of Beclin-1 and Atg5 improved the survival of HAMLET-treated tumor cells and inhibited the increase in granular LC3-GFP staining. The results show that HAMLET triggers macroautophagy in tumor cells and suggest that macroautophagy contributes to HAMLET-induced tumor cell death.

  16. Bottom-up nutrient and top-down fish impacts on insect-mediated mercury flux from aquatic ecosystems.

    Science.gov (United States)

    Jones, Taylor A; Chumchal, Matthew M; Drenner, Ray W; Timmins, Gabrielle N; Nowlin, Weston H

    2013-03-01

    Methyl mercury (MeHg) is one of the most hazardous contaminants in the environment, adversely affecting the health of wildlife and humans. Recent studies have demonstrated that aquatic insects biotransport MeHg and other contaminants to terrestrial consumers, but the factors that regulate the flux of MeHg out of aquatic ecosystems via emergent insects have not been studied. The authors used experimental mesocosms to test the hypothesis that insect emergence and the associated flux of MeHg from aquatic to terrestrial ecosystems is affected by both bottom-up nutrient effects and top-down fish consumer effects. In the present study, nutrient addition led to an increase in MeHg flux primarily by enhancing the biomass of emerging insects whose tissues were contaminated with MeHg, whereas fish decreased MeHg flux primarily by reducing the biomass of emerging insects. Furthermore, the authors found that these factors are interdependent such that the effects of nutrients are more pronounced when fish are absent, and the effects of fish are more pronounced when nutrient concentrations are high. The present study is the first to demonstrate that the flux of MeHg from aquatic to terrestrial ecosystems is strongly enhanced by bottom-up nutrient effects and diminished by top-down consumer effects. Copyright © 2012 SETAC.

  17. 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...... to these general questions by distinguishing between two concepts: mediation and mediatization. The media effects tradition generally considers the effects of the media to be a result of individuals being exposed to media content, i.e. effects are seen as an outcome of mediated communication. Mediatization...... 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...

  18. Evaluation of the Cytotoxic and Autophagic Effects of Atorvastatin on MCF-7 Breast Cancer Cells

    Directory of Open Access Journals (Sweden)

    Tuğba Alarcon Martinez

    2018-05-01

    Full Text Available Background: Recently, cytotoxic effects of statins on breast cancer cells have been reported. However, the mechanism of anti-proliferative effects is currently unknown. Autophagy is non-apoptotic programmed cell death, which is characterized by degradation of cytoplasmic components and as having a role in cancer pathogenesis. Aims: To investigate the anti-proliferative effects of atorvastatin on MCF-7 human breast adenocarcinoma cells with respect to both autophagy and apoptosis. Study Design: Cell culture study. Methods: Cell viability was analyzed using WST-1 cell proliferation assay. Apoptosis was determined by the TUNEL method, whereas autophagy was assessed by Beclin-1 and LC3B immunofluorescence staining. Ultrastructural analysis of cells was performed by electron microscopy. Results: 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. A statistically significant increase in the apoptotic index was detected with higher concentrations of atorvastatin at 24 h and 48 h (p<0.05. Conclusion: The anti-proliferative effects of atorvastatin on breast cancer cells is mediated by the induction of both apoptosis and autophagy which shows statins as a potential treatment option for breast cancer.

  19. 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.

  20. Testosterone regulates the autophagic clearance of androgen binding protein in rat Sertoli cells

    Science.gov (United States)

    Ma, Yi; Yang, Hao-Zheng; Xu, Long-Mei; Huang, Yi-Ran; Dai, Hui-Li; Kang, Xiao-Nan

    2015-01-01

    Dysregulation of androgen-binding protein (ABP) is associated with a number of endocrine and andrology diseases. However, the ABP metabolism in Sertoli cells is largely unknown. We report that autophagy degrades ABP in rat Sertoli cells, and the autophagic clearance of ABP is regulated by testosterone, which prolongs the ABP biological half-life by inhibiting autophagy. Further studies identified that the autophagic clearance of ABP might be selectively regulated by testosterone, independent of stress (hypoxia)-induced autophagic degradation. These data demonstrate that testosterone up-regulates ABP expression at least partially by suppressing the autophagic degradation. We report a novel finding with respect to the mechanisms by which ABP is cleared, and by which the process is regulated in Sertoli cells. PMID:25745956

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

    Energy Technology Data Exchange (ETDEWEB)

    Raja, C R.E. [Stat-Math Unit, Indian Statistical Institute, Bangalore (India); [Abdus Salam International Centre for Theoretical Physics, Trieste (Italy)]. E-mail: creraja@isibang.ac.in

    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{sub 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)

  2. Nanoparticle-induced neuronal toxicity across placental barriers is mediated by autophagy and dependent on astrocytes

    Science.gov (United States)

    Hawkins, Simon J.; Crompton, Lucy A.; Sood, Aman; Saunders, Margaret; Boyle, Noreen T.; Buckley, Amy; Minogue, Aedín M.; McComish, Sarah F.; Jiménez-Moreno, Natalia; Cordero-Llana, Oscar; Stathakos, Petros; Gilmore, Catherine E.; Kelly, Stephen; Lane, Jon D.; Case, C. Patrick; Caldwell, Maeve A.

    2018-05-01

    The potential for maternal nanoparticle (NP) exposures to cause developmental toxicity in the fetus without the direct passage of NPs has previously been shown, but the mechanism remained elusive. We now demonstrate that exposure of cobalt and chromium NPs to BeWo cell barriers, an in vitro model of the human placenta, triggers impairment of the autophagic flux and release of interleukin-6. This contributes to the altered differentiation of human neural progenitor cells and DNA damage in the derived neurons and astrocytes. Crucially, neuronal DNA damage is mediated by astrocytes. Inhibiting the autophagic degradation in the BeWo barrier by overexpression of the dominant-negative human ATG4BC74A significantly reduces the levels of DNA damage in astrocytes. In vivo, indirect NP toxicity in mice results in neurodevelopmental abnormalities with reactive astrogliosis and increased DNA damage in the fetal hippocampus. Our results demonstrate the potential importance of autophagy to elicit NP toxicity and the risk of indirect developmental neurotoxicity after maternal NP exposure.

  3. Autophagic clearance of mitochondria in the kidney copes with metabolic acidosis.

    Science.gov (United States)

    Namba, Tomoko; Takabatake, Yoshitsugu; Kimura, Tomonori; Takahashi, Atsushi; Yamamoto, Takeshi; Matsuda, Jun; Kitamura, Harumi; Niimura, Fumio; Matsusaka, Taiji; Iwatani, Hirotsugu; Matsui, Isao; Kaimori, Junya; Kioka, Hidetaka; Isaka, Yoshitaka; Rakugi, Hiromi

    2014-10-01

    Metabolic acidosis, a common complication of CKD, causes mitochondrial stress by undefined mechanisms. Selective autophagy of impaired mitochondria, called mitophagy, contributes toward maintaining cellular homeostasis in various settings. We hypothesized that mitophagy is involved in proximal tubular cell adaptations to chronic metabolic acidosis. In transgenic mice expressing green fluorescent protein-tagged microtubule-associated protein 1 light chain 3 (GFP-LC3), NH4Cl loading increased the number of GFP puncta exclusively in the proximal tubule. In vitro, culture in acidic medium produced similar results in proximal tubular cell lines stably expressing GFP-LC3 and facilitated the degradation of SQSTM1/p62 in wild-type cells, indicating enhanced autophagic flux. Upon acid loading, proximal tubule-specific autophagy-deficient (Atg5-deficient) mice displayed significantly reduced ammonium production and severe metabolic acidosis compared with wild-type mice. In vitro and in vivo, acid loading caused Atg5-deficient proximal tubular cells to exhibit reduced mitochondrial respiratory chain activity, reduced mitochondrial membrane potential, and fragmented morphology with marked swelling in mitochondria. GFP-LC3-tagged autophagosomes colocalized with ubiquitinated mitochondria in proximal tubular cells cultured in acidic medium, suggesting that metabolic acidosis induces mitophagy. Furthermore, restoration of Atg5-intact nuclei in Atg5-deficient proximal tubular cells increased mitochondrial membrane potential and ammoniagenesis. In conclusion, metabolic acidosis induces autophagy in proximal tubular cells, which is indispensable for maintaining proper mitochondrial functions including ammoniagenesis, and thus for adapted urinary acid excretion. Our results provide a rationale for the beneficial effect of alkali supplementation in CKD, a condition in which autophagy may be reduced, and suggest a new therapeutic option for acidosis by modulating autophagy. Copyright

  4. ATG13: just a companion, or an executor of the autophagic program?

    Science.gov (United States)

    Alers, Sebastian; Wesselborg, Sebastian; Stork, Björn

    2014-06-01

    During the past 20 years, autophagy signaling has entered the main stage of the cell biological theater. Autophagy represents an intracellular degradation process that is involved in both the bulk recycling of cytoplasmic components and the selective removal of organelles, protein aggregates, or intracellular pathogens. The understanding of autophagy has been greatly facilitated by the characterization of the molecular machinery governing this process. In yeast, initiation of autophagy is controlled by the Atg1 kinase complex, which is composed of the Ser/Thr kinase Atg1, the adaptor protein Atg13, and the ternary complex of Atg17-Atg31-Atg29. In vertebrates, the orthologous ULK1 kinase complex contains the Ser/Thr kinase ULK1 and the accessory proteins ATG13, RB1CC1, and ATG101. Among these components, Atg1/ULK1 have gained major attention in the past, i.e., for the identification of upstream regulatory kinases, the characterization of downstream substrates controlling the autophagic flux, or as a druggable target for the modulation of autophagy. However, accumulating data indicate that the function of Atg13/ATG13 has been likely underestimated so far. In addition to ensuring proper Atg1/ULK1 recruitment and activity, this adaptor molecule has been implicated in ULK1-independent autophagy processes. Furthermore, recent data have identified additional binding partners of Atg13/ATG13 besides the components of the Atg1/ULK1 complex, e.g., Atg8 family proteins or acidic phospholipids. Therefore, in this review we will center the spotlight on Atg13/ATG13 and summarize the role that Atg13/ATG13 assumes in the autophagy stage play.

  5. Autophagic lysosome reformation dysfunction in glucocerebrosidase deficient cells: relevance to Parkinson disease.

    Science.gov (United States)

    Magalhaes, Joana; Gegg, Matthew E; Migdalska-Richards, Anna; Doherty, Mary K; Whitfield, Phillip D; Schapira, Anthony H V

    2016-08-15

    Glucocerebrosidase (GBA1) gene mutations increase the risk of Parkinson disease (PD). While the cellular mechanisms associating GBA1 mutations and PD are unknown, loss of the glucocerebrosidase enzyme (GCase) activity, inhibition of autophagy and increased α-synuclein levels have been implicated. Here we show that autophagy lysosomal reformation (ALR) is compromised in cells lacking functional GCase. ALR is a cellular process controlled by mTOR which regenerates functional lysosomes from autolysosomes formed during macroautophagy. A decrease in phopho-S6K levels, a marker of mTOR activity, was observed in models of GCase deficiency, including primary mouse neurons and the PD patient derived fibroblasts with GBA1 mutations, suggesting that ALR is compromised. Importantly Rab7, a GTPase crucial for endosome-lysosome trafficking and ALR, accumulated in GCase deficient cells, supporting the notion that lysosomal recycling is impaired. Recombinant GCase treatment reversed ALR inhibition and lysosomal dysfunction. Moreover, ALR dysfunction was accompanied by impairment of macroautophagy and chaperone-mediated autophagy, increased levels of total and phosphorylated (S129) monomeric α-synuclein, evidence of amyloid oligomers and increased α-synuclein release. Concurrently, we found increased cholesterol and altered glucosylceramide homeostasis which could compromise ALR. We propose that GCase deficiency in PD inhibits lysosomal recycling. Consequently neurons are unable to maintain the pool of mature and functional lysosomes required for the autophagic clearance of α-synuclein, leading to the accumulation and spread of pathogenic α-synuclein species in the brain. Since GCase deficiency and lysosomal dysfunction occur with ageing and sporadic PD pathology, the decrease in lysosomal reformation may be a common feature in PD. © The Author 2016. Published by Oxford University Press.

  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. Propofol prevents autophagic cell death following oxygen and glucose deprivation in PC12 cells and cerebral ischemia-reperfusion injury in rats.

    Directory of Open Access Journals (Sweden)

    Derong Cui

    Full Text Available Propofol exerts protective effects on neuronal cells, in part through the inhibition of programmed cell death. Autophagic cell death is a type of programmed cell death that plays elusive roles in controlling neuronal damage and metabolic homeostasis. We therefore studied whether propofol could attenuate the formation of autophagosomes, and if so, whether the inhibition of autophagic cell death mediates the neuroprotective effects observed with propofol.The cell model was established by depriving the cells of oxygen and glucose (OGD for 6 hours, and the rat model of ischemia was introduced by a transient two-vessel occlusion for 10 minutes. Transmission electron microscopy (TEM revealed that the formation of autophagosomes and autolysosomes in both neuronal PC12 cells and pyramidal rat hippocampal neurons after respective OGD and ischemia/reperfusion (I/R insults. A western blot analysis revealed that the autophagy-related proteins, such as microtubule-associated protein 1 light chain 3 (LC3-II, Beclin-1 and class III PI3K, were also increased accordingly, but cytoprotective Bcl-2 protein was decreased. The negative effects of OGD and I/R, including the formation of autophagosomes and autolysosomes, the increase in LC3-II, Beclin-1 and class III PI3K expression and the decline in Bcl-2 production were all inhibited by propofol and specific inhibitors of autophagy, such as 3-methyladenine (3-MA, LY294002 and Bafilomycin A1 (Baf,. Furthermore, in vitro OGD cultures and in vivo I/R rats showed an increase in cell survival following the administration of propofol, as assessed by an MTT assay or histochemical analyses.Our data suggest that propofol can markedly attenuate autophagic processes via the decreased expression of autophagy-related proteins in vitro and in vivo. This inhibition improves cell survival, which provides a novel explanation for the pleiotropic effects of propofol that benefit the nervous system.

  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. 8-C-(E-phenylethenyl)quercetin from onion/beef soup induces autophagic cell death in colon cancer cells through ERK activation.

    Science.gov (United States)

    Zhao, Yueliang; Fan, Daming; Zheng, Zong-Ping; Li, Edmund T S; Chen, Feng; Cheng, Ka-Wing; Wang, Mingfu

    2017-02-01

    Quercetin, a flavonoid, widely distributed in edible fruits and vegetables, was reported to effectively inhibit 2-amino-1-methyl-6-phenylimidazo[4, 5-b]pyridine (PhIP) formation in a food model (roast beef patties) with itself being converted into a novel compound 8-C-(E-phenylethenyl)quercetin (8-CEPQ). Here we investigated whether 8-CEPQ could be formed in a real food system, and tested its anticancer activity in human colon cancer cell lines. LC-MS was applied for the determination of 8-CEPQ formation in onion/beef soup. Anticancer activity of 8-CEPQ was evaluated by using cell viability assay and flow cytometry. Results showed that 8-CEPQ suppressed proliferation and caused G 2 phase arrest in colon cancer cells. Based on immunofluorescent staining assay, western blot assay, and RNA knockdown data, we found that 8-CEPQ did not cause apoptotic cell death. Instead, it induced autophagic cell death. Moreover, treatment with 8-CEPQ induced phosphorylation of extracellular signal-regulated kinase (ERK). Inhibition of ERK phosphorylation by the mitogen-activated protein kinase kinase (MEK)/ERK inhibitor U0126 attenuated 8-CEPQ-induced autophagy and reversed 8-CEPQ-mediated cell growth inhibition. Our results demonstrate that 8-CEPQ, a novel quercetin derivative, could be formed in onion/beef soup. 8-CEPQ inhibited colon cancer cell growth by inducing autophagic cell death through ERK activation. © 2016 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

  10. Mild MPP+ exposure impairs autophagic degradation through a novel lysosomal acidity-independent mechanism.

    Science.gov (United States)

    Miyara, Masatsugu; Kotake, Yaichiro; Tokunaga, Wataru; Sanoh, Seigo; Ohta, Shigeru

    2016-10-01

    Parkinson's disease (PD) is the second most common neurodegenerative disorder, but its underlying cause remains unknown. Although recent studies using PD-related neurotoxin MPP + suggest autophagy involvement in the pathogenesis of PD, the effect of MPP + on autophagic processes under mild exposure, which mimics the slow progressive nature of PD, remains largely unclear. We examined the effect of mild MPP + exposure (10 and 200 μM for 48 h), which induces a more slowly developing cell death, on autophagic processes and the mechanistic differences with acute MPP + toxicity (2.5 and 5 mM for 24 h). In SH-SY5Y cells, mild MPP + exposure predominantly inhibited autophagosome degradation, whereas acute MPP + exposure inhibited both autophagosome degradation and basal autophagy. Mild MPP + exposure reduced lysosomal hydrolase cathepsin D activity without changing lysosomal acidity, whereas acute exposure decreased lysosomal density. Lysosome biogenesis enhancers trehalose and rapamycin partially alleviated mild MPP + exposure induced impaired autophagosome degradation and cell death, but did not prevent the pathogenic response to acute MPP + exposure, suggesting irreversible lysosomal damage. We demonstrated impaired autophagic degradation by MPP + exposure and mechanistic differences between mild and acute MPP + toxicities. Mild MPP + toxicity impaired autophagosome degradation through novel lysosomal acidity-independent mechanisms. Sustained mild lysosomal damage may contribute to PD. We examined the effects of MPP + on autophagic processes under mild exposure, which mimics the slow progressive nature of Parkinson's disease, in SH-SY5Y cells. This study demonstrated impaired autophagic degradation through a reduction in lysosomal cathepsin D activity without altering lysosomal acidity by mild MPP + exposure. Mechanistic differences between acute and mild MPP + toxicity were also observed. Sustained mild damage of lysosome may be an underlying cause of Parkinson

  11. Capriccio For Strings: Collision-Mediated Parallel Transport in Curved Landscapes and Conifold-Enhanced Hierarchies among Mirror Quintic Flux Vacua

    Science.gov (United States)

    Eckerle, Kate

    This dissertation begins with a review of Calabi-Yau manifolds and their moduli spaces, flux compactification largely tailored to the case of type IIb supergravity, and Coleman-De Luccia vacuum decay. The three chapters that follow present the results of novel research conducted as a graduate student. Our first project is concerned with bubble collisions in single scalar field theories with multiple vacua. Lorentz boosted solitons traveling in one spatial dimension are used as a proxy to the colliding 3-dimensional spherical bubble walls. Recent work found that at sufficiently high impact velocities collisions between such bubble vacua are governed by "free passage" dynamics in which field interactions can be ignored during the collision, providing a systematic process for populating local minima without quantum nucleation. We focus on the time period that follows the bubble collision and provide evidence that, for certain potentials, interactions can drive significant deviations from the free passage bubble profile, thwarting the production of a new patch with different field value. However, for simple polynomial potentials a fine-tuning of vacuum locations is required to reverse the free passage kick enough that the field in the collision region returns to the original bubble vacuum. Hence we deem classical transitions mediated by free passage robust. Our second project continues with soliton collisions in the limit of relativistic impact velocity, but with the new feature of nontrivial field space curvature. We establish a simple geometrical interpretation of such collisions in terms of a double family of field profiles whose tangent vector fields stand in mutual parallel transport. This provides a generalization of the well-known limit in flat field space (free passage). We investigate the limits of this approximation and illustrate our analytical results with numerical simulations. In our third and final project we investigate the distribution of field

  12. Beneficial Autophagic Activities, Mitochondrial Function, and Metabolic Phenotype Adaptations Promoted by High-Intensity Interval Training in a Rat Model

    Directory of Open Access Journals (Sweden)

    Fang-Hui Li

    2018-05-01

    Full Text Available The effects of high-intensity interval (HIIT and moderate-intensity continuous training (MICT on basal autophagy and mitochondrial function in cardiac and skeletal muscle and plasma metabolic phenotypes have not been clearly characterized. Here, we investigated how 10-weeks HIIT and MICT differentially modify basal autophagy and mitochondrial markers in cardiac and skeletal muscle and conducted an untargeted metabolomics study with proton nuclear magnetic resonance (1H NMR spectroscopy and multivariate statistical analysis of plasma metabolic phenotypes. Male Sprague–Dawley rats were separated into three groups: sedentary control (SED, MICT, and HIIT. Rats underwent evaluation of exercise performance, including exercise tolerance and grip strength, and blood lactate levels were measured immediately after an incremental exercise test. Plasma samples were analyzed by 1H NMR. The expression of autophagy and mitochondrial markers and autophagic flux (LC3II/LC3-I ratio in cardiac, rectus femoris, and soleus muscle were analyzed by western blotting. Time to exhaustion and grip strength increased significantly following HIIT compared with that in both SED and MICT groups. Compared with those in the SED group, blood lactate level, and the expression of SDH, COX-IV, and SIRT3 significantly increased in rectus femoris and soleus muscle of both HIIT and MICT groups. Meanwhile, SDH and COX-IV content of cardiac muscle and COX-IV and SIRT3 content of rectus femoris and soleus muscle increased significantly following HIIT compared with that following MICT. The expression of LC3-II, ATG-3, and Beclin-1 and LC3II/LC3-I ratio were significantly increased only in soleus and cardiac muscle following HIIT. These data indicate that HIIT was more effective for improving physical performance and facilitating cardiac and skeletal muscle adaptations that increase mitochondrial function and basal autophagic activities. Moreover, 1H NMR spectroscopy and multivariate

  13. Beneficial Autophagic Activities, Mitochondrial Function, and Metabolic Phenotype Adaptations Promoted by High-Intensity Interval Training in a Rat Model.

    Science.gov (United States)

    Li, Fang-Hui; Li, Tao; Ai, Jing-Yi; Sun, Lei; Min, Zhu; Duan, Rui; Zhu, Ling; Liu, Yan-Ying; Liu, Timon Cheng-Yi

    2018-01-01

    The effects of high-intensity interval (HIIT) and moderate-intensity continuous training (MICT) on basal autophagy and mitochondrial function in cardiac and skeletal muscle and plasma metabolic phenotypes have not been clearly characterized. Here, we investigated how 10-weeks HIIT and MICT differentially modify basal autophagy and mitochondrial markers in cardiac and skeletal muscle and conducted an untargeted metabolomics study with proton nuclear magnetic resonance ( 1 H NMR) spectroscopy and multivariate statistical analysis of plasma metabolic phenotypes. Male Sprague-Dawley rats were separated into three groups: sedentary control (SED), MICT, and HIIT. Rats underwent evaluation of exercise performance, including exercise tolerance and grip strength, and blood lactate levels were measured immediately after an incremental exercise test. Plasma samples were analyzed by 1 H NMR. The expression of autophagy and mitochondrial markers and autophagic flux (LC3II/LC3-I ratio) in cardiac, rectus femoris, and soleus muscle were analyzed by western blotting. Time to exhaustion and grip strength increased significantly following HIIT compared with that in both SED and MICT groups. Compared with those in the SED group, blood lactate level, and the expression of SDH, COX-IV, and SIRT3 significantly increased in rectus femoris and soleus muscle of both HIIT and MICT groups. Meanwhile, SDH and COX-IV content of cardiac muscle and COX-IV and SIRT3 content of rectus femoris and soleus muscle increased significantly following HIIT compared with that following MICT. The expression of LC3-II, ATG-3, and Beclin-1 and LC3II/LC3-I ratio were significantly increased only in soleus and cardiac muscle following HIIT. These data indicate that HIIT was more effective for improving physical performance and facilitating cardiac and skeletal muscle adaptations that increase mitochondrial function and basal autophagic activities. Moreover, 1 H NMR spectroscopy and multivariate statistical

  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. Huaier Extract Induces Autophagic Cell Death by Inhibiting the mTOR/S6K Pathway in Breast Cancer Cells.

    Directory of Open Access Journals (Sweden)

    Xiaolong Wang

    Full Text Available Huaier extract is attracting increased attention due to its biological activities, including antitumor, anti-parasite and immunomodulatory effects. Here, we investigated the role of autophagy in Huaier-induced cytotoxicity in MDA-MB-231, MDA-MB-468 and MCF7 breast cancer cells. Huaier treatment inhibited cell viability in all three cell lines and induced various large membranous vacuoles in the cytoplasm. In addition, electron microscopy, MDC staining, accumulated expression of autophagy markers and flow cytometry revealed that Huaier extract triggered autophagy. Inhibition of autophagy attenuated Huaier-induced cell death. Furthermore, Huaier extract inhibited the mammalian target of the rapamycin (mTOR/S6K pathway in breast cancer cells. After implanting MDA-MB-231 cells subcutaneously into the right flank of BALB/c nu/nu mice, Huaier extract induced autophagy and effectively inhibited xenograft tumor growth. This study is the first to show that Huaier-induced cytotoxicity is partially mediated through autophagic cell death in breast cancer cells through suppression of the mTOR/S6K pathway.

  16. Modulation of apoptosis sensitivity through the interplay with autophagic and proteasomal degradation pathways

    Science.gov (United States)

    Delgado, M E; Dyck, L; Laussmann, M A; Rehm, M

    2014-01-01

    Autophagic and proteasomal degradation constitute the major cellular proteolysis pathways. Their physiological and pathophysiological adaptation and perturbation modulates the relative abundance of apoptosis-transducing proteins and thereby can positively or negatively adjust cell death susceptibility. In addition to balancing protein expression amounts, components of the autophagic and proteasomal degradation machineries directly interact with and co-regulate apoptosis signal transduction. The influence of autophagic and proteasomal activity on apoptosis susceptibility is now rapidly gaining more attention as a significant modulator of cell death signalling in the context of human health and disease. Here we present a concise and critical overview of the latest knowledge on the molecular interplay between apoptosis signalling, autophagy and proteasomal protein degradation. We highlight that these three pathways constitute an intricate signalling triangle that can govern and modulate cell fate decisions between death and survival. Owing to rapid research progress in recent years, it is now possible to provide detailed insight into the mechanisms of pathway crosstalk, common signalling nodes and the role of multi-functional proteins in co-regulating both protein degradation and cell death. PMID:24457955

  17. 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.

  18. 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

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

    International Nuclear Information System (INIS)

    Nakadera, Eisuke; Yamashina, Shunhei; Izumi, Kousuke; Inami, Yoshihiro; Sato, Toshifumi; Fukushima, Hirofumi; Kon, Kazuyoshi; Ikejima, Kenichi; Ueno, Takashi; Watanabe, Sumio

    2016-01-01

    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

  20. 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

  1. Dynamic autophagic activity affected the development of thoracic aortic dissection by regulating functional properties of smooth muscle cells

    International Nuclear Information System (INIS)

    Wang, Yang; Zhao, Zhi-Min; Zhang, Guan-Xin; Yang, Fan; Yan, Yan; Liu, Su-Xuan; Li, Song-Hua; Wang, Guo-Kun; Xu, Zhi-Yun

    2016-01-01

    The aortic medial degeneration is the key histopathologic feature of Thoracic aortic dissection (TAD). The aim of this study was to identify the change of autophagic activity in the aortic wall during TAD development, and to explore the roles of autophagy on regulating functional properties of smooth muscle cells (SMCs). Firstly, compared with control group (n = 11), the increased expression of autophagic markers Beclin1 and LC3 was detected in the aortic wall from TAD group (n = 23) by immunochemistry and western blot. We found that more autophagic vacuoles were present in the aortic wall of TAD patients using Transmission electron microscopy. Next, autophagic activity was examined in AD mice model established by β-aminopropionitrile fumarate (BAPN) and angiotensin II. Immunochemistry proved that autophagic activity was dynamically changed during AD development. Beclin1 and LC3 were detected up-regulated in the aortic wall in the second week after BAPN feeding, earlier than the fragmentation or loss of elastic fibers. When AD occurred in the 4th week, the expression of Beclin1 and LC3 began to decrease, but still higher than the control. Furthermore, autophagy was found to inhibit starvation-induced apoptosis of SMCs. Meanwhile, blockage of autophagy could suppress PDGF-induced phenotypic switch of SMCs. Taken together, autophagic activity was dynamically changed in the aortic wall during TAD development. The abnormal autophagy could regulate the functional properties of aortic SMCs, which might be the potential pathogenesis of TAD. - Highlights: • Autophagy is up-regulated in aorta wall from thoracic aorta dissection (TAD) patient. • Autophagic activity is dynamically changed during TAD development. • Dynamically change of autophagy is associated with pathological process of TAD. • Autophagy participate in the development of TAD by regulating function of SMCs.

  2. 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....... Complex interactions between seasonal changes in O2 and mineral-N availability following near-surface WL fluctuations in combination with plant-mediated gas transport by P. arundinacea controlled the subsurface N2O concentrations and gas transport mechanisms responsible for N2O fluxes across the soil......–atmosphere interface. Results demonstrate the necessity for addressing this high temporal variability and potential plant transport of N2O in future studies of net N2O exchange across the soil–atmosphere interface....

  3. 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.

  4. Calpain Determines the Propensity of Adult Hippocampal Neural Stem Cells to Autophagic Cell Death Following Insulin Withdrawal.

    Science.gov (United States)

    Chung, Kyung Min; Park, Hyunhee; Jung, Seonghee; Ha, Shinwon; Yoo, Seung-Jun; Woo, Hanwoong; Lee, Hyang Ju; Kim, Seong Who; Kim, Eun-Kyoung; Moon, Cheil; Yu, Seong-Woon

    2015-10-01

    Programmed cell death (PCD) has significant effects on the function of neural stem cells (NSCs) during brain development and degeneration. We have previously reported that adult rat hippocampal neural stem (HCN) cells underwent autophagic cell death (ACD) rather than apoptosis following insulin withdrawal despite their intact apoptotic capabilities. Here, we report a switch in the mode of cell death in HCN cells with calpain as a critical determinant. In HCN cells, calpain 1 expression was barely detectable while calpain 2 was predominant. Inhibition of calpain in insulin-deprived HCN cells further augmented ACD. In contrast, expression of calpain 1 switched ACD to apoptosis. The proteasome inhibitor lactacystin blocked calpain 2 degradation and elevated the intracellular Ca(2+) concentration. In combination, these effects potentiated calpain activity and converted the mode of cell death to apoptosis. Our results indicate that low calpain activity, due to absence of calpain 1 and degradation of calpain 2, results in a preference for ACD over apoptosis in insulin-deprived HCN cells. On the other hand, conditions leading to high calpain activity completely switch the mode of cell death to apoptosis. This is the first report on the PCD mode switching mechanism in NSCs. The dynamic change in calpain activity through the proteasome-mediated modulation of the calpain and intracellular Ca(2+) levels may be the critical contributor to the demise of NSCs. Our findings provide a novel insight into the complex mechanisms interconnecting autophagy and apoptosis and their roles in the regulation of NSC death. © 2015 AlphaMed Press.

  5. 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.

  6. 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.

  7. Vitamin K3 attenuates cerulein-induced acute pancreatitis through inhibition of the autophagic pathway.

    Science.gov (United States)

    Chinzei, Ryo; Masuda, Atsuhiro; Nishiumi, Shin; Nishida, Masayuki; Onoyama, Mitsuko; Sanuki, Tsuyoshi; Fujita, Tsuyoshi; Moritoh, Satoshi; Itoh, Tomoo; Kutsumi, Hiromu; Mizuno, Shigeto; Azuma, Takeshi; Yoshida, Masaru

    2011-01-01

    The discovery of novel and effective treatment methods would be of great help to patients with acute pancreatitis. The aims of this study were to determine the inhibitory effects of vitamin K3 (VK3) against cerulein-induced acute pancreatitis in mice and to examine the mechanisms behind these effects. Acute pancreatitis in mice was induced by intraperitoneal injection of cerulein 6 times at hourly intervals. Vitamin K3 was administered once before the first injection of cerulein or twice before and after the first injection of cerulein. The degrees of inflammation and autophagy in the pancreatic tissue were estimated by histological examination, measurement of enzyme activity, confocal microscopy, and Western blotting. The inhibitory effects of VK3 against rapamycin-induced autophagy were also examined using HeLa cells stably expressing green fluorescent protein LC3. Cerulein-induced acute pancreatitis was markedly attenuated by the administration of VK3. In addition, VK3 led to the inhibition of cerulein-evoked autophagic changes and colocalization of autophagosomes and lysosomes in the pancreatic tissue. Vitamin K3 also reduced rapamycin-induced autophagy in HeLa/green fluorescent protein LC3 cells. Our data suggest that the administration of VK3 reduces pancreatic inflammation in acute pancreatitis through inhibition of the autophagic pathway. Vitamin K3 may be an effective therapeutic strategy against acute pancreatitis.

  8. Orphan nuclear receptor TR3 acts in autophagic cell death via mitochondrial signaling pathway.

    Science.gov (United States)

    Wang, Wei-jia; Wang, Yuan; Chen, Hang-zi; Xing, Yong-zhen; Li, Feng-wei; Zhang, Qian; Zhou, Bo; Zhang, Hong-kui; Zhang, Jie; Bian, Xue-li; Li, Li; Liu, Yuan; Zhao, Bi-xing; Chen, Yan; Wu, Rong; Li, An-zhong; Yao, Lu-ming; Chen, Ping; Zhang, Yi; Tian, Xu-yang; Beermann, Friedrich; Wu, Mian; Han, Jiahuai; Huang, Pei-qiang; Lin, Tianwei; Wu, Qiao

    2014-02-01

    Autophagy is linked to cell death, yet the associated mechanisms are largely undercharacterized. We discovered that melanoma, which is generally resistant to drug-induced apoptosis, can undergo autophagic cell death with the participation of orphan nuclear receptor TR3. A sequence of molecular events leading to cellular demise is launched by a specific chemical compound, 1-(3,4,5-trihydroxyphenyl)nonan-1-one, newly acquired from screening a library of TR3-targeting compounds. The autophagic cascade comprises TR3 translocation to mitochondria through interaction with the mitochondrial outer membrane protein Nix, crossing into the mitochondrial inner membrane through Tom40 and Tom70 channel proteins, dissipation of mitochondrial membrane potential by the permeability transition pore complex ANT1-VDAC1 and induction of autophagy. This process leads to excessive mitochondria clearance and irreversible cell death. It implicates a new approach to melanoma therapy through activation of a mitochondrial signaling pathway that integrates a nuclear receptor with autophagy for cell death.

  9. Hepatic steatosis inhibits autophagic proteolysis via impairment of autophagosomal acidification and cathepsin expression

    International Nuclear Information System (INIS)

    Inami, Yoshihiro; Yamashina, Shunhei; Izumi, Kousuke; Ueno, Takashi; Tanida, Isei; Ikejima, Kenichi; Watanabe, Sumio

    2011-01-01

    Highlights: → Acidification of autophagosome was blunted in steatotic hepatocytes. → Hepatic steatosis did not disturb fusion of isolated autophagosome and lysosome. → Proteinase activity of cathepsin B and L in autolysosomes was inhibited by steatosis. → Hepatic expression of cathepsin B and L was suppressed by steatosis. -- Abstract: Autophagy, one of protein degradation system, contributes to maintain cellular homeostasis and cell defense. Recently, some evidences indicated that autophagy and lipid metabolism are interrelated. Here, we demonstrate that hepatic steatosis impairs autophagic proteolysis. Though accumulation of autophagosome is observed in hepatocytes from ob/ob mice, expression of p62 was augmented in liver from ob/ob mice more than control mice. Moreover, degradation of the long-lived protein leucine was significantly suppressed in hepatocytes isolated from ob/ob mice. More than 80% of autophagosomes were stained by LysoTracker Red (LTR) in hepatocytes from control mice; however, rate of LTR-stained autophagosomes in hepatocytes were suppressed in ob/ob mice. On the other hand, clearance of autolysosomes loaded with LTR was blunted in hepatocytes from ob/ob mice. Although fusion of isolated autophagosome and lysosome was not disturbed, proteinase activity of cathepsin B and L in autolysosomes and cathepsin B and L expression of liver were suppressed in ob/ob mice. These results indicate that lipid accumulation blunts autophagic proteolysis via impairment of autophagosomal acidification and cathepsin expression.

  10. Hepatic steatosis inhibits autophagic proteolysis via impairment of autophagosomal acidification and cathepsin expression

    Energy Technology Data Exchange (ETDEWEB)

    Inami, Yoshihiro [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 [Department of Gastroenterology, Juntendo University School of Medicine, Hongo 2-1-1, Bunkyo-ku, Tokyo 113-8421 (Japan); Ueno, Takashi [Department of Biochemistry, Juntendo University School of Medicine, Hongo 2-1-1, Bunkyo-ku, Tokyo 113-8421 (Japan); Tanida, Isei [Department of Biochemistry and Cell Biology, Laboratory of Biomembranes, National Institute of Infectious Disease, Toyama 1-23-1, Shinjuku-ku, Tokyo 162-8640 (Japan); Ikejima, Kenichi; Watanabe, Sumio [Department of Gastroenterology, Juntendo University School of Medicine, Hongo 2-1-1, Bunkyo-ku, Tokyo 113-8421 (Japan)

    2011-09-09

    Highlights: {yields} Acidification of autophagosome was blunted in steatotic hepatocytes. {yields} Hepatic steatosis did not disturb fusion of isolated autophagosome and lysosome. {yields} Proteinase activity of cathepsin B and L in autolysosomes was inhibited by steatosis. {yields} Hepatic expression of cathepsin B and L was suppressed by steatosis. -- Abstract: Autophagy, one of protein degradation system, contributes to maintain cellular homeostasis and cell defense. Recently, some evidences indicated that autophagy and lipid metabolism are interrelated. Here, we demonstrate that hepatic steatosis impairs autophagic proteolysis. Though accumulation of autophagosome is observed in hepatocytes from ob/ob mice, expression of p62 was augmented in liver from ob/ob mice more than control mice. Moreover, degradation of the long-lived protein leucine was significantly suppressed in hepatocytes isolated from ob/ob mice. More than 80% of autophagosomes were stained by LysoTracker Red (LTR) in hepatocytes from control mice; however, rate of LTR-stained autophagosomes in hepatocytes were suppressed in ob/ob mice. On the other hand, clearance of autolysosomes loaded with LTR was blunted in hepatocytes from ob/ob mice. Although fusion of isolated autophagosome and lysosome was not disturbed, proteinase activity of cathepsin B and L in autolysosomes and cathepsin B and L expression of liver were suppressed in ob/ob mice. These results indicate that lipid accumulation blunts autophagic proteolysis via impairment of autophagosomal acidification and cathepsin expression.

  11. 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.

  12. 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.

  13. 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.

  14. 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.

  15. 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.

  16. Deoxycholate, an Endogenous Cytotoxin/Genotoxin, Induces the Autophagic Stress-Survival Pathway: Implications for Colon Carcinogenesis

    Directory of Open Access Journals (Sweden)

    Claire M. Payne

    2009-01-01

    Full Text Available 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 monodansycadaverine and lysotracker 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. Rapamycin (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. Rapamycin 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.

  17. 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.

  18. 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

  19. Opposite Effects of Two Human ATG10 Isoforms on Replication of a HCV Sub-genomic Replicon Are Mediated via Regulating Autophagy Flux in Zebrafish

    Directory of Open Access Journals (Sweden)

    Yu-Chen Li

    2018-04-01

    Full Text Available Autophagy is a host mechanism for cellular homeostatic control. Intracellular stresses are symptoms of, and responses to, dysregulation of the physiological environment of the cell. Alternative gene transcription splicing is a mechanism potentially used by a host to respond to physiological or pathological challenges. Here, we aimed to confirm opposite effects of two isoforms of the human autophagy-related protein ATG10 on an HCV subgenomic replicon in zebrafish. A liver-specific HCV subreplicon model was established and exhibited several changes in gene expression typically induced by HCV infection, including overexpression of several HCV-dependent genes (argsyn, leugpcr, rasgbd, and scaf-2, as well as overexpression of several ER stress related genes (atf4, chop, atf6, and bip. Autophagy flux was blocked in the HCV model. Our results indicated that the replication of the HCV subreplicon was suppressed via a decrease in autophagosome formation caused by the autophagy inhibitor 3MA, but enhanced via dysfunction in the lysosomal degradation caused by another autophagy inhibitor CQ. Human ATG10, a canonical isoform in autophagy, facilitated the amplification of the HCV-subgenomic replicon via promoting autophagosome formation. ATG10S, a non-canonical short isoform of the ATG10 protein, promoted autophagy flux, leading to lysosomal degradation of the HCV-subgenomic replicon. Human ATG10S may therefore inhibit HCV replication, and may be an appropriate target for future antiviral drug screening.

  20. Acadesine kills chronic myelogenous leukemia (CML cells through PKC-dependent induction of autophagic cell death.

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    Guillaume Robert

    Full Text Available CML is an hematopoietic stem cell disease characterized by the t(9;22 (q34;q11 translocation encoding the oncoprotein p210BCR-ABL. The effect of acadesine (AICAR, 5-Aminoimidazole-4-carboxamide-1-beta-D-ribofuranoside a compound with known antileukemic effect on B cell chronic lymphoblastic leukemia (B-CLL was investigated in different CML cell lines. Acadesine triggered loss of cell metabolism in K562, LAMA-84 and JURL-MK1 and was also effective in killing imatinib-resistant K562 cells and Ba/F3 cells carrying the T315I-BCR-ABL mutation. The anti-leukemic effect of acadesine did not involve apoptosis but required rather induction of autophagic cell death. AMPK knock-down by Sh-RNA failed to prevent the effect of acadesine, indicating an AMPK-independent mechanism. The effect of acadesine was abrogated by GF109203X and Ro-32-0432, both inhibitor of classical and new PKCs and accordingly, acadesine triggered relocation and activation of several PKC isoforms in K562 cells. In addition, this compound exhibited a potent anti-leukemic effect in clonogenic assays of CML cells in methyl cellulose and in a xenograft model of K562 cells in nude mice. In conclusion, our work identifies an original and unexpected mechanism by which acadesine triggers autophagic cell death through PKC activation. Therefore, in addition to its promising effects in B-CLL, acadesine might also be beneficial for Imatinib-resistant CML patients.

  1. Autophagy Inhibition Enhances the Mitochondrial-Mediated Apoptosis Induced by Mangrove (Avicennia marina) Extract in Human Breast Cancer Cells

    KAUST Repository

    Esau, Luke; Sagar, Sunil; Bajic, Vladimir B.; Kaur, Mandeep

    2015-01-01

    Conclusion: Our data provide evidence that AM extract triggers ROS-mediated autophagy as well as caspase-independent apoptosis. The results also strengthen the view that concurrent targeting of apoptotic and autophagic pathways may provide effective therapeutic strategy against cancer.

  2. Xenophagic pathways and their bacterial subversion in cellular self-defense - παντα ρει - everything is in flux.

    Science.gov (United States)

    Radomski, Nadine; Rebbig, Annica; Leonhardt, Ralf M; Knittler, Michael R

    2017-11-02

    Autophagy is an evolutionarily ancient and highly conserved eukaryotic mechanism that targets cytoplasmic material for degradation. Autophagic flux involves the formation of autophagosomes and their degradation by lysosomes. The process plays a crucial role in maintaining cellular homeostasis and responds to various environmental conditions. While autophagy had previously been thought to be a non-selective process, it is now clear that it can also selectively target cellular organelles, such as mitochondria (referred to as mitophagy) and/or invading pathogens (referred to as xenophagy). Selective autophagy is characterized by specific substrate recognition and requires distinct cellular adaptor proteins. Here we review xenophagic mechanisms involved in the recognition and autolysosomal or autophagolysosomal degradation of different intracellular bacteria. In this context, we also discuss a recently discovered cellular self-defense pathway, termed mito-xenophagy, which occurs during bacterial infection of dendritic cells and depends on a TNF-α-mediated metabolic switch from oxidative phosphorylation to glycolysis. Copyright © 2017 Elsevier GmbH. All rights reserved.

  3. Flux-mediated syntheses, structural characterization and low-temperature polymorphism of the p-type semiconductor Cu2Ta4O11

    Science.gov (United States)

    King, Nacole; Sullivan, Ian; Watkins-Curry, Pilanda; Chan, Julia Y.; Maggard, Paul A.

    2016-04-01

    A new low-temperature polymorph of the copper(I)-tantalate, α-Cu2Ta4O11, has been synthesized in a molten CuCl-flux reaction at 665 °C for 1 h and characterized by powder X-ray diffraction Rietveld refinements (space group Cc (#9), a=10.734(1) Å, b = 6.2506(3) Å, c=12.887(1) Å, β = 106.070(4)°). The α-Cu2Ta4O11 phase is a lower-symmetry monoclinic polymorph of the rhombohedral Cu2Ta4O11 structure (i.e., β-Cu2Ta4O11 space group R 3 ̅ c (#167), a = 6.2190(2) Å, c=37.107(1) Å), and related crystallographically by ahex=amono/√3, bhex=bmono, and chex=3cmonosinβmono. Its structure is similar to the rhombohedral β-Cu2Ta4O11 and is composed of single layers of highly-distorted and edge-shared TaO7 and TaO6 polyhedra alternating with layers of nearly linearly-coordinated Cu(I) cations and isolated TaO6 octahedra. Temperature dependent powder X-ray diffraction data show the α-Cu2Ta4O11 phase is relatively stable under vacuum at 223 K and 298 K, but reversibly transforms to β-Cu2Ta4O11 by at least 523 K and higher temperatures. The symmetry-lowering distortions from β-Cu2Ta4O11 to α-Cu2Ta4O11 arise from the out-of-center displacements of the Ta 5d0 cations in the TaO7 pentagonal bipyramids. The UV-vis diffuse reflectance spectrum of the monoclinic α-Cu2Ta4O11 shows an indirect bandgap transition of ∼2.6 eV, with the higher-energy direct transitions starting at ∼2.7 eV. Photoelectrochemical measurements on polycrystalline films of α-Cu2Ta4O11 show strong cathodic photocurrents of ∼1.5 mA/cm2 under AM 1.5 G solar irradiation.

  4. Autophagic signaling and proteolytic enzyme activity in cardiac and skeletal muscle of spontaneously hypertensive rats following chronic aerobic exercise.

    Directory of Open Access Journals (Sweden)

    Elliott M McMillan

    Full Text Available Hypertension is a cardiovascular disease associated with deleterious effects in skeletal and cardiac muscle. Autophagy is a degradative process essential to muscle health. Acute exercise can alter autophagic signaling. Therefore, we aimed to characterize the effects of chronic endurance exercise on autophagy in skeletal and cardiac muscle of normotensive and hypertensive rats. Male Wistar Kyoto (WKY and spontaneously hypertensive rats (SHR were assigned to a sedentary condition or 6 weeks of treadmill running. White gastrocnemius (WG of hypertensive rats had higher (p<0.05 caspase-3 and proteasome activity, as well as elevated calpain activity. In addition, skeletal muscle of hypertensive animals had elevated (p<0.05 ATG7 and LC3I protein, LAMP2 mRNA, and cathepsin activity, indicative of enhanced autophagic signaling. Interestingly, chronic exercise training increased (p<0.05 Beclin-1, LC3, and p62 mRNA as well as proteasome activity, but reduced (p<0.05 Beclin-1 and ATG7 protein, as well as decreased (p<0.05 caspase-3, calpain, and cathepsin activity. Left ventricle (LV of hypertensive rats had reduced (p<0.05 AMPKα and LC3II protein, as well as elevated (p<0.05 p-AKT, p-p70S6K, LC3I and p62 protein, which collectively suggest reduced autophagic signaling. Exercise training had little effect on autophagy-related signaling factors in LV; however, exercise training increased (p<0.05 proteasome activity but reduced (p<0.05 caspase-3 and calpain activity. Our results suggest that autophagic signaling is altered in skeletal and cardiac muscle of hypertensive animals. Regular aerobic exercise can effectively alter the proteolytic environment in both cardiac and skeletal muscle, as well as influence several autophagy-related factors in skeletal muscle of normotensive and hypertensive rats.

  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. 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.

  9. 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.

  10. Polyploid tumour cells elicit paradiploid progeny through depolyploidizing divisions and regulated autophagic degradation.

    Science.gov (United States)

    Erenpreisa, Jekaterina; Salmina, Kristine; Huna, Anda; Kosmacek, Elizabeth A; Cragg, Mark S; Ianzini, Fiorenza; Anisimov, Alim P

    2011-07-01

    'Neosis' describes the process whereby p53 function-deficient tumour cells undergo self-renewal after genotoxic damage apparently via senescing ETCs (endopolyploid tumour cells). We previously reported that autophagic digestion and extrusion of DNA occurs in ETC and subsequently revealed that self-renewal transcription factors are also activated under these conditions. Here, we further studied this phenomenon in a range of cell lines after genotoxic damage induced by gamma irradiation, ETO (etoposide) or PXT (paclitaxel) treatment. These experiments revealed that chromatin degradation by autophagy was compatible with continuing mitotic activity in ETC. While the actively polyploidizing primary ETC produced early after genotoxic insult activated self-renewal factors throughout the polygenome, the secondary ETC restored after failed multipolar mitosis underwent subnuclei differentiation. As such, only a subset of subnuclei continued to express OCT4 and NANOG, while those lacking these factors stopped DNA replication and underwent degradation and elimination through autophagy. The surviving subnuclei sequestered nascent cytoplasm to form subcells, while being retained within the confines of the old ETC. Finally, the preformed paradiploid subcells became released from their linking chromosome bridges through autophagy and subsequently began cell divisions. These data show that 'neotic' ETC resulting from genotoxically damaged p53 function-deficient tumour cells develop through a heteronuclear system differentiating the polyploid genome into rejuvenated 'viable' subcells (which provide mitotically propagating paradiploid descendents) and subnuclei, which become degraded and eliminated by autophagy. The whole process reduces aneuploidy in descendants of ETC.

  11. Endo-lysosomal and autophagic dysfunction: a driving factor in Alzheimer's disease?

    Science.gov (United States)

    Whyte, Lauren S; Lau, Adeline A; Hemsley, Kim M; Hopwood, John J; Sargeant, Timothy J

    2017-03-01

    Alzheimer's disease (AD) is the most common cause of dementia, and its prevalence will increase significantly in the coming decades. Although important progress has been made, fundamental pathogenic mechanisms as well as most hereditary contributions to the sporadic form of the disease remain unknown. In this review, we examine the now substantial links between AD pathogenesis and lysosomal biology. The lysosome hydrolyses and processes cargo delivered by multiple pathways, including endocytosis and autophagy. The endo-lysosomal and autophagic networks are central to clearance of cellular macromolecules, which is important given there is a deficit in clearance of amyloid-β in AD. Numerous studies show prominent lysosomal dysfunction in AD, including perturbed trafficking of lysosomal enzymes and accumulation of the same substrates that accumulate in lysosomal storage disorders. Examination of the brain in lysosomal storage disorders shows the accumulation of amyloid precursor protein metabolites, which further links lysosomal dysfunction with AD. This and other evidence leads us to hypothesise that genetic variation in lysosomal genes modifies the disease course of sporadic AD. © 2016 International Society for Neurochemistry.

  12. 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.

  13. 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.

  14. 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...... length, step height, and.flux start level. Filtrating 8 kg/m(3) yeast cell suspensions by a vibrating 0.45 x 10(-6) m pore size microfiltration hollow fiber module, critical fluxes from 5.6 x 10(-6) to 1.2 x 10(-5) m/s have been measured using various step lengths from 300 to 1200 seconds. Thus......, 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...

  15. Aging and Autophagic Function Influences the Progressive Decline of Adult Drosophila Behaviors.

    Directory of Open Access Journals (Sweden)

    Eric P Ratliff

    Full Text Available Multiple neurological disorders are characterized by the abnormal accumulation of protein aggregates and the progressive impairment of complex behaviors. Our Drosophila studies demonstrate that middle-aged wild-type flies (WT, ~4-weeks exhibit a marked accumulation of neural aggregates that is commensurate with the decline of the autophagy pathway. However, enhancing autophagy via neuronal over-expression of Atg8a (Atg8a-OE reduces the age-dependent accumulation of aggregates. Here we assess basal locomotor activity profiles for single- and group-housed male and female WT flies and observed that only modest behavioral changes occurred by 4-weeks of age, with the noted exception of group-housed male flies. Male flies in same-sex social groups exhibit a progressive increase in nighttime activity. Infrared videos show aged group-housed males (4-weeks are engaged in extensive bouts of courtship during periods of darkness, which is partly repressed during lighted conditions. Together, these nighttime courtship behaviors were nearly absent in young WT flies and aged Atg8a-OE flies. Previous studies have indicated a regulatory role for olfaction in male courtship partner choice. Coincidently, the mRNA expression profiles of several olfactory genes decline with age in WT flies; however, they are maintained in age-matched Atg8a-OE flies. Together, these results suggest that middle-aged male flies develop impairments in olfaction, which could contribute to the dysregulation of courtship behaviors during dark time periods. Combined, our results demonstrate that as Drosophila age, they develop early behavior defects that are coordinate with protein aggregate accumulation in the nervous system. In addition, the nighttime activity behavior is preserved when neuronal autophagy is maintained (Atg8a-OE flies. Thus, environmental or genetic factors that modify autophagic capacity could have a positive impact on neuronal aging and complex behaviors.

  16. 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.

  17. Serosal-to-mucosal urea flux across the isolated ruminal epithelium is mediated via urea transporter-B and aquaporins when Holstein calves are abruptly changed to a moderately fermentable diet.

    Science.gov (United States)

    Walpole, M E; Schurmann, B L; Górka, P; Penner, G B; Loewen, M E; Mutsvangwa, T

    2015-02-01

    Urea transport (UT-B) proteins are known to facilitate urea movement across the ruminal epithelium; however, other mechanisms may be involved as well because inhibiting UT-B does not completely abolish urea transport. Of the aquaporins (AQP), which are a family of membrane-spanning proteins that are predominantly involved in the movement of water, AQP-3, AQP-7, and AQP-10 are also permeable to urea, but it is not clear if they contribute to urea transport across the ruminal epithelium. The objectives of this study were to determine (1) the functional roles of AQP and UT-B in the serosal-to-mucosal urea flux (Jsm-urea) across rumen epithelium; and (2) whether functional adaptation occurs in response to increased diet fermentability. Twenty-five Holstein steer calves (n=5) were assigned to a control diet (CON; 91.5% hay and 8.5% vitamin and mineral supplement) or a medium grain diet (MGD; 41.5% barley grain, 50% hay, and 8.5% vitamin and mineral) that was fed for 3, 7, 14, or 21 d. Calves were killed and ruminal epithelium was collected for mounting in Ussing chambers under short-circuit conditions and for analysis of mRNA abundance of UT-B and AQP-3, AQP-7, and AQP-10. To mimic physiologic conditions, the mucosal buffer (pH 6.2) contained no urea, whereas the serosal buffer (pH 7.4) contained 1 mM urea. The fluxes of (14)C-urea (Jsm-urea; 26 kBq/10 mL) and (3)H-mannitol (Jsm-mannitol; 37 kBq/10 mL) were measured, with Jsm-mannitol being used as an indicator of paracellular or hydrophilic movement. Serosal addition of phloretin (1 mM) was used to inhibit UT-B-mediated urea transport, whereas NiCl2 (1 mM) was used to inhibit AQP-mediated urea transport. Across treatments, the addition of phloretin or NiCl2 reduced the Jsm-urea from 116.5 to 54.0 and 89.5 nmol/(cm(2) × h), respectively. When both inhibitors were added simultaneously, Jsm-urea was further reduced to 36.8 nmol/(cm(2) × h). Phloretin-sensitive and NiCl2-sensitive Jsm-urea were not affected by diet. The

  18. Polysaccharide from Fuzi protects against Ox-LDL-induced calcification of human vascular smooth muscle cells by increasing autophagic activity

    Science.gov (United States)

    Liao, Lizhen; Zhuang, Xiaodong; Li, Weidong; Su, Qibiao; Zhao, Jie; Liu, Ying

    2018-01-01

    Polysaccharide from Fuzi (FPS) is a water-soluble polysaccharide isolated from the traditional Chinese herbal medicine Fuzi. It has been demonstrated to protect hepatocytes against ischemia-reperfusion injury through its potent antioxidant effects, and to attenuate starvation-induced cytotoxicity in H9c2 cells by increasing autophagic activity. In the present study, Alizarin Red S staining was used to detect mineral deposition and reverse transcription-quantitative polymerase chain reaction was used to detect the core binding factor α1 and smooth muscle 22α mRNA expression. To analyze autophagic activity, western blotting was used to detect microtubule-associated protein 1A/1B light chain 3 and nucleoporin P62 expression. In addition, green fluorescent protein-LC3 dots-per-cell was observed by fluorescence microscopy. It was demonstrated that oxidized low-density lipoprotein (Ox-LDL) could increase the calcification of human vascular smooth muscle cells (VSMCs) in a concentration-dependent manner, and that FPS treatment had a significant protective effect against Ox-LDL-induced calcification of human VSMCs. Furthermore, FPS treatment alleviated the Ox-LDL-induced downregulation of autophagic activity, and the protective effect of FPS on Ox-LDL-induced calcification was attenuated by the autophagy inhibitor 3-methyladenine. In conclusion, the present study demonstrated for the first time to the best of the authors' knowledge that FPS can protect against Ox-LDL-induced vascular calcification in human VSMCs, and that this likely occurs via the activation of autophagy. This supports the hypothesis that autophagy may be an endogenous protective mechanism counteracting vascular calcification, and that FPS may be used as a potential therapeutic for vascular calcification. PMID:29393437

  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. Minkowski vacuum transitions in (nongeometric) flux compactifications

    International Nuclear Information System (INIS)

    Herrera-Suarez, Wilberth; Loaiza-Brito, Oscar

    2010-01-01

    In this work we study the generalization of twisted homology to geometric and nongeometric backgrounds. In the process, we describe the necessary conditions to wrap a network of D-branes on twisted cycles. If the cycle is localized in time, we show how by an instantonic brane mediation, some D-branes transform into fluxes on different backgrounds, including nongeometric fluxes. As a consequence, we show that in the case of a IIB six-dimensional torus compactification on a simple orientifold, the flux superpotential is not invariant by this brane-flux transition, allowing the connection among different Minkowski vacuum solutions. For the case in which nongeometric fluxes are turned on, we also discuss some topological restrictions for the transition to occur. In this context, we show that there are some vacuum solutions protected to change by a brane-flux transition.

  1. Constitutive upregulation of chaperone-mediated autophagy in Huntington's disease.

    Science.gov (United States)

    Koga, Hiroshi; Martinez-Vicente, Marta; Arias, Esperanza; Kaushik, Susmita; Sulzer, David; Cuervo, Ana Maria

    2011-12-14

    Autophagy contributes to the removal of prone-to-aggregate proteins, but in several instances these pathogenic proteins have been shown to interfere with autophagic activity. In the case of Huntington's disease (HD), a congenital neurodegenerative disorder resulting from mutation in the huntingtin protein, we have previously described that the mutant protein interferes with the ability of autophagic vacuoles to recognize cytosolic cargo. Growing evidence supports the existence of cross talk among autophagic pathways, suggesting the possibility of functional compensation when one of them is compromised. In this study, we have identified a compensatory upregulation of chaperone-mediated autophagy (CMA) in different cellular and mouse models of HD. Components of CMA, namely the lysosome-associated membrane protein type 2A (LAMP-2A) and lysosomal-hsc70, are markedly increased in HD models. The increase in LAMP-2A is achieved through both an increase in the stability of this protein at the lysosomal membrane and transcriptional upregulation of this splice variant of the lamp-2 gene. We propose that CMA activity increases in response to macroautophagic dysfunction in the early stages of HD, but that the efficiency of this compensatory mechanism may decrease with age and so contribute to cellular failure and the onset of pathological manifestations.

  2. Magnetic-flux pump

    Science.gov (United States)

    Hildebrandt, A. F.; Elleman, D. D.; Whitmore, F. C. (Inventor)

    1966-01-01

    A magnetic flux pump is described for increasing the intensity of a magnetic field by transferring flux from one location to the magnetic field. The device includes a pair of communicating cavities formed in a block of superconducting material, and a piston for displacing the trapped magnetic flux into the secondary cavity producing a field having an intense flux density.

  3. 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

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

    DEFF Research Database (Denmark)

    Fernandes, H. J. R.; Hartfield, E. M.; Christian Kjeldsen, Hans

    2016-01-01

    -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. © 2016 The Authors....

  5. Soft supersymmetry breaking in KKLT flux compactification

    International Nuclear Information System (INIS)

    Choi, K.; Falkowski, A.; Nilles, H.P.; Olechowski, M.

    2005-01-01

    We examine the structure of soft supersymmetry breaking terms in KKLT models of flux compactification with low energy supersymmetry. Moduli are stabilized by fluxes and nonperturbative dynamics while a de Sitter vacuum is obtained by adding supersymmetry breaking anti-branes. We discuss the characteristic pattern of mass scales in such a set-up as well as some features of 4D N=1 supergravity breakdown by anti-branes. Anomaly mediation is found to always give an important contribution and one can easily arrange for flavor-independent soft terms. In its most attractive realization, the modulus mediation is comparable to the anomaly mediation, yielding a quite distinctive sparticle spectrum. In addition, the axion component of the modulus/dilaton superfield dynamically cancels the relative CP phase between the contributions of anomaly and modulus mediation, thereby avoiding dangerous SUSY CP violation

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

    Directory of Open Access Journals (Sweden)

    Rita-Eva Varga

    2015-08-01

    Full Text Available 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.

  10. Andrographolide alleviates imiquimod-induced psoriasis in mice via inducing autophagic proteolysis of MyD88.

    Science.gov (United States)

    Shao, Fenli; Tan, Tao; Tan, Yang; Sun, Yang; Wu, Xingxin; Xu, Qiang

    2016-09-01

    Psoriasis is a chronic inflammatory skin disease with excessive activation of toll-like receptors (TLRs), which play important roles in developing psoriasis. Targeting TLR signaling remains a challenge for treating psoriasis. Here, we found that andrographolide (Andro), a small-molecule natural product, alleviated imiquimod- but not interleukin 23 (IL-23)-induced psoriasis in mice with reducing expressions of IL-23 and IL-1β in the skin. The improvement in imiquimod-induced psoriasis by Andro was not observed in microtubule-associated protein 1 light chain 3 beta (MAP1LC3B) knockout mice. Furthermore, Andro inhibited mRNA expressions of IL-23, IL-6 and IL-1β but not CD80 and CD86 in bone-marrow derived dendritic cells (BMDCs) treated with lipopolysaccharide (LPS) in a MAP1LC3B-dependent manner. In addition, Andro inhibited imiquimod-induced mRNA expressions of IL-23, IL-6, IL-1β, CD80 and CD86 in BMDCs from mice. Interestingly, Andro induced a degradation of myeloid differentiation factor 88 (MyD88) and blocked the recruitment of TNF receptor-associated factor 6 (TRAF6) to MyD88 upon LPS stimulation in BMDCs from mice. Blockade of autophagic proteolysis using NH4Cl or MAP1LC3B(-/-) BMDCs abolished the Andro-induced MyD88 degradation. In conclusion, Andro controls activation of MyD88-dependent cytokines and alleviates psoriasis in mice via inducing autophagic proteolysis of MyD88, which could be a novel strategy to treat psoriasis. Copyright © 2016 Elsevier Inc. All rights reserved.

  11. 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.

  12. 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

  13. 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...

  14. Fluoxetine induces autophagic cell death via eEF2K-AMPK-mTOR-ULK complex axis in triple negative breast cancer.

    Science.gov (United States)

    Sun, Dejuan; Zhu, Lingjuan; Zhao, Yuqian; Jiang, Yingnan; Chen, Lixia; Yu, Yang; Ouyang, Liang

    2018-04-01

    Triple negative breast cancer (TNBC) is a complex and intrinsically aggressive tumour with poor prognosis, and the discovery of targeted small-molecule drugs for TNBC treatment still remains in its infancy. In this study, we aimed to discover a small-molecule agent for TNBC treatment and illuminate its potential mechanisms. Cell viability was detected by using methylthiazoltetrazolium (MTT) assay. Electron microscopy, GFP-LC3 transfection, monodansylcadaverine staining and apoptosis assay were performed to determine Fluoxetine-induced autophagy and apoptosis. Western blotting and siRNA transfection were carried out to investigate the mechanisms of Fluoxetine-induced autophagy. iTRAQ-based proteomics analysis was used to explore the underlying mechanisms. We have demonstrated that Fluoxetine had remarkable anti-proliferative activities and induced autophagic cell death in MDA-MB-231 and MDA-MB-436 cells. The mechanism for Fluoxetine-induced autophagic cell death was associated with inhibition of eEF2K and activation of AMPK-mTOR-ULK complex axis. Further iTRAQ-based proteomics and network analyses revealed that Fluoxetine-induced mechanism was involved in BIRC6, BNIP1, SNAP29 and Bif-1. These results demonstrate that Fluoxetine induces apoptosis and autophagic cell death in TNBC, which will hold a promise for the future TNBC therapy. © 2017 John Wiley & Sons Ltd.

  15. AoAtg26, a putative sterol glucosyltransferase, is required for autophagic degradation of peroxisomes, mitochondria, and nuclei in the filamentous fungus Aspergillus oryzae.

    Science.gov (United States)

    Kikuma, Takashi; Tadokoro, Takayuki; Maruyama, Jun-Ichi; Kitamoto, Katsuhiko

    2017-02-01

    Autophagy is a conserved process in eukaryotic cells for degradation of cellular proteins and organelles. In filamentous fungi, autophagic degradation of organelles such as peroxisomes, mitochondria, and nuclei occurs in basal cells after the prolonged culture, but its mechanism is not well understood. Here, we functionally analyzed the filamentous fungus Aspergillus oryzae AoAtg26, an ortholog of the sterol glucosyltransferase PpAtg26 involved in pexophagy in the yeast Pichia pastoris. Deletion of Aoatg26 caused a severe decrease in conidiation and aerial hyphae formation, which is typically observed in the autophagy-deficient A. oryzae strains. In addition, cup-shaped AoAtg8-positive membrane structures were accumulated in the Aoatg26 deletion strain, indicating that autophagic process is impaired. Indeed, the Aoatg26 deletion strain was defective in the degradation of peroxisomes, mitochondria, and nuclei. Taken together, AoAtg26 plays an important role for autophagic degradation of organelles in A. oryzae, which may physiologically contribute to the differentiation in filamentous fungi.

  16. 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

  17. 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.

  18. Functional drug screening reveals anticonvulsants as enhancers of mTOR-independent autophagic killing of Mycobacterium tuberculosis through inositol depletion.

    Science.gov (United States)

    Schiebler, Mark; Brown, Karen; Hegyi, Krisztina; Newton, Sandra M; Renna, Maurizio; Hepburn, Lucy; Klapholz, Catherine; Coulter, Sarah; Obregón-Henao, Andres; Henao Tamayo, Marcela; Basaraba, Randall; Kampmann, Beate; Henry, Katherine M; Burgon, Joseph; Renshaw, Stephen A; Fleming, Angeleen; Kay, Robert R; Anderson, Karen E; Hawkins, Phillip T; Ordway, Diane J; Rubinsztein, David C; Floto, Rodrigo Andres

    2015-02-01

    Mycobacterium tuberculosis (MTB) remains a major challenge to global health made worse by the spread of multidrug resistance. We therefore examined whether stimulating intracellular killing of mycobacteria through pharmacological enhancement of macroautophagy might provide a novel therapeutic strategy. Despite the resistance of MTB to killing by basal autophagy, cell-based screening of FDA-approved drugs revealed two anticonvulsants, carbamazepine and valproic acid, that were able to stimulate autophagic killing of intracellular M. tuberculosis within primary human macrophages at concentrations achievable in humans. Using a zebrafish model, we show that carbamazepine can stimulate autophagy in vivo and enhance clearance of M. marinum, while in mice infected with a highly virulent multidrug-resistant MTB strain, carbamazepine treatment reduced bacterial burden, improved lung pathology and stimulated adaptive immunity. We show that carbamazepine induces antimicrobial autophagy through a novel, evolutionarily conserved, mTOR-independent pathway controlled by cellular depletion of myo-inositol. While strain-specific differences in susceptibility to in vivo carbamazepine treatment may exist, autophagy enhancement by repurposed drugs provides an easily implementable potential therapy for the treatment of multidrug-resistant mycobacterial infection. © 2014 The Authors. Published under the terms of the CC BY 4.0 license.

  19. Cell survival under nutrient stress is dependent on metabolic conditions regulated by Akt and not by autophagic vacuoles.

    Science.gov (United States)

    Bruno, P; Calastretti, A; Priulla, M; Asnaghi, L; Scarlatti, F; Nicolin, A; Canti, G

    2007-10-01

    Akt activation assists tumor cell survival and promotes resistance to chemotherapy. Here we show that constitutively active Akt (CA-Akt) cells are highly sensitized to cell death induced by nutrient and growth factor deprivation, whereas dominant-negative Akt (DN-Akt) cells have a high rate of survival. The content of autophagosomes in starved CA-Akt cells was high, while DN-Akt cells expressed autophagic vacuoles constitutively, independently of nutrition conditions. Thus Akt down-regulation and downstream events can induce autophagosomes which were not directly determinants of cell death. Biochemical analysis in Akt-mutated cells show that (i) Akt and mTOR proteins were degraded more rapidly than the housekeeping proteins, (ii) mTOR phosphorylation at position Thr(2446) was relatively high in DN-Akt and low in CA-Akt cells, induced by starvation in mock cells only, which suggests reduced autoregulation of these pathways in Akt-mutated cells, (iii) both protein synthesis and protein degradation were significantly higher in starved CA-Akt cells than in starved DN-Akt cells or mock cells. In conclusion, constitutively active Akt, unable to control synthesis and wasting of proteins, accelerates the death of starved cells.

  20. 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.

  1. Megestrol acetate improves cardiac function in a model of cancer cachexia-induced cardiomyopathy by autophagic modulation.

    Science.gov (United States)

    Musolino, Vincenzo; Palus, Sandra; Tschirner, Anika; Drescher, Cathleen; Gliozzi, Micaela; Carresi, Cristina; Vitale, Cristiana; Muscoli, Carolina; Doehner, Wolfram; von Haehling, Stephan; Anker, Stefan D; Mollace, Vincenzo; Springer, Jochen

    2016-12-01

    Cachexia is a complex metabolic syndrome associated with cancer. One of the features of cachexia is the loss of muscle mass, characterized by an imbalance between protein synthesis and protein degradation. Muscle atrophy is caused by the hyperactivation of some of the main cellular catabolic pathways, including autophagy. Cachexia also affects the cardiac muscle. As a consequence of the atrophy of the heart, cardiac function is impaired and mortality is increased. Anti-cachectic therapy in patients with cancer cachexia is so far limited to nutritional support and anabolic steroids. The use of the appetite stimulant megestrol acetate (MA) has been discussed as a treatment for cachexia. In this study the effects of MA were tested in cachectic tumour-bearing rats (Yoshida AH-130 ascites hepatoma). Rats were treated daily with 100 mg/kg of MA or placebo starting one day after tumour inoculation, and for a period of 16 days. Body weight and body composition were assessed at baseline and at the end of the study. Cardiac function was analysed by echocardiography at baseline and at day 11. Locomotor activity and food intake were assessed before tumour inoculation and at day 11. Autophagic markers were assessed in gastrocnemius muscle and heart by western blot analysis. Treatment with 100 mg/kg/day MA significantly attenuated the loss of body weight (-9 ± 12%, P  cachexia-induced cardiomyopathy.

  2. 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 ...

  3. Autophagy plays an important role in Sunitinib-mediated cell death in H9c2 cardiac muscle cells

    International Nuclear Information System (INIS)

    Zhao Yuqin; Xue Tao; Yang Xiaochun; Zhu Hong; Ding Xiaofei; Lou Liming; Lu Wei; Yang Bo; He Qiaojun

    2010-01-01

    Sunitinib, which is a multitargeted tyrosine-kinase inhibitor, exhibits antiangiogenic and antitumor activity, and extends survival of patients with metastatic renal-cell carcinoma (mRCC) and gastrointestinal stromal tumors (GIST). This molecule has also been reported to be associated with cardiotoxicity at a high frequency, but the mechanism is still unknown. In the present study, we observed that Sunitinib showed high anti-proliferative effect on H9c2 cardiac muscle cells measured by PI staining and the MTT assay. But apoptotic markers (PARP cleavage, caspase 3 cleavage and chromatin condensation) were uniformly negative in H9c2 cells after Sunitinib treatment for 48 h, indicating that another cell death pathway may be involved in Sunitinib-induced cardiotoxicity. Here we found Sunitinib dramatically increased autophagic flux in H9c2 cells. Acidic vesicle fluorescence and high expression of LC3-II in H9c2 cells identified autophagy as a Sunitinib-induced process that might be associated with cytotoxicity. Furthermore, knocking down Beclin 1 by RNA-interference to block autophagy in H9c2 cells revealed that the death rate was decreased when treated with Sunitinib in comparison to control cells. These results confirmed that autophagy plays an important role in Sunitinib-mediated H9c2 cells cytotoxicity. Taken together, the data presented here strongly suggest that autophagy is associated with Sunitinib-induced cardiotoxicity, and that inhibition of autophagy constitutes a viable strategy for reducing Sunitinib-induced cardiomyocyte death thereby alleviating Sunitinib cardiotoxicity.

  4. Primary cosmic ray flux

    Energy Technology Data Exchange (ETDEWEB)

    Stanev, Todor

    2001-05-01

    We discuss the primary cosmic ray flux from the point of view of particle interactions and production of atmospheric neutrinos. The overall normalization of the cosmic ray flux and its time variations and site dependence are major ingredients of the atmospheric neutrino predictions and the basis for the derivation of the neutrino oscillation parameters.

  5. Flux cutting in superconductors

    International Nuclear Information System (INIS)

    Campbell, A M

    2011-01-01

    This paper describes experiments and theories of flux cutting in superconductors. The use of the flux line picture in free space is discussed. In superconductors cutting can either be by means of flux at an angle to other layers of flux, as in longitudinal current experiments, or due to shearing of the vortex lattice as in grain boundaries in YBCO. Experiments on longitudinal currents can be interpreted in terms of flux rings penetrating axial lines. More physical models of flux cutting are discussed but all predict much larger flux cutting forces than are observed. Also, cutting is occurring at angles between vortices of about one millidegree which is hard to explain. The double critical state model and its developments are discussed in relation to experiments on crossed and rotating fields. A new experiment suggested by Clem gives more direct information. It shows that an elliptical yield surface of the critical state works well, but none of the theoretical proposals for determining the direction of E are universally applicable. It appears that, as soon as any flux flow takes place, cutting also occurs. The conclusion is that new theories are required. (perspective)

  6. 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.

  7. An autophagic mechanism is involved in the 6-hydroxydopamine-induced neurotoxicity in vivo.

    Science.gov (United States)

    He, Xin; Yuan, Wei; Li, Zijian; Feng, Juan

    2017-10-05

    6-hydroxydopamine (6-OHDA) is one of the most common agents for modeling dopaminergic neuron degeneration in Parkinson's disease (PD). So far, the role of autophagy in 6-OHDA-induced neurotoxicity remains controversial and most evidence is collected from in vitro studies. In this study, we determined the role of autophagy activation in 6-OHDA-induced neurotoxicity in a rat model of PD. Following 6-OHDA treatment, we observed a concomitant activation of autophagy and apoptosis. To further explore the interaction between autophagy and apoptosis induced by 6-OHDA, autophagy inhibitor 3-methylademine (3-MA) or cysteine protease inhibitor Z-FA-fmk was applied. We found that both 3-MA and Z-FA-fmk could not only exert immediate protection against 6-OHDA-induced neuronal apoptosis, but also prevent dopaminergic neuron loss in the long-term, which was related to reduced autophagosome formation. Furthermore, by monitoring the sequential changes of mTOR-related signaling pathways, we found that reactive oxygen species (ROS)-mediated AKT/AMPK-mTOR signaling pathway participated in but was not the initial cause of autophagy activation by 6-OHDA. Collectively, our data suggest that 6-OHDA-induced autophagy activation contributes to its neurotoxicity and targeting autophagy activation or cysteine proteases could be promising for developing neuroprotective agents for PD. Copyright © 2017 Elsevier B.V. All rights reserved.

  8. Heat flux microsensor measurements

    Science.gov (United States)

    Terrell, J. P.; Hager, J. M.; Onishi, S.; Diller, T. E.

    1992-01-01

    A thin-film heat flux sensor has been fabricated on a stainless steel substrate. The thermocouple elements of the heat flux sensor were nickel and nichrome, and the temperature resistance sensor was platinum. The completed heat flux microsensor was calibrated at the AEDC radiation facility. The gage output was linear with heat flux with no apparent temperature effect on sensitivity. The gage was used for heat flux measurements at the NASA Langley Vitiated Air Test Facility. Vitiated air was expanded to Mach 3.0 and hydrogen fuel was injected. Measurements were made on the wall of a diverging duct downstream of the injector during all stages of the hydrogen combustion tests. Because the wall and the gage were not actively cooled, the wall temperature reached over 1000 C (1900 F) during the most severe test.

  9. Small-Molecule Sigma1 Modulator Induces Autophagic Degradation of PD-L1.

    Science.gov (United States)

    Maher, Christina M; Thomas, Jeffrey D; Haas, Derick A; Longen, Charles G; Oyer, Halley M; Tong, Jane Y; Kim, Felix J

    2018-02-01

    Emerging evidence suggests that Sigma1 ( SIGMAR1 , also known as sigma-1 receptor) is a unique ligand-regulated integral membrane scaffolding protein that contributes to cellular protein and lipid homeostasis. Previously, we demonstrated that some small-molecule modulators of Sigma1 alter endoplasmic reticulum (ER)-associated protein homeostasis pathways in cancer cells, including the unfolded protein response and autophagy. Programmed death-ligand 1 (PD-L1) is a type I integral membrane glycoprotein that is cotranslationally inserted into the ER and is processed and transported through the secretory pathway. Once at the surface of cancer cells, PD-L1 acts as a T-cell inhibitory checkpoint molecule and suppresses antitumor immunity. Here, we demonstrate that in Sigma1-expressing triple-negative breast and androgen-independent prostate cancer cells, PD-L1 protein levels were suppressed by RNAi knockdown of Sigma1 and by small-molecule inhibition of Sigma1. Sigma1-mediated action was confirmed by pharmacologic competition between Sigma1-selective inhibitor and activator ligands. When administered alone, the Sigma1 inhibitor decreased cell surface PD-L1 expression and suppressed functional interaction of PD-1 and PD-L1 in a coculture of T cells and cancer cells. Conversely, the Sigma1 activator increased PD-L1 cell surface expression, demonstrating the ability to positively and negatively modulate Sigma1 associated PD-L1 processing. We discovered that the Sigma1 inhibitor induced degradation of PD-L1 via autophagy, by a mechanism distinct from bulk macroautophagy or general ER stress-associated autophagy. Finally, the Sigma1 inhibitor suppressed IFNγ-induced PD-L1. Our data demonstrate that small-molecule Sigma1 modulators can be used to regulate PD-L1 in cancer cells and trigger its degradation by selective autophagy. Implications: Sigma1 modulators sequester and eliminate PD-L1 by autophagy, thus preventing functional PD-L1 expression at the cell surface. This

  10. Intercultural Mediation

    OpenAIRE

    Dragos Marian Radulescu; Denisa Mitrut

    2012-01-01

    The Intercultural Mediator facilitates exchanges between people of different socio-cultural backgrounds and acts as a bridge between immigrants and national and local associations, health organizations, services and offices in order to foster integration of every single individual. As the use mediation increases, mediators are more likely to be involved in cross-cultural mediation, but only the best mediators have the opportunity to mediate cross border business disputes or international poli...

  11. Continuous magnetic flux pump

    Science.gov (United States)

    Hildebrandt, A. F.; Elleman, D. D.; Whitmore, F. C. (Inventor)

    1966-01-01

    A method and means for altering the intensity of a magnetic field by transposing flux from one location to the location desired fro the magnetic field are examined. The device described includes a pair of communicating cavities formed in a block of superconducting material, is dimensioned to be insertable into one of the cavities and to substantially fill the cavity. Magnetic flux is first trapped in the cavities by establishing a magnetic field while the superconducting material is above the critical temperature at which it goes superconducting. Thereafter, the temperature of the material is reduced below the critical value, and then the exciting magnetic field may be removed. By varying the ratios of the areas of the two cavities, it is possible to produce a field having much greater flux density in the second, smaller cavity, into which the flux transposed.

  12. 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

  13. Flux shunts for undulators

    International Nuclear Information System (INIS)

    Hoyer, E.; Chin, J.; Hassenzahl, W.V.

    1993-05-01

    Undulators for high-performance applications in synchrotron-radiation sources and periodic magnetic structures for free-electron lasers have stringent requirements on the curvature of the electron's average trajectory. Undulators using the permanent magnet hybrid configuration often have fields in their central region that produce a curved trajectory caused by local, ambient magnetic fields such as those of the earth. The 4.6 m long Advanced Light Source (ALS) undulators use flux shunts to reduce this effect. These flux shunts are magnetic linkages of very high permeability material connecting the two steel beams that support the magnetic structures. The shunts reduce the scalar potential difference between the supporting beams and carry substantial flux that would normally appear in the undulator gap. Magnetic design, mechanical configuration of the flux shunts and magnetic measurements of their effect on the ALS undulators are described

  14. 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.)

  15. 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.)

  16. S1P in HDL promotes interaction between SR-BI and S1PR1 and activates S1PR1-mediated biological functions: calcium flux and S1PR1 internalization[S

    Science.gov (United States)

    Lee, Mi-Hye; Appleton, Kathryn M.; El-Shewy, Hesham M.; Sorci-Thomas, Mary G.; Thomas, Michael J.; Lopes-Virella, Maria F.; Luttrell, Louis M.; Hammad, Samar M.; Klein, Richard L.

    2017-01-01

    HDL normally transports about 50–70% of plasma sphingosine 1-phosphate (S1P), and the S1P in HDL reportedly mediates several HDL-associated biological effects and signaling pathways. The HDL receptor, SR-BI, as well as the cell surface receptors for S1P (S1PRs) may be involved partially and/or completely in these HDL-induced processes. Here we investigate the nature of the HDL-stimulated interaction between the HDL receptor, SR-BI, and S1PR1 using a protein-fragment complementation assay and confocal microscopy. In both primary rat aortic vascular smooth muscle cells and HEK293 cells, the S1P content in HDL particles increased intracellular calcium concentration, which was mediated by S1PR1. Mechanistic studies performed in HEK293 cells showed that incubation of cells with HDL led to an increase in the physical interaction between the SR-BI and S1PR1 receptors that mainly occurred on the plasma membrane. Model recombinant HDL (rHDL) particles formed in vitro with S1P incorporated into the particle initiated the internalization of S1PR1, whereas rHDL without supplemented S1P did not, suggesting that S1P transported in HDL can selectively activate S1PR1. In conclusion, these data suggest that S1P in HDL stimulates the transient interaction between SR-BI and S1PRs that can activate S1PRs and induce an elevation in intracellular calcium concentration. PMID:27881715

  17. S1P in HDL promotes interaction between SR-BI and S1PR1 and activates S1PR1-mediated biological functions: calcium flux and S1PR1 internalization.

    Science.gov (United States)

    Lee, Mi-Hye; Appleton, Kathryn M; El-Shewy, Hesham M; Sorci-Thomas, Mary G; Thomas, Michael J; Lopes-Virella, Maria F; Luttrell, Louis M; Hammad, Samar M; Klein, Richard L

    2017-02-01

    HDL normally transports about 50-70% of plasma sphingosine 1-phosphate (S1P), and the S1P in HDL reportedly mediates several HDL-associated biological effects and signaling pathways. The HDL receptor, SR-BI, as well as the cell surface receptors for S1P (S1PRs) may be involved partially and/or completely in these HDL-induced processes. Here we investigate the nature of the HDL-stimulated interaction between the HDL receptor, SR-BI, and S1PR1 using a protein-fragment complementation assay and confocal microscopy. In both primary rat aortic vascular smooth muscle cells and HEK293 cells, the S1P content in HDL particles increased intracellular calcium concentration, which was mediated by S1PR1. Mechanistic studies performed in HEK293 cells showed that incubation of cells with HDL led to an increase in the physical interaction between the SR-BI and S1PR1 receptors that mainly occurred on the plasma membrane. Model recombinant HDL (rHDL) particles formed in vitro with S1P incorporated into the particle initiated the internalization of S1PR1, whereas rHDL without supplemented S1P did not, suggesting that S1P transported in HDL can selectively activate S1PR1. In conclusion, these data suggest that S1P in HDL stimulates the transient interaction between SR-BI and S1PRs that can activate S1PRs and induce an elevation in intracellular calcium concentration.

  18. The Open Flux Problem

    Science.gov (United States)

    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.

    2017-10-01

    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.

  19. The Open Flux Problem

    Energy Technology Data Exchange (ETDEWEB)

    Linker, J. A.; Caplan, R. M.; Downs, C.; Riley, P.; Mikic, Z.; Lionello, R. [Predictive Science Inc., 9990 Mesa Rim Road, Suite 170, San Diego, CA 92121 (United States); Henney, C. J. [Air Force Research Lab/Space Vehicles Directorate, 3550 Aberdeen Avenue SE, Kirtland AFB, NM (United States); Arge, C. N. [Science and Exploration Directorate, NASA/GSFC, Greenbelt, MD 20771 (United States); Liu, Y. [W. W. Hansen Experimental Physics Laboratory, Stanford University, Stanford, CA 94305 (United States); Derosa, M. L. [Lockheed Martin Solar and Astrophysics Laboratory, 3251 Hanover Street B/252, Palo Alto, CA 94304 (United States); Yeates, A. [Department of Mathematical Sciences, Durham University, Durham, DH1 3LE (United Kingdom); Owens, M. J., E-mail: linkerj@predsci.com [Space and Atmospheric Electricity Group, Department of Meteorology, University of Reading, Earley Gate, P.O. Box 243, Reading RG6 6BB (United Kingdom)

    2017-10-10

    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.

  20. Meromorphic flux compactification

    Energy Technology Data Exchange (ETDEWEB)

    Damian, Cesar [Departamento de Ingeniería Mecánica, Universidad de Guanajuato,Carretera Salamanca-Valle de Santiago Km 3.5+1.8 Comunidad de Palo Blanco,Salamanca (Mexico); Loaiza-Brito, Oscar [Departamento de Física, Universidad de Guanajuato,Loma del Bosque No. 103 Col. Lomas del Campestre C.P 37150 León, Guanajuato (Mexico)

    2017-04-26

    We present exact solutions of four-dimensional Einstein’s equations related to Minkoswki vacuum constructed from Type IIB string theory with non-trivial fluxes. Following https://www.doi.org/10.1007/JHEP02(2015)187; https://www.doi.org/10.1007/JHEP02(2015)188 we study a non-trivial flux compactification on a fibered product by a four-dimensional torus and a two-dimensional sphere punctured by 5- and 7-branes. By considering only 3-form fluxes and the dilaton, as functions on the internal sphere coordinates, we show that these solutions correspond to a family of supersymmetric solutions constructed by the use of G-theory. Meromorphicity on functions constructed in terms of fluxes and warping factors guarantees that flux and 5-brane contributions to the scalar curvature vanish while fulfilling stringent constraints as tadpole cancelation and Bianchi identities. Different Einstein’s solutions are shown to be related by U-dualities. We present three supersymmetric non-trivial Minkowski vacuum solutions and compute the corresponding soft terms. We also construct a non-supersymmetric solution and study its stability.

  1. Meromorphic flux compactification

    International Nuclear Information System (INIS)

    Damian, Cesar; Loaiza-Brito, Oscar

    2017-01-01

    We present exact solutions of four-dimensional Einstein’s equations related to Minkoswki vacuum constructed from Type IIB string theory with non-trivial fluxes. Following https://www.doi.org/10.1007/JHEP02(2015)187; https://www.doi.org/10.1007/JHEP02(2015)188 we study a non-trivial flux compactification on a fibered product by a four-dimensional torus and a two-dimensional sphere punctured by 5- and 7-branes. By considering only 3-form fluxes and the dilaton, as functions on the internal sphere coordinates, we show that these solutions correspond to a family of supersymmetric solutions constructed by the use of G-theory. Meromorphicity on functions constructed in terms of fluxes and warping factors guarantees that flux and 5-brane contributions to the scalar curvature vanish while fulfilling stringent constraints as tadpole cancelation and Bianchi identities. Different Einstein’s solutions are shown to be related by U-dualities. We present three supersymmetric non-trivial Minkowski vacuum solutions and compute the corresponding soft terms. We also construct a non-supersymmetric solution and study its stability.

  2. Flux Pinning in Superconductors

    CERN Document Server

    Matsushita, Teruo

    2007-01-01

    The book covers the flux pinning mechanisms and properties and the electromagnetic phenomena caused by the flux pinning common for metallic, high-Tc and MgB2 superconductors. The condensation energy interaction known for normal precipitates or grain boundaries and the kinetic energy interaction proposed for artificial Nb pins in Nb-Ti, etc., are introduced for the pinning mechanism. Summation theories to derive the critical current density are discussed in detail. Irreversible magnetization and AC loss caused by the flux pinning are also discussed. The loss originally stems from the ohmic dissipation of normal electrons in the normal core driven by the electric field induced by the flux motion. The readers will learn why the resultant loss is of hysteresis type in spite of such mechanism. The influence of the flux pinning on the vortex phase diagram in high Tc superconductors is discussed, and the dependencies of the irreversibility field are also described on other quantities such as anisotropy of supercondu...

  3. 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.

  4. 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

  5. Autophagy fails to prevent glucose deprivation/glucose reintroduction-induced neuronal death due to calpain-mediated lysosomal dysfunction in cortical neurons.

    Science.gov (United States)

    Gerónimo-Olvera, Cristian; Montiel, Teresa; Rincon-Heredia, Ruth; Castro-Obregón, Susana; Massieu, Lourdes

    2017-06-29

    Autophagy is triggered during nutrient and energy deprivation in a variety of cells as a homeostatic response to metabolic stress. In the CNS, deficient autophagy has been implicated in neurodegenerative diseases and ischemic brain injury. However, its role in hypoglycemic damage is poorly understood and the dynamics of autophagy during the hypoglycemic and the glucose reperfusion periods, has not been fully described. In the present study, we analyzed the changes in the content of the autophagy proteins BECN1, LC3-II and p62/SQSTM1 by western blot, and autophagosome formation was followed through time-lapse experiments, during glucose deprivation (GD) and glucose reintroduction (GR) in cortical cultures. According to the results, autophagosome formation rapidly increased during GD, and was followed by an active autophagic flux early after glucose replenishment. However, cells progressively died during GR and autophagy inhibition reduced neuronal death. Neurons undergoing apoptosis during GR did not form autophagosomes, while those surviving up to late GR showed autophagosomes. Calpain activity strongly increased during GR and remained elevated during progressive neuronal death. Its activation led to the cleavage of LAMP2 resulting in lysosome membrane permeabilization (LMP) and release of cathepsin B to the cytosol. Calpain inhibition prevented LMP and increased the number of neurons containing lysosomes and autophagosomes increasing cell viability. Taken together, the present results suggest that calpain-mediated lysosome dysfunction during GR turns an adaptive autophagy response to energy stress into a defective autophagy pathway, which contributes to neuronal death. In these conditions, autophagy inhibition results in the improvement of cell survival.

  6. Neutron flux monitoring device

    International Nuclear Information System (INIS)

    Goto, Yasushi; Mitsubori, Minehisa; Ohashi, Kazunori.

    1997-01-01

    The present invention provides a neutron flux monitoring device for preventing occurrence of erroneous reactor scram caused by the elevation of the indication of a start region monitor (SRM) due to a factor different from actual increase of neutron fluxes. Namely, judgement based on measured values obtained by a pulse counting method and a judgment based on measured values obtained by a Cambel method are combined. A logic of switching neutron flux measuring method to be used for monitoring, namely, switching to an intermediate region when both of the judgements are valid is adopted. Then, even if the indication value is elevated based on the Cambel method with no increase of the counter rate in a neutron source region, the switching to the intermediate region is not conducted. As a result, erroneous reactor scram such as 'shorter reactor period' can be avoided. (I.S.)

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

    Directory of Open Access Journals (Sweden)

    María Belén Mestre

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

  9. 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.

  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. 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.

  12. Autophagic cell death induced by reactive oxygen species is involved in hyperthermic sensitization to ionizing radiation in human hepatocellular carcinoma cells.

    Science.gov (United States)

    Yuan, Guang-Jin; Deng, Jun-Jian; Cao, De-Dong; Shi, Lei; Chen, Xin; Lei, Jin-Ju; Xu, Xi-Ming

    2017-08-14

    To investigate whether autophagic cell death is involved in hyperthermic sensitization to ionizing radiation in human hepatocellular carcinoma cells, and to explore the underlying mechanism. Human hepatocellular carcinoma cells were treated with hyperthermia and ionizing radiation. MTT and clonogenic assays were performed to determine cell survival. Cell autophagy was detected using acridine orange staining and flow cytometric analysis, and the expression of autophagy-associated proteins, LC3 and p62, was determined by Western blot analysis. Intracellular reactive oxygen species (ROS) were quantified using the fluorescent probe DCFH-DA. Treatment with hyperthermia and ionizing radiation significantly decreased cell viability and surviving fraction as compared with hyperthermia or ionizing radiation alone. Cell autophagy was significantly increased after ionizing radiation combined with hyperthermia treatment, as evidenced by increased formation of acidic vesicular organelles, increased expression of LC3II and decreased expression of p62. Intracellular ROS were also increased after combined treatment with hyperthermia and ionizing radiation. Pretreatment with N-acetylcysteine, an ROS scavenger, markedly inhibited the cytotoxicity and cell autophagy induced by hyperthermia and ionizing radiation. Autophagic cell death is involved in hyperthermic sensitization of cancer cells to ionizing radiation, and its induction may be due to the increased intracellular ROS.

  13. 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.

  14. Carbon and nitrogen depletion-induced nucleophagy and selective autophagic sequestration of a whole nucleus in multinucleate cells of the filamentous fungus Aspergillus oryzae.

    Science.gov (United States)

    Kikuma, Takashi; Mitani, Takahiro; Kohara, Takahiro; Maruyama, Jun-Ichi; Kitamoto, Katsuhiko

    2017-05-12

    Autophagy is a conserved cellular degradation process in eukaryotes, in which cytoplasmic components and organelles are digested in vacuoles/lysosomes. Recently, autophagic degradation of nuclear materials, termed "nucleophagy", has been reported. In the multinucleate filamentous fungus Aspergillus oryzae, a whole nucleus is degraded by nucleophagy after prolonged culture. While developing an H2B-EGFP processing assay for the evaluation of nucleophagy in A. oryzae, we found that nucleophagy is efficiently induced by carbon or nitrogen depletion. Microscopic observations in a carbon depletion condition clearly demonstrated that autophagosomes selectively sequester a particular nucleus, despite the presence of multiple nuclei in the same cell. Furthermore, AoNsp1, the A. oryzae homolog of the yeast nucleoporin Nsp1p, mainly localized at the nuclear periphery, but its localization was restricted to the opposite side of the autophagosome being formed around a nucleus. In contrast, the perinuclear ER visualized with the calnexin AoClxA was not morphologically affected by nucleophagy. The findings of nucleophagy-inducing conditions enabled us to characterize the morphological process of autophagic degradation of a whole nucleus in multinucleate cells.

  15. Atmospheric neutrino fluxes

    International Nuclear Information System (INIS)

    Honda, M.; Kasahara, K.; Hidaka, K.; Midorikawa, S.

    1990-02-01

    A detailed Monte Carlo simulation of neutrino fluxes of atmospheric origin is made taking into account the muon polarization effect on neutrinos from muon decay. We calculate the fluxes with energies above 3 MeV for future experiments. There still remains a significant discrepancy between the calculated (ν e +antiν e )/(ν μ +antiν μ ) ratio and that observed by the Kamiokande group. However, the ratio evaluated at the Frejus site shows a good agreement with the data. (author)

  16. 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.

  17. Mediation Analysis with Multiple Mediators.

    Science.gov (United States)

    VanderWeele, T J; Vansteelandt, S

    2014-01-01

    Recent advances in the causal inference literature on mediation have extended traditional approaches to direct and indirect effects to settings that allow for interactions and non-linearities. In this paper, these approaches from causal inference are further extended to settings in which multiple mediators may be of interest. Two analytic approaches, one based on regression and one based on weighting are proposed to estimate the effect mediated through multiple mediators and the effects through other pathways. The approaches proposed here accommodate exposure-mediator interactions and, to a certain extent, mediator-mediator interactions as well. The methods handle binary or continuous mediators and binary, continuous or count outcomes. When the mediators affect one another, the strategy of trying to assess direct and indirect effects one mediator at a time will in general fail; the approach given in this paper can still be used. A characterization is moreover given as to when the sum of the mediated effects for multiple mediators considered separately will be equal to the mediated effect of all of the mediators considered jointly. The approach proposed in this paper is robust to unmeasured common causes of two or more mediators.

  18. 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

  19. 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,...

  20. Flux vacua and supermanifolds

    Energy Technology Data Exchange (ETDEWEB)

    Grassi, Pietro Antonio [CERN, Theory Unit, CH-1211 Geneva, 23 (Switzerland); Marescotti, Matteo [Dipartimento di Fisica Teorica, Universita di Torino, Via Giuria 1, I-10125, Turin (Italy)

    2007-01-15

    As been recently pointed out, physically relevant models derived from string theory require the presence of non-vanishing form fluxes besides the usual geometrical constraints. In the case of NS-NS fluxes, the Generalized Complex Geometry encodes these informations in a beautiful geometrical structure. On the other hand, the R-R fluxes call for supergeometry as the underlying mathematical framework. In this context, we analyze the possibility of constructing interesting supermanifolds recasting the geometrical data and RR fluxes. To characterize these supermanifolds we have been guided by the fact topological strings on supermanifolds require the super-Ricci flatness of the target space. This can be achieved by adding to a given bosonic manifold enough anticommuting coordinates and new constraints on the bosonic sub-manifold. We study these constraints at the linear and non-linear level for a pure geometrical setting and in the presence of p-form field strengths. We find that certain spaces admit several super-extensions and we give a parameterization in a simple case of d bosonic coordinates and two fermionic coordinates. In addition, we comment on the role of the RR field in the construction of the super-metric. We give several examples based on supergroup manifolds and coset supermanifolds.

  1. Flux vacua and supermanifolds

    International Nuclear Information System (INIS)

    Grassi, Pietro Antonio; Marescotti, Matteo

    2007-01-01

    As been recently pointed out, physically relevant models derived from string theory require the presence of non-vanishing form fluxes besides the usual geometrical constraints. In the case of NS-NS fluxes, the Generalized Complex Geometry encodes these informations in a beautiful geometrical structure. On the other hand, the R-R fluxes call for supergeometry as the underlying mathematical framework. In this context, we analyze the possibility of constructing interesting supermanifolds recasting the geometrical data and RR fluxes. To characterize these supermanifolds we have been guided by the fact topological strings on supermanifolds require the super-Ricci flatness of the target space. This can be achieved by adding to a given bosonic manifold enough anticommuting coordinates and new constraints on the bosonic sub-manifold. We study these constraints at the linear and non-linear level for a pure geometrical setting and in the presence of p-form field strengths. We find that certain spaces admit several super-extensions and we give a parameterization in a simple case of d bosonic coordinates and two fermionic coordinates. In addition, we comment on the role of the RR field in the construction of the super-metric. We give several examples based on supergroup manifolds and coset supermanifolds

  2. Atmospheric neutrino fluxes

    International Nuclear Information System (INIS)

    Perkins, D.H.

    1984-01-01

    The atmospheric neutrino fluxes, which are responsible for the main background in proton decay experiments, have been calculated by two independent methods. There are discrepancies between the two sets of results regarding latitude effects and up-down asymmetries, especially for neutrino energies Esub(ν) < 1 GeV. (author)

  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. Apigenin potentiates the antitumor activity of 5-FU on solid Ehrlich carcinoma: Crosstalk between apoptotic and JNK-mediated autophagic cell death platforms

    Energy Technology Data Exchange (ETDEWEB)

    Gaballah, Hanaa H., E-mail: hanaahibishy@hotmail.com [Medical Biochemistry and Molecular Biology Department, Faculty of Medicine, Tanta University, Tanta, 3111 (Egypt); Gaber, Rasha A. [Medical Biochemistry and Molecular Biology Department, Faculty of Medicine, Tanta University, Tanta, 3111 (Egypt); Mohamed, Darin A. [Histopathology Department, Faculty of Medicine, Tanta University, Tanta, 3111 (Egypt)

    2017-02-01

    Background: Although 5- Fluorouracil (5-FU) has exhibited effectiveness against cancer, novel therapeutic strategies are needed to enhance its antitumor efficiency and modulate its cytotoxity. Apigenin, a flavonoid present in fruits and vegetables, is a potent dietary phytochemical effective in cancer chemoprevention. Aim: This study was undertaken to investigate the potential synergistic antitumor activity of apigenin and 5-FU on Solid Ehrlich carcinoma (SEC). Methods: Eighty Swiss albino male mice were divided into four equal groups: vehicle treated control SEC, SEC + 5-FU, SEC + apigenin, SEC + 5-FU + apigenin. Beclin-1 and caspases 3, 9 and JNK activities were estimated by ELISA; mRNA expression levels of the antiapoptotic gene Mcl-1 were estimated using quantitative real-time RT-PCR, while tissue malondialdehyde (MDA), glutathione peroxidase and total antioxidant capacity were evaluated spectrophotometrically. A part of the tumor was examined for histopathological and Ki-67 immunohistochemistry analysis. Results: 5-FU and/or apigenin caused significant increase in tissue levels of Beclin-1, caspases 3, 9 and JNK activities, MDA with significant decrease in tumor volume, Mcl-1expression, tissue glutathione peroxidase and total antioxidant capacity and alleviated the histopathological changes with significant decrease of Ki-67 proliferation index compared to vehicle treated SEC control group. In conclusion: The combination of 5-FU and apigenin had a greater effect than each of 5-FU or apigenin alone against solid Ehrlich carcinoma in mice. - Highlights: • Apigenin potentiated 5-FU cytotoxicity in EAC solid tumor models in vivo. • It acted via autophagy stimulation, downregulating MCL-1 and Ki-67 expression. • It caused JNK activation and ROS accumulation; resulted in tumor growth inhibition. • Apigenin can be used as a co-adjuvant agent in cancer therapy.

  5. 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

  6. Downregulation of protein kinase CK2 activity facilitates tumor necrosis factor-α-mediated chondrocyte death through apoptosis and autophagy.

    Directory of Open Access Journals (Sweden)

    Sung Won Lee

    Full Text Available Despite the numerous studies of protein kinase CK2, little progress has been made in understanding its function in chondrocyte death. Our previous study first demonstrated that CK2 is involved in apoptosis of rat articular chondrocytes. Recent studies have suggested that CK2 downregulation is associated with aging. Thus examining the involvement of CK2 downregulation in chondrocyte death is an urgently required task. We undertook this study to examine whether CK2 downregulation modulates chondrocyte death. We first measured CK2 activity in articular chondrocytes of 6-, 21- and 30-month-old rats. Noticeably, CK2 activity was downregulated in chondrocytes with advancing age. To build an in vitro experimental system for simulating tumor necrosis factor (TNF-α-induced cell death in aged chondrocytes with decreased CK2 activity, chondrocytes were co-treated with CK2 inhibitors and TNF-α. Viability assay demonstrated that CK2 inhibitors facilitated TNF-α-mediated chondrocyte death. Pulsed-field gel electrophoresis, nuclear staining, flow cytometry, TUNEL staining, confocal microscopy, western blot and transmission electron microscopy were conducted to assess cell death modes. The results of multiple assays showed that this cell death was mediated by apoptosis. Importantly, autophagy was also involved in this process, as supported by the appearance of a punctuate LC3 pattern and autophagic vacuoles. The inhibition of autophagy by silencing of autophage-related genes 5 and 7 as well as by 3-methyladenine treatment protected chondrocytes against cell death and caspase activation, indicating that autophagy led to the induction of apoptosis. Autophagic cells were observed in cartilage obtained from osteoarthritis (OA model rats and human OA patients. Our findings indicate that CK2 down regulation facilitates TNF-α-mediated chondrocyte death through apoptosis and autophagy. It should be clarified in the future if autophagy observed is a consequence

  7. Design of a flux buffer based on the flux shuttle

    International Nuclear Information System (INIS)

    Gershenson, M.

    1991-01-01

    This paper discusses the design considerations for a flux buffer based on the flux-shuttle concept. Particular attention is given to the issues of flux popping, stability of operation and saturation levels for a large input. Modulation techniques used in order to minimize 1/f noise, in addition to offsets are also analyzed. Advantages over conventional approaches using a SQUID for a flux buffer are discussed. Results of computer simulations are presented

  8. Lobotomy of flux compactifications

    Energy Technology Data Exchange (ETDEWEB)

    Dibitetto, Giuseppe [Institutionen för fysik och astronomi, University of Uppsala,Box 803, SE-751 08 Uppsala (Sweden); Guarino, Adolfo [Albert Einstein Center for Fundamental Physics, Institute for Theoretical Physics,Bern University, Sidlerstrasse 5, CH-3012 Bern (Switzerland); Roest, Diederik [Centre for Theoretical Physics, University of Groningen,Nijenborgh 4 9747 AG Groningen (Netherlands)

    2014-05-15

    We provide the dictionary between four-dimensional gauged supergravity and type II compactifications on T{sup 6} with metric and gauge fluxes in the absence of supersymmetry breaking sources, such as branes and orientifold planes. Secondly, we prove that there is a unique isotropic compactification allowing for critical points. It corresponds to a type IIA background given by a product of two 3-tori with SO(3) twists and results in a unique theory (gauging) with a non-semisimple gauge algebra. Besides the known four AdS solutions surviving the orientifold projection to N=4 induced by O6-planes, this theory contains a novel AdS solution that requires non-trivial orientifold-odd fluxes, hence being a genuine critical point of the N=8 theory.

  9. Mediation Analysis with Multiple Mediators

    OpenAIRE

    VanderWeele, T.J.; Vansteelandt, S.

    2014-01-01

    Recent advances in the causal inference literature on mediation have extended traditional approaches to direct and indirect effects to settings that allow for interactions and non-linearities. In this paper, these approaches from causal inference are further extended to settings in which multiple mediators may be of interest. Two analytic approaches, one based on regression and one based on weighting are proposed to estimate the effect mediated through multiple mediators and the effects throu...

  10. HDAC4 preserves skeletal muscle structure following long-term denervation by mediating distinct cellular responses.

    Science.gov (United States)

    Pigna, Eva; Renzini, Alessandra; Greco, Emanuela; Simonazzi, Elena; Fulle, Stefania; Mancinelli, Rosa; Moresi, Viviana; Adamo, Sergio

    2018-02-24

    Denervation triggers numerous molecular responses in skeletal muscle, including the activation of catabolic pathways and oxidative stress, leading to progressive muscle atrophy. Histone deacetylase 4 (HDAC4) mediates skeletal muscle response to denervation, suggesting the use of HDAC inhibitors as a therapeutic approach to neurogenic muscle atrophy. However, the effects of HDAC4 inhibition in skeletal muscle in response to long-term denervation have not been described yet. To further study HDAC4 functions in response to denervation, we analyzed mutant mice in which HDAC4 is specifically deleted in skeletal muscle. After an initial phase of resistance to neurogenic muscle atrophy, skeletal muscle with a deletion of HDAC4 lost structural integrity after 4 weeks of denervation. Deletion of HDAC4 impaired the activation of the ubiquitin-proteasome system, delayed the autophagic response, and dampened the OS response in skeletal muscle. Inhibition of the ubiquitin-proteasome system or the autophagic response, if on the one hand, conferred resistance to neurogenic muscle atrophy; on the other hand, induced loss of muscle integrity and inflammation in mice lacking HDAC4 in skeletal muscle. Moreover, treatment with the antioxidant drug Trolox prevented loss of muscle integrity and inflammation in in mice lacking HDAC4 in skeletal muscle, despite the resistance to neurogenic muscle atrophy. These results reveal new functions of HDAC4 in mediating skeletal muscle response to denervation and lead us to propose the combined use of HDAC inhibitors and antioxidant drugs to treat neurogenic muscle atrophy.

  11. 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.

  12. 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.

  13. 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

  14. 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.

  15. Critical heat flux evaluation

    International Nuclear Information System (INIS)

    Banner, D.

    1995-01-01

    Critical heat flux (CHF) is of importance for nuclear safety and represents the major limiting factors for reactor cores. Critical heat flux is caused by a sharp reduction in the heat transfer coefficient located at the outer surface of fuel rods. Safety requires that this phenomenon also called the boiling crisis should be precluded under nominal or incidental conditions (Class I and II events). CHF evaluation in reactor cores is basically a two-step approach. Fuel assemblies are first tested in experimental loops in order to determine CHF limits under various flow conditions. Then, core thermal-hydraulic calculations are performed for safety evaluation. The paper will go into more details about the boiling crisis in order to pinpoint complexity and lack of fundamental understanding in many areas. Experimental test sections needed to collect data over wide thermal-hydraulic and geometric ranges are described CHF safety margin evaluation in reactors cores is discussed by presenting how uncertainties are mentioned. From basic considerations to current concerns, the following topics are discussed; knowledge of the boiling crisis, CHF predictors, and advances thermal-hydraulic codes. (authors). 15 refs., 4 figs

  16. Neutron flux monitor

    International Nuclear Information System (INIS)

    Seki, Eiji; Tai, Ichiro.

    1984-01-01

    Purpose: To maintain the measuring accuracy and the reponse time within an allowable range in accordance with the change of neutron fluxes in a nuclear reactor pressure vessel. Constitution: Neutron fluxes within a nuclear reactor pressure vessel are detected by detectors, converted into pulse signals and amplified in a range switching amplifier. The amplified signals are further converted through an A/D converter and digital signals from the converter are subjected to a square operation in an square operation circuit. The output from the circuit is inputted into an integration circuit to selectively accumulate the constant of 1/2n, 1 - 1/2n (n is a positive integer) respectively for two continuing signals to perform weighing. Then, the addition is carried out to calculate the integrated value and the addition number is changed by the chane in the number n to vary the integrating time. The integrated value is inputted into a control circuit to control the value of n so that the fluctuation and the calculation time for the integrated value are within a predetermined range and, at the same time, the gain of the range switching amplifier is controlled. (Seki, T.)

  17. 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....

  18. 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.

  19. Fast Flux Test Facility

    International Nuclear Information System (INIS)

    Munn, W.I.

    1981-01-01

    The Fast Flux Test Facility (FFTF), located on the Hanford site a few miles north of Richland, Washington, is a major link in the chain of development required to sustain and advance Liquid Metal Fast Breeder Reactor (LMFBR) technology in the United States. This 400 MWt sodium cooled reactor is a three loop design, is operated by Westinghouse Hanford Company for the US Department of Energy, and is the largest research reactor of its kind in the world. The purpose of the facility is three-fold: (1) to provide a test bed for components, materials, and breeder reactor fuels which can significantly extend resource reserves; (2) to produce a complete body of base data for the use of liquid sodium in heat transfer systens; and (3) to demonstrate inherent safety characteristics of LMFBR designs

  20. 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

  1. Flux compactifications and generalized geometries

    Energy Technology Data Exchange (ETDEWEB)

    Grana, Mariana [Service de Physique Theorique, CEA/Saclay, 91191 Gif-sur-Yvette Cedex (France)

    2006-11-07

    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{sup 6} /(Z{sub 3} x Z{sub 3}) torus in IIA. We finish by studying the effective action and flux vacua for generalized geometries in the context of generalized complex geometry.

  2. 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....

  3. Salp contributions to vertical carbon flux in the Sargasso Sea

    Science.gov (United States)

    Stone, Joshua P.; Steinberg, Deborah K.

    2016-07-01

    We developed a one-dimensional model to estimate salp contributions to vertical carbon flux at the Bermuda Atlantic Time-series Study (BATS) site in the North Atlantic subtropical gyre for a 17-yr period (April 1994 to December 2011). We based the model parameters on published rates of salp physiology and experimentally determined sinking and decomposition rates of salp carcasses. Salp grazing was low during non-bloom conditions, but routinely exceeded 100% of chlorophyll standing stock and primary production during blooms. Fecal pellet production was the largest source of salp carbon flux (78% of total), followed by respiration below 200 m (19%), sinking of carcasses (3%), and DOC excretion below 200 m (salp-mediated carbon flux. Seasonally, salp flux was higher during spring-summer than fall-winter, due to seasonal changes in species composition and abundance. Salp carbon export to 200 m was on average 2.3 mg C m-2 d-1 across the entire time series. This is equivalent to 11% of the mean 200 m POC flux measured by sediment traps in the region. During years with significant salp blooms, however, annually-averaged salp carbon export was the equivalent of up to 60% of trap POC flux at 200 m. Salp carbon flux attenuated slowly, and at 3200 m the average modeled carbon from salps was 109% of the POC flux measured in sediment traps at that depth. Migratory and carcass carbon export pathways should also be considered (alongside fecal pellet flux) as facilitating carbon export to sequestration depths in future studies.

  4. 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.

  5. 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

  6. Tetraspanin CD63 Bridges Autophagic and Endosomal Processes To Regulate Exosomal Secretion and Intracellular Signaling of Epstein-Barr Virus LMP1

    Science.gov (United States)

    Hurwitz, Stephanie N; Cheerathodi, Mujeeb R; Nkosi, Dingani; York, Sara B; Meckes, David G

    2018-03-01

    The tetraspanin protein CD63 has been recently described as a key factor in extracellular vesicle (EV) production and endosomal cargo sorting. In the context of Epstein-Barr virus (EBV) infection, CD63 is required for the efficient packaging of the major viral oncoprotein latent membrane protein 1 (LMP1) into exosomes and other EV populations and acts as a negative regulator of LMP1 intracellular signaling. Accumulating evidence has also pointed to intersections of the endosomal and autophagy pathways in maintaining cellular secretory processes and as sites for viral assembly and replication. Indeed, LMP1 can activate the mammalian target of rapamycin (mTOR) pathway to suppress host cell autophagy and facilitate cell growth and proliferation. Despite the growing recognition of cross talk between endosomes and autophagosomes and its relevance to viral infection, little is understood about the molecular mechanisms governing endosomal and autophagy convergence. Here, we demonstrate that CD63-dependent vesicle protein secretion directly opposes intracellular signaling activation downstream of LMP1, including mTOR-associated proteins. Conversely, disruption of normal autolysosomal processes increases LMP1 secretion and dampens signal transduction by the viral protein. Increases in mTOR activation following CD63 knockout are coincident with the development of serum-dependent autophagic vacuoles that are acidified in the presence of high LMP1 levels. Altogether, these findings suggest a key role of CD63 in regulating the interactions between endosomal and autophagy processes and limiting cellular signaling activity in both noninfected and virally infected cells. IMPORTANCE The close connection between extracellular vesicles and viruses is becoming rapidly and more widely appreciated. EBV, a human gamma herpesvirus that contributes to the progression of a multitude of lymphomas and carcinomas in immunocompromised or genetically susceptible populations, packages its major

  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. Paclitaxel and the dietary flavonoid fisetin: a synergistic combination that induces mitotic catastrophe and autophagic cell death in A549 non-small cell lung cancer cells.

    Science.gov (United States)

    Klimaszewska-Wisniewska, Anna; Halas-Wisniewska, Marta; Tadrowski, Tadeusz; Gagat, Maciej; Grzanka, Dariusz; Grzanka, Alina

    2016-01-01

    The use of the dietary polyphenols as chemosensitizing agents to enhance the efficacy of conventional cytostatic drugs has recently gained the attention of scientists and clinicians as a plausible approach for overcoming the limitations of chemotherapy (e.g. drug resistance and cytotoxicity). The aim of this study was to investigate whether a naturally occurring diet-based flavonoid, fisetin, at physiologically attainable concentrations, could act synergistically with clinically achievable doses of paclitaxel to produce growth inhibitory and/or pro-death effects on A549 non-small cell lung cancer cells, and if it does, what mechanisms might be involved. The drug-drug interactions were analyzed based on the combination index method of Chou and Talalay and the data from MTT assays. To provide some insights into the mechanism underlying the synergistic action of fisetin and paclitaxel, selected morphological, biochemical and molecular parameters were examined, including the morphology of cell nuclei and mitotic spindles, the pattern of LC3-II immunostaining, the formation of autophagic vacuoles at the electron and fluorescence microscopic level, the disruption of cell membrane asymmetry/integrity, cell cycle progression and the expression level of LC3-II, Bax, Bcl-2 and caspase-3 mRNA. Here, we reported the first experimental evidence for the existence of synergism between fisetin and paclitaxel in the in vitro model of non-small cell lung cancer. This synergism was, at least partially, ascribed to the induction of mitotic catastrophe. The switch from the cytoprotective autophagy to the autophagic cell death was also implicated in the mechanism of the synergistic action of fisetin and paclitaxel in the A549 cells. In addition, we revealed that the synergism between fisetin and paclitaxel was cell line-specific as well as that fisetin synergizes with arsenic trioxide, but not with mitoxantrone and methotrexate in the A549 cells. Our results provide rationale for

  9. 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

  10. Ceramide-mediated macroautophagy involves inhibition of protein kinase B and up-regulation of beclin 1.

    Science.gov (United States)

    Scarlatti, Francesca; Bauvy, Chantal; Ventruti, Annamaria; Sala, Giusy; Cluzeaud, Françoise; Vandewalle, Alain; Ghidoni, Riccardo; Codogno, Patrice

    2004-04-30

    The sphingolipid ceramide is involved in the cellular stress response. Here we demonstrate that ceramide controls macroautophagy, a major lysosomal catabolic pathway. Exogenous C(2)-ceramide stimulates macroautophagy (proteolysis and accumulation of autophagic vacuoles) in the human colon cancer HT-29 cells by increasing the endogenous pool of long chain ceramides as demonstrated by the use of the ceramide synthase inhibitor fumonisin B(1). Ceramide reverted the interleukin 13-dependent inhibition of macroautophagy by interfering with the activation of protein kinase B. In addition, C(2)-ceramide stimulated the expression of the autophagy gene product beclin 1. Ceramide is also the mediator of the tamoxifen-dependent accumulation of autophagic vacuoles in the human breast cancer MCF-7 cells. Monodansylcadaverine staining and electron microscopy showed that this accumulation was abrogated by myriocin, an inhibitor of de novo synthesis ceramide. The tamoxifen-dependent accumulation of vacuoles was mimicked by 1-phenyl-2-decanoylamino-3-morpholino-1-propanol, an inhibitor of glucosylceramide synthase. 1-Phenyl-2-decanoylamino-3-morpholino-1-propanol, tamoxifen, and C(2)-ceramide stimulated the expression of beclin 1, whereas myriocin antagonized the tamoxifen-dependent up-regulation. Tamoxifen and C(2)-ceramide interfere with the activation of protein kinase B, whereas myriocin relieved the inhibitory effect of tamoxifen. In conclusion, the control of macroautophagy by ceramide provides a novel function for this lipid mediator in a cell process with major biological outcomes.

  11. Physics of Intrinsic Rotation in Flux-Driven ITG Turbulence

    International Nuclear Information System (INIS)

    Ku, S.; Abiteboul, J.; Dimond, P.H.; Dif-Pradalier, G.; Kwon, J.M.; Sarazin, Y.; Hahm, T.S.; Garbet, X.; Chang, C.S.; Latu, G.; Yoon, E.S.; Ghendrih, Ph.; Yi, S.; Strugarek, A.; Solomon, W.; Grandgirard, V.

    2012-01-01

    Global, heat flux-driven ITG gyrokinetic simulations which manifest the formation of macroscopic, mean toroidal flow profiles with peak thermal Mach number 0.05, are reported. Both a particle-in-cell (XGC1p) and a semi-Lagrangian (GYSELA) approach are utilized without a priori assumptions of scale-separation between turbulence and mean fields. Flux-driven ITG simulations with different edge flow boundary conditions show in both approaches the development of net unidirectional intrinsic rotation in the co-current direction. Intrinsic torque is shown to scale approximately linearly with the inverse scale length of the ion temperature gradient. External momentum input is shown to effectively cancel the intrinsic rotation profile, thus confirming the existence of a local residual stress and intrinsic torque. Fluctuation intensity, intrinsic torque and mean flow are demonstrated to develop inwards from the boundary. The measured correlations between residual stress and two fluctuation spectrum symmetry breakers, namely E x B shear and intensity gradient, are similar. Avalanches of (positive) heat flux, which propagate either outwards or inwards, are correlated with avalanches of (negative) parallel momentum flux, so that outward transport of heat and inward transport of parallel momentum are correlated and mediated by avalanches. The probability distribution functions of the outward heat flux and the inward momentum flux show strong structural similarity

  12. Flux trapping in superconducting cavities

    International Nuclear Information System (INIS)

    Vallet, C.; Bolore, M.; Bonin, B.; Charrier, J.P.; Daillant, B.; Gratadour, J.; Koechlin, F.; Safa, H.

    1992-01-01

    The flux trapped in various field cooled Nb and Pb samples has been measured. For ambient fields smaller than 3 Gauss, 100% of the flux is trapped. The consequences of this result on the behavior of superconducting RF cavities are discussed. (author) 12 refs.; 2 figs

  13. 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...

  14. 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....

  15. Solar proton fluxes since 1956

    International Nuclear Information System (INIS)

    Reedy, R.C.

    1977-01-01

    The fluxes of protons emitted during solar flares since 1956 were evaluated. The depth-versus-activity profiles of 56 Co in several lunar rocks are consistent with the solar-proton fluxes detected by experiments on several satellites. Only about 20% of the solar-proton-induced activities of 22 Na and 55 Fe in lunar rocks from early Apollo missions were produced by protons emitted from the sun during solar cycle 20 (1965--1975). The depth-versus-activity data for these radionuclides in several lunar rocks were used to determine the fluxes of protons during solar cycle 19 (1954--1964). The average proton fluxes for cycle 19 are about five times those for both the last million years and for cycle 20. These solar-proton flux variations correlate with changes in sunspot activity

  16. Attenuation of everolimus-induced cytotoxicity by a protective autophagic pathway involving ERK activation in renal cell carcinoma cells

    Science.gov (United States)

    Zeng, Yizhou; Tian, Xiaofang; Wang, Quan; He, Weiyang; Fan, Jing; Gou, Xin

    2018-01-01

    Aim The mammalian target of rapamycin (mTOR) pathway is a critical target for cancer treatment and the mTOR inhibitor everolimus (RAD001) has been approved for treatment of renal cell carcinoma (RCC). However, the limited efficacy of RAD001 has led to the development of drug resistance. Autophagy is closely related to cell survival and death, which may be activated under RAD001 stimulation. The aim of the present study was to identify the underlying mechanisms of RAD001 resistance in RCC cells through cytoprotective autophagy involving activation of the extracellular signal-regulated kinase (ERK) pathway. Methods and results: RAD001 strongly induced autophagy of RCC cells in a dose- and time-dependent manner, as confirmed by Western blot analysis. Importantly, suppression of autophagy by the pharmacological inhibitor chloroquine effectively enhanced RAD001-induced apoptotic cytotoxicity, as demonstrated by the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay and Western blot analysis, indicating a cytoprotective role for RAD001-induced autophagy. In addition, as was shown by the MTT assay, flow cytometry, and Western blot analysis, RAD001 robustly activated ERK, but not c-Jun N-terminal kinase and p38. Activation of ERK was inhibited by the pharmacological inhibitor selumetinib (AZD6244), which effectively promoted RAD001-induced cell death. Moreover, employing AZD6244 markedly attenuated RAD001-induced autophagy and enhanced RAD001-induced apoptosis, which play a central role in RAD001-induced cell death. Furthermore, RAD001-induced autophagy is regulated by ERK-mediated phosphorylation of Beclin-1 and B-cell lymphoma 2, as confirmed by Western blot analysis. Conclusion These results suggest that RAD001-induced autophagy involves activation of the ERK, which may impair cytotoxicity of RAD001 in RCC cells. Thus, inhibition of the activation of ERK pathway-mediated autophagy may be useful to overcome chemoresistance to RAD001. PMID:29719377

  17. Fractional flux excitations and flux creep in a superconducting film

    International Nuclear Information System (INIS)

    Lyuksyutov, I.F.

    1995-01-01

    We consider the transport properties of a modulated superconducting film in a magnetic field parallel to the film. Modulation can be either intrinsic, due to the layered structure of the high-T c superconductors, or artificial, e.g. due to thickness modulation. This system has an infinite set ( >) of pinned phases. In the pinned phase the excitation of flux loops with a fractional number of flux quanta by the applied current j results in flux creep with a generated voltage V ∝ exp[-jo/j[. (orig.)

  18. Autophagic kinases SmVPS34 and SmVPS15 are required for viability in the filamentous ascomycete Sordaria macrospora.

    Science.gov (United States)

    Voigt, Oliver; Herzog, Britta; Jakobshagen, Antonia; Pöggeler, Stefanie

    2014-01-01

    Autophagy is a tightly controlled degradation process of all eukaryotes. It includes the sequestration of cytoplasmic contents and organelles within a double-membraned autophagosome. Autophagy involves core autophagy related (atg) genes as well as genes regulating vesicle trafficking. Previously, we analyzed the impact of proteins of the core autophagic machinery SmATG7, SmATG8 and SmATG4 on the sexual and vegetative development of the filamentous ascomycete Sordaria macrospora. While deletion of Smatg8 and Smatg4 abolished fruiting-body formation and impaired vegetative growth, Smatg7 is required for viability. In yeast, the phosphatidylinositol 3-kinase vacuolar protein sorting 34 (Vps34) and its myristoylated membrane targeting unit, the protein kinase Vps15 have been shown to be important regulators of autophagy and vacuolar protein sorting. However, their exact role in filamentous ascomycetes remains elusive. To determine the function of Smvps34 and Smvps15 we isolated genes with high sequence similarity to Saccharomyces cerevisiae VPS34 and VPS15. For both genes we were not able to generate a homokaryotic knockout mutant in S. macrospora, suggesting that Smvps34 and Smvps15 are required for viability. Furthermore, we analyzed the repertoire of vps genes encoded by S. macrospora and could identify putative homologs of nearly all of the 61 VPS genes of S. cerevisiae. Copyright © 2013 Elsevier GmbH. All rights reserved.

  19. 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.

  20. The role of tumor necrosis factor-α-related apoptosis-inducing ligand (TRAIL) in mediating autophagy in myositis skeletal muscle: A potential non-immune mechanism of muscle damage

    Science.gov (United States)

    Alger, Heather M.; Raben, Nina; Pistilli, Emidio; Francia, Dwight; Rawat, Rashmi; Getnet, Derese; Ghimbovschi, Svetlana; Chen, Yi-Wen; Lundberg, Ingrid E.; Nagaraju, Kanneboyina

    2011-01-01

    Objective Multinucleated cells are relatively resistant to classical apoptosis, and the factors initiating cell-death and damage in myositis are not well defined. We hypothesized that non-immune autophagic cell death may play a role in muscle fiber damage. Recent literature indicates that tumor necrosis factor-alpha-related apoptosis inducing ligand (TRAIL) may induce both NFκB (nuclear factor kappa-light chain enhancer of activated B cells) activation and autophagic cell death in other systems. Here, we have investigated its role in cell death and pathogenesis in vitro and in vivo using myositis (human and mouse) muscle tissues. Methods Gene expression profiling indicated that expression of TRAIL and several autophagy markers was specifically upregulated in myositis muscle tissue; these results were confirmed by immunohistochemistry and immunoblotting. We also analyzed TRAIL-induced cell death (apoptosis and autophagy) and NFκB activation in vitro in cultured cells. Results TRAIL was expressed predominantly in muscle fibers of myositis, but not in biopsies from normal or other dystrophic-diseased muscle. Autophagy markers were upregulated in human and mouse models of myositis. TRAIL expression was restricted to regenerating/atrophic areas of muscle fascicles, blood vessels, and infiltrating lymphocytes. TRAIL induced NFκB activation and IκB degradation in cultured cells that are resistant to TRAIL-induced apoptosis but undergo autophagic cell death. Conclusion Our data demonstrate that TRAIL is expressed in myositis muscle and may mediate both activation of NFκB and autophagic cell death in myositis. Thus, this non-immune pathway may be an attractive target for therapeutic intervention in myositis. PMID:21769834

  1. Monte Carlo surface flux tallies

    International Nuclear Information System (INIS)

    Favorite, Jeffrey A.

    2010-01-01

    Particle fluxes on surfaces are difficult to calculate with Monte Carlo codes because the score requires a division by the surface-crossing angle cosine, and grazing angles lead to inaccuracies. We revisit the standard practice of dividing by half of a cosine 'cutoff' for particles whose surface-crossing cosines are below the cutoff. The theory behind this approximation is sound, but the application of the theory to all possible situations does not account for two implicit assumptions: (1) the grazing band must be symmetric about 0, and (2) a single linear expansion for the angular flux must be applied in the entire grazing band. These assumptions are violated in common circumstances; for example, for separate in-going and out-going flux tallies on internal surfaces, and for out-going flux tallies on external surfaces. In some situations, dividing by two-thirds of the cosine cutoff is more appropriate. If users were able to control both the cosine cutoff and the substitute value, they could use these parameters to make accurate surface flux tallies. The procedure is demonstrated in a test problem in which Monte Carlo surface fluxes in cosine bins are converted to angular fluxes and compared with the results of a discrete ordinates calculation.

  2. 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....

  3. 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....

  4. 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.)

  5. 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.)

  6. 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.

  7. Physics of Magnetic Flux Ropes

    CERN Document Server

    Priest, E R; Lee, L C

    1990-01-01

    The American Geophysical Union Chapman Conference on the Physics of Magnetic Flux Ropes was held at the Hamilton Princess Hotel, Hamilton, Bermuda on March 27–31, 1989. Topics discussed ranged from solar flux ropes, such as photospheric flux tubes, coronal loops and prominences, to flux ropes in the solar wind, in planetary ionospheres, at the Earth's magnetopause, in the geomagnetic tail and deep in the Earth's magnetosphere. Papers presented at that conference form the nucleus of this book, but the book is more than just a proceedings of the conference. We have solicited articles from all interested in this topic. Thus, there is some material in the book not discussed at the conference. Even in the case of papers presented at the conference, there is generally a much more detailed and rigorous presentation than was possible in the time allowed by the oral and poster presentations.

  8. 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

  9. Specification of ROP flux shape

    International Nuclear Information System (INIS)

    Min, Byung Joo; Gray, A.

    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

  10. 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.

  11. 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...

  12. Flux networks in metabolic graphs

    International Nuclear Information System (INIS)

    Warren, P B; Queiros, S M Duarte; Jones, J L

    2009-01-01

    A metabolic model can be represented as a bipartite graph comprising linked reaction and metabolite nodes. Here it is shown how a network of conserved fluxes can be assigned to the edges of such a graph by combining the reaction fluxes with a conserved metabolite property such as molecular weight. A similar flux network can be constructed by combining the primal and dual solutions to the linear programming problem that typically arises in constraint-based modelling. Such constructions may help with the visualization of flux distributions in complex metabolic networks. The analysis also explains the strong correlation observed between metabolite shadow prices (the dual linear programming variables) and conserved metabolite properties. The methods were applied to recent metabolic models for Escherichia coli, Saccharomyces cerevisiae and Methanosarcina barkeri. Detailed results are reported for E. coli; similar results were found for other organisms

  13. Boundary fluxes for nonlocal diffusion

    Science.gov (United States)

    Cortazar, Carmen; Elgueta, Manuel; Rossi, Julio D.; Wolanski, Noemi

    We study a nonlocal diffusion operator in a bounded smooth domain prescribing the flux through the boundary. This problem may be seen as a generalization of the usual Neumann problem for the heat equation. First, we prove existence, uniqueness and a comparison principle. Next, we study the behavior of solutions for some prescribed boundary data including blowing up ones. Finally, we look at a nonlinear flux boundary condition.

  14. Energy flux of hot atoms

    International Nuclear Information System (INIS)

    Wotzak, G.P.; Kostin, M.D.

    1976-01-01

    The process in which hot atoms collide with thermal atoms of a gas, transfer kinetic energy to them, and produce additional hot atoms is investigated. A stochastic method is used to obtain numerical results for the spatial and time dependent energy flux of hot atoms in a gas. The results indicate that in hot atom systems a front followed by an intense energy flux of hot atoms may develop

  15. Proteotoxic stress induces phosphorylation of p62/SQSTM1 by ULK1 to regulate selective autophagic clearance of protein aggregates.

    Directory of Open Access Journals (Sweden)

    Junghyun Lim

    Full Text Available Disruption of proteostasis, or protein homeostasis, is often associated with aberrant accumulation of misfolded proteins or protein aggregates. Autophagy offers protection to cells by removing toxic protein aggregates and injured organelles in response to proteotoxic stress. However, the exact mechanism whereby autophagy recognizes and degrades misfolded or aggregated proteins has yet to be elucidated. Mounting evidence demonstrates the selectivity of autophagy, which is mediated through autophagy receptor proteins (e.g. p62/SQSTM1 linking autophagy cargos and autophagosomes. Here we report that proteotoxic stress imposed by the proteasome inhibition or expression of polyglutamine expanded huntingtin (polyQ-Htt induces p62 phosphorylation at its ubiquitin-association (UBA domain that regulates its binding to ubiquitinated proteins. We find that autophagy-related kinase ULK1 phosphorylates p62 at a novel phosphorylation site S409 in UBA domain. Interestingly, phosphorylation of p62 by ULK1 does not occur upon nutrient starvation, in spite of its role in canonical autophagy signaling. ULK1 also phosphorylates S405, while S409 phosphorylation critically regulates S405 phosphorylation. We find that S409 phosphorylation destabilizes the UBA dimer interface, and increases binding affinity of p62 to ubiquitin. Furthermore, lack of S409 phosphorylation causes accumulation of p62, aberrant localization of autophagy proteins and inhibition of the clearance of ubiquitinated proteins or polyQ-Htt. Therefore, our data provide mechanistic insights into the regulation of selective autophagy by ULK1 and p62 upon proteotoxic stress. Our study suggests a potential novel drug target in developing autophagy-based therapeutics for the treatment of proteinopathies including Huntington's disease.

  16. 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.

  17. 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.

  18. P fluxes and exotic branes

    Energy Technology Data Exchange (ETDEWEB)

    Lombardo, Davide M. [Dipartimento di Fisica, Università di Roma “La Sapienza”,Piazzale Aldo Moro 2, 00185 Roma (Italy); Riccioni, Fabio [INFN - Sezione di Roma, Dipartimento di Fisica, Università di Roma “La Sapienza”,Piazzale Aldo Moro 2, 00185 Roma (Italy); Risoli, Stefano [Dipartimento di Fisica, Università di Roma “La Sapienza”,Piazzale Aldo Moro 2, 00185 Roma (Italy); INFN - Sezione di Roma, Dipartimento di Fisica, Università di Roma “La Sapienza”,Piazzale Aldo Moro 2, 00185 Roma (Italy)

    2016-12-21

    We consider the N=1 superpotential generated in type-II orientifold models by non-geometric fluxes. In particular, we focus on the family of P fluxes, that are related by T-duality transformations to the S-dual of the Q flux. We determine the general rule that transforms a given flux in this family under a single T-duality transformation. This rule allows to derive a complete expression for the superpotential for both the IIA and the IIB theory for the particular case of a T{sup 6}/[ℤ{sub 2}×ℤ{sub 2}] orientifold. We then consider how these fluxes modify the generalised Bianchi identities. In particular, we derive a fully consistent set of quadratic constraints coming from the NS-NS Bianchi identities. On the other hand, the P flux Bianchi identities induce tadpoles, and we determine a set of exotic branes that can be consistently included in order to cancel them. This is achieved by determining a universal transformation rule under T-duality satisfied by all the branes in string theory.

  19. P fluxes and exotic branes

    International Nuclear Information System (INIS)

    Lombardo, Davide M.; Riccioni, Fabio; Risoli, Stefano

    2016-01-01

    We consider the N=1 superpotential generated in type-II orientifold models by non-geometric fluxes. In particular, we focus on the family of P fluxes, that are related by T-duality transformations to the S-dual of the Q flux. We determine the general rule that transforms a given flux in this family under a single T-duality transformation. This rule allows to derive a complete expression for the superpotential for both the IIA and the IIB theory for the particular case of a T 6 /[ℤ 2 ×ℤ 2 ] orientifold. We then consider how these fluxes modify the generalised Bianchi identities. In particular, we derive a fully consistent set of quadratic constraints coming from the NS-NS Bianchi identities. On the other hand, the P flux Bianchi identities induce tadpoles, and we determine a set of exotic branes that can be consistently included in order to cancel them. This is achieved by determining a universal transformation rule under T-duality satisfied by all the branes in string theory.

  20. 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...

  1. 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.

  2. 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

  3. Vapb/Amyotrophic lateral sclerosis 8 knock-in mice display slowly progressive motor behavior defects accompanying ER stress and autophagic response.

    Science.gov (United States)

    Larroquette, Frédérique; Seto, Lesley; Gaub, Perrine L; Kamal, Brishna; Wallis, Deeann; Larivière, Roxanne; Vallée, Joanne; Robitaille, Richard; Tsuda, Hiroshi

    2015-11-15

    Missense mutations (P56S) in Vapb are associated with autosomal dominant motor neuron diseases: amyotrophic lateral sclerosis and lower motor neuron disease. Although transgenic mice overexpressing the mutant vesicle-associated membrane protein-associated protein B (VAPB) protein with neuron-specific promoters have provided some insight into the toxic properties of the mutant proteins, their role in pathogenesis remains unclear. To identify pathological defects in animals expressing the P56S mutant VAPB protein at physiological levels in the appropriate tissues, we have generated Vapb knock-in mice replacing wild-type Vapb gene with P56S mutant Vapb gene and analyzed the resulting pathological phenotypes. Heterozygous P56S Vapb knock-in mice show mild age-dependent defects in motor behaviors as characteristic features of the disease. The homozygous P56S Vapb knock-in mice show more severe defects compared with heterozygous mice reflecting the dominant and dose-dependent effects of P56S mutation. Significantly, the knock-in mice demonstrate accumulation of P56S VAPB protein and ubiquitinated proteins in cytoplasmic inclusions, selectively in motor neurons. The mutant mice demonstrate induction of ER stress and autophagic response in motor neurons before obvious onset of behavioral defects, suggesting that these cellular biological defects might contribute to the initiation of the disease. The P56S Vapb knock-in mice could be a valuable tool to gain a better understanding of the mechanisms by which the disease arises. © The Author 2015. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oup.com.

  4. 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.

  5. 1,1-Bis(3'-indolyl)-1-(p-substituted phenyl)methanes induce autophagic cell death in estrogen receptor negative breast cancer

    International Nuclear Information System (INIS)

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

    2010-01-01

    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-pPhCF 3 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

  6. Flux flow and flux dynamics in high-Tc superconductors

    International Nuclear Information System (INIS)

    Bennett, L.H.; Turchinskaya, M.; Swartzendruber, L.J.; Roitburd, A.; Lundy, D.; Ritter, J.; Kaiser, D.L.

    1991-01-01

    Because high temperature superconductors, including BYCO and BSSCO, are type 2 superconductors with relatively low H(sub c 1) values and high H(sub c 2) values, they will be in a critical state for many of their applications. In the critical state, with the applied field between H(sub c 1) and H(sub c 2), flux lines have penetrated the material and can form a flux lattice and can be pinned by structural defects, chemical inhomogeneities, and impurities. A detailed knowledge of how flux penetrates the material and its behavior under the influence of applied fields and current flow, and the effect of material processing on these properties, is required in order to apply, and to improve the properties of these superconductors. When the applied field is changed rapidly, the time dependence of flux change can be divided into three regions, an initial region which occurs very rapidly, a second region in which the magnetization has a 1n(t) behavior, and a saturation region at very long times. A critical field is defined for depinning, H(sub c,p) as that field at which the hysteresis loop changes from irreversible to reversible. As a function of temperature, it is found that H(sub c,p) is well described by a power law with an exponent between 1.5 and 2.5. The behavior of H(sub c,p) for various materials and its relationship to flux flow and flux dynamics are discussed

  7. Thermality of the Hawking flux

    Energy Technology Data Exchange (ETDEWEB)

    Visser, Matt [School of Mathematics, Statistics, and Operations Research,Victoria University of Wellington, PO Box 600, Wellington 6140 (New Zealand)

    2015-07-03

    Is the Hawking flux “thermal”? Unfortunately, the answer to this seemingly innocent question depends on a number of often unstated, but quite crucial, technical assumptions built into modern (mis-)interpretations of the word “thermal”. The original 1850’s notions of thermality — based on classical thermodynamic reasoning applied to idealized “black bodies” or “lamp black surfaces” — when supplemented by specific basic quantum ideas from the early 1900’s, immediately led to the notion of the black-body spectrum, (the Planck-shaped spectrum), but without any specific assumptions or conclusions regarding correlations between the quanta. Many (not all) modern authors (often implicitly and unintentionally) add an extra, quite unnecessary, assumption that there are no correlations in the black-body radiation; but such usage is profoundly ahistorical and dangerously misleading. Specifically, the Hawking flux from an evaporating black hole, (just like the radiation flux from a leaky furnace or a burning lump of coal), is only approximately Planck-shaped over an explicitly bounded range of frequencies. Standard physics (phase space and adiabaticity effects) explicitly bound the frequency range over which the Hawking flux is approximately Planck-shaped from both above and below — the Hawking flux is certainly not exactly Planckian, and there is no compelling physics reason to assume the Hawking photons are uncorrelated.

  8. Thermality of the Hawking flux

    International Nuclear Information System (INIS)

    Visser, Matt

    2015-01-01

    Is the Hawking flux “thermal”? Unfortunately, the answer to this seemingly innocent question depends on a number of often unstated, but quite crucial, technical assumptions built into modern (mis-)interpretations of the word “thermal”. The original 1850’s notions of thermality — based on classical thermodynamic reasoning applied to idealized “black bodies” or “lamp black surfaces” — when supplemented by specific basic quantum ideas from the early 1900’s, immediately led to the notion of the black-body spectrum, (the Planck-shaped spectrum), but without any specific assumptions or conclusions regarding correlations between the quanta. Many (not all) modern authors (often implicitly and unintentionally) add an extra, quite unnecessary, assumption that there are no correlations in the black-body radiation; but such usage is profoundly ahistorical and dangerously misleading. Specifically, the Hawking flux from an evaporating black hole, (just like the radiation flux from a leaky furnace or a burning lump of coal), is only approximately Planck-shaped over an explicitly bounded range of frequencies. Standard physics (phase space and adiabaticity effects) explicitly bound the frequency range over which the Hawking flux is approximately Planck-shaped from both above and below — the Hawking flux is certainly not exactly Planckian, and there is no compelling physics reason to assume the Hawking photons are uncorrelated.

  9. 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...

  10. 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)

  11. Methane flux from boreal peatlands

    International Nuclear Information System (INIS)

    Crill, P.; Bartlett, K.; Roulet, N.

    1992-01-01

    The peatlands in the boreal zone (roughly 45 deg - 60 degN) store a significant reservoir of carbon, much of which is potentially available for exchange with the atmosphere. The anaerobic conditions that cause these soils to accumulate carbon also makes wet, boreal peatlands significant sources of methane to the global troposphere. It is estimated that boreal wetlands contribute approximately 19.5 Tg methane per year. The data available on the magnitude of boreal methane emissions have rapidly accumulated in the past twenty years. This paper offers a short review of the flux measured (with range roughly 1 - 2000 mg methane/m2d), considers environmental controls of the flux and briefly discusses how climate change might affect future fluxes

  12. Wide range neutron flux monitor

    International Nuclear Information System (INIS)

    Endo, Yorimasa; Fukushima, Toshiki.

    1983-01-01

    Purpose: To provide a wide range neutron-flux monitor adapted such that the flux monitoring function and alarming function can automatically by shifted from pulse counting system to cambel method system. Constitution: A wide range neutron-flux monitor comprises (la) pulse counting system and (lb) cambel-method system for inputting detection signals from neutron detectors and separating them into signals for the pulse measuring system and the cambel measuring system, (2) overlap detection and calculation circuit for detecting the existence of the overlap of two output signals from the (la) and (lb) systems, and (3) trip circuit for judging the abnormal state of neutron detectors upon input of the detection signals. (Seki, T.)

  13. High heat flux facility GLADIS

    International Nuclear Information System (INIS)

    Greuner, H.; Boeswirth, B.; Boscary, J.; McNeely, P.

    2007-01-01

    The new ion beam facility GLADIS started the operation at IPP Garching. The facility is equipped with two individual 1.1 MW power ion sources for testing actively cooled plasma facing components under high heat fluxes. Each ion source generates heat loads between 3 and 55 MW/m 2 with a beam diameter of 70 mm at the target position. These parameters allow effective testing from probes to large components up to 2 m length. The high heat flux allows the target to be installed inclined to the beam and thus increases the heated surface length up to 200 mm for a heat flux of 15 MW/m 2 in the standard operating regime. Thus the facility has the potential capability for testing of full scale ITER divertor targets. Heat load tests on the WENDELSTEIN 7-X pre-series divertor targets have been successfully started. These tests will validate the design and manufacturing for the production of 950 elements

  14. Heat flux driven ion turbulence

    International Nuclear Information System (INIS)

    Garbet, X.

    1998-01-01

    This work is an analysis of an ion turbulence in a tokamak in the case where the thermal flux is fixed and the temperature profile is allowed to fluctuate. The system exhibits some features of Self-Organized Critical systems. In particular, avalanches are observed. Also the frequency spectrum of the thermal flux exhibits a structure similar to the one of a sand pile automaton, including a 1/f behavior. However, the time average temperature profile is found to be supercritical, i.e. the temperature gradient stays above the critical value. Moreover, the heat diffusivity is lower for a turbulence calculated at fixed flux than a fixed temperature gradient, with the same time average temperature. This behavior is attributed to a stabilizing effect of avalanches. (author)

  15. Ideal flux field dielectric concentrators.

    Science.gov (United States)

    García-Botella, Angel

    2011-10-01

    The concept of the vector flux field was first introduced as a photometrical theory and later developed in the field of nonimaging optics; it has provided new perspectives in the design of concentrators, overcoming standard ray tracing techniques. The flux field method has shown that reflective concentrators with the geometry of the field lines achieve the theoretical limit of concentration. In this paper we study the role of surfaces orthogonal to the field vector J. For rotationally symmetric systems J is orthogonal to its curl, and then a family of surfaces orthogonal to the lines of J exists, which can be called the family of surfaces of constant pseudopotential. Using the concept of the flux tube, it is possible to demonstrate that refractive concentrators with the shape of these pseudopotential surfaces achieve the theoretical limit of concentration.

  16. Flux flow and flux creep in thick films of YBCO. [Y-Ba-Cu-O

    Energy Technology Data Exchange (ETDEWEB)

    Rickets, J.; Vinen, W.F.; Abell, J.S.; Shields, T.C. (Superconductivity Research Group, Univ. of Birmingham (United Kingdom))

    1991-12-01

    The results are described of new experiments designed to study flux creep and flux flow along a single flux percolation path in thick films of YBCO. The flux flow regime is studied by a four-point resistive technique using pulsed currents, and the flux creep regime by observing the rate at which flux enters a superconducting loop in parallel with the resistance that is associated with the flux percolation path. (orig.).

  17. 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)

  18. 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 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....

  19. Simple models with ALICE fluxes

    CERN Document Server

    Striet, J

    2000-01-01

    We introduce two simple models which feature an Alice electrodynamics phase. In a well defined sense the Alice flux solutions we obtain in these models obey first order equations similar to those of the Nielsen-Olesen fluxtube in the abelian higgs model in the Bogomol'nyi limit. Some numerical solutions are presented as well.

  20. Exposure to low-dose X-rays promotes peculiar autophagic cell death in Drosophila melanogaster, an effect that can be regulated by the inducible expression of Hml dsRNA

    Energy Technology Data Exchange (ETDEWEB)

    Kanao, Tomoko [Department of Radiological Sciences, International University of Health and Welfare, Kitakanemaru 2600-1, Ohtawara-shi, Tochigi-ken 324-8501 (Japan); Miyachi, Yukihisa [Department of Radiological Sciences, International University of Health and Welfare, Kitakanemaru 2600-1, Ohtawara-shi, Tochigi-ken 324-8501 (Japan)]. E-mail: ymiyachi@iuhw.ac.jp

    2006-03-20

    We previously reported that to induce an early emergence effect with low-dose X-irradiation in Drosophila, exposure during the prepupae stage is necessary. The present study examined the mechanism by which low-dose radiation rapidly eliminates larval cells and activates the formation of the imaginal discs during metamorphosis. Upon exposure to 0.5 Gy X-rays at 2 h after puparium formation (APF), the larval salivary glands swelled and were surrounded by remarkably thick structures containing an acid phosphatase (Acph) enzyme, implicating a peculiar autophagic cell death. TUNEL staining revealed the presence of DNA fragmentations compared with cells from sham controls which remained unchanged until 12 h APF. Additionally, the salivary glands of exposed flies were completely destroyed by 10 h APF. Furthermore, exposure to 0.5 Gy X-rays also facilitated the activity of the engulfment function of dendritic cells (DCs); they were generated in the larval salivary glands, engulfed the cell corpses and finally moved to the fat body. Data from an experiment demonstrating the inducible expression of Hml double-stranded RNA (dsRNA) indicate that a slow rate of engulfment of larval cells results in a longer time to emergence. Thus, the animals subjected to low-dose X-rays activated autophagic processes, resulting in significantly faster adult eclosion.

  1. Exposure to low-dose X-rays promotes peculiar autophagic cell death in Drosophila melanogaster, an effect that can be regulated by the inducible expression of Hml dsRNA

    International Nuclear Information System (INIS)

    Kanao, Tomoko; Miyachi, Yukihisa

    2006-01-01

    We previously reported that to induce an early emergence effect with low-dose X-irradiation in Drosophila, exposure during the prepupae stage is necessary. The present study examined the mechanism by which low-dose radiation rapidly eliminates larval cells and activates the formation of the imaginal discs during metamorphosis. Upon exposure to 0.5 Gy X-rays at 2 h after puparium formation (APF), the larval salivary glands swelled and were surrounded by remarkably thick structures containing an acid phosphatase (Acph) enzyme, implicating a peculiar autophagic cell death. TUNEL staining revealed the presence of DNA fragmentations compared with cells from sham controls which remained unchanged until 12 h APF. Additionally, the salivary glands of exposed flies were completely destroyed by 10 h APF. Furthermore, exposure to 0.5 Gy X-rays also facilitated the activity of the engulfment function of dendritic cells (DCs); they were generated in the larval salivary glands, engulfed the cell corpses and finally moved to the fat body. Data from an experiment demonstrating the inducible expression of Hml double-stranded RNA (dsRNA) indicate that a slow rate of engulfment of larval cells results in a longer time to emergence. Thus, the animals subjected to low-dose X-rays activated autophagic processes, resulting in significantly faster adult eclosion

  2. 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.

  3. 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

  4. Heisenberg groups and noncommutative fluxes

    International Nuclear Information System (INIS)

    Freed, Daniel S.; Moore, Gregory W.; Segal, Graeme

    2007-01-01

    We develop a group-theoretical approach to the formulation of generalized abelian gauge theories, such as those appearing in string theory and M-theory. We explore several applications of this approach. First, we show that there is an uncertainty relation which obstructs simultaneous measurement of electric and magnetic flux when torsion fluxes are included. Next, we show how to define the Hilbert space of a self-dual field. The Hilbert space is Z 2 -graded and we show that, in general, self-dual theories (including the RR fields of string theory) have fermionic sectors. We indicate how rational conformal field theories associated to the two-dimensional Gaussian model generalize to (4k+2)-dimensional conformal field theories. When our ideas are applied to the RR fields of string theory we learn that it is impossible to measure the K-theory class of a RR field. Only the reduction modulo torsion can be measured

  5. Neutron flux enhancement at LASREF

    International Nuclear Information System (INIS)

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

    1992-01-01

    The accelerator at the Los Alamos Meson Physiscs 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 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 10 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. (orig.)

  6. 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.

  7. Absolute flux scale for radioastronomy

    International Nuclear Information System (INIS)

    Ivanov, V.P.; Stankevich, K.S.

    1986-01-01

    The authors propose and provide support for a new absolute flux scale for radio astronomy, which is not encumbered with the inadequacies of the previous scales. In constructing it the method of relative spectra was used (a powerful tool for choosing reference spectra). A review is given of previous flux scales. The authors compare the AIS scale with the scale they propose. Both scales are based on absolute measurements by the ''artificial moon'' method, and they are practically coincident in the range from 0.96 to 6 GHz. At frequencies above 6 GHz, 0.96 GHz, the AIS scale is overestimated because of incorrect extrapolation of the spectra of the primary and secondary standards. The major results which have emerged from this review of absolute scales in radio astronomy are summarized

  8. Rapid reconnection of flux lines

    International Nuclear Information System (INIS)

    Samain, A.

    1982-01-01

    The rapid reconnection of flux lines in an incompressible fluid through a singular layer of the current density is discussed. It is shown that the liberated magnetic energy must partially appear in the form of plasma kinetic energy. A laminar structure of the flow is possible, but Alfven velocity must be achieved in eddies of growing size at the ends of the layer. The gross structure of the flow and the magnetic configuration may be obtained from variational principles. (author)

  9. 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)

  10. 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.

  11. Generalized drift-flux correlation

    International Nuclear Information System (INIS)

    Takeuchi, K.; Young, M.Y.; Hochreiter, L.E.

    1991-01-01

    A one-dimensional drift-flux model with five conservation equations is frequently employed in major computer codes, such as TRAC-PD2, and in simulator codes. In this method, the relative velocity between liquid and vapor phases, or slip ratio, is given by correlations, rather than by direct solution of the phasic momentum equations, as in the case of the two-fluid model used in TRAC-PF1. The correlations for churn-turbulent bubbly flow and slug flow regimes were given in terms of drift velocities by Zuber and Findlay. For the annular flow regime, the drift velocity correlations were developed by Ishii et al., using interphasic force balances. Another approach is to define the drift velocity so that flooding and liquid hold-up conditions are properly simulated, as reported here. The generalized correlation is used to reanalyze the MB-2 test data for two-phase flow in a large-diameter pipe. The results are applied to the generalized drift flux velocity, whose relationship to the other correlations is discussed. Finally, the generalized drift flux correlation is implemented in TRAC-PD2. Flow reversal from countercurrent to cocurrent flow is computed in small-diameter U-shaped tubes and is compared with the flooding curve

  12. Modeling the electromechanical interactions in a null-flux electrodynamic maglev system

    NARCIS (Netherlands)

    Boeij, de J.; Steinbuch, M.; Gutierrez, H.M.

    2005-01-01

    The fundamental electromechanical interactions in a passive -flux electrodynamic maglev system (EDS) are mediated by the voltages induced in the levitation coils by the sled magnets, and by the forces exerted on the sled as a result of the induced currents. This work presents a reliable and compact

  13. Force sensor using changes in magnetic flux

    Science.gov (United States)

    Pickens, Herman L. (Inventor); Richard, James A. (Inventor)

    2012-01-01

    A force sensor includes a magnetostrictive material and a magnetic field generator positioned in proximity thereto. A magnetic field is induced in and surrounding the magnetostrictive material such that lines of magnetic flux pass through the magnetostrictive material. A sensor positioned in the vicinity of the magnetostrictive material measures changes in one of flux angle and flux density when the magnetostrictive material experiences an applied force that is aligned with the lines of magnetic flux.

  14. mediation: R package for causal mediation analysis

    OpenAIRE

    Tingley, Dustin; Yamamoto, Teppei; Hirose, Kentaro; Keele, Luke; Imai, Kosuke

    2012-01-01

    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 su...

  15. Reluctance motor employing superconducting magnetic flux switches

    International Nuclear Information System (INIS)

    Spyker, R.L.; Ruckstadter, E.J.

    1992-01-01

    This paper reports that superconducting flux switches controlling the magnetic flux in the poles of a motor will enable the implementation of a reluctance motor using one central single phase winding. A superconducting flux switch consists of a ring of superconducting material surrounding a ferromagnetic pole of the motor. When in the superconducting state the switch will block all magnetic flux attempting to flow in the ferromagnetic core. When switched to the normal state the superconducting switch will allow the magnetic flux to flow freely in that pole. By using one high turns-count coil as a flux generator, and selectively channeling flux among the various poles using the superconducting flux switch, 3-phase operation can be emulated with a single-hase central AC source. The motor will also operate when the flux generating coil is driven by a DC current, provided the magnetic flux switches see a continuously varying magnetic flux. Rotor rotation provides this varying flux due to the change in stator pole inductance it produces

  16. Induction of mitophagy-mediated antitumor activity with folate-appended methyl-β-cyclodextrin.

    Science.gov (United States)

    Kameyama, Kazuhisa; Motoyama, Keiichi; Tanaka, Nao; Yamashita, Yuki; Higashi, Taishi; Arima, Hidetoshi

    2017-01-01

    Mitophagy is the specific autophagic elimination system of mitochondria, which regulates cellular survival via the removal of damaged mitochondria. Recently, we revealed that folate-appended methyl-β-cyclodextrin (FA-M-β-CyD) provides selective antitumor activity in folate receptor-α (FR-α)-expressing cells by the induction of autophagy. In this study, to gain insight into the detailed mechanism of this antitumor activity, we focused on the induction of mitophagy by the treatment of FR-α-expressing tumor cells with FA-M-β-CyD. In contrast to methyl-β-cyclodextrin, FA-M-β-CyD entered KB cells, human epithelial cells from a fatal cervical carcinoma (FR-α (+)) through FR-α-mediated endocytosis. The transmembrane potential of isolated mitochondria after treatment with FA-M-β-CyD was significantly elevated. In addition, FA-M-β-CyD lowered adenosine triphosphate (ATP) production and promoted reactive oxygen species production in KB cells (FR-α (+)). Importantly, FA-M-β-CyD enhanced light chain 3 (LC3) conversion (LC3-I to LC3-II) in KB cells (FR-α (+)) and induced PTEN-induced putative kinase 1 (PINK1) protein expression, which is involved in the induction of mitophagy. Furthermore, FA-M-β-CyD had potent antitumor activity in BALB/c nu/nu mice xenografted with KB cells (FR-α (+)) without any significant side effects. Taken together, these findings demonstrate that the autophagic cell death elicited by FA-M-β-CyD could be associated with mitophagy induced by an impaired mitochondrial function.

  17. Micro dynamics in mediation

    OpenAIRE

    Boserup, Hans

    2014-01-01

    The author has identified a number of styles in mediation, which lead to different processes and different outcomes. Through discourse and conversation analysis he examines the micro dynamics in three of these, the postmodern styles: systemic, transformative and narrative mediation. The differences between the three mediation ideologies and practice is illustrated through role play scripts enacted in each style. Mediator and providers of mediation and trainers in mediation are encouraged to a...

  18. 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

  19. Evaluation of apoptotic- and autophagic-related protein expressions before and after IVM of fresh, slow-frozen and vitrified pre-pubertal mouse testicular tissue.

    Science.gov (United States)

    Dumont, L; Chalmel, F; Oblette, A; Berby, B; Rives, A; Duchesne, V; Rondanino, C; Rives, N

    2017-11-01

    Do freezing and in vitro culture procedures enhance the expression of proteins involved in apoptotic or autophagic pathways in murine pre-pubertal testicular tissue? IVM strongly modified apoptosis- and autophagy-related relative protein levels in mice testicular tissue whereas the impact of cryopreservation procedures was minimal at the end of the culture. In vitro spermatogenesis remains a challenging technical issue as it imposes to find a very close balance between survival and death of germ cell natural precursors (i.e. gonocytes and spermatogonia), which will eventually undergo a complete spermatogenesis close to in vivo conditions. The establishment of efficient culture conditions coupled with suitable cryopreservation procedures (e.g. controlled slow freezing [CSF] and solid surface vitrification [SSV]) of pre-pubertal testicular tissue is a crucial step in the fields of fertility preservation and restoration to improve the spermatic yield obtained in vitro. Here, we study cryopreservation procedures (i.e. CSF or SSV) and the impact of culture media compositions. A first set of 66 mouse pre-pubertal testes were directly cultured during 30, 36, 38 and 60 days (D) from 2.5 to 6.5-day-old CD-1 mice to evaluate the impact of time-aspect of culture and to endorse the reverse phase protein microarrays (RPPM) technique as an adapted experimental tool for the field of in vitro spermatogenesis. Ninety others fresh, slow-frozen and vitrified pre-pubertal testes were cultured during 30 days for the principal study to evaluate the impact of cryopreservation procedures before and after culture. Thirty-four testes dissected from 2.5, 6.5, 36.5, 40.5, 42.5 and 62.5 days postpartum (dpp) mice, corresponding to the time frames of spermatogenesis orchestrated in vitro, were used as in vivo controls. After in vitro culture, testicular tissue samples originated from 2.5 or 6.5-day-old CD-1 male mice were analyzed using RPPM. This targeted proteomic technique allowed us to

  20. 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)

  1. Framework for Flux Qubit Design

    Science.gov (United States)

    Yan, Fei; Kamal, Archana; Krantz, Philip; Campbell, Daniel; Kim, David; Yoder, Jonilyn; Orlando, Terry; Gustavsson, Simon; Oliver, William; Engineering Quantum Systems Team

    A qubit design for higher performance relies on the understanding of how various qubit properties are related to design parameters. We construct a framework for understanding the qubit design in the flux regime. We explore different parameter regimes, looking for features desirable for certain purpose in the context of quantum computing. This research was funded by the Office of the Director of National Intelligence (ODNI), Intelligence Advanced Research Projects Activity (IARPA) via MIT Lincoln Laboratory under Air Force Contract No. FA8721-05-C-0002.

  2. FSFE: Fake Spectra Flux Extractor

    Science.gov (United States)

    Bird, Simeon

    2017-10-01

    The fake spectra flux extractor generates simulated quasar absorption spectra from a particle or adaptive mesh-based hydrodynamic simulation. It is implemented as a python module. It can produce both hydrogen and metal line spectra, if the simulation includes metals. The cloudy table for metal ionization fractions is included. Unlike earlier spectral generation codes, it produces absorption from each particle close to the sight-line individually, rather than first producing an average density in each spectral pixel, thus substantially preserving more of the small-scale velocity structure of the gas. The code supports both Gadget (ascl:0003.001) and AREPO.

  3. 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)

  4. Structure of Energetic Particle Mediated Shocks Revisited

    International Nuclear Information System (INIS)

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

    2017-01-01

    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.

  5. 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.

  6. Triode for magnetic flux quanta.

    Science.gov (United States)

    Vlasko-Vlasov, Vitalii; Colauto, Fabiano; Benseman, Timothy; Rosenmann, Daniel; Kwok, Wai-Kwong

    We designed a magnetic vortex triode using an array of closely spaced soft magnetic Py strips on top of a Nb superconducting film. The strips act similar to the grid electrode in an electronic triode, where the electron flow is regulated by the grid potential. In our case, we tune the vortex motion by the magnetic charge potential of the strip edges, using a small magnetic field rotating in the film plane. The magnetic charges emerging at the stripe edges and proportional to the magnetization component perpendicular to the edge direction, form linear potential barriers or valleys for vortex motion in the superconducting layer. We directly imaged the normal flux penetration into the Py/Nb films and observed retarded or accelerated entry of the normal vortices depending on the in-plane magnetization direction in the stripes. The observed flux behavior is explained by interactions between magnetically charged lines and magnetic monopoles of vortices similar to those between electrically charged strings and point charges. We discuss the possibility of using our design for manipulation of individual vortices in high-speed, low-power superconducting electronic circuits. This work was supported by the U.S. DOE, Office of Science, Materials Sciences and Engineering Division, and Office of BES (contract DE-AC02-06CH11357). F. Colauto thanks the Sao Paulo Research Foundation FAPESP (Grant No. 2015/06.085-3).

  7. 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

  8. Neutron flux enhancement at LASREF

    Energy Technology Data Exchange (ETDEWEB)

    Sommer, W.F. (Los Alamos National Lab., Los Alamos, NM (United States)); Ferguson, P.D. (Univ. of Missouri, Rolla, MO (United States)); Wechsler, M.S. (Iowa State Univ., Ames, IA (United States))

    1992-09-01

    The accelerator at the Los Alamos Meson Physiscs 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 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 10 from the present level of about 5 E + 17 m[sup -2] s[sup -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. (orig.).

  9. 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.

  10. LOFT gamma densitometer background fluxes

    International Nuclear Information System (INIS)

    Grimesey, R.A.; McCracken, R.T.

    1978-01-01

    Background gamma-ray fluxes were calculated at the location of the γ densitometers without integral shielding at both the hot-leg and cold-leg primary piping locations. The principal sources for background radiation at the γ densitometers are 16 N activity from the primary piping H 2 O and γ radiation from reactor internal sources. The background radiation was calculated by the point-kernel codes QAD-BSA and QAD-P5A. Reasonable assumptions were required to convert the response functions calculated by point-kernel procedures into the gamma-ray spectrum from reactor internal sources. A brief summary of point-kernel equations and theory is included

  11. 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

  12. Dynamics of warped flux compactifications

    International Nuclear Information System (INIS)

    Shiu, Gary; Underwood, Bret; Torroba, Gonzalo; Douglas, Michael R.

    2008-01-01

    We discuss the four dimensional effective action for type IIB flux compactifications, and obtain the quadratic terms taking warp effects into account. The analysis includes both the 4-d zero modes and their KK excitations, which become light at large warping. We identify an 'axial' type gauge for the supergravity fluctuations, which makes the four dimensional degrees of freedom manifest. The other key ingredient is the existence of constraints coming from the ten dimensional equations of motion. Applying these conditions leads to considerable simplifications, enabling us to obtain the low energy lagrangian explicitly. In particular, the warped Kaehler potential for metric moduli is computed and it is shown that there are no mixings with the KK fluctuations and the result differs from previous proposals. The four dimensional potential contains a generalization of the Gukov-Vafa-Witten term, plus usual mass terms for KK modes.

  13. 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.

  14. rf SQUID system as tunable flux qubit

    Energy Technology Data Exchange (ETDEWEB)

    Ruggiero, B. [Istituto di Cibernetica ' E. Caianiello' del Consiglio Nazionale delle Ricerche, I-80078 Pozzuoli (Italy)]. E-mail: b.ruggiero@cib.na.cnr.it; Granata, C. [Istituto di Cibernetica ' E. Caianiello' del Consiglio Nazionale delle Ricerche, I-80078 Pozzuoli (Italy); Vettoliere, A. [Istituto di Cibernetica ' E. Caianiello' del Consiglio Nazionale delle Ricerche, I-80078 Pozzuoli (Italy); Rombetto, S. [Istituto di Cibernetica ' E. Caianiello' del Consiglio Nazionale delle Ricerche, I-80078 Pozzuoli (Italy); Russo, R. [Istituto di Cibernetica ' E. Caianiello' del Consiglio Nazionale delle Ricerche, I-80078 Pozzuoli (Italy); Russo, M. [Istituto di Cibernetica ' E. Caianiello' del Consiglio Nazionale delle Ricerche, I-80078 Pozzuoli (Italy); Corato, V. [Dipartimento di Ingegneria dell' Informazione, Seconda Universita di Napoli, I-81031 Aversa (Italy); Istituto di Cibernetica ' E. Caianiello' del Consiglio Nazionale delle Ricerche, I-80078 Pozzuoli (Italy); Silvestrini, P. [Dipartimento di Ingegneria dell' Informazione, Seconda Universita di Napoli, I-81031 Aversa (Italy); Istituto di Cibernetica ' E. Caianiello' del Consiglio Nazionale delle Ricerche, I-80078 Pozzuoli (Italy)

    2006-08-21

    We present a fully integrated rf SQUID-based system as flux qubit with a high control of the flux transfer function of the superconducting transformer modulating the coupling between the flux qubit and the readout system. The control of the system is possible by including into the superconducting flux transformer a vertical two-Josephson-junctions interferometer (VJI) in which the Josephson current is precisely modulated from a maximum to zero by a transversal magnetic field parallel to the flux transformer plane. The proposed system can be also used in a more general configuration to control the off-diagonal terms in the Hamiltonian of the flux qubit and to turn on and off the coupling between two or more qubits.

  15. Gauge-mediated supersymmetry breaking in string compactifications

    International Nuclear Information System (INIS)

    Diaconescu, Duiliu-Emanuel; Florea, Bogdan; Kachru, Shamit; Svrcek, Peter

    2006-01-01

    We provide string theory examples where a toy model of a SUSY GUT or the MSSM is embedded in a compactification along with a gauge sector which dynamically breaks supersymmetry. We argue that by changing microscopic details of the model (such as precise choices of flux), one can arrange for the dominant mediation mechanism transmitting SUSY breaking to the Standard Model to be either gravity mediation or gauge mediation. Systematic improvement of such examples may lead to top-down models incorporating a solution to the SUSY flavor problem

  16. Fast heat flux modulation at the nanoscale

    OpenAIRE

    van Zwol, P. J.; Joulain, K.; Abdallah, P. Ben; Greffet, J. J.; Chevrier, J.

    2011-01-01

    We introduce a new concept for electrically controlled heat flux modulation. A flux contrast larger than 10 dB is expected with switching time on the order of tens of nanoseconds. Heat flux modulation is based on the interplay between radiative heat transfer at the nanoscale and phase change materials. Such large contrasts are not obtainable in solids, or in far field. As such this opens up new horizons for temperature modulation and actuation at the nanoscale.

  17. 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)

  18. 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

  19. 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.

  20. 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.

  1. 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....

  2. 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 Ni...

  3. 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.)

  4. 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

  5. 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

  6. 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

  7. 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.

  8. FILAMENT INTERACTION MODELED BY FLUX ROPE RECONNECTION

    International Nuclear Information System (INIS)

    Toeroek, T.; Chandra, R.; Pariat, E.; Demoulin, P.; Schmieder, B.; Aulanier, G.; Linton, M. G.; Mandrini, C. H.

    2011-01-01

    Hα observations of solar active region NOAA 10501 on 2003 November 20 revealed a very uncommon dynamic process: during the development of a nearby flare, two adjacent elongated filaments approached each other, merged at their middle sections, and separated again, thereby forming stable configurations with new footpoint connections. The observed dynamic pattern is indicative of 'slingshot' reconnection between two magnetic flux ropes. We test this scenario by means of a three-dimensional zero β magnetohydrodynamic simulation, using a modified version of the coronal flux rope model by Titov and Demoulin as the initial condition for the magnetic field. To this end, a configuration is constructed that contains two flux ropes which are oriented side-by-side and are embedded in an ambient potential field. The choice of the magnetic orientation of the flux ropes and of the topology of the potential field is guided by the observations. Quasi-static boundary flows are then imposed to bring the middle sections of the flux ropes into contact. After sufficient driving, the ropes reconnect and two new flux ropes are formed, which now connect the former adjacent flux rope footpoints of opposite polarity. The corresponding evolution of filament material is modeled by calculating the positions of field line dips at all times. The dips follow the morphological evolution of the flux ropes, in qualitative agreement with the observed filaments.

  9. 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

  10. 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

  11. 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 ...

  12. 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)

  13. Bayesian Mediation Analysis

    OpenAIRE

    Yuan, Ying; MacKinnon, David P.

    2009-01-01

    This article proposes Bayesian analysis of mediation effects. Compared to 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 mediation analysis, inference is straightforward and exact, which makes it appealing for studies with small samples. Third, the Bayesian approach is conceptua...

  14. 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....

  15. Plasma crowbars in cylindrical flux compression experiments

    International Nuclear Information System (INIS)

    Suter, L.J.

    1979-01-01

    We have done a series of one- and two-dimensional calculations of hard-core Z-pinch flux compression experiments in order to study the effect of a plasma on these systems. These calculations show that including a plasma can reduce the amount of flux lost during the compression. Flux losses to the outer wall of such experiments can be greatly reduced by a plasma conducting sheath which forms along the wall. This conducting sheath consists of a cold, dense high β, unmagnetized plasma which has enough pressure to balance a large field gradient. Flux which is lost into the center conductor is not effectively stopped by this plasma sheath until late in the implosion, at which time a layer similar to the one formed at the outer wall is created. Two-dimensionl simulations show that flux losses due to arching along the sliding contact of the experiment can be effectively stopped by the formation of a plasma conducting sheath

  16. 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.

  17. 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…

  18. 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

  19. 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)

  20. FluxVisualizer, a Software to Visualize Fluxes through Metabolic Networks

    Directory of Open Access Journals (Sweden)

    Tim Daniel Rose

    2018-04-01

    Full Text Available FluxVisualizer (Version 1.0, 2017, freely available at https://fluxvisualizer.ibgc.cnrs.fr is a software to visualize fluxes values on a scalable vector graphic (SVG representation of a metabolic network by colouring or increasing the width of reaction arrows of the SVG file. FluxVisualizer does not aim to draw metabolic networks but to use a customer’s SVG file allowing him to exploit his representation standards with a minimum of constraints. FluxVisualizer is especially suitable for small to medium size metabolic networks, where a visual representation of the fluxes makes sense. The flux distribution can either be an elementary flux mode (EFM, a flux balance analysis (FBA result or any other flux distribution. It allows the automatic visualization of a series of pathways of the same network as is needed for a set of EFMs. The software is coded in python3 and provides a graphical user interface (GUI and an application programming interface (API. All functionalities of the program can be used from the API and the GUI and allows advanced users to add their own functionalities. The software is able to work with various formats of flux distributions (Metatool, CellNetAnalyzer, COPASI and FAME export files as well as with Excel files. This simple software can save a lot of time when evaluating fluxes simulations on a metabolic network.

  1. Topology of magnetic flux ropes and formation of fossil flux transfer events and boundary layer plasmas

    Science.gov (United States)

    Lee, L. C.; Ma, Z. W.; Fu, Z. F.; Otto, A.

    1993-01-01

    A mechanism for the formation of fossil flux transfer events and the low-level boundary layer within the framework of multiple X-line reconnection is proposed. Attention is given to conditions for which the bulk of magnetic flux in a flux rope of finite extent has a simple magnetic topology, where the four possible connections of magnetic field lines are: IMF to MSP, MSP to IMF, IMF to IMF, and MSP to MSP. For a sufficient relative shift of the X lines, magnetic flux may enter a flux rope from the magnetosphere and exit into the magnetosphere. This process leads to the formation of magnetic flux ropes which contain a considerable amount of magnetosheath plasma on closed magnetospheric field lines. This process is discussed as a possible explanation for the formation of fossil flux transfer events in the magnetosphere and the formation of the low-latitude boundary layer.

  2. Bayesian dynamic mediation analysis.

    Science.gov (United States)

    Huang, Jing; Yuan, Ying

    2017-12-01

    Most existing methods for mediation analysis assume that mediation is a stationary, time-invariant process, which overlooks the inherently dynamic nature of many human psychological processes and behavioral activities. In this article, we consider mediation as a dynamic process that continuously changes over time. We propose Bayesian multilevel time-varying coefficient models to describe and estimate such dynamic mediation effects. By taking the nonparametric penalized spline approach, the proposed method is flexible and able to accommodate any shape of the relationship between time and mediation effects. Simulation studies show that the proposed method works well and faithfully reflects the true nature of the mediation process. By modeling mediation effect nonparametrically as a continuous function of time, our method provides a valuable tool to help researchers obtain a more complete understanding of the dynamic nature of the mediation process underlying psychological and behavioral phenomena. We also briefly discuss an alternative approach of using dynamic autoregressive mediation model to estimate the dynamic mediation effect. The computer code is provided to implement the proposed Bayesian dynamic mediation analysis. (PsycINFO Database Record (c) 2017 APA, all rights reserved).

  3. 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

  4. 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.

  5. 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

  6. Activation of sea urchin sperm motility is accompanied by an increase in the creatine kinase exchange flux

    NARCIS (Netherlands)

    Dorsten, van F.A.; Wyss, M.; Wallimann, T.; Nicolaij, K.

    1997-01-01

    The kinetics of the creatine kinase (CK) reaction were studied in suspensions of quiescent and active, intact sea-urchin spermatozoa in artificial seawater, using 31P-NMR magnetization transfer. In inactive sperm, no CK-mediated exchange flux was detected, whereas in activated motile sperm, the

  7. Predicting radon flux from uranium mill tailings

    International Nuclear Information System (INIS)

    Freeman, H.D.; Hartley, J.N.

    1983-11-01

    Pacific Northwest Laboratory (PNL), under contract to the US Department of Energy (DOE) Uranium Mill Tailings Remedial Action Project (UMTRAP) office, is developing technology for the design of radon barriers for uranium mill tailings piles. To properly design a radon cover for a particular tailings pile, the radon flux emanating from the bare tailings must be known. The tailings characteristics required to calculate the radon flux include radium-226 content, emanating power, bulk density, and radon diffusivity. This paper presents theoretical and practical aspects of estimating the radon flux from an uranium tailings pile. Results of field measurements to verify the calculation methodology are also discussed. 24 references, 4 figures, 4 tables

  8. A time-varying magnetic flux concentrator

    International Nuclear Information System (INIS)

    Kibret, B; Premaratne, M; Lewis, P M; Thomson, R; Fitzgerald, P B

    2016-01-01

    It is known that diverse technological applications require the use of focused magnetic fields. This has driven the quest for controlling the magnetic field. Recently, the principles in transformation optics and metamaterials have allowed the realization of practical static magnetic flux concentrators. Extending such progress, here, we propose a time-varying magnetic flux concentrator cylindrical shell that uses electric conductors and ferromagnetic materials to guide magnetic flux to its center. Its performance is discussed based on finite-element simulation results. Our proposed design has potential applications in magnetic sensors, medical devices, wireless power transfer, and near-field wireless communications. (paper)

  9. Energy flux correlations and moving mirrors

    International Nuclear Information System (INIS)

    Ford, L.H.; Roman, Thomas A.

    2004-01-01

    We study the quantum stress tensor correlation function for a massless scalar field in a flat two-dimensional spacetime containing a moving mirror. We construct the correlation functions for right-moving and left-moving fluxes for an arbitrary trajectory, and then specialize them to the case of a mirror trajectory for which the expectation value of the stress tensor describes a pair of delta-function pulses, one of negative energy and one of positive energy. The flux correlation function describes the fluctuations around this mean stress tensor, and reveals subtle changes in the correlations between regions where the mean flux vanishes

  10. 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.

  11. Exponentially tapered Josephson flux-flow oscillator

    DEFF Research Database (Denmark)

    Benabdallah, A.; Caputo, J. G.; Scott, Alwyn C.

    1996-01-01

    We introduce an exponentially tapered Josephson flux-flow oscillator that is tuned by applying a bias current to the larger end of the junction. Numerical and analytical studies show that above a threshold level of bias current the static solution becomes unstable and gives rise to a train...... of fluxons moving toward the unbiased smaller end, as in the standard flux-flow oscillator. An exponentially shaped junction provides several advantages over a rectangular junction including: (i) smaller linewidth, (ii) increased output power, (iii) no trapped flux because of the type of current injection...

  12. Diamagnetic flux measurement in Aditya tokamak

    International Nuclear Information System (INIS)

    Kumar, Sameer; Jha, Ratneshwar; Lal, Praveen; Hansaliya, Chandresh; Gopalkrishna, M. V.; Kulkarni, Sanjay; Mishra, Kishore

    2010-01-01

    Measurements of diamagnetic flux in Aditya tokamak for different discharge conditions are reported for the first time. The measured diamagnetic flux in a typical discharge is less than 0.6 mWb and therefore it has required careful compensation for various kinds of pick-ups. The hardware and software compensations employed in this measurement are described. We introduce compensation of a pick-up due to plasma current of less than 20 kA in short duration discharges, in which plasma pressure gradient is supposed to be negligible. The flux measurement during radio frequency heating is also presented in order to validate compensation.

  13. High heat flux cooling for accelerator targets

    International Nuclear Information System (INIS)

    Silverman, I.; Nagler, A.

    2002-01-01

    Accelerator targets, both for radioisotope production and for high neutron flux sources generate very high thermal power in the target material which absorbs the particles beam. Generally, the geometric size of the targets is very small and the power density is high. The design of these targets requires dealing with very high heat fluxes and very efficient heat removal techniques in order to preserve the integrity of the target. Normal heat fluxes from these targets are in the order of 1 kw/cm 2 and may reach levels of an order of magnitude higher

  14. 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.

  15. Mapping carbon flux uncertainty and selecting optimal locations for future flux towers in the Great Plains

    Science.gov (United States)

    Gu, Yingxin; Howard, Daniel M.; Wylie, Bruce K.; Zhang, Li

    2012-01-01

    Flux tower networks (e. g., AmeriFlux, Agriflux) provide continuous observations of ecosystem exchanges of carbon (e. g., net ecosystem exchange), water vapor (e. g., evapotranspiration), and energy between terrestrial ecosystems and the atmosphere. The long-term time series of flux tower data are essential for studying and understanding terrestrial carbon cycles, ecosystem services, and climate changes. Currently, there are 13 flux towers located within the Great Plains (GP). The towers are sparsely distributed and do not adequately represent the varieties of vegetation cover types, climate conditions, and geophysical and biophysical conditions in the GP. This study assessed how well the available flux towers represent the environmental conditions or "ecological envelopes" across the GP and identified optimal locations for future flux towers in the GP. Regression-based remote sensing and weather-driven net ecosystem production (NEP) models derived from different extrapolation ranges (10 and 50%) were used to identify areas where ecological conditions were poorly represented by the flux tower sites and years previously used for mapping grassland fluxes. The optimal lands suitable for future flux towers within the GP were mapped. Results from this study provide information to optimize the usefulness of future flux towers in the GP and serve as a proxy for the uncertainty of the NEP map.

  16. Causal mediation analysis with multiple mediators.

    Science.gov (United States)

    Daniel, R M; De Stavola, B L; Cousens, S N; Vansteelandt, S

    2015-03-01

    In diverse fields of empirical research-including many in the biological sciences-attempts are made to decompose the effect of an exposure on an outcome into its effects via a number of different pathways. For example, we may wish to separate the effect of heavy alcohol consumption on systolic blood pressure (SBP) into effects via body mass index (BMI), via gamma-glutamyl transpeptidase (GGT), and via other pathways. Much progress has been made, mainly due to contributions from the field of causal inference, in understanding the precise nature of statistical estimands that capture such intuitive effects, the assumptions under which they can be identified, and statistical methods for doing so. These contributions have focused almost entirely on settings with a single mediator, or a set of mediators considered en bloc; in many applications, however, researchers attempt a much more ambitious decomposition into numerous path-specific effects through many mediators. In this article, we give counterfactual definitions of such path-specific estimands in settings with multiple mediators, when earlier mediators may affect later ones, showing that there are many ways in which decomposition can be done. We discuss the strong assumptions under which the effects are identified, suggesting a sensitivity analysis approach when a particular subset of the assumptions cannot be justified. These ideas are illustrated using data on alcohol consumption, SBP, BMI, and GGT from the Izhevsk Family Study. We aim to bridge the gap from "single mediator theory" to "multiple mediator practice," highlighting the ambitious nature of this endeavor and giving practical suggestions on how to proceed. © 2014 The Authors Biometrics published by Wiley Periodicals, Inc. on behalf of International Biometric Society.

  17. Alpha-tocopheryl succinate inhibits autophagic survival of prostate cancer cells induced by vitamin K3 and ascorbate to trigger cell death.

    Science.gov (United States)

    Tomasetti, Marco; Nocchi, Linda; Neuzil, Jiri; Goodwin, Jacob; Nguyen, Maria; Dong, Lanfeng; Manzella, Nicola; Staffolani, Sara; Milanese, Claudio; Garrone, Beatrice; Alleva, Renata; Borghi, Battista; Santarelli, Lory; Guerrieri, Roberto

    2012-01-01

    The redox-silent vitamin E analog α-tocopheryl succinate (α-TOS) was found to synergistically cooperate with vitamin K3 (VK3) plus ascorbic acid (AA) in the induction of cancer cell-selective apoptosis via a caspase-independent pathway. Here we investigated the molecular mechanism(s) underlying cell death induced in prostate cancer cells by α-TOS, VK3 and AA, and the potential use of targeted drug combination in the treatment of prostate cancer. The generation of ROS, cellular response to oxidative stress, and autophagy were investigated in PC3 prostate cancer cells by using drugs at sub-toxic doses. We evaluated whether PARP1-mediated apoptosis-inducing factor (AIF) release plays a role in apoptosis induced by the combination of the agents. Next, the effect of the combination of α-TOS, VK3 and AA on tumor growth was examined in nude mice. VK3 plus AA induced early ROS formation associated with induction of autophagy in response to oxidative stress, which was reduced by α-TOS, preventing the formation of autophagosomes. α-TOS induced mitochondrial destabilization leading to the release of AIF. Translocation of AIF from mitochondria to the nucleus, a result of the combinatorial treatment, was mediated by PARP1 activation. The inhibition of AIF as well as of PARP1 efficiently attenuated apoptosis triggered by the drug combination. Using a mouse model of prostate cancer, the combination of α-TOS, VK3 and AA was more efficient in tumor suppression than when the drugs were given separately, without deleterious side effects. α-TOS, a mitochondria-targeting apoptotic agent, switches at sub-apoptotic doses from autophagy-dependent survival of cancer cells to their demise by promoting the induction of apoptosis. Given the grim prognosis for cancer patients, this finding is of potential clinical relevance.

  18. Alpha-tocopheryl succinate inhibits autophagic survival of prostate cancer cells induced by vitamin K3 and ascorbate to trigger cell death.

    Directory of Open Access Journals (Sweden)

    Marco Tomasetti

    Full Text Available BACKGROUND: The redox-silent vitamin E analog α-tocopheryl succinate (α-TOS was found to synergistically cooperate with vitamin K3 (VK3 plus ascorbic acid (AA in the induction of cancer cell-selective apoptosis via a caspase-independent pathway. Here we investigated the molecular mechanism(s underlying cell death induced in prostate cancer cells by α-TOS, VK3 and AA, and the potential use of targeted drug combination in the treatment of prostate cancer. METHODOLOGY/PRINCIPAL FINDINGS: The generation of ROS, cellular response to oxidative stress, and autophagy were investigated in PC3 prostate cancer cells by using drugs at sub-toxic doses. We evaluated whether PARP1-mediated apoptosis-inducing factor (AIF release plays a role in apoptosis induced by the combination of the agents. Next, the effect of the combination of α-TOS, VK3 and AA on tumor growth was examined in nude mice. VK3 plus AA induced early ROS formation associated with induction of autophagy in response to oxidative stress, which was reduced by α-TOS, preventing the formation of autophagosomes. α-TOS induced mitochondrial destabilization leading to the release of AIF. Translocation of AIF from mitochondria to the nucleus, a result of the combinatorial treatment, was mediated by PARP1 activation. The inhibition of AIF as well as of PARP1 efficiently attenuated apoptosis triggered by the drug combination. Using a mouse model of prostate cancer, the combination of α-TOS, VK3 and AA was more efficient in tumor suppression than when the drugs were given separately, without deleterious side effects. CONCLUSIONS/SIGNIFICANCE: α-TOS, a mitochondria-targeting apoptotic agent, switches at sub-apoptotic doses from autophagy-dependent survival of cancer cells to their demise by promoting the induction of apoptosis. Given the grim prognosis for cancer patients, this finding is of potential clinical relevance.

  19. Neutron flux measurements in PUSPATI Triga Reactor

    International Nuclear Information System (INIS)

    Gui Ah Auu; Mohamad Amin Sharifuldin Salleh; Mohamad Ali Sufi.

    1983-01-01

    Neutron flux measurement in the PUSPATI TRIGA Reactor (PTR) was initiated after its commissioning on 28 June 1982. Initial measured thermal neutron flux at the bottom of the rotary specimen rack (rotating) and in-core pneumatic terminus were 3.81E+11 n/cm 2 sec and 1.10E+12n/cm 2 sec respectively at 100KW. Work to complete the neutron flux data are still going on. The cadmium ratio, thermal and epithermal neutron flux are measured in the reactor core, rotary specimen rack, in-core pneumatic terminus and thermal column. Bare and Cadmium covered gold foils and wires are used for the above measurement. The activities of the irradiated gold foils and wires are determined using Ge(Li) and hyperpure germinium detectors. (author)

  20. 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

  1. Modeling radon flux from the earth's surface

    International Nuclear Information System (INIS)

    Schery, S.D.; Wasiolek, M.A.

    1998-01-01

    We report development of a 222 Rn flux density model and its use to estimate the 222 Rn flux density over the earth's land surface. The resulting maps are generated on a grid spacing of 1 0 x 1 0 using as input global data for soil radium, soil moisture, and surface temperature. While only a first approximation, the maps suggest a significant regional variation (a factor of three is not uncommon) and a significant seasonal variation (a factor of two is not uncommon) in 222 Rn flux density over the earth's surface. The estimated average global flux density from ice-free land is 34 ± 9 mBq m -2 s -1 . (author)

  2. 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...

  3. 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

  4. High Flux Isotope Reactor technical specifications

    International Nuclear Information System (INIS)

    1985-11-01

    This report gives technical specifications for the High Flux Isotope Reactor (HFIR) on the following: safety limits and limiting safety system settings; limiting conditions for operation; surveillance requirements; design features; and administrative controls

  5. Heat flux microsensor measurements and calibrations

    Science.gov (United States)

    Terrell, James P.; Hager, Jon M.; Onishi, Shinzo; Diller, Thomas E.

    1992-01-01

    A new thin-film heat flux gage has been fabricated specifically for severe high temperature operation using platinum and platinum-10 percent rhodium for the thermocouple elements. Radiation calibrations of this gage were performed at the AEDC facility over the available heat flux range (approx. 1.0 - 1,000 W/cu cm). The gage output was linear with heat flux with a slight increase in sensitivity with increasing surface temperature. Survivability of gages was demonstrated in quench tests from 500 C into liquid nitrogen. Successful operation of gages to surface temperatures of 750 C has been achieved. No additional cooling of the gages is required because the gages are always at the same temperature as the substrate material. A video of oxyacetylene flame tests with real-time heat flux and temperature output is available.

  6. High energy neutrinos: sources and fluxes

    Energy Technology Data Exchange (ETDEWEB)

    Stanev, Todor [Bartol Research Institute, Department of Physics and Astronomy, University of Delaware, Newark DE 19716 (United States)

    2006-05-15

    We discuss briefly the potential sources of high energy astrophysical neutrinos and show estimates of the neutrino fluxes that they can produce. A special attention is paid to the connection between the highest energy cosmic rays and astrophysical neutrinos.

  7. 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

  8. 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.

  9. On the Tensorial Nature of Fluxes in Continuous Media.

    Science.gov (United States)

    Stokes, Vijay Kumar; Ramkrishna, Doraiswami

    1982-01-01

    Argues that mass and energy fluxes in a fluid are vectors. Topics include the stress tensor, theorem for tensor fields, mass flux as a vector, stress as a second order tensor, and energy flux as a tensor. (SK)

  10. sizing of wind powered axial flux permanent magnet alternator using

    African Journals Online (AJOL)

    user

    2016-10-04

    Oct 4, 2016 ... Keywords: Wind-Power, Axial flux, Axial Flux Permanent Machines (AFPM), Axial Flux Permanent Magnet ... energy for power generation, a high constraint is the .... arrangements as Single-Rotor Single-Stator Structure.

  11. Boundary fluxes for non-local diffusion

    OpenAIRE

    Cortazar, C.; Elgueta, M.; Rossi, J. D.; Wolanski, N.

    2006-01-01

    We study a nonlocal diffusion operator in a bounded smooth domain prescribing the flux through the boundary. This problem may be seen as a generalization of the usual Neumann problem for the heat equation. First, we prove existence, uniqueness and a comparison principle. Next, we study the behavior of solutions for some prescribed boundary data including blowing up ones. Finally, we look at a nonlinear flux boundary condition.

  12. 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

  13. Splitting of inviscid fluxes for real gases

    Science.gov (United States)

    Liou, Meng-Sing; Van Leer, Bram; Shuen, Jian-Shun

    1990-01-01

    Flux-vector and flux-difference splittings for the inviscid terms of the compressible flow equations are derived under the assumption of a general equation of state for a real gas in equilibrium. No necessary assumptions, approximations for auxiliary quantities are introduced. The formulas derived include several particular cases known for ideal gases and readily apply to curvilinear coordinates. Applications of the formulas in a TVD algorithm to one-dimensional shock-tube and nozzle problems show their quality and robustness.

  14. Vertical Josephson Interferometer for Tunable Flux Qubit

    Energy Technology Data Exchange (ETDEWEB)

    Granata, C [Istituto di Cibernetica ' E. Caianiello' del Consiglio Nazionale delle Ricerche, I- 80078, Pozzuoli (Italy); Vettoliere, A [Istituto di Cibernetica ' E. Caianiello' del Consiglio Nazionale delle Ricerche, I- 80078, Pozzuoli (Italy); Lisitskiy, M [Istituto di Cibernetica ' E. Caianiello' del Consiglio Nazionale delle Ricerche, I- 80078, Pozzuoli (Italy); Rombetto, S [Istituto di Cibernetica ' E. Caianiello' del Consiglio Nazionale delle Ricerche, I- 80078, Pozzuoli (Italy); Russo, M [Istituto di Cibernetica ' E. Caianiello' del Consiglio Nazionale delle Ricerche, I- 80078, Pozzuoli (Italy); Ruggiero, B [Istituto di Cibernetica ' E. Caianiello' del Consiglio Nazionale delle Ricerche, I- 80078, Pozzuoli (Italy); Corato, V [Dipartimento di Ingegneria dell' Informazione, Seconda Universita di Napoli, I-8 1031, Aversa (Italy) and Istituto di Cibernetica ' E. Caianiello' del CNR, I-80078, Pozzuoli (Italy); Russo, R [Dipartimento di Ingegneria dell' Informazione, Seconda Universita di Napoli, I-8 1031, Aversa (Italy) and Istituto di Cibernetica ' E. Caianiello' del CNR, I-80078, Pozzuoli (Italy); Silvestrini, P [Dipartimento di Ingegneria dell' Informazione, Seconda Universita di Napoli, I-8 1031, Aversa (Italy) and Istituto di Cibernetica ' E. Caianiello' del CNR, I-80078, Pozzuoli (Italy)

    2006-06-01

    We present a niobium-based Josephson device as prototype for quantum computation with flux qubits. The most interesting feature of this device is the use of a Josephson vertical interferometer to tune the flux qubit allowing the control of the off-diagonal Hamiltonian terms of the system. In the vertical interferometer, the Josephson current is precisely modulated from a maximum to zero with fine control by a small transversal magnetic field parallel to the rf superconducting loop plane.

  15. Self-powered neutron flux detector

    International Nuclear Information System (INIS)

    Kroon, J.

    1979-01-01

    A self-powered neutron flux detector having an emitter electrode, at least a major portion of which is, 95 Mo encased in a tubular collector electrode and separated therefrom by dielectric material. The 95 Mo emitter electrode has experimentally shown a 98% prompt response, is primarily sensitive to neutron flux, has adequate sensitivity and has low burn up. Preferably the emitter electrode is molybdenum which has been enriched 75% to 99% by weight with 95 Mo

  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. Data bank of critical heat flux

    International Nuclear Information System (INIS)

    Balino, J.L.; Ruival, M.H.

    1985-01-01

    More than 13.000 measurements of critical heat flux are classified in a data bank. From each experiment the following information can be obtained: cooling medium (light water, freon 12 or freon 21), geometry of the test section and thermalhydraulic parameters. The data management is performed by a computer program called CHFTRAT. A brief study of the influence of different parameters in the critical heat flux is presented, as an example of how to use the program. (M.E.L.) [es

  18. Anisotropic flux pinning in high Tc superconductors

    International Nuclear Information System (INIS)

    Kolesnik, S.; Igalson, J.; Skoskiewicz, T.; Szymczak, R.; Baran, M.; Pytel, K.; Pytel, B.

    1995-01-01

    In this paper we present a comparison of the results of FC magnetization measurements on several Pb-Sr-(Y,Ca)-Cu-O crystals representing various levels of flux pinning. The pinning centers in our crystals have been set up during the crystal growth process or introduced by neutron irradiation. Some possible explanations of the observed effects, including surface barrier, flux-center distribution and sample-shape effects, are discussed. ((orig.))

  19. Lycium barbarum polysaccharide protects against oxygen glucose deprivation/reoxygenation-induced apoptosis and autophagic cell death via the PI3K/Akt/mTOR signaling pathway in primary cultured hippocampal neurons.

    Science.gov (United States)

    Yu, Yang; Wu, Xiuquan; Pu, Jingnan; Luo, Peng; Ma, Wenke; Wang, Jiu; Wei, Jialiang; Wang, Yuanxin; Fei, Zhou

    2018-01-01

    Lycium barbarum polysaccharide (LBP) is the main active ingredient of Lycium barbarum, which exhibits several beneficial effects, including neuroprotection, anti-aging and anti-oxidation. However, the mechanism by which LBP protects against cerebral ischemia/reperfusion-induced injury remains obscure. In this study, we found that LBP pretreatment greatly attenuated oxygen glucose deprivation/reperfusion (OGD/R) injury in primary cultured hippocampal neurons. LBP also suppressed OGD/R-induced lactate dehydrogenase (LDH) leakage, and ameliorated oxidative stress. In addition, LBP significantly reduced OGD/R-induced apoptosis and autophagic cell death. LBP caused the down-regulation of cleaved Caspase-3/Caspase-3, LC3II/LC3I and Beclin 1, as well as up-regulation of Bcl-2/Bax and p62. Furthermore, mechanistic studies indicated that LBP pretreatment increased p-Akt and p-mTOR levels after OGD/R. In summary, our results indicated that LBP protects against OGD/R-induced neuronal injury in primary hippocampal neurons by activating the PI3K/Akt/mTOR signaling pathway. Copyright © 2017 Elsevier Inc. All rights reserved.

  20. 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.

  1. Technology-Use Mediation

    DEFF Research Database (Denmark)

    Bansler, Jørgen P.; Havn, Erling C.

    2003-01-01

    This study analyzes how a group of ‘mediators’ in a large, multinational company adapted a computer-mediated communication technology (a ‘virtual workspace’) to the organizational context (and vice versa) by modifying features of the technology, providing ongoing support for users, and promoting...... appropriate conventions of use. Our findings corroborate earlier research on technology-use mediation, which suggests that such mediators can exert considerable influence on how a particular technology will be established and used in an organization. However, this study also indicates that the process...... of technology-use mediation is more complex and indeterminate than earlier literature suggests. In particular, we want to draw attention to the fact that advanced computer-mediated communication technologies are equivocal and that technology-use mediation consequently requires ongoing sensemaking (Weick 1995)....

  2. 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......In the past several years great attention has been dedicated to the characterization of the Mediator complex in a different range of model organisms. Mediator is a conserved co-activator complex involved in transcriptional regulation and it conveys signals from regulatory transcription factors...... to the basal transcription machinery. Mediator was initially isolated from Saccharomyces cerevisiae based on its ability to render a RNA polymerase II in vitro transcription system responsive to activators. Additionally, structural studies have revealed striking structural similarities between S. cerevisiae...

  3. Neutron flux distribution forecasting device of reactor

    International Nuclear Information System (INIS)

    Uematsu, Hitoshi

    1991-01-01

    A neutron flux distribution is forecast by using current data obtained from a reactor. That is, the device of the present invention comprises (1) a neutron flux monitor disposed in various positions in the reactor, (2) a forecasting means for calculating and forecasting a one-dimensional neutron flux distribution relative to imaginable events by using data obtained from the neutron flux monitor and physical models, and (3) a display means for displaying the results forecast in the forecasting means to a reactor operation console. Since the forecast values for the one-dimensional neutron flux distribution relative to the imaginable events are calculated in the device of the present invention by using data obtained from the neutron flux monitor and the physical models, the data as a base of the calculation are new and the period for calculating the forecast values can be shortened. Accordingly, although there is a worry of providing some errors in the forecast values, they can be utilized sufficiently as reference data. As a result, the reactor can be operated more appropriately. (I.N.)

  4. TRANSHEX, 2-D Thermal Neutron Flux Distribution from Epithermal Flux in Hexagonal Geometry

    International Nuclear Information System (INIS)

    Patrakka, E.

    1994-01-01

    1 - Description of program or function: TRANSHEX is a multigroup integral transport program that determines the thermal scalar flux distribution arising from a known epithermal flux in two- dimensional hexagonal geometry. 2 - Method of solution: The program solves the isotropic collision probability equations for a region-averaged scalar flux by an iterative method. Either a successive over-relaxation or an inner-outer iteration technique is applied. Flat flux collision probabilities between trigonal space regions with white boundary condition are utilized. The effect of epithermal flux is taken into consideration as a slowing-down source that is calculated for a given spatial distribution and 1/E energy dependence of the epithermal flux

  5. 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...

  6. 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...

  7. 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

  8. Oxidation flux change on spermatozoa membrane in important pathologic conditions leading to male infertility.

    Science.gov (United States)

    Wiwanitkit, V

    2008-06-01

    Free radicals or reactive oxygen species mediate their action through proinflammatory cytokines and this mechanism has been proposed as a common underlying factor for male infertility. There is extensive literature on oxidative stress and its role in male infertility and sperm DNA damage and its effects on assisted reproductive techniques. However, there has never been a report on the oxidation flux change in spermatozoa. Here, the author determined the oxidation flux change in such hypoxic cases, using the simulation test based on nanomedicine technique is used. Of interest, change of flux can be detected. The main pathogenesis should be the direct injury of membrane structure of spermatozoa by free radicals which can lead to sperm defect. Therefore, this work can support the finding that the oxidation flux change corresponding to oxygen pressure change in spermatozoa does not exist. However, the flux change can be seen if the membrane thickness of spermatozoa is varied. Thin membrane spermatozoa are more prone to oxidative stress than thick membrane ones. The defect in the enzymatic system within the spermatozoa should be a better explanation for vulnerability of spermatozoa to oxidative stress. The use of enzymatic modification technique by antioxidants can be useful alternative in management of male infertility.

  9. 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.

  10. 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.

  11. A technical basis for the flux corrected local conditions critical heat flux correlation

    International Nuclear Information System (INIS)

    Luxat, J.C.

    2008-01-01

    The so-called 'flux-corrected' local conditions CHF correlation was developed at Ontario Hydro in the 1980's and was demonstrated to successfully correlate the Onset of Intermittent Dryout (OID) CHF data for 37-element fuel with a downstream-skewed axial heat flux distribution. However, because the heat flux correction factor appeared to be an ad-hoc, albeit a successful modifying factor in the correlation, there was reluctance to accept the correlation more generally. This paper presents a thermalhydraulic basis, derived from two-phase flow considerations, that supports the appropriateness of the heat flux correction as a local effects modifying factor. (author)

  12. MAGNETIC FLUX EXPULSION IN STAR FORMATION

    International Nuclear Information System (INIS)

    Zhao Bo; Li Zhiyun; Nakamura, Fumitaka; Krasnopolsky, Ruben; Shang, Hsien

    2011-01-01

    Stars form in dense cores of magnetized molecular clouds. If the magnetic flux threading the cores is dragged into the stars, the stellar field would be orders of magnitude stronger than observed. This well-known 'magnetic flux problem' demands that most of the core magnetic flux be decoupled from the matter that enters the star. We carry out the first exploration of what happens to the decoupled magnetic flux in three dimensions, using a magnetohydrodynamic (MHD) version of the ENZO adaptive mesh refinement code. The field-matter decoupling is achieved through a sink particle treatment, which is needed to follow the protostellar accretion phase of star formation. We find that the accumulation of the decoupled flux near the accreting protostar leads to a magnetic pressure buildup. The high pressure is released anisotropically along the path of least resistance. It drives a low-density expanding region in which the decoupled magnetic flux is expelled. This decoupling-enabled magnetic structure has never been seen before in three-dimensional MHD simulations of star formation. It generates a strong asymmetry in the protostellar accretion flow, potentially giving a kick to the star. In the presence of an initial core rotation, the structure presents an obstacle to the formation of a rotationally supported disk, in addition to magnetic braking, by acting as a rigid magnetic wall that prevents the rotating gas from completing a full orbit around the central object. We conclude that the decoupled magnetic flux from the stellar matter can strongly affect the protostellar collapse dynamics.

  13. 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.

  14. Flux Cancellation Leading to CME Filament Eruptions

    Science.gov (United States)

    Popescu, Roxana M.; Panesar, Navdeep K.; Sterling, Alphonse C.; Moore, Ronald L.

    2016-01-01

    Solar filaments are strands of relatively cool, dense plasma magnetically suspended in the lower density hotter solar corona. They trace magnetic polarity inversion lines (PILs) in the photosphere below, and are supported against gravity at heights of up to approx.100 Mm above the chromosphere by the magnetic field in and around them. This field erupts when it is rendered unstable, often by magnetic flux cancellation or emergence at or near the PIL. We have studied the evolution of photospheric magnetic flux leading to ten observed filament eruptions. Specifically, we look for gradual magnetic changes in the neighborhood of the PIL prior to and during eruption. We use Extreme Ultraviolet (EUV) images from the Atmospheric Imaging Assembly (AIA), and magnetograms from the Helioseismic and Magnetic Imager (HMI), both on board the Solar Dynamics Observatory (SDO), to study filament eruptions and their photospheric magnetic fields. We examine whether flux cancellation or/and emergence leads to filament eruptions. We find that continuous flux cancellation was present at the PIL for many hours prior to each eruption. We present two CME-producing eruptions in detail and find the following: (a) the pre-eruption filament-holding core field is highly sheared and appears in the shape of a sigmoid above the PIL; (b) at the start of the eruption the opposite arms of the sigmoid reconnect in the middle above the site of (tether-cutting) flux cancellation at the PIL; (c) the filaments first show a slow-rise, followed by a fast-rise as they erupt. We conclude that these two filament eruptions result from flux cancellation in the middle of the sheared field, and thereafter evolve in agreement with the standard model for a CME/flare filament eruption from a closed bipolar magnetic field [flux cancellation (van Ballegooijen and Martens 1989 and Moore and Roumelrotis 1992) and runaway tether-cutting (Moore et. al 2001)].

  15. 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

  16. 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.

  17. Teaching Mediated Public Relations.

    Science.gov (United States)

    Kent, Michael L.

    2001-01-01

    Discusses approaches to teaching a mediated public relations course, emphasizing the World Wide Web. Outlines five course objectives, assignments and activities, evaluation, texts, and lecture topics. Argues that students mastering these course objectives will understand ethical issues relating to media use, using mediated technology in public…

  18. Fashion, Mediations & Method Assemblages

    DEFF Research Database (Denmark)

    Sommerlund, Julie; Jespersen, Astrid Pernille

    of handling multiple, fluid realities with multiple, fluid methods. Empirically, the paper works with mediation in fashion - that is efforts the active shaping of relations between producer and consumer through communication, marketing and PR. Fashion mediation is by no means simple, but organise complex...

  19. The Mediated Transparent Society

    DEFF Research Database (Denmark)

    Backer, Lise

    2001-01-01

    in the mediated transparent society. The paper concludes that, based on these analyses, the mediated panopticism working on the business segment is not an effective disciplinary apparatus, which can guarantee that business corporations are carrying out important ecological or ethical improvements....

  20. 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

  1. 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

  2. Modelling of Power Fluxes during Thermal Quenches

    International Nuclear Information System (INIS)

    Konz, C.; Coster, D. P.; Lackner, K.; Pautasso, G.

    2005-01-01

    Plasma disruptions, i. e. the sudden loss of magnetic confinement, are unavoidable, at least occasionally, in present day and future tokamaks. The expected energy fluxes to the plasma facing components (PFCs) during disruptions in ITER lie in the range of tens of GW/m''2 for timescales of about a millisecond. Since high energy fluxes can cause severe damage to the PFCs, their design heavily depends on the spatial and temporal distribution of the energy fluxes during disruptions. We investigate the nature of power fluxes during the thermal quench phase of disruptions by means of numerical simulations with the B2 SOLPS fluid code. Based on an ASDEX Upgrade shot, steady-state pre-disruption equilibria are generated which are then subjected to a simulated thermal quench by artificially enhancing the perpendicular transport in the ion and electron channels. The enhanced transport coefficients flows the Rechester and Rosenbluth model (1978) for ergodic transport in a tokamak with destroyed flux surfaces, i. e. χ, D∼const. xT''5/2 where the constants differ by the square root of the mass ratio for ions and electrons. By varying the steady-state neutral puffing rate we can modify the divertor conditions in terms of plasma temperature and density. Our numerical findings indicate that the disruption characteristics depend on the pre disruptive divertor conditions. We study the timescales and the spatial distribution of the divertor power fluxes. The simulated disruptions show rise and decay timescales in the range observed at ASDEX Upgrade. The decay timescale for the central electron temperature of ∼800 μs is typical for non-ITB disruptions. Varying the divertor conditions we find a distinct transition from a regime with symmetric power fluxes to inboard and outboard divertors to a regime where the bulk of the power flux goes to the outboard divertor. This asymmetry in the divertor peak fluxes for the higher puffing case is accompanied by a time delay between the

  3. 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

  4. The multitalented Mediator complex.

    Science.gov (United States)

    Carlsten, Jonas O P; Zhu, Xuefeng; Gustafsson, Claes M

    2013-11-01

    The Mediator complex is needed for regulated transcription of RNA polymerase II (Pol II)-dependent genes. Initially, Mediator was only seen as a protein bridge that conveyed regulatory information from enhancers to the promoter. Later studies have added many other functions to the Mediator repertoire. Indeed, recent findings show that Mediator influences nearly all stages of transcription and coordinates these events with concomitant changes in chromatin organization. We review the multitude of activities associated with Mediator and discuss how this complex coordinates transcription with other cellular events. We also discuss the inherent difficulties associated with in vivo characterization of a coactivator complex that can indirectly affect diverse cellular processes via changes in gene transcription. Copyright © 2013 Elsevier Ltd. All rights reserved.

  5. Music, radio and mediatization

    DEFF Research Database (Denmark)

    Michelsen, Morten; Krogh, Mads

    2016-01-01

    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.......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...

  6. Turbulent transport across invariant canonical flux surfaces

    International Nuclear Information System (INIS)

    Hollenberg, J.B.; Callen, J.D.

    1994-07-01

    Net transport due to a combination of Coulomb collisions and turbulence effects in a plasma is investigated using a fluid moment description that allows for kinetic and nonlinear effects via closure relations. The model considered allows for ''ideal'' turbulent fluctuations that distort but preserve the topology of species-dependent canonical flux surfaces ψ number-sign,s triple-bond ∫ dF · B number-sign,s triple-bond ∇ x [A + (m s /q s )u s ] in which u s is the flow velocity of the fluid species. Equations for the net transport relative to these surfaces due to ''nonideal'' dissipative processes are found for the total number of particles and total entropy enclosed by a moving canonical flux surface. The corresponding particle transport flux is calculated using a toroidal axisymmetry approximation of the ideal surfaces. The resulting Lagrangian transport flux includes classical, neoclassical-like, and anomalous contributions and shows for the first time how these various contributions should be summed to obtain the total particle transport flux

  7. 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

  8. 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)

  9. 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 CO 2 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 CO 2 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 CO 2 with a volume fraction of at least 16 vol %. A lower limit CO 2 flux of 1.4 kg s -1 (117 t d -1 ) was determined, in line with the CO 2 flux from the Javanese mud volcano LUSI. Extrapolating these results to mud volcanism from the whole of Java suggests an order of magnitude total CO 2 flux of 3 kt d -1 , comparable with the expected back-arc efflux of magmatic CO 2 . After discussing geochemical, geological, and geophysical evidence we conclude that the source of CO 2 observed at Bledug Kuwu is likely a mixture of thermogenic, biogenic, and magmatic CO 2 , 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 CO 2 fluxes.

  10. 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)

  11. Flux-pinning-induced stresses in a hollow superconducting cylinder with flux creep and viscosity properties

    International Nuclear Information System (INIS)

    Feng, W.J.; Gao, S.W.

    2014-01-01

    Highlights: • Magnetoelastic problem for a superconducting cylinder with a hole is investigated. • The effects of both flux creep and viscous flux flow on stresses are analyzed. • For the FC case, the maximal hoop tensile stress always occurs at hole edge. • For the ZFC case, the maximal hoop stress is not certain to occur at hole edge. - Abstract: The magnetoelastic problem for a superconducting cylinder with a concentric hole placed in a magnetic field is investigated, where the flux creep and viscous flux flow have been considered. The stress distributions are derived and numerical calculated for the descending field in both the zero-field cooling (ZFC) and field cooling (FC) processes. The effects of applied magnetic field, flux creep and viscous flux flow on the maximal radial and hoop stresses are discussed in detail, and some novel phenomena are found. Among others, for the FC case, the maximal hoop tensile stress always occurs at the hole edge, whist for the ZFC case, the maximal stresses including both hoop and radial stresses either occur in the vicinity of the hole or occur at the position of flux frontier in the remagnetization process. For the descending field, in general, both the flux creep and viscosity parameters have important effects on the maximal radial and hoop stresses. All these phenomena are perhaps of vital importance for the application of superconductors

  12. Fast Flux Watch: A mechanism for online detection of fast flux networks

    Directory of Open Access Journals (Sweden)

    Basheer N. Al-Duwairi

    2014-07-01

    Full Text Available Fast flux networks represent a special type of botnets that are used to provide highly available web services to a backend server, which usually hosts malicious content. Detection of fast flux networks continues to be a challenging issue because of the similar behavior between these networks and other legitimate infrastructures, such as CDNs and server farms. This paper proposes Fast Flux Watch (FF-Watch, a mechanism for online detection of fast flux agents. FF-Watch is envisioned to exist as a software agent at leaf routers that connect stub networks to the Internet. The core mechanism of FF-Watch is based on the inherent feature of fast flux networks: flux agents within stub networks take the role of relaying client requests to point-of-sale websites of spam campaigns. The main idea of FF-Watch is to correlate incoming TCP connection requests to flux agents within a stub network with outgoing TCP connection requests from the same agents to the point-of-sale website. Theoretical and traffic trace driven analysis shows that the proposed mechanism can be utilized to efficiently detect fast flux agents within a stub network.

  13. TropFlux: air-sea fluxes for the global tropical oceans-description and evaluation

    Digital Repository Service at National Institute of Oceanography (India)

    PraveenKumar, B.; Vialard, J.; Lengaigne, M.; Murty, V.S.N.; McPhaden, M.J.

    This paper evaluates several timely, daily air-sea heat flux products (NCEP, NCEP2, ERA-Interim and OAFlux/ISCCP) against observations and present the newly developed TropFlux product. This new product uses bias-corrected ERA-interim and ISCCP data...

  14. 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.

  15. Nitrous oxide fluxes from grassland in the Netherlands. 1. Statistical analysis of flux-chamber measurements

    NARCIS (Netherlands)

    Velthof, G.L.; Oenema, O.

    1995-01-01

    Accurate estimates of total nitrous oxide (N2O) losses from grasslands derived from flux-chamber measurements are hampered by the large spatial and temporal variability of N2O fluxes from these sites. In this study, four methods for the calculation o

  16. EL-2 reactor: Thermal neutron flux distribution; EL-2: Repartition du flux de neutrons thermiques

    Energy Technology Data Exchange (ETDEWEB)

    Rousseau, A; Genthon, J P [Commissariat a l' Energie Atomique, Saclay (France). Centre d' Etudes Nucleaires

    1958-07-01

    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.)

  17. 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.

  18. Warped Kähler potentials and fluxes

    Energy Technology Data Exchange (ETDEWEB)

    Martucci, Luca [Dipartimento di Fisica ed Astronomia “Galileo Galilei' ,Università di Padova & I.N.F.N. Sezione di Padova,Via Marzolo 8, 35131 Padova (Italy)

    2017-01-13

    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.

  19. Hidden symmetry in the presence of fluxes

    International Nuclear Information System (INIS)

    Kubiznak, David; Warnick, Claude M.; Krtous, Pavel

    2011-01-01

    We derive the most general first-order symmetry operator for the Dirac equation coupled to arbitrary fluxes. Such an operator is given in terms of an inhomogeneous form ω which is a solution to a coupled system of first-order partial differential equations which we call the generalized conformal Killing-Yano system. Except trivial fluxes, solutions of this system are subject to additional constraints. We discuss various special cases of physical interest. In particular, we demonstrate that in the case of a Dirac operator coupled to the skew symmetric torsion and U(1) field, the system of generalized conformal Killing-Yano equations decouples into the homogeneous conformal Killing-Yano equations with torsion introduced in D. Kubiznak et al. (2009) and the symmetry operator is essentially the one derived in T. Houri et al. (2010) . We also discuss the Dirac field coupled to a scalar potential and in the presence of 5-form and 7-form fluxes.

  20. Comments on the 'minimum flux corona' concept

    International Nuclear Information System (INIS)

    Antiochos, S.K.; Underwood, J.H.

    1978-01-01

    Hearn's (1975) models of the energy balance and mass loss of stellar coronae, based on a 'minimum flux corona' concept, are critically examined. First, it is shown that the neglect of the relevant length scales for coronal temperature variation leads to an inconsistent computation of the total energy flux F. The stability arguments upon which the minimum flux concept is based are shown to be fallacious. Errors in the computation of the stellar wind contribution to the energy budget are identified. Finally we criticize Hearn's (1977) suggestion that the model, with a value of the thermal conductivity modified by the magnetic field, can explain the difference between solar coronal holes and quiet coronal regions. (orig.) 891 WL [de

  1. The transient transpiration heat flux meter

    International Nuclear Information System (INIS)

    Martins, N.; Calisto, H.; Afgan, N.; Leontiev, A.I.

    2006-01-01

    A new heat flux measurement principle, based on the transient response of a transpiration radiometer, is proposed. The measurement principle of current transpiration radiometers is based on a steady-state temperature measurement in a porous element. Since it may typically take several seconds to reach these conditions, there are obvious benefits in reducing the instrument response time. This can be achieved through the analysis of its transient response in order to predict the incident heat flux. In addition, the proposed methodology enables the separate measurement of the radiative and convective components of incident heat fluxes, without compromising the known advantages of transpiration radiometers. The availability of such an instrument may enable the development of advanced monitoring, diagnostic and control systems for thermal equipment

  2. 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 brightness of Jupiter and Saturn at the three frequencies of the Planck Low Frequency Instrument (30, 44, and 70 GHz). The results provide constraints on the intrinsic brightness and the brightness time-variability of these planets. The majority of the planet flux density estimates are limited by systematic...... errors, but still yield better than 1% measurements in many cases. Applying data from Planck HFI, the Wilkinson Microwave Anisotropy Probe (WMAP), and the Atacama Cosmology Telescope (ACT) to a model that incorporates contributions from Saturn’s rings to the planet’s total flux density suggests a best...

  3. Fractional flux quanta in Josephson junctions

    Energy Technology Data Exchange (ETDEWEB)

    Goldobin, E.; Buckenmaier, K.; Gaber, T.; Kemmler, M.; Pfeiffer, J.; Koelle, D.; Kleiner, R. [Physikalisches Inst. - Experimentalphysik II, Univ. Tuebingen (Germany); Weides, M.; Kohlstedt, H. [Center of Nanoelectronic Systems for Information Technology (CNI), Research Centre Juelich (Germany); Siegel, M. [Inst. fuer Mikro- und Nanoelektronische Systeme, Univ. Karlsruhe (Germany)

    2007-07-01

    Fractional Josephson vortices may appear in the so-called 0-{kappa} Josephson junctions ({kappa} is an arbitrary number) and carry magnetic flux {phi}, which is a fraction of the magnetic flux quantum {phi}{sub 0}{approx}2.07 x 10{sup -15} Wb. Their properties are very different from the usual integer fluxons: they are pinned, and often represent the ground state of the system with spontaneous circulating supercurrent. They behave as well controlled macroscopic spins and can be used to construct bits, qubits, tunable photonic crystals and to study the (quantum) physics of spin systems. In this talk we discuss recent advances in 0-{pi} junction technology and present recent experimental results: evidence of the spontaneous flux in the ground state, spectroscopy of the fractional vortex eigenfrequencies and observation of dynamics effects related to the flipping of the fractional vortices. (orig.)

  4. Heat transfer for ultrahigh flux reactor

    International Nuclear Information System (INIS)

    Wadkins, R.P.; Lake, J.A.; Oh, C.H.

    1987-01-01

    The use of a uniquely designed nuclear reactor to supply neutrons for materials research is the focus of recent reactor design efforts. The biological, materials, and fundamental physics aspects of research require neutron fluxes much higher than present research and testing facilities can produce. The most advanced research using neutrons as probing detectors is being done in the High Flux Reactor at the Institut Laue Langeuin, France. The design of a reactor that can produce neutron fluxes of 1.0 x 10 16 n/cm 2 .s requires a relatively high power (300 MW range) and a small core volume (approximately 30 liters). This combination of power and volume leads to a high power density which places increased demands on thermal hydraulic margins

  5. 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...

  6. 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.

  7. Sun's pole-equator flux differences

    Energy Technology Data Exchange (ETDEWEB)

    Belvedere, G [Istituto di Astronomia dell' Universita di Catania, Italy; Paterno, L [Osservatorio Astrofisico di Catania, Italy

    1977-04-01

    The possibility that large flux differences between the poles and the equator at the bottom of the solar convective zone are compatible with the small differences observed at the surface is studied. The consequences of increasing the depth of the convective zone due to overshooting are explored. A Boussinesq model is used for the convective zone and it is assumed that the interaction of the global convection with rotation is modelled through a convective flux coefficient whose perturbed part is proportional to the local Taylor number. The numerical integration of the equations of motion and energy shows that coexistence between large pole-equator flux differences at the bottom and small ones at the surface is possible if the solar convective zone extends to a depth of 0.4 R(Sun). The angular velocity distribution inside the convective zone is in agreement with the ..cap alpha omega..-dynamo theories of the solar cycle.

  8. 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.

  9. 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

  10. 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.

  11. Synthetic magnetic fluxes on the honeycomb lattice

    Energy Technology Data Exchange (ETDEWEB)

    Gorecka, Agnieszka [Centre for Quantum Technologies, National University of Singapore, 3 Science Drive 2, Singapore 117543 (Singapore); Gremaud, Benoit [Centre for Quantum Technologies, National University of Singapore, 3 Science Drive 2, Singapore 117543 (Singapore); Department of Physics, National University of Singapore, 2 Science Drive 3, Singapore 117542 (Singapore); Laboratoire Kastler Brossel, Ecole Normale Superieure, CNRS, UPMC, 4 Place Jussieu, FR-75005 Paris (France); Miniatura, Christian [Centre for Quantum Technologies, National University of Singapore, 3 Science Drive 2, Singapore 117543 (Singapore); Department of Physics, National University of Singapore, 2 Science Drive 3, Singapore 117542 (Singapore); Institut Non Lineaire de Nice, UMR 6618, UNS, CNRS, 1361 Route des Lucioles, FR-06560 Valbonne (France); Institute of Advanced Studies, Nanyang Technological university, 60 Nanyang View, Singapore 639673 (Singapore)

    2011-08-15

    We devise experimental schemes that are able to mimic uniform and staggered magnetic fluxes acting on ultracold two-electron atoms, such as ytterbium atoms, propagating in a honeycomb lattice. The atoms are first trapped into two independent state-selective triangular lattices and then further exposed to a suitable configuration of resonant Raman laser beams. These beams induce hops between the two triangular lattices and make atoms move in a honeycomb lattice. Atoms traveling around each unit cell of this honeycomb lattice pick up a nonzero phase. In the uniform case, the artificial magnetic flux sustained by each cell can reach about two flux quanta, thereby realizing a cold-atom analog of the Harper model with its notorious Hofstadter's butterfly structure. Different condensed-matter phenomena such as the relativistic integer and fractional quantum Hall effects, as observed in graphene samples, could be targeted with this scheme.

  12. 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.

  13. 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.

  14. 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.

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

    Indian Academy of Sciences (India)

    42

    of energy fluxes showed dominance of latent heat fluxes over sensible heat flux. .... for measurement of air temperature, rainfall, relative humidity, wind speed etc. ... within the radius of 100 m around the tower by using plant canopy analyzer ..... 2001), similar mechanisms might operate in our study resulting in flux deficit.

  16. 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 ...

  17. 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

  18. Induction of mitophagy-mediated antitumor activity with folate-appended methyl-β-cyclodextrin

    Directory of Open Access Journals (Sweden)

    Kameyama K

    2017-04-01

    Full Text Available Kazuhisa Kameyama,1,* Keiichi Motoyama,1,* Nao Tanaka,1 Yuki Yamashita,1 Taishi Higashi,1 Hidetoshi Arima1,2,* 1Department of Physical Pharmaceutics, Graduate School of Pharmaceutical Sciences, 2Program for Leading Graduate Schools “HIGO (Health Life Science: Interdisciplinary and Glocal Oriented Program,” Kumamoto University, Kumamoto, Japan *These authors contributed equally to this work Abstract: Mitophagy is the specific autophagic elimination system of mitochondria, which regulates cellular survival via the removal of damaged mitochondria. Recently, we revealed that folate-appended methyl-β-cyclodextrin (FA-M-β-CyD provides selective antitumor activity in folate receptor-α (FR-α-expressing cells by the induction of autophagy. In this study, to gain insight into the detailed mechanism of this antitumor activity, we focused on the induction of mitophagy by the treatment of FR-α-expressing tumor cells with FA-M-β-CyD. In contrast to methyl-β-cyclodextrin, FA-M-β-CyD entered KB cells, human epithelial cells from a fatal cervical carcinoma (FR-α (+ through FR-α-mediated endocytosis. The transmembrane potential of isolated mitochondria after treatment with FA-M-β-CyD was significantly elevated. In addition, FA-M-β-CyD lowered adenosine triphosphate (ATP production and promoted reactive oxygen species production in KB cells (FR-α (+. Importantly, FA-M-β-CyD enhanced light chain 3 (LC3 conversion (LC3-I to LC3-II in KB cells (FR-α (+ and induced PTEN-induced putative kinase 1 (PINK1 protein expression, which is involved in the induction of mitophagy. Furthermore, FA-M-β-CyD had potent antitumor activity in BALB/c nu/nu mice xenografted with KB cells (FR-α (+ without any significant side effects. Taken together, these findings demonstrate that the autophagic cell death elicited by FA-M-β-CyD could be associated with mitophagy induced by an impaired mitochondrial function. Keywords: mitophagy, autophagy, folate receptor, methyl

  19. CURRENT BUILDUP IN EMERGING SERPENTINE FLUX TUBES

    International Nuclear Information System (INIS)

    Pariat, E.; Masson, S.; Aulanier, G.

    2009-01-01

    The increase of magnetic flux in the solar atmosphere during active-region formation involves the transport of the magnetic field from the solar convection zone through the lowest layers of the solar atmosphere, through which the plasma β changes from >1 to <1 with altitude. The crossing of this magnetic transition zone requires the magnetic field to adopt a serpentine shape also known as the sea-serpent topology. In the frame of the resistive flux-emergence model, the rising of the magnetic flux is believed to be dynamically driven by a succession of magnetic reconnections which are commonly observed in emerging flux regions as Ellerman bombs. Using a data-driven, three-dimensional (3D) magnetohydrodynamic numerical simulation of flux emergence occurring in active region 10191 on 2002 November 16-17, we study the development of 3D electric current sheets. We show that these currents buildup along the 3D serpentine magnetic-field structure as a result of photospheric diverging horizontal line-tied motions that emulate the observed photospheric evolution. We observe that reconnection can not only develop following a pinching evolution of the serpentine field line, as usually assumed in two-dimensional geometry, but can also result from 3D shearing deformation of the magnetic structure. In addition, we report for the first time on the observation in the UV domain with the Transition Region and Coronal Explorer (TRACE) of extremely transient loop-like features, appearing within the emerging flux domain, which link several Ellermam bombs with one another. We argue that these loop transients can be explained as a consequence of the currents that build up along the serpentine magnetic field.

  20. Element fluxes from Copahue Volcano, Argentina

    Science.gov (United States)

    Varekamp, J. C.

    2003-12-01

    Copahue volcano in Argentina has an active volcano-magmatic hydrothermal system that emits fluids with pH=0.3 that feed a river system. River flux measurements and analytical data provide element flux data from 1997 to 2003, which includes the eruptive period of July to December 2000. The fluids have up to 6.5 percent sulfate, 1 percent Cl and ppm levels of B, As, Cu, Zn and Pb. The hydrothermal system acts as a perfect scrubber for magmatic gases during the periods of passive degassing, although the dissolved magmatic gases are modified through water rock interaction and mineral precipitation. The magmatic SO2 disproportionates into sulfate and liquid elemental sulfur at about 300 C; the sulfate is discharged with the fluids, whereas the liquid sulfur is temporarily retained in the reservoir but ejected during phreatic and hydrothermal eruptions. The intrusion and chemical attack of new magma in the hydrothermal reservoir in early 2000 was indicated by strongly increased Mg concentrations and Mg fluxes, and higher Mg/Cl and Mg/K values. The hydrothermal discharge has acidified a large glacial lake (0.5 km3) to pH=2 and the lake effluents acidify the exiting river. Even more than 100 km downstream, the effects of acid pulses from the lake are evident from red coated boulders and fish die-offs. The river-bound sulfate fluxes from the system range from 70 to 200 kilotonnes/year. The equivalent SO2 output of the whole volcanic system ranges from 150 to 500 tonnes/day, which includes the fraction of native sulfur that formed inside the mountain but does not include the release of SO2 into the atmosphere during the eruptions. Trace element fluxes of the river will be scaled up and compared with global element fluxes from meteoric river waters (subterranean volcanic weathering versus watershed weathering).

  1. Diffusive flux of methane from warm wetlands

    Energy Technology Data Exchange (ETDEWEB)

    Barber, T.R.; Burke, R.A.; Sackett, W.M. (Univ. of South Florida, St. Petersburg (USA))

    1988-12-01

    Diffusion of methane across the air-water interface from several wetland environments in south Florida was estimated from measured surface water concentrations using an empirically derived gas exchange model. The flux from the Everglades sawgrass marsh system varied widely, ranging from 0.18 + or{minus}0.21 mol CH{sub 4}/sq m/yr for densely vegetated regions to 2.01 + or{minus}0.88 for sparsely vegetated, calcitic mud areas. Despite brackish salinities, a strong methane flux, 1.87 + or{minus}0.63 mol CH{sub 4}/sq m/yr, was estimated for an organic-rich mangrove pond near Florida Bay. The diffusive flux accounted for 23, 36, and 13% of the total amount of CH{sub 4} emitted to the atmosphere from these environments, respectively. The average dissolved methane concentration for an organic-rich forested swamp was the highest of any site at 12.6 microM; however, the calculated diffusive flux from this location, 2.57 + or{minus}1.88 mol CH{sub 4}/sq m/yr, was diminished by an extensive plant canopy that sheltered the air-water interface from the wind. The mean diffusive flux from four freshwater lakes, 0.77 + or{minus}0.73 mol CH{sub 4}/sq m/yr, demonstrated little temperature dependence. The mean diffusive flux for an urbanized, subtropical estuary was 0.06 + or{minus}0.05 mol CH{sub 4}/sq m/yr.

  2. 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.

  3. 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.

  4. 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.

  5. Evaluation of NASA's Carbon Monitoring System (CMS) Flux Pilot: Terrestrial CO2 Fluxes

    Science.gov (United States)

    Fisher, J. B.; Polhamus, A.; Bowman, K. W.; Collatz, G. J.; Potter, C. S.; Lee, M.; Liu, J.; Jung, M.; Reichstein, M.

    2011-12-01

    NASA's Carbon Monitoring System (CMS) flux pilot project combines NASA's Earth System models in land, ocean and atmosphere to track surface CO2 fluxes. The system is constrained by atmospheric measurements of XCO2 from the Japanese GOSAT satellite, giving a "big picture" view of total CO2 in Earth's atmosphere. Combining two land models (CASA-Ames and CASA-GFED), two ocean models (ECCO2 and NOBM) and two atmospheric chemistry and inversion models (GEOS-5 and GEOS-Chem), the system brings together the stand-alone component models of the Earth System, all of which are run diagnostically constrained by a multitude of other remotely sensed data. Here, we evaluate the biospheric land surface CO2 fluxes (i.e., net ecosystem exchange, NEE) as estimated from the atmospheric flux inversion. We compare against the prior bottom-up estimates (e.g., the CASA models) as well. Our evaluation dataset is the independently derived global wall-to-wall MPI-BGC product, which uses a machine learning algorithm and model tree ensemble to "scale-up" a network of in situ CO2 flux measurements from 253 globally-distributed sites in the FLUXNET network. The measurements are based on the eddy covariance method, which uses observations of co-varying fluxes of CO2 (and water and energy) from instruments on towers extending above ecosystem canopies; the towers integrate fluxes over large spatial areas (~1 km2). We present global maps of CO2 fluxes and differences between products, summaries of fluxes by TRANSCOM region, country, latitude, and biome type, and assess the time series, including timing of minimum and maximum fluxes. This evaluation shows both where the CMS is performing well, and where improvements should be directed in further work.

  6. 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....

  7. Multidimensional flux-limited advection schemes

    International Nuclear Information System (INIS)

    Thuburn, J.

    1996-01-01

    A general method for building multidimensional shape preserving advection schemes using flux limiters is presented. The method works for advected passive scalars in either compressible or incompressible flow and on arbitrary grids. With a minor modification it can be applied to the equation for fluid density. Schemes using the simplest form of the flux limiter can cause distortion of the advected profile, particularly sideways spreading, depending on the orientation of the flow relative to the grid. This is partly because the simple limiter is too restrictive. However, some straightforward refinements lead to a shape-preserving scheme that gives satisfactory results, with negligible grid-flow angle-dependent distortion

  8. On the topology of flux transfer events

    Science.gov (United States)

    Hesse, Michael; Birn, Joachim; Schindler, Karl

    1990-01-01

    A topological analysis is made of a simple model magnetic field of a perturbation at the magnetopause that shares magnetic properties with flux transfer events. The aim is to clarify a number of topological aspects that arise in the case of fully three-dimensional magnetic fields. It is shown that a localized perturbation at the magnetopause can in principle open a closed magnetosphere by establishing magnetic connections across the magnetopause by the formation of a ropelike magnetic field structure. For this purpose a global topological model of a closed magnetosphere is considered as the unperturbed state. The topological substructure of the model flux rope is discussed in detail.

  9. 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

  10. 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.

  11. CFRMF neutron flux gradient and spectral determinations

    International Nuclear Information System (INIS)

    Rogers, J.W.; Turk, E.H.; Hogg, C.H.

    1976-01-01

    Recently more accurate and complete measurements of the flux gradient have been measured by the activation of 235 U and Au samples. Neutron spectrum characteristics were studied by making activation measurements with and without the ends of the CFRMF test region plugged with 10 B. These measurements define the flux gradient to +-1 to 2% and indicate there is no detectable streaming of thermal or resonance neutrons from the ends in the central 30 cm of the CFRMF test region. Measurements of the Cd ratio of Au foil activations were conducted and these results also indicate there is no streaming of thermal and resonance neutrons into the CFRMF test region

  12. 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

  13. 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

  14. 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

  15. 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

  16. 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.

  17. General resonance mediation

    Energy Technology Data Exchange (ETDEWEB)

    McGarrie, Moritz

    2012-07-15

    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 {sigma}(visible {yields} hidden) in these resonance models. We will also give formulas for soft masses, A-terms and demonstrate the framework with a holographic setup.

  18. Positively deflected anomaly mediation

    International Nuclear Information System (INIS)

    Okada, Nobuchika

    2002-01-01

    We generalize the so-called 'deflected anomaly mediation' scenario to the case where threshold corrections of heavy messengers to the sparticle squared masses are positive. A concrete model realizing this scenario is also presented. The tachyonic slepton problem can be fixed with only a pair of messengers. The resultant sparticle mass spectrum is quite different from that in the conventional deflected anomaly mediation scenario, but is similar to the one in the gauge mediation scenario. The lightest sparticle is mostly B-ino

  19. Polyarene mediators for mediated redox flow battery

    Science.gov (United States)

    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.

  20. Statistical mechanics of flux lines in high-temperature superconductors

    International Nuclear Information System (INIS)

    Dasgupta, C.

    1992-01-01

    The shortness of the low temperature coherence lengths of high T c materials leads to new mechanisms of pinning of flux lines. Lattice periodic modulations of the order parameters itself acts to pin vortex lines in regions of the unit cell were the order parameter is small. A presentation of flux creep and flux noise at low temperature and magnetic fields in terms of motion of simple metastable defects on flux lines is made, with a calculation of flux lattice melting. 12 refs

  1. 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

  2. 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

  3. High Torque Density Transverse Flux Machine without the Need to Use SMC Material for 3D Flux Paths

    DEFF Research Database (Denmark)

    Lu, Kaiyuan; Wu, Weimin

    2015-01-01

    This paper presents a new transverse flux permanent magnet machine. In a normal transverse flux machine, complicated 3-D flux paths often exist. Such 3-D flux paths would require the use of soft magnetic composites material instead of laminations for construction of the machine stator. In the new...... machine topology proposed in this paper, by advantageously utilizing the magnetic flux path provided by an additional rotor, use of laminations that allow 2-D flux paths only will be sufficient to accomplish the required 3-D flux paths. The machine also has a high torque density and is therefore...

  4. Evolution of the magnetic helicity flux during the formation and eruption of flux ropes

    Energy Technology Data Exchange (ETDEWEB)

    Romano, P. [INAF—Osservatorio Astrofisico di Catania, Via S. Sofia 78, I-95123 Catania (Italy); Zuccarello, F. P. [Centre for Mathematical Plasma-Astrophysics, KU Leuven, Celestijnenlaan 200B, B-3001 Leuven (Belgium); Guglielmino, S. L.; Zuccarello, F., E-mail: paolo.romano@oact.inaf.it [Dipartimento di Fisica e Astronomia—Sezione Astrofisica, Università di Catania, Via S. Sofia 78, I-95123 Catania (Italy)

    2014-10-20

    We describe the evolution and the magnetic helicity flux for two active regions (ARs) since their appearance on the solar disk: NOAA 11318 and NOAA 11675. Both ARs hosted the formation and destabilization of magnetic flux ropes. In the former AR, the formation of the flux rope culminated in a flare of C2.3 GOES class and a coronal mass ejection (CME) observed by Large Angle and Spectrometric Coronagraph Experiment. In the latter AR, the region hosting the flux rope was involved in several flares, but only a partial eruption with signatures of a minor plasma outflow was observed. We found a different behavior in the accumulation of the magnetic helicity flux in the corona, depending on the magnetic configuration and on the location of the flux ropes in the ARs. Our results suggest that the complexity and strength of the photospheric magnetic field is only a partial indicator of the real likelihood of an AR producing the eruption of a flux rope and a subsequent CME.

  5. Fast modeling of flux trapping cascaded explosively driven magnetic flux compression generators.

    Science.gov (United States)

    Wang, Yuwei; Zhang, Jiande; Chen, Dongqun; Cao, Shengguang; Li, Da; Liu, Chebo

    2013-01-01

    To predict the performance of flux trapping cascaded flux compression generators, a calculation model based on an equivalent circuit is investigated. The system circuit is analyzed according to its operation characteristics in different steps. Flux conservation coefficients are added to the driving terms of circuit differential equations to account for intrinsic flux losses. To calculate the currents in the circuit by solving the circuit equations, a simple zero-dimensional model is used to calculate the time-varying inductance and dc resistance of the generator. Then a fast computer code is programmed based on this calculation model. As an example, a two-staged flux trapping generator is simulated by using this computer code. Good agreements are achieved by comparing the simulation results with the measurements. Furthermore, it is obvious that this fast calculation model can be easily applied to predict performances of other flux trapping cascaded flux compression generators with complex structures such as conical stator or conical armature sections and so on for design purpose.

  6. Comparison of nonflare solar soft x ray flux with 10.7-cm radio flux

    International Nuclear Information System (INIS)

    Donnelly, R.F.

    1982-01-01

    The similarities and differences of the nonflare solar 1- to 8-A X ray flux and the daily 10.7-cm Ottawa solar radio flux are examined. The radio flux is shown to be much less sensitive than the soft X ray flux on the average to the coronal emission of active regions located near or beyond the solar chromospheric limb relative to regions near the center of the solar disk. This is caused by the solar soft X ray emission's being optically thin while much of the 10.7-cm active region emission is from optical depths of tauapprox.1. The radio flux includes a large quiet sun flux which is emitted mostly from the tenuous chromosphere-corona transition region (Tapprox.10 4 --10 6 0 K) and partly from the cooler portions of the quiet corona Tapprox.1.5 x 10 6 0 K. Conversely, the solar soft X ray flux has a very small quiet sun component

  7. High Flux Materials Testing Reactor (HFR), Petten

    International Nuclear Information System (INIS)

    1975-09-01

    After conversion to burnable poison fuel elements, the High Flux Materials Testing Reactor (HFR) Petten (Netherlands), operated through 1974 for 280 days at 45 MW. Equipment for irradiation experiments has been replaced and extended. The average annual occupation by experiments was 55% as compared to 38% in 1973. Work continued on thirty irradiation projects and ten development activities

  8. 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.

  9. Optical magnetic flux generation in superconductor

    Indian Academy of Sciences (India)

    Keywords. Ultrafast phenomena; femtosecond laser; optical magnetic flux generation. PACS Nos 85.25.Oj; 74.25.-q; 42.65.Re. 1. Introduction. Excitation and observation of ultrafast phenomena in solid states are of essential interest in the field of condensed matter physics. Recent femtosecond (fs) laser technology is now.

  10. 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

  11. 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

  12. 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

  13. Diameter effect on critical heat flux

    International Nuclear Information System (INIS)

    Tanase, A.; Cheng, S.C.; Groeneveld, D.C.; Shan, J.Q.

    2009-01-01

    The critical heat flux look-up table (CHF LUT) is widely used to predict CHF for various applications, including design and safety analysis of nuclear reactors. Using the CHF LUT for round tubes having inside diameters different from the reference 8 mm involves conversion of CHF to 8 mm. Different authors [Becker, K.M., 1965. An Analytical and Experimental Study of Burnout Conditions in Vertical Round Ducts, Aktiebolaget Atomenergie Report AE 177, Sweden; Boltenko, E.A., et al., 1989. Effect of tube diameter on CHF at various two phase flow regimes, Report IPE-1989; Biasi, L., Clerici, G.C., Garriba, S., Sala, R., Tozzi, A., 1967. Studies on Burnout, Part 3, Energia Nucleare, vol. 14, pp. 530-536; Groeneveld, D.C., Cheng, S.C., Doan, T., 1986. AECL-UO critical heat flux look-up table. Heat Transfer Eng., 7, 46-62; Groeneveld et al., 1996; Hall, D.D., Mudawar, I., 2000. Critical heat flux for water flow in tubes - II subcooled CHF correlations. Int. J. Heat Mass Transfer, 43, 2605-2640; Wong, W.C., 1996. Effect of tube diameter on critical heat flux, MaSC dissertation, Ottawa Carleton Institute for Mechanical and Aeronautical Engineering, University of Ottawa] have proposed several types of correlations or factors to describe the diameter effect on CHF. The present work describes the derivation of new diameter correction factor and compares it with several existing prediction methods

  14. maximum neutron flux at thermal nuclear reactors

    International Nuclear Information System (INIS)

    Strugar, P.

    1968-10-01

    Since actual research reactors are technically complicated and expensive facilities it is important to achieve savings by appropriate reactor lattice configurations. There is a number of papers, and practical examples of reactors with central reflector, dealing with spatial distribution of fuel elements which would result in higher neutron flux. Common disadvantage of all the solutions is that the choice of best solution is done starting from the anticipated spatial distributions of fuel elements. The weakness of these approaches is lack of defined optimization criteria. Direct approach is defined as follows: determine the spatial distribution of fuel concentration starting from the condition of maximum neutron flux by fulfilling the thermal constraints. Thus the problem of determining the maximum neutron flux is solving a variational problem which is beyond the possibilities of classical variational calculation. This variational problem has been successfully solved by applying the maximum principle of Pontrjagin. Optimum distribution of fuel concentration was obtained in explicit analytical form. Thus, spatial distribution of the neutron flux and critical dimensions of quite complex reactor system are calculated in a relatively simple way. In addition to the fact that the results are innovative this approach is interesting because of the optimization procedure itself [sr

  15. 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

  16. Fast flux test facility hazards assessment

    International Nuclear Information System (INIS)

    Sutton, L.N.

    1994-01-01

    This document establishes the technical basis in support of Emergency Planning Activities for the Fast Flux Test Facility on the Hanford Site. The document represents an acceptable interpretation of the implementing guidance document for DOE Order 5500.3A. Through this document, the technical basis for the development of facility specific Emergency Action Levels and the Emergency Planning Zone is demonstrated

  17. Fast Flux Test Facility (FFTF) maintenance provisions

    International Nuclear Information System (INIS)

    Marshall, J.L.

    1981-05-01

    The Fast Flux Test Facility (FFTF) was designed with maintainability as a primary parameter, and facilities and provisions were designed into the plant to accommodate the maintenance function. This paper describes the FFTF and its systems. Special maintenance equipment and facilities for performing maintenance on radioactive components are discussed. Maintenance provisions designed into the plant to enhance maintainability are also described

  18. Diffusion piecewise homogenization via flux discontinuity ratios

    International Nuclear Information System (INIS)

    Sanchez, Richard; Dante, Giorgio; Zmijarevic, Igor

    2013-01-01

    We analyze piecewise homogenization with flux-weighted cross sections and preservation of averaged currents at the boundary of the homogenized domain. Introduction of a set of flux discontinuity ratios (FDR) that preserve reference interface currents leads to preservation of averaged region reaction rates and fluxes. We consider the class of numerical discretizations with one degree of freedom per volume and per surface and prove that when the homogenization and computing meshes are equal there is a unique solution for the FDRs which exactly preserve interface currents. For diffusion sub-meshing we introduce a Jacobian-Free Newton-Krylov method and for all cases considered obtain an 'exact' numerical solution (eight digits for the interface currents). The homogenization is completed by extending the familiar full assembly homogenization via flux discontinuity factors to the sides of regions laying on the boundary of the piecewise homogenized domain. Finally, for the familiar nodal discretization we numerically find that the FDRs obtained with no sub-mesh (nearly at no cost) can be effectively used for whole-core diffusion calculations with sub-mesh. This is not the case, however, for cell-centered finite differences. (authors)

  19. 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...

  20. AmeriFlux Data System Looking Forward

    Science.gov (United States)

    Agarwal, D.; Cheah, Y. W.; Chu, H.; Keenan, T. F.; Pastorello, G.; Torn, M. S.; Humphrey, M.; Beekwilder, N.

    2016-12-01

    The AmeriFlux data system is turning 20 along with the network. This anniversary provides an opportunity to reimagine the data system and services to support the next 20 years of AmeriFlux. The next generation goals of the data system will be continuous data quality and consistency improvements, and also increased services to both tower owners and data users. An example change is new data citation capabilities and support leveraging Digital Object Identifiers (DOI) to enable easier citation and improved tracking of data usage. A new processing pipeline will enable more regular production of gap-filled and partitioned datasets. Automation will be continuously increased to help improve the time from data submission to user data availability. New standard data submission and processing formats will enable automation of the data submission and improved QA/QC processes. This new data system is made possible by the extensive work that the AmeriFlux data team at CDIAC has done over the last 20 years in close collaboration with the tower teams. This presentation will provide both a historical perspective and a vision for the future of the AmeriFlux data system.